Burden of Illness and Treatment Patterns Among Patients With von Willebrand Disease in US Clinical Practice

Abstract

In this retrospective cohort study, data from an integrated US healthcare system containing both electronic medical record data and linked claims data (from 01/2004 to 12/2020) were used to evaluate the clinical burden, treatment patterns, and healthcare resource use (HRU) in patients with von Willebrand disease (VWD). Two patient cohorts were analyzed: the overall VWD population (n  =  396) and a subset of these patients (n  =  75) who were considered potentially eligible for prophylaxis treatment with von Willebrand factor (VWF) based on a history of severe and frequent bleeding. HRU (hospitalizations, outpatient visits, and emergency department visits) were measured in patients with linked claims data (n  =  110, overall VWD patients; n  =  23 potentially VWF-prophylaxis-eligible VWD patients). In general, patients with VWD experienced a substantial burden of bleeding events, comorbidities, and HRU. Patients with VWD who were considered potentially eligible for prophylaxis owing to severe and frequent bleeds suffered from a higher clinical burden and HRU than the overall VWD population, and thus may benefit from VWF prophylactic treatment. The findings from this study could help improve clinical outcomes and manage HRU for patients with VWD.

Introduction

von Willebrand disease (VWD) is a common bleeding disorder that affects men and women equally. ¹ VWD is caused by a reduction or functional defects in von Willebrand factor (VWF), a plasma glycoprotein crucial for normal primary and secondary hemostasis. ² Patients with VWD commonly experience mucocutaneous bleeding, but bleeding phenotype and the severity of bleeds vary between individuals and by VWD type. ³ While the overall prevalence of VWD in the United States is estimated at 1%,^1,4 symptomatic VWD requiring treatment is rare (prevalence around 1 in 10,000). ⁵ Women with VWD can be affected by heavy menstrual bleeding (HMB), so they are more likely to report as symptomatic than men with VWD.^1,4

Bleeds in patients with VWD can be life-threatening ⁶ or lead to long-term complications such as arthropathy and anemia. ⁷ Patients with VWD also experience reduced health-related quality of life (HRQoL) compared with the general population.^8,9 In addition, patients with VWD who experience major bleeding events incur higher healthcare resource use (HRU) and associated costs than those who do not. ¹⁰ Long-term prophylaxis with recombinant or plasma-derived VWF products has been reported to reduce or prevent recurrent bleeds in patients with severe bleeding tendencies.^11-17 It is hypothesized that long-term VWF prophylaxis in patients with severe VWD will reduce the risk of VWD-related complications and improve HRQoL. ¹⁸ Recent international guidelines for the management of VWD conditionally recommended long-term VWF prophylaxis in patients with VWD and a history of severe and frequent bleeds, although further studies are needed to develop evidence-based guidelines for prophylaxis in people with VWD. ¹⁹

The aim of this retrospective cohort study was to evaluate the real-world treatment patterns, clinical burden, and HRU among patients with VWD in the United States in general, as well as in a defined subset of patients considered potentially eligible for VWF prophylaxis, to understand unmet needs in the VWD patient population.

Methods

Study Design and Patient Populations

This non-interventional, retrospective cohort study used de-identified electronic medical records (EMR) data and linked claims data from a rural integrated healthcare system (HS) in the United States serving north-eastern and central Pennsylvania and southern New Jersey. The database contains longitudinal, de-identified, EMR data for services provided to patients of all ages and with any insurance coverage. In addition, the database contains administrative claims data for a subset of insured patients (about 30%). Two patient cohorts were identified and analyzed: patients with VWD overall and a subset of these patients who were considered potentially eligible for prophylaxis treatment.

Main Eligibility Criteria for the Overall Population of Patients With VWD

All patients selected from the EMR database who had ≥2 diagnoses of VWD between January 2004 and December 2020, confirmed on separate days, were eligible for inclusion in the overall population of patients with VWD. Diagnosis of VWD was based on International Classification of Diseases (ICD), Ninth Revision (ICD-9), Clinical Modification (CM) code 286.4 and Tenth Revision (ICD-10) CM code D68.0. Eligible patients were required to have no diagnoses of acquired coagulation factor deficiency or hemophilia, be enrolled in the HS for ≥6 months before the first VWD diagnosis, and have ≥6 months of follow-up after the first recorded VWD diagnosis (index date 1). The baseline period was defined as the 6 months prior to the index date. The study period was defined as the period between the index date and a patient's death date, last HS interaction, or end of data availability (December 31, 2020), whichever occurred first (Figure 1).

Figure 1.

Study design.

Abbreviations: HS, healthcare system; VWD, von Willebrand disease.

Criteria Used to Define Potential Eligibility for Prophylaxis (ie, History of Severe/Frequent Bleeds)

The conditions that defined potential eligibility for VWF prophylaxis in this study were a history of either ≥3 joint bleeds, ≥2 gastrointestinal (GI) bleeds, ≥5 total bleeds in the last 12 months, or ≥1 major bleed. A major bleed was defined as either a medical claim associated with a diagnosis code for intracranial, GI, or eye bleed in a hospital or outpatient setting, or a medical claim for HMB, epistaxis, or joint bleed that required a transfusion with blood products either during hospitalization or on or within 7 days after the date of diagnosis in the outpatient setting. Patients who were potentially prophylaxis eligible had to have ≥6 months of follow-up after the first date that they met the defined prophylaxis eligibility criteria (index date 2) (Figure 1).

Outcome Measures and Statistical Analysis

Patient demographics and clinical characteristics, treatment patterns, bleeding events, and HRU were assessed for the overall population of patients with VWD and the subset of potentially prophylaxis-eligible patients with VWD during the baseline and study periods. The following treatments were included in this analysis: hemostatic treatments such as antifibrinolytic drugs (including tranexamic acid), desmopressin acetate injection (DDAVP), desmopressin acetate nasal spray, VWF replacement therapy (recombinant VWF [rVWF, vonicog alfa, VONVENDI (US)/VEYVONDI (Europe), Takeda Pharmaceuticals USA, Lexington, MA, USA] or plasma-derived antihemophilic factor/VWF complex concentrates), antihemophilic factor alone, and red blood cell transfusion. Also included were other concomitant VWD and comorbidity treatments such as anticoagulants, antidepressants, hormone treatments, iron therapy, and local hemostatic treatments. Treatment was categorized as either on-demand, defined as receipt of a VWD-related treatment within 2 days of a bleeding event, or perioperative management, defined as receipt of a VWD-related treatment within 2 days of a surgery/procedure to prevent or reduce bleeds. Although the proportion of patients receiving prophylaxis for VWD was assessed, no patients in the sample met the criteria for prophylaxis treatment, possibly because prophylaxis was not an approved indication for any of the licensed VWF products for VWD in the United States at the time of the study.

Bleeding events were described in terms of location of the bleed (ie, GI, intracranial, eye, HMB, epistaxis, joint, and other bleeds) and annualized bleeding rates (ABRs). New bleeds were defined as any bleed occurring in a different location >3 days after the last treatment or >3 days after the onset of a previous bleed if untreated. To be considered as on-demand treatment, treatment had to take place within 2 days of a bleed. Therefore, bleeds that occurred in the same location >3 days after the last treatment or previous untreated bleed were considered as new bleeds. Bleeds that occurred in a different location within 3 days after the previous bleed were also considered as new bleeds. Recurrent bleeds were defined as any bleed occurring in the same location within 3 days of the last treatment or within 3 days after the onset of the previous untreated bleed. The ABR was calculated for each patient as the number of new bleeding episodes during the baseline or study period annualized to 1 year.

A subset of each of the main cohorts with linked claims data available was identified for the HRU analysis. All-cause and VWD-related HRU outcomes (inpatient stays, emergency department visits, and outpatient visits) were assessed during the baseline period and the 6-month period after the index date. VWD-related HRU was defined as any visit with an ICD-9/10-CM code for VWD or a bleed.

Analyses were descriptive and exploratory in nature. Means and standard deviations (SDs) were reported for continuous variables; frequencies and percentages were reported for categorical variables. Analyses were conducted using R version 3.6.3 and SAS Enterprise Guide 7.1.

Results

Patient Population

Data from 466 patients with VWD were obtained from the EMR. After implementing the study eligibility criteria, 396 patients with VWD were included in the overall VWD population with a subset of 75 patients being identified as potentially eligible for VWF prophylaxis treatment (Figure 2). The mean (SD) age of patients in the overall VWD population was 34.7 (20.4) years and 76.3% were female. For the subset of patients identified as potentially eligible for VWF prophylaxis treatment, mean (SD) age was 44.1 (22.0) years and 76.0% were female. Except for older age in the potentially prophylaxis-eligible cohort, patient demographics at baseline were similar in the overall VWD population and the potentially prophylaxis-eligible subset. The mean (SD) length of follow-up was 8.16 (4.67) years and 6.26 (3.31) years, respectively (Table 1).

Figure 2.

Sample selection of the overall VWD population and the subset of patients potentially eligible for VWF prophylaxis.

^a Including bleeds that occur on or after the index date with an encounter setting of “emergency department only,” “emergency department to inpatient,” “inpatient only,” “outpatient,” “surgery,” and “procedure.”

^b Major bleeds were defined as a medical claim associated with a diagnosis code for intracranial, GI, or eye bleed in a hospital or outpatient setting, or a medical claim for HMB, epistaxis, or joint bleed that required a transfusion with blood products either during hospitalization or on or within 7 days after the date of diagnosis in the outpatient setting.

Abbreviations: GI, gastrointestinal; HMB, heavy menstrual bleeding; VWD, von Willebrand disease.

Table 1.

Patient Demographics and Clinical Characteristics at Baseline in the Overall VWD Population and the Subset of Patients Potentially Eligible for VWF Prophylaxis.

	Overall VWD Population (n  =  396)	Potentially VWF-Prophylaxis-Eligible Subset (n  =  75)
Age at index date a (years), mean (SD)	34.7 (20.4)	44.1 (22.0)
Length of follow-up b (years), mean (SD)	8.16 (4.67)	6.26 (3.31)
Sex, n (%)
Female	302 (76.3)	57 (76.0)
Male	94 (23.7)	18 (24.0)
Race, n (%)
White	383 (96.7)	71 (94.7)
Black or African American	9 (2.3)	3 (4.0)
Asian	2 (0.5)	0
Native Hawaiian or other Pacific Islander	2 (0.5)	1 (1.3)
Body mass index, mean (SD)	27.3 (8.4)	28.8 (8.1)
Family history of VWD, n (%)	42 (10.6)	13 (17.3)
History of smoking, n (%)
Current or former smoker	124 (31.3)	32 (42.7)
Never smoker	160 (40.4)	38 (50.7)
Not available	112 (28.3)	5 (6.7)
Blood type, n (%)
A positive	51 (12.9)	15 (20.0)
B positive	7 (1.8)	1 (1.3)
AB positive	1 (0.3)	0
O positive	119 (30.1)	29 (38.7)
Negative blood types	32 (8.1)	6 (8.0)
Missing	186 (47.0)	24 (32.0)
Comorbidities associated with VWD c , n (%)
Anemia	23 (5.8)	11 (14.7)
Obesity	18 (4.5)	8 (10.7)
Anxiety	28 (7.1)	11 (14.7)
Depression	17 (4.3)	4 (5.3)
Thromboembolic events	3 (0.8)	4 (5.3)
CCI, mean (SD)	0.28 (0.77)	0.87 (1.46)
Insurance plan type, n (%)
Commercial	141 (35.6)	27 (36.0)
US healthcare system health plan	110 (27.8)	15 (20.0)
Medicare	90 (22.7)	25 (33.3)
Medicaid	33 (8.3)	4 (5.3)
Other d	22 (5.6)	4 (5.3)
Index treating physician type, n (%)
General practitioner	130 (32.8)	29 (38.7)
Obstetrician/gynecologist	22 (5.6)	7 (9.3)
Pediatrician	22 (5.6)	6 (8.0)
Hematologist/oncologist	51 (12.9)	4 (5.3)
Oncologist	28 (7.1)	2 (2.7)
Emergency medicine specialist	16 (4.0)	11 (14.7)
Gastroenterologist	2 (0.5)	1 (1.3)
Other	68 (17.2)	11 (14.7)
Missing	32 (8.1)	3 (4.0)

Abbreviations: CCI, Charlson Comorbidity Index; SD, standard deviation; VWD, von Willebrand disease; VWF, von Willebrand factor.

^a  The index date is defined as the date of first VWD diagnosis for the overall VWD population, and the first date of recorded prophylaxis eligibility for the potentially VWF-prophylaxis-eligible subset.

^b  Calculated as the time between the index date and the patient death, last interaction with the healthcare system, or end of the data availability (December 31, 2020), whichever occurred first.

^c  Most common comorbidities reported.

^d  Includes military insurance, self-pay, and other unspecified forms of insurance.

Patient clinical characteristics, including body mass index, family history of VWD, smoking history, and blood type, were generally similar in the overall VWD population and the potentially VWF-prophylaxis-eligible subset at baseline (Table 1). Approximately one-third of patients had ≥1 VWF ristocetin cofactor (VWF:RCo), factor VIII activity (FVIII:C), or VWF antigen (VWF:Ag) test result during the baseline period (Table 2). The availability of VWF:RCo, FVIII:C, and VWF:Ag test results remained limited during the study period, with approximately half of the patients missing results (data not shown). Baseline VWF levels were similar between the overall VWD population and potentially prophylaxis-eligible subset: mean (SD) VWF:RCo levels were 85.3 (79.2) IU/dL and 91.8 (85.6) IU/dL, respectively, and VWF:Ag levels were 80.4 (57.3) IU/dL and 106.2 (78.3) IU/dL, respectively (Table 2).

Table 2.

VWF Test Status and Levels in the Overall VWD Population and the Subset of Patients Potentially Eligible for VWF Prophylaxis During the Baseline Period.

	Overall VWD Population (n  =  396)	Potentially VWF-Prophylaxis-Eligible Subset (n  =  75)
Patients with ≥1 laboratory test
VWF:RCo
n (%) mean (SD) number of tests per patient	136 (34.3) 1.7 (1.6)	25 (33.3) 1.8 (2.0)
FVIII:C
n (%) mean (SD) number of tests per patient	104 (26.3) 1.6 (1.5)	20 (26.7) 2.5 (5.6)
VWF:Ag
n (%) mean (SD) number of tests per patient	135 (34.1) 1.6 (1.1)	25 (33.3) 1.4 (2.7)
Hemoglobin
n (%) mean (SD) number of tests per patient	252 (63.6) 3.1 (4.8)	61 (81.3) 7.3 (8.9)
Platelets
n (%) mean (SD) number of tests per patient	249 (62.9) 2.8 (3.7)	61 (81.3) 6.6 (8.3)
VWF:RCo (IU/dL), mean (SD) at baseline	85.3 (79.2)	91.8 (85.6)
VWF:Ag (IU/dL), mean (SD) at baseline	80.4 (57.3)	106.2 (78.3)

Abbreviations: Ag, antigen; FVIII:C, factor VIII activity; RCo, ristocetin cofactor; SD, standard deviation; VWF, von Willebrand factor; VWD, von Willebrand disease.

Bleeding Events

During the study period, the proportions of patients with bleeds were higher in the potentially VWF-prophylaxis-eligible subset than in the overall VWD population, which was expected given that severe and frequent bleeding was the criterion used to select the patients potentially eligible for prophylaxis (Figure 3). Accordingly, the mean (SD) ABR was also higher in the patients potentially eligible for prophylaxis (0.84 [0.84]) compared with the overall VWD population (0.25 [0.45]) (Figure 3). Patients experienced more new bleeds than recurrent bleeds overall and from the same anatomical location (Supplemental Table 1).

Figure 3.

Recorded bleeding events during the study period^a.

^a Both treated and untreated bleeds are included.

^b Percentage of patients with ≥1 bleeding event during the study period (≥6 months).

^c The “Other” bleeds category comprised several bleed types that did not fall under the main bleed categories; examples of other bleeds included hematuria, otorrhagia, and unclassified hemorrhages.

Denominators for the calculation of percentages are the total numbers of patients in each cohort (ie, n  =  396 and n  =  75 for the overall VWD population and prophylaxis-eligible subset, respectively). Bleeding episodes were identified using relevant ICD-9 and ICD-10 codes.

Abbreviations: ABR, annualized bleeding rate; GI, gastrointestinal; HMB, heavy menstrual bleeding; ICD, International Classification of Disease; VWD, von Willebrand disease.

Comorbidities

The most common comorbidities during the study period were anemia, obesity, anxiety, depression, and thromboembolic events (Table 3). With the exception of anxiety, the proportions of patients with comorbidities generally appeared higher in the potentially VWF-prophylaxis-eligible patient subset than the overall VWD population (Table 3): 41.3% and 23.7% of patients had anemia, respectively, 37.3% and 34.9% had obesity, 33.3% and 33.8% had anxiety, 30.7% and 27.5% had depression, and 17.3% and 8.8% had thromboembolic events. The mean (SD) Charlson Comorbidity Index (CCI), a widely used comorbidity index that takes into account 19 pre-defined comorbid conditions, ²⁰ was also higher in the potentially prophylaxis-eligible patient subset than the overall VWD population during the study period (1.41 [2.03] in the overall VWD population and 2.39 [2.91] in the potentially prophylaxis-eligible patient subset). The most common CCI component comorbid condition in this study was chronic obstructive pulmonary disease (COPD), which occurred in 44.4% and 50.7% of patients, respectively (Table 3).

Table 3.

Comorbidities During the Study Period in the Overall VWD Population and the Subset of Patients Potentially Eligible for VWF Prophylaxis.

	Overall VWD Population (n  =  396)	Potentially VWF-Prophylaxis- Eligible Subset (n  =  75)
Comorbidities associated with VWD a , n (%)
Anemia	94 (23.7)	31 (41.3)
Obesity	138 (34.9)	28 (37.3)
Anxiety	134 (33.8)	25 (33.3)
Depression	109 (27.5)	23 (30.7)
Thromboembolic events	35 (8.8)	13 (17.3)
CCI, mean (SD)	1.41 (2.03)	2.39 (2.91)
CCI component comorbid conditions a , n (%)
Cerebrovascular disease	37 (9.3)	15 (20.0)
Chronic pulmonary disease	176 (44.4)	38 (50.7)
Liver disease, mild	47 (11.9)	20 (26.7)
Peripheral vascular disease	33 (8.3)	11 (14.7)
Rheumatic disease	37 (9.3)	10 (13.3)
Diabetes without chronic complications	41 (10.4)	10 (13.3)
Renal disease	24 (6.1)	11 (14.7)
Any malignancy b	36 (9.1)	13 (17.3)

Abbreviations: CCI, Charlson Comorbidity Index; SD, standard deviation; VWD, von Willebrand disease; VWF, von Willebrand factor.

^a  Comorbidities reported in ≥10% of patients in either cohort.

^b  Including leukemia and lymphoma, except for malignant neoplasm of skin.

Treatment Patterns

Patients received treatments such as antifibrinolytics (including tranexamic acid), desmopressin, or VWF products to treat bleeds during the study period. The proportion of patients requiring on-demand treatment to control a bleed was higher among the subset of patients who were potentially eligible for VWF prophylaxis (57.3%, n  =  43) compared with the overall VWD population (23.7%, n  =  94). Similarly, 56.0% (n  =  42) of patients who were potentially eligible for VWF prophylaxis required treatments for surgeries/procedures during the study period compared with 45.2% (n  =  179) of the overall VWD population. No patients were treated with long-term or intermittent prophylaxis for VWD, possibly as prophylaxis was not an approved indication for any of the licensed VWF products for VWD in the United States at the time of the study.

Healthcare Resource use

Out of the 396 patients in the overall VWD population, 110 had linked claims data and ≥6 months of continuous eligibility following the index date and were eligible for inclusion in the HRU analysis. Of the 75 patients in the subset of patients potentially eligible for VWF prophylaxis treatment, 23 had data available for HRU analysis. During the 6-month period following the index date, 20.0% of the overall VWD population were hospitalized for any cause and 16.4% were hospitalized for a VWD-related event. In the subset of patients potentially eligible for prophylaxis, a similar proportion of patients were hospitalized for any cause (21.7%) or for a VWD-related event (17.4%). This subset also experienced a higher mean number of inpatient stays and duration of inpatient stays than the overall VWD population (Figure 4A and B). Nearly all patients had 1 or more all-cause outpatient visits (Figure 4C), with a mean (SD) of 11.0 (11.6) visits in the overall population and 9.7 (7.9) in the potentially prophylaxis-eligible subset. Almost half of potentially prophylaxis-eligible patients with VWD (48%) had an all-cause emergency department visit versus 28% of the overall VWD cohort (Figure 4D). The mean (SD) number of all-cause emergency department visits (1.6 [1.2]) was similar in the overall VWD population and the potentially VWF-prophylaxis-eligible subset (1.6 [1.0]). The proportion of patients with ≥1 VWD-related outpatient or emergency department visits was higher for the potentially prophylaxis-eligible patient subset than the overall VWD population (Figure 4C and D).

Figure 4.

All-cause and VWD-related HRU during the 6-month study period with respect to (A) the number and (B) duration of inpatient stays, and (C) the proportion of patients with outpatient or (D) emergency department visits.

VWD-related HRU was defined as any visit with an ICD-9/10-CM code for VWD or a bleed.

Abbreviations: HRU, healthcare resource use; ICD, International Classification of Disease; SD, standard deviation; VWD, von Willebrand disease.

Discussion

This non-interventional, retrospective cohort study provides real-world data on the treatment patterns and clinical burden of patients with VWD in the United States. The linkage of EMR data with claims data further enabled a comprehensive assessment of the healthcare burden of patients with VWD included in this study. The findings showed that a high burden of bleeding events was experienced by patients with VWD overall and more new bleeds than recurrent bleeding was recorded. For the subset of patients who were considered potentially eligible for VWF prophylaxis treatment, the proportion with bleed events, the ABR, mean number of bleeds per person, and rates of comorbidities were generally even higher than in the overall VWD cohort. The most common bleeding events in this study for both cohorts were GI bleeds, epistaxis, and HMB. It is possible that not all bleeds were captured in this study because bleeds would only be recorded where there were interactions with the HS (medical visit or prescription). While home use of prescribed treatment was included, bleeds that did not require a medical visit or prescription were not recorded, and if patients sought medical treatment for bleeds at a hospital outside the HS, this would also not be included.

HRQoL can be negatively impacted in patients with VWD who experience bleeds,^8,21 including in women with VWD and HMB. ²² In nationwide surveys conducted in the Netherlands, HRQoL was shown to be substantially reduced in patients with VWD compared with the general population, with the effects most pronounced in patients with the more severe bleeding phenotypes.^8,21 In particular, joint bleeds are also known to be associated with reduced HRQoL in patients with VWD as they can lead to arthropathy.^23,24 In the present study, joint bleeds occurred in 3.3% of the overall VWD population and 6.7% among the subset considered potentially eligible for prophylaxis, which is consistent with other reports that joint bleeds occur in the minority of patients with VWD.^23,24

This study also reports a high burden of comorbidities in patients with VWD. Anemia was reported in 24% and 41% of patients in the overall VWD population and potentially VWF-prophylaxis-eligible subset, respectively. Anemia is a common symptom of VWD, particularly in women with HMB.^1,4 In a retrospective UK database study, women with VWD were significantly more likely to have HMB or to undergo hysterectomy than women without VWD. ²⁵ Similarly, in a single-center study in Sweden, women with VWD were found to have a high incidence of HMB, despite pharmacologic treatment. ²² Thromboembolic events occurred in a high proportion (8.8%) of the overall VWD population during the study period, with a higher proportion (17.3%) in the potentially prophylaxis-eligible subset. Potentially prophylaxis-eligible patients were older, and a higher proportion of them received on-demand treatment to control bleeds and treatment to prevent or reduce bleeds for surgery/procedures during the study period, which could explain the higher rate of thromboembolic events. Older age, use of coagulation factor concentrates, and surgery all increase the risk of thromboembolic events in patients with VWD. ²⁶

Other commonly reported comorbidities in this study were obesity, anxiety, and depression. The incidence of obesity in this population (∼35%) may be a reflection of the incidence in the general US population (∼40%), ²⁷ although patients with severe VWD often have severe limitations on physical activity that could contribute to obesity. ²⁸ The presence of obesity can also predispose patients to a higher risk of bleeding symptoms compared with patients of normal bodyweight. ²⁹ Mental health issues, such as anxiety and depression, are commonly reported in patients with bleeding disorders such as VWD, and are associated with daily management of symptoms, the unpredictable nature of the disease, and concerns about the future. ³⁰ The most common CCI component comorbid condition in this study was COPD, which is not an expected comorbidity in patients with VWD. A possible explanation is that the HS covers a rural and low-income population, which is more likely to experience chronic pulmonary diseases than individuals living in urban areas or with higher incomes.^31,32

A higher proportion of potentially prophylaxis-eligible patients in this study received on-demand treatment and treatment for surgery/procedures during the study period than the overall VWD population, and they had a comparatively higher HRU. Prophylaxis with VWF products was not a US Food and Drugs Administration (FDA)-approved treatment during the timeframe of this study, and this is reflected in the observation that there was no use of long-term or intermittent prophylaxis treatment among these patients. Meanwhile, the FDA recently approved rVWF for routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe type 3 VWD receiving on-demand therapy. ³³

During the baseline period, the proportion of VWD patients with VWF laboratory results was low (∼30%). A possible explanation is that some patients in this study may have been diagnosed with VWD at a different medical center before being transferred to this HS. In addition, where data were available, baseline VWF:RCo and VWF:Ag values were within the normal range. This could also be because patients may have transferred from another medical center where VWF treatment had already begun, elevating VWF levels. Identifying patients who may benefit from VWF prophylaxis treatment could be important as long-term prophylaxis for patients with VWD with severe bleeding tendencies has been shown to reduce bleed events compared with on-demand treatment, ³⁴ and compared with the time prior to prophylaxis.^11,12,17,35 In addition, long-term VWF prophylaxis can provide adequate hemostasis, ¹⁸ prevent arthropathy in patients who begin prophylaxis at an early age ¹³ and improve HRQoL and HRU by reducing hospitalizations. ¹⁶ Recent international guidelines conditionally recommend VWF prophylaxis treatment for patients with VWD who have a history of severe and frequent bleeds, supporting the utility of VWF prophylaxis for patients with VWD. ¹⁹

This report also highlights the healthcare burden borne by patients with symptomatic VWD, and is consistent with previous claims database analyses of HRU in patients with VWD.^10,36 For example, HRU and overall costs were reported to be higher in patients with VWD who had major bleeding events compared with patients without major bleeding events, and were primarily driven by hospitalization costs. ¹⁰ In another study, patients with VWD undergoing major surgery had significantly increased healthcare costs compared with patients without VWD who had major surgeries, including increases in inpatient, outpatient, and emergency department costs. ³⁶

Limitations

There are some inherent limitations in the use of EMR and claims databases in studies such as these. First, EMR databases contain information only about visits that occurred within that network of providers, so medical visits occurring outside of that system are not captured. Second, the claims data were only available for a subset of patients included in the EMR, and the small sample with claims data may not be representative of the overall sample. Further, the HS database used in this study covers only patients from north-eastern and central Pennsylvania and southern New Jersey, and may therefore not be representative of the population across the United States and in other countries. Another consideration is that there are no well-established standards on how best to define eligibility for VWF prophylaxis in VWD, and with the definition used in this study, based on frequency and severity of bleeds, not all potentially VWF-prophylaxis-eligible patients may have been captured. Finally, the VWD type of the patients in this study was unknown.

Conclusions

This retrospective cohort study of US EMR and claims data indicates that patients with VWD experience a high disease burden. Nearly 20% of patients in this study were considered as potentially eligible for VWF prophylaxis owing to the occurrence of severe and frequent bleeds. It is possible that none of these patients received a prophylaxis treatment approach due to the lack of approved prophylaxis treatment options in the United States at the time of the study. These patients had a higher clinical burden and HRU than the overall VWD population and thus may have benefited from VWF prophylaxis. The results of this study could help improve clinical outcomes and manage HRU for patients with VWD.