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Abstract

This European observational chart review assessed the efficacy/safety of recombinant von Willebrand factor (rVWF) for on-demand treatment of spontaneous/traumatic bleeds and prevention and/or treatment of surgery-related bleeding in adults with von Willebrand disease (VWD). Patients (n = 91) were enrolled at first rVWF administration (index). Data were collected for the 12 months before index and until death, loss to follow-up, or end of study (3-12 months after index). Fifteen patients reported an rVWF-treated spontaneous/traumatic bleed at index. Bleed resolution was obtained for 14 patients (unknown status, n = 1), and investigators assessed treatment satisfaction for 13 rVWF prescriptions (2 moderate, 5 good, and 6 excellent). rVWF was used to prevent/treat surgery-related bleeds at index in 76 patients. Bleed resolution was achieved in 25/58 rVWF-treated surgeries; bleed resolution was not applicable for 33 surgeries. In both groups, there were no reports of treatment-emergent adverse events after initiating rVWF, including hypersensitivity reactions, thrombotic events, and VWF inhibitor development. rVWF was shown to be effective for the on-demand treatment of spontaneous/traumatic bleeds, and for the prevention and treatment of surgical bleeds in this real-world VWD population.

Keywords

von Willebrand disease recombinant von Willebrand factor chart review on demand surgery bleeding

Introduction

von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting an estimated 0.6% to 1.3% of the global population, although clinically significant disease has a much lower prevalence of ∼0.01%.^1–4 It occurs in both sexes, although the prevalence in women presenting with bleeding symptoms is approximately double that in men, which may be related to heavy menstrual bleeding.¹

Mutations in the von Willebrand factor (VWF) gene lead to decreased levels or deficiencies in the function of VWF. This multimeric glycoprotein plays a key role in hemostasis, including mediation of platelet adhesion to the damaged vessel wall and platelet aggregation, and as a carrier protein for clotting factor VIII (FVIII).^1,5 VWD is classified by the nature and extent of VWF deficiency. Type 1 VWD (65%-80% of cases) involves partial quantitative VWF deficiency, Type 2 (20%-35% of cases)—further categorized into subtypes 2A, 2B, 2M, and 2N—is associated with qualitative defects, and Type 3, which is very rare (∼1 in 1 million people) is characterized by almost-complete VWF deficiency.^6,7

Symptoms of Type 1 VWD are usually mild, whereas patients with Type 2 VWD typically have mild to moderate bleeding symptoms, and Type 3 VWD is characterized by severe bleeding.⁸ Patients with VWD can experience epistaxis, easy bruising, heavy menstrual bleeding, gastrointestinal and/or musculoskeletal bleeding, as well as bleeding after surgery, childbirth or dental issues.⁹ Patients with VWD and a severe bleeding phenotype experience impaired health-related quality of life (vs the general population, as well as those with less severe bleeding symptoms) and have a risk of complications and potentially life-threatening bleeds.^10–13

Recombinant VWF (rVWF, vonicog alfa, VONVENDI^® [US/Japan/Canada]/VEYVONDI^® [Europe (including Switzerland and the UK)/Australia], Takeda Pharmaceuticals USA, Lexington, MA, USA) has been shown to be effective for on-demand and peri-operative management of bleeding in patients with VWD in phase 3 clinical trials.^14,15 There are, however, limited data on rVWF use in real-world practice. Here, we present data from a European chart review of adults with VWD who received rVWF for on-demand treatment of a spontaneous/traumatic bleed, or to prevent/treat surgery-related bleeding.

Methods

Objectives

The primary objectives of the study were to describe the real-world use of rVWF in adults with congenital VWD or symptomatic low VWF levels in the on-demand treatment of spontaneous/traumatic bleeds and in the prevention and treatment of surgical bleeds, including subsequent bleed-related outcomes. Secondary objectives were to describe all reported spontaneous/traumatic bleeds and treatment/prevention of surgical bleeds occurring in the 12 months before index and in the 3 to 12 months after index.

Study Design

This was an observational, retrospective chart review conducted at multiple sites in Austria, Denmark, France, Germany, the Netherlands, and Sweden. Patients were enrolled at the time of their first rVWF administration (index date) between January 1, 2019 and October 31, 2020. Data were collected covering the 12 months before the index date until death, loss to follow-up, or the end of study period (ie, 3-12 months after the index date), whichever came first (Figure 1).

Figure 1.

Study design.

Data on patient demographics and clinical outcomes were collected from patients’ electronic or paper medical records. Retrospectively collected data were extracted and entered onto an electronic case report form by the treating physicians or clinical research nurses at each study site. Patient characteristics, including demographics and clinical information at the time of VWD diagnosis, were also collected for each patient.

The study was conducted in accordance with the guidelines of the European Union for retrospective observational studies, and the guidelines for Good Pharmacoepidemiology Practices. Full ethical approval was obtained according to local legal requirements in all participating countries.

Patient Population

Eligible patients were adults (age ≥18 years at the time of first rVWF administration) with congenital VWD or symptomatic low VWF levels (30%-50% based on VWF antigen assay) and at least 3 months’ follow-up after the index date. Between January 1, 2019 and October 31, 2020, all patients must have had a confirmed instance of either ≥1 spontaneous or traumatic bleed treated on-demand with rVWF (either a new bleed or ongoing bleed for which treatment switched to rVWF), or treatment with rVWF to prevent and/or treat a surgical bleed. All patients provided informed consent which was required by local ethics committees.

Patients were excluded if they were diagnosed with any other bleeding disorder or factor deficiency, including acquired von Willebrand syndrome, or had neutralizing antibodies to VWF. Patients were also excluded if they were prescribed intermittent or long-term prophylaxis with plasma-derived VWF (pdVWF) or rVWF during the pre- or post-index periods, except for peri-operative management, such as in pre-, intra-, and post-operative settings, or after a major bleed. Patients who participated in a clinical trial of an investigational medical product during the study period were also excluded.

Assessments

For the assessment of on-demand rVWF treatment for spontaneous or traumatic bleeds, data collected at pre-index, index, and post-index included: number of patients and bleed events across the study period; number of bleeds per bleed type; bleed severity (mild, moderate, or severe); treatment-emergent adverse events; treatment of bleed (including number of infusions received by the patient, average dose/kg, total dose received, and treatment duration for rVWF plus any other drugs used [eg, pdVWF concentrates, FVIII products, desmopressin, and tranexamic acid—TXA]); and treatment switches, including the reason for switching. The following assessments were also recorded according to the opinion of the treating physician: bleed control (ie, the bleed is brought under control and is expected to stop; assessed as yes, no, or partial); bleed resolution (ie, the bleed has stopped completely after treatment; assessed as yes or no); and investigator-assessed satisfaction with rVWF treatment based on a 4-point scale (excellent, good, moderate, or poor).

For the assessment of rVWF for the management of surgical bleeds, the data collected included: number of surgeries in which rVWF was administered as prophylaxis or for treatment of surgical bleeds, including type and severity of surgery; treatment-emergent adverse events; number of patients treated with rVWF prophylactically to prevent bleeding during and after surgery; number of patients treated pre-, intra-, and post-operatively; prevention or treatment of surgical bleeds (including number of infusions received by the patient, average dose/kg, total dose received, and treatment duration for rVWF plus any other drugs used [eg, pdVWF concentrates, FVIII products, desmopressin, and TXA]); bleed resolution (where applicable, as defined above); treatment switches, including the reason for switching; and investigator-assessed satisfaction with rVWF treatment (as described above).

Statistical Analysis

Descriptive statistics were summarized for all patients. Categorical and discrete variables were presented as frequencies and percentages (%), with continuous variables summarized as mean (standard deviation [SD]) and range (ie, minimum and maximum values). The proportion of patients who experienced an event was reported and was based on the total number of patients for whom the event was relevant.

Endpoints are reported separately for the index bleed or surgery and any prior or subsequent bleeds or surgeries (12 months before and after the index bleed or surgery). Patients who underwent a treatment switch to any intermittent or long-term prophylaxis regimen were censored at the time of prophylaxis initiation or limited to 3 months post-index if the prophylaxis start date was unknown. Analyses were performed using STATA 17 (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC) and Microsoft Excel (version 2202).

Results

Patient Demographics and Clinical Characteristics

In total, 91 patients were included in the study from 13 sites. At the index date, the mean ± SD age of the enrolled patients was 47.6 ± 16.6 years, 64.8% of patients were female, and mean ± SD body mass index (BMI) was 27.2 ± 6.5 kg/m²; 67.0% were in the overweight, obese, and morbidly obese BMI categories. Mean ± SD time since diagnosis of VWD was 22.5 ± 18.5 years, and over half of patients had Type 2 VWD (54.9%) whereas Type 1 and Type 3 VWD were observed in 35.2% and 1.1% of patients, respectively. The remaining patients had either unclassified VWD (4.4%) or symptomatic low VWF levels (4.4%). VWD type was reported by the treating physician; the specific method used to diagnose and classify VWD was not reported. Patient characteristics at the index date are shown in Table 1 and Supplemental Table 1.

Table 1.

Patient Characteristics at the Index Date.

Characteristics	Total population(N = 91)
Age, mean ± SD, years	47.6 ± 16.6
Age groups, n (%), years
18-29	11 (12.1)
30-44	31 (34.1)
45-64	30 (33.0)
≥65	19 (20.9)
Sex, n (%)
Male	32 (35.2)
Female	59 (64.8)
Body mass index category, n (%)
Underweight, <18.5	1 (1.1)
Normal, 18.5-24.9	27 (29.7)
Overweight, 25.0-29.9	41 (45.1)
Obese, 30.0-39.9	15 (16.5)
Morbidly obese, ≥40	5 (5.5)
Missing	2 (2.2)
Time since diagnosis^a, n (%)
0-10 years	30 (33.0)
>10 years	61 (67.0)
Country of residence, n (%)
Austria	1 (1.1)
Denmark	2 (2.2)
France	72 (79.1)
Germany	5 (5.5)
The Netherlands	8 (8.8)
Sweden	3 (3.3)
VWD type
1	32 (35.2)
2A	27 (29.7)
2B	4 (4.4)
2M	16 (17.6)
2N	3 (3.3)
3	1 (1.1)
Unclassified	4 (4.4)
Symptomatic low VWF (30%-50%)	4 (4.4)
Family history of VWD
Yes	53 (58.2)
Parent	39 (73.6)
Sibling	21 (39.6)
Grandparent	6 (11.3)
Other	10 (18.9)
No	18 (19.8)
Unknown	20 (22.0)
Comorbidities at index date(within 2 years of data abstraction)
0	46 (50.5)
1	25 (27.5)
2	15 (16.5)
≥3	5 (5.5)

Abbreviations: SD, standard deviation; VWD, von Willebrand disease; VWF, von Willebrand factor.

Time between confirmed clinical diagnosis and completion of data collection for patient.

On-demand Treatment of Spontaneous or Traumatic Bleeds at Index Date

In total, 15 patients reported an rVWF-treated bleed at the index date, including 6 pregnancy-related bleeds (antepartum hemorrhage, n = 2; primary post-partum hemorrhage, n = 2; type not specified, n = 2), 3 traumatic (non-surgical) bleeds, 2 gastrointestinal (GI) bleeds, and 1 case each of epistaxis, oral bleed, hemarthrosis, and menorrhagia. Of the 15 bleeds, 9 were moderate in severity, 4 were mild, and 2 were severe.

Four patients were switched to rVWF from another hemostatic product at the index date (Supplemental Table 2): 1 patient with an oral bleed switched from TXA, 1 patient with a GI bleed switched from pdVWF/FVIII concentrate (Haemate P^®; antihemophilic factor/VWF complex [human], CSL Behring GmbH, Marburg, Germany), and 2 patients (1 each with epistaxis and menorrhagia) for whom the prior treatment is unknown. Reasons for switching were more appropriate treatment based on the ratio of VWF/FVIII (n = 2; 1 from Haemate P, 1 from an unknown product), tolerability/adverse events (n = 1; from an unknown product), and other (n = 1; from TXA). Of the remaining 11 patients (who did not switch treatment), 4 received rVWF alone at the index date, 5 received rVWF and TXA, 1 received rVWF, TXA, and red blood cell transfusion, and 1 received rVWF plus FVIII (Supplemental Table 2).

Consumption and associated outcomes for rVWF and the other hemostatic treatments used for the index bleed are summarized in Table 2. Of 15 patients whose index bleed was treated with rVWF, 14 (93.3%) achieved full bleed control and 1 (6.7%) achieved partial bleed control. Bleed resolution was achieved in all 14 patients for whom information on bleed resolution was available (bleed resolution was recorded as unknown in 1 patient). Investigator-assessed satisfaction with rVWF at index date was reported for 13 prescriptions (excellent, n = 6; good, n = 5; moderate, n = 2; poor, n = 0) and was missing for the remaining 3 prescriptions.

Table 2.

Dosing and Outcomes Associated With On-Demand Treatment With Hemostatic Products per Bleed Event at Index.

	Treatments administered for bleed event at index (n = 15)^a
	rVWF (IU)(n = 15)	TXA (mg)(n = 7)	pdVWF/FVIII(Haemate P) (IU)(n = 1)	FVIII^b (IU)(n = 1)	Red blood cell transfusion (Units)(n = 1)
Dosing, mean ± SD^c
Number of infusions^d	2.7 ± 2.5	36.4 ± 25.4	2.0	1.0	1.0
Average dose per patient	2502 ± 996	643 ± 244	1040	2000	400
Average weight-adjusted (kg) dose per patient	36.5 ± 13.1	9.2 ± 3.8	20.0	27.8	6.8
Total dose^d	6093 ± 4337	22 500 ± 1547	2060	2000	400
Treatment duration (days)	2.3 ± 2.5	12.1 ± 8.5	2.0	1.0	1.0
Bleed control^e, n (%)
Yes	14 (93.3)	5 (71.4)	0	0	1 (100)
Partial	1 (6.7)^f	1 (14.3)^f	1 (100)	1 (100)	0
No	0	1 (14.3)	0	0	0
Bleed resolution^g, n (%)
Yes	14 (93.3)	5 (71.4)	0	0	1 (100)
No	0	1 (14.3)	1 (100)	0	0
Unknown	1 (6.7)^f	1 (14.3)^f	0	1 (100)	0

Abbreviations: FVIII, factor FVIII; IU, international unit; n, number of patients; pd, plasma derived; SD, standard deviation; TXA, tranexamic acid; VWF, von Willebrand factor.

Haemate P^® (antihemophilic factor/VWF complex [human], CSL Behring GmbH, Marburg, Germany).

All bleeds were treated with rVWF, alone or with the additional hemostatic products shown in the table.

Data on specific FVIII product used not collected.

Average refers to dosing per patient; mean refers to dosing across study population.

^d Number of infusions or total dose required to resolve the index bleed per patient.

Based on opinion of treating physician; bleed control defined as bleed brought under control and is expected to stop.

Patient had trauma bleed and was treated with rVWF and TXA.

Based on opinion of treating physician; bleed resolution defined as bleed has stopped completely after treatment.

Prevention and Treatment of Surgical Bleeds at Index

In total, 76 patients received rVWF at index to prevent and/or treat surgical bleeds, two-thirds of whom underwent elective surgery (n = 52; 68.4%) and around half of whom (n = 39; 51.3%) underwent major surgery, of which one was related to trauma, and the remainder underwent minor (n = 23; 30.3%) or dental surgeries (n = 14, 18.4%) (Supplemental Table 3). Life-threatening bleeds during surgery were reported in 2 patients (2.6%) who underwent cardiothoracic or male-to-female transsexualism (aidopoiesis) surgery.

All patients with a surgery at index had rVWF prophylactically to prevent bleeding or on demand to treat bleeding during surgery. Of the 39 patients who received prophylactic treatment in preparation for surgery prior to the day of surgery, 34 (87.2%) received rVWF, with or without another hemostatic treatment (Table 3 and Supplemental Table 4). Of the patients who received rVWF, 24 received rVWF alone, and 10 received rVWF with either TXA (n = 6), FVIII (n = 2), FVIII and TXA (n = 1), or another (unspecified) product (n = 1). Of the remaining 5 patients, 2 received pdVWF/FVIII (Wilate^®; human FVIII/human VWF; Octapharma AG, Lachen, Switzerland, n = 1; Haemate P, n = 1) alone, 1 received pdVWF/FVIII (Haemate P) plus TXA, 1 received FVIII and TXA, and 1 received TXA alone.

Table 3.

Characteristics of rVWF and Concomitant Hemostatic and Non-hemostatic Therapies Received as Prophylaxis in Preparation for Surgery at Index.

	Treatments administered as prophylaxis in preparation for surgery at index (n = 39)^a
	rVWF(IU)(n = 34)	TXA(mg)(n = 10)	FVIII^b(IU)(n = 4)	pdVWF/FVIII (Haemate P)(IU)(n = 2)	pdVWF/FVIII(Wilate)(IU)(n = 1)
Dosing, mean ± SD^c
Number of infusions^d	1.2 ± 0.6	21.7 ± 10.9	1.0 ± 0.0	2.0 ± 1.4	1.0
Average dose per patient	2670 ± 935	950 ± 158	1625 ± 479	3500 ± 735	3685
Average weight-adjusted (kg) dose per patient	36.3 ± 11.3	13.6 ± 3.6	23.3 ± 6.9	45.4 ± 11.2	55.0
Total dose^d	3441 ± 2472	20 200 ± 10 696	1625 ± 479	6440 ± 3451	3685
Treatment duration (days)	1.2 ± 0.5	7.3 ± 3.5	1.0 ± 0.0	2.0 ± 1.4	1.0

Abbreviations: FVIII, factor VIII; IU, international units; n, number of patients; pd, plasma derived; rVWF, recombinant von Willebrand factor; TXA, tranexamic acid.

Haemate P^® (antihemophilic factor/VWF complex [human], CSL Behring GmbH, Marburg, Germany); Wilate^® (human FVIII/human VWF; Octapharma AG, Lachen, Switzerland).

Patients could receive prophylaxis comprising rVWF alone, rVWF with the additional hemostatic/non-hemostatic products, or other hemostatic agents without rVWF as shown in the table.

Data on specific FVIII product used not collected.

Average refers to dosing per patient; mean refers to dosing across study population.

Number of infusions or total dose administered per patient as prophylaxis in preparation for surgery.

Of the 58 patients who received rVWF on the day of surgery (ie, pre-, intra-, or post-operatively), 54 (93.1%) received rVWF (alone or in combination with another hemostatic agent) as initial therapy (Table 4 and Supplemental Table 4): 42 received rVWF alone, and 12 received rVWF with either TXA (n = 4), FVIII (n = 3), FVIII and TXA (n = 2), desmopressin (n = 1), or another (unspecified) product (n = 2). The remaining 4 patients initially received pdVWF/FVIII and switched to rVWF, including 1 patient undergoing minor surgery who was switched from pdVWF/FVIII (Wilate) and 3 patients undergoing major surgery who were switched from either pdVWF/FVIII (Haemate P, n = 2) or pdVWF/FVIII (Haemate P) plus TXA (n = 1). Reasons for switching were more appropriate treatment based on the ratio of VWF/FVIII (n = 2; from Haemate P or Wilate), thrombotic events (n = 1; from Haemate P), and other (n = 1; from Haemate P plus TXA to rVWF plus TXA).

Table 4.

Dosing and Outcomes Associated With Prevention/Treatment of Surgery-Associated Bleeds With Hemostatic and Unspecified Products per Bleed Event at Index (n = 58).

	rVWF(IU)(n = 58)	TXA(mg)(n = 7)	FVIII^a (IU)(n = 5)	pdVWF/FVIII(Haemate P)(IU)(n = 3)	pdVWF/ FVIII(Wilate)(IU)(n = 1)	DDVAP(μg)(n = 1)	Other(n = 2)
Dosing, mean ± SD^b
Number of infusions^c	3.4 ± 4.5	54.1 ± 48.9	1.0 ± 0.0	6.0 ± 7.0	1.0	1.0	26.5 ± 26.2
Average dose per patient	2355 ± 878	1000 ± 0.0	1691 ± 666	2566 ± 493	3484	20.0	2025 ± 2793
Average weight-adjusted (kg) dose per patient	31.0 ± 10.9	15.1 ± 3.6	24.2 ± 10.2	34.0 ± 4.5	52.0	0.3	23.3 ± 32.1
Total dose^c	7189 ± 8081	54 143 ± 48 889	1691 ± 666	16 637 ± 19 668	3484	20.0	90 200 ± 126 996
Treatment duration (days)	4.4 ± 11.9	19.9 ± 19.4	1.0 ± 0.0	5.3 ± 5.9	1.0	1.0	37.5 ± 10.6
Bleed resolution, n (%)
Yes	25 (43.1)	5 (71.4)	1 (20.0)	1 (33.3)	0	1 (100)	2 (100)
No	0	0	0	0	0	0	0
Not applicable	33 (56.9)	2 (28.6)	4 (80.0)	2 (66.7)	1 (100)	0	0

Abbreviations: DDVAP, desmopressin; FVIII, factor FVIII; IU, international unit; n, number of patients; SD, standard deviation; rVWF, recombinant von Willebrand factor; TXA, tranexamic acid.

Haemate P^® (antihemophilic factor/VWF complex [human], CSL Behring GmbH, Marburg, Germany); Wilate^® (human FVIII/human VWF; Octapharma AG, Lachen, Switzerland).

Data on specific FVIII product used not collected.

Average refers to dosing per patient; mean refers to dosing across study population.

Number of infusions or total dose required to resolve the index bleed per patient.

Pre-, intra-, and post-operative rVWF doses were administered to 39, 13, and 30 patients, respectively, with mean ± SD average doses of 24.1 ± 13.7, 17.4 ± 9.7, and 20.1 ± 9.9 IU/kg. The mean number of infusions was 1.1 ± 0.4, 2.1 ± 1.8, and 4.3 ± 5.7, respectively. Bleed resolution was reported for 25 of the 58 patients who received rVWF on the day of surgery (43.1%) (Table 4) and not applicable for the remaining 33 patients (56.9%). All 33 patients for whom bleed resolution was reported as “not applicable” were given rVWF to prevent bleeding (at any stage of the surgery; pre-operative, intra-operative, or post-operative), and therefore bleed resolution can be assumed to be not applicable. A rating of investigator satisfaction was available for 67 rVWF prescriptions (excellent, n = 29, good, n = 37, and poor, n = 1), and was missing for 82 prescriptions.

Spontaneous/Traumatic Bleeds and Surgeries During the Pre-index and Post-index Periods

In the pre-index period (in which by definition no bleeds were treated with rVWF), 7 patients had 15 spontaneous/traumatic bleeds (including 7 cases of epistaxis, 4 GI bleeds, 3 trauma-related bleeds, and 1 muscle hematoma), and 14 patients had 16 surgeries (9 minor, 5 major, and 2 dental surgeries). Administered treatments are summarized in Supplemental Tables 2 and 4.

The sample size for the post-index period was 88 patients, as 3 patients initiated long-term prophylaxis during this period and were excluded from the analysis. Eight patients had 10 bleeds (including 4 cases of menorrhagia, 2 GI bleeds, 2 epistaxis, and 1 case each of oral bleed and muscle hematoma), and 21 patients had 23 surgeries (13 minor, 8 major, and 2 dental surgeries) in the post-index period. In total, 1 of the 10 bleeds (10.0%) in the post-index period was treated with rVWF alone (Supplemental Table 2). Of the 23 surgeries at post-index, rVWF alone was used as prophylaxis in preparation for 8 surgeries (34.8%), rVWF alone was used for peri-operative management in 4 surgeries (17.4%) without prophylaxis prior, and finally rVWF was used alone as a prophylaxis in preparation for surgery and for peri-operative management of surgery in 2 surgeries (Supplemental Table 4).

Safety

There were no reports of treatment-emergent adverse events, hypersensitivity/allergic reactions, thrombotic events, VWF neutralizing antibody development, transfusion-transmitted infections, malignancy, cardiovascular events, neurological events, or death at index, or during the pre-index and post-index periods. Of the 76 patients who underwent surgery at index, 1 patient (1.3%) who switched from a pdVWF/FVIII concentrate to rVWF experienced a thrombotic event prior to rVWF use. The thrombotic event that occurred while the patient was receiving pdVWF/FVIII was cited as the reason for switching treatment.

Discussion

This European chart review is one of the largest international studies reporting on real-world treatment outcomes for patients with VWD receiving rVWF. The results show that rVWF is effective for on-demand treatment of spontaneous and traumatic bleeds, as well as for the prevention and treatment of surgical bleeds in patients who predominantly had Type 1 or 2 VWD. Bleed resolution was reported for all rVWF-treated patients with spontaneous/traumatic bleeds (with a known outcome) at the index date, as well as for all patients receiving rVWF for peri-operative management at index for whom bleed resolution was applicable. Bleed resolution was reported as “not applicable” for the remaining patients undergoing surgery (eg, cases in which rVWF was used to prevent bleeding and thus no “resolution” was possible). Treatment was rated as good/excellent by physicians for 85% and 99% of rVWF prescriptions used to treat spontaneous/traumatic bleeds or to prevent and/or treat surgical bleeds at index, respectively, where ratings were available (ie, non-missing sample).

The efficacy of rVWF in this chart review is consistent with clinical trial data derived from patient populations with severe VWD (53%-78% of patients with Type 3 VWD), as well as real-world data.^14–16 In a pivotal study, on-demand treatment with a single infusion of rVWF given with recombinant FVIII (rFVIII) was effective in 82% of bleeds in 22 patients with severe VWD, with bleed control rated as good or excellent in 100% of bleeds.¹⁴ In the phase 3 surgery study (N = 15), rVWF (with concomitant rFVIII in 11% of bleeds) was associated with overall and intra-operative hemostatic efficacy ratings of good or excellent in all patients with severe VWD.¹⁵ Overall clinical efficacy for rVWF was also rated as excellent or good in 97% of surgeries (n = 63) in patients with VWD included in a retrospective analysis.¹⁶

Importantly, rVWF did not result in any treatment-emergent adverse events (including hypersensitivity, thrombotic events, VWF inhibitor development, and transfusion-related infections) in a real-world population, consistent with the safety profile of rVWF demonstrated in clinical trials and a retrospective analysis of rVWF use in surgical procedures.^14–16 In this chart review, among patients receiving initial rVWF therapy at index, 10/11, 31/34, and 49/54 patients received rVWF therapy without FVIII for the treatment of spontaneous/traumatic bleeds, prophylaxis in preparation for surgery, or peri-operative management (on or after the day of surgery), respectively. Administration of rVWF without FVIII in these patients potentially reduced the risk of thromboembolic events, which although rare have been reported in patients with VWD, elevated FVIII levels, and risk factors for thrombosis.^17–19 Co-administration of a recombinant FVIII product with the first dose of rVWF is required to achieve hemostatic levels of FVIII:C, if the patient's baseline FVIII:C is <40% or unknown, or in clinical settings where rapid correction of hemostasis is required. However, if an immediate increase in FVIII:C is not required or FVIII:C is at a sufficient level for hemostasis, co-administration of rFVIII can be omitted with the first rVWF infusion.²⁰

The mean average rVWF treatment dose in patients with spontaneous/traumatic bleeds at index (36.5 IU/kg) was slightly lower than the recommended dose for on-demand treatment (40-80 IU/kg, depending on the severity of the bleed²⁰), even for the mild/moderate bleeds predominantly observed in the present study. Real-world use of rVWF in surgical settings in the present study generally followed international treatment guidelines, which recommend treatment with desmopressin or VWF concentrate plus TXA to increase VWF activity levels to ≥0.5 IU/mL in patients scheduled to undergo minor surgery or minor invasive procedures.²¹ Treatment should be individualized based on the procedure and the patient's needs. Patients with Type 3 VWD, and many with Type 2 VWD, will require VWF therapy to achieve a significant increase in VWF activity.²¹

In surgical settings, the recommended dose of rVWF is dependent on the VWF and FVIII levels of the patient, and the type/severity of the expected bleed, with concomitant use of rFVIII recommended in patients with inadequate FVIII levels (<0.4 IU/mL for minor and oral surgery and <0.8 IU/mL for major surgery²⁰). In this chart review study, rVWF plus FVIII was given to 3 patients for prophylaxis prior to the day of surgery and to 5 patients for the prevention/treatment of surgical bleeds on the day of the index surgery.

In this chart review study, the use of rVWF and/or other hemostatic agents for the prevention of surgical bleeds was split into prophylaxis in preparation for surgery (ie, administration prior to the day of surgery) and administration on or after the day of surgery. Although the timing of prophylaxis was not specified in the case report form, the mean treatment duration of prophylaxis in preparation for surgery with rVWF was 1.2 days and ranged from 1.0 to 2.0 for pdVWF/FVIII concentrates. Although the exact hour of dosing was not specified in the case report form, this range is generally in line with recommendations to initiate rVWF or pdVWF/FVIII concentrates 12 to 24 h prior to elective surgery to ensure adequate FVIII levels.^20,22

It should be noted that the present study was conducted at sites with experience in managing patients with VWD. This may have led to a higher likelihood of patients being treated according to guidelines than the overall VWD population, as a previous chart review in patients with VWD undergoing surgery showed that patients treated at non-specialist centers were less likely to receive VWD-specific therapy in line with guidelines.²³

The difficulty in identifying and recruiting patients who met the inclusion criteria, combined with the impact of the COVID-19 pandemic, was the greatest limiting factor, leading to a smaller overall sample size than expected. Most patients in the study (79%) came from France, which may reflect a reliance on study sites involved in previous rVWF studies and could limit the generalizability of the results to other countries. In addition, only 1% of patients in the study had Type 3 VWD, reflecting the rarity of this condition, as well as the fact that these patients were likely to be receiving long-term prophylaxis, and therefore, excluded from the study. Patient characteristics (sex, age, and/or VWD type) were, however, broadly in line with published real-world data on patient populations with VWD, particularly those at specialist treatment centers.^10,23–27 Another limitation was the lack of information on medications used other than rVWF and other reported hemostatic treatments. As a result, the impact of concomitant medications and treatments for comorbidities cannot be fully assessed. Furthermore, patient data were collected retrospectively, so the level and quality of data that could be extracted was dependent on the data recorded in individual patient records.

Conclusions

In this European chart review, rVWF was effective for the on-demand treatment of spontaneous/traumatic bleeds, and for the prevention and treatment of surgical bleeds, including when administered alone. In this real-world population, rVWF was not associated with any treatment-emergent adverse events such as hypersensitivity/allergic reactions, thrombotic events, and VWF inhibitor development.

Supplemental Material

sj-docx-1-cat-10.1177_10760296231177294 - Supplemental material for Outcomes in Patients With von Willebrand Disease Receiving Recombinant von Willebrand Factor on Demand and in Surgical Settings: Chart Review

Supplemental material, sj-docx-1-cat-10.1177_10760296231177294 for Outcomes in Patients With von Willebrand Disease Receiving Recombinant von Willebrand Factor on Demand and in Surgical Settings: Chart Review by Shawn X. Sun, Shannely Lowndes, Rosa Willock, Cheryl Jones and Sarah Brighton in Clinical and Applied Thrombosis/Hemostasis

Footnotes

Acknowledgments

The authors would like to thank Françoise Truong Berthoz and Nataliya Kemenyash from Takeda Pharmaceuticals International AG,Zurich,Switzerland,and Ping Du from Takeda Development Center Americas,Inc.,Cambridge,MA,USA,for their contributions to the study design. Under the direction of the authors,medical writing support was provided by Joanne Vaughan of Excel Medical Affairs (Fairfield,CT,USA),and was funded by Takeda Development Center Americas,Inc.,Lexington,MA,USA.

Author Contributions

Sarah Brighton conducted data analysis,critical review of results,and development of statistical plan,report,and manuscript. Cheryl Jones conducted data analysis,critical review of results,and development of statistical plan,report,and manuscript. Shannely Lowndes contributed to the study design,critical review of results,and development of report and manuscript. Shawn X. Sun contributed to the conceptualization of study,study design,critical review of results,and development of statistical plan,report,and manuscript. Rosa Willock contributed to the critical review of results,development of statistical plan,report,and manuscript. All authors approved the final version of the manuscript.

Data Availability

The datasets,including the redacted study protocol,redacted statistical analysis plan,and individual participants’ data supporting the results reported in this article,will be made available within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification,in compliance with applicable privacy laws,data protection,and requirements for consent and anonymization.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research,authorship,and/or publication of this article: Shawn X. Sun is an employee of Takeda Development Center Americas,Inc.,Cambridge,MA,USA,and holds stock in Takeda. Shannely Lowndes is an employee of Takeda Pharmaceuticals International AG,Zurich,Switzerland,and holds stock in Takeda. Rosa Willock,Cheryl Jones,and Sarah Brighton are employees of HCD Economics,Daresbury,UK,and received research funding from Baxalta USA Inc.,a Takeda company,Lexington,MA,USA,for this study.

Ethics Approval

Full ethical approval was obtained according to local legal requirements in all participating countries.

Funding

The authors disclosed receipt of the following financial support for the research,authorship,and/or publication of this article: This study was funded by Baxalta US Inc.,a Takeda company,Lexington,MA,USA.

Informed Consent

All patients provided informed consent where required by local ethics committees.

ORCID iDs

Shawn X. Sun

Shannely Lowndes

Sarah Brighton

Trademark Statement

Haemate P ® is a registered trademark of CSL Behring GmbH,Marburg,Germany.

Wilate ® is a registered trademark of Octapharma AG,Lachen,Switzerland.

Willfact ® and Wilfactin ® are registered trademarks of Laboratoire Français du Fractionnement et des Biotechnologies,Les Ulis,France.

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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