1 INTRODUCTION

Von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterized by excessive mucocutaneous bleeding.1, 2 Symptoms can include ecchymosis, epistaxis, prolonged bleeding from minor wounds, heavy menstrual bleeding (HMB), oral bleeding and bleeding after surgery or childbirth.1, 2 It is estimated that .01% to .1% of the population has clinically relevant VWD symptoms.3, 4 However, bleeding severity varies widely and is poorly defined despite its importance in treatment decisions.5-8

VWD remains underrecognized and underdiagnosed owing to a lack of awareness, heterogeneity of phenotypes and the need for repeated, complex diagnostic tests,9-12 and there may be a significant number of patients with symptomatic but undiagnosed VWD.13 There is a need to optimize VWD management, particularly for difficult bleed types such as HMB and gastrointestinal (GI) bleeding.10, 14-16 Up to one-third of female and one-fifth of male patients may experience continued bleeding in the year after diagnosis, which can affect quality of life and healthcare utilization, especially if there are comorbidities such as anaemia.17-20

The objective of the current analysis was to characterize bleeding patterns in patients with VWD before and after diagnosis and identify characteristics of those who continued to bleed following diagnosis compared with those in whom bleeding resolved. Additionally, bleeding and treatment patterns were evaluated in patients with bleeding from a single site, compared with those with bleeding from multiple sites.

2 MATERIALS AND METHODS

This was a longitudinal retrospective analysis of de-identified healthcare claims information from commercially insured patients in the IQVIA PharMetrics Plus US database between January 2006 and June 2015. The IQVIA PharMetrics® Plus US database consists of fully adjudicated medical and pharmacy claims. It contains a longitudinal view of inpatient and outpatient services, prescription and office/outpatient administered drugs, cost and enrolment information. An enrolled patient can be tracked across all sites of care.

Patients eligible for analysis had ≥2 insurance claims for VWD (ICD-9 code 286.4, of which the first claim was designated as the date of diagnosis), and continuous health-plan enrolment for ≥2 years before, and ≥2 years after, diagnosis. Exclusion criteria were a primary diagnosis for haemophilia A, qualitative platelet disorders or anticoagulant treatment. Ethical approval was not required because de-identified data were used.

The time periods analysed were the 18 months before diagnosis and from 7 to 24 months after diagnosis (the 6-month post-diagnosis period was omitted because initial analyses suggested treatments were still being optimized). Extracted data for eligible patients included demographics, bleed event types, specialty of the treating physician for bleed management visits (for inpatients, this was the admitting physician only) and type of VWD treatment. Extracted bleed claims were for menorrhagia (ICD-9 claim codes 626.2, 626.3, 626.4, 626.6, 626.8, 626.9, 627.0, 627.1, 627.4), post-partum bleeding (666.x), epistaxis (784.7, 21.0x, R04.0), prolonged bleeding (790.92), GI bleeds (578.9, 578.x), gum bleeds (523.8), joint bleeds (719.1x), haemorrhage complicating a delivery (641.9), bleeding complicating a procedure (998.11), coagulation defects complicating pregnancy, childbirth or the puerperium (649.3x), haemorrhage unspecified (459.0) and other bleeds (641.3x, 287.5, 287.4x, 287.3x, 782.7). Claims for anaemia (codes 280.xx and 285.xx) were documented. Information on VWD subtype was not available.

Bleeding phenotype was defined as multiple-site (≥2 types of bleed claim) or single site (one type of bleed claim) bleeding before VWD diagnosis. Bleeding status was defined as continued bleeding (≥1 post-diagnosis bleed claim) or resolved bleeding (no post-diagnosis bleed claims). Extracted data were analysed according to pre-diagnosis bleeding phenotype, post-diagnosis bleeding status and sex. The t-test was used to compare mean age at VWD diagnosis, and the Chi-square test to compare occurrence of pre-diagnosis bleed type claims and pre- and post-diagnosis claims for treatment types, by bleeding status and phenotype. Multiple logistic regression analysis was conducted to evaluate associations of pre-diagnostic bleed types, and pre- and post-diagnosis treatments, with bleeding phenotype and status, and of post-diagnosis treatments with post-diagnosis bleed types. Age (exact), sex and haematologist visit history were included in the model as control variables. All analyses were conducted using SAS software version 9.4.

3 RESULTS 3.1 Patient population

Overall, 3756 patients met the inclusion criteria, of whom 72.6% were female and 71.0% were adults (≥18 years) at VWD diagnosis (Figure 1). Overall, 1707 (45.4%) patients had ≥1 bleed claims during the 18-month pre-VWD diagnosis analysis period. Pre-diagnosis bleeding phenotype could be assigned for 1447 patients: 642 patients (17.1% of total population) had single bleed sites, and 805 (21.4%) had multiple bleed sites. Women comprised a slightly higher proportion of the single-bleed-site (76.2%) than the multiple-bleed-site (67.3%) group (Figure 1).

Derivation and characteristics of analysis population.

VWD, von Willebrand disease.

aOne patient was missing data on sex.

b1447 of 1707 patients with bleeding event claims during the 18-month pre-VWD diagnosis period could be assigned a pre-diagnosis bleed phenotype. ‘Single bleed sites’ and ‘multiple bleed sites’ refer to patients with one type of bleed claim or at least two types of bleed claim in the pre-VWD diagnosis period, respectively. ‘Resolved bleeding’ and ‘continued bleeding’ refer to absence or presence of claims for bleeds in the post-VWD diagnosis period, respectively

Post-diagnosis, 2493/3756 (66.4%) patients had resolved bleeding (excluding claims for maintenance visits), while 1263 (33.6%) patients (38.5% of female and 20.8% of male patients) had continued bleeding. Women comprised 83.1% of the continued-bleeding group, and 67.3% of the resolved-bleeding group.

3.2 Age at VWD diagnosis

Mean age at VWD diagnosis was 34.3 (standard deviation [SD] 19.6) years (median [range] 34 [2–82] years). Among men and women combined, age at diagnosis was significantly lower among patients with multiple (vs single) bleed sites and with continued (vs resolved) bleeding (Table 1). These differences were also statistically significant among women (P = .0002, multiple- vs single site bleeding; P < .0001, continued vs resolved bleeding), but not men (P > .05 for each comparison). Mean (SD) age at diagnosis was significantly lower for men than women, both in the overall population and among patients with single site, resolved and continued bleeding.

TABLE 1. Comparison of mean age at diagnosis of von Willebrand disease according to sex, pre-diagnosis bleeding phenotype and post-diagnosis bleeding status Patient population Comparison n Mean (SD) age at VWD diagnosis (y) P(t-test) All patients (N = 3756)a Male 1026 30.6 (21.9) < .0001b Female 2727 35.7 (18.5) Patients with bleed claims and an ascertainable bleed phenotype in the 18 months pre-diagnosis (n = 1447) Single bleed site 642 32.1 (19.0) .0107b Multiple bleed sites 805 29.8 (17.7) All patients (N = 3756)a Resolved bleeding 2491 35.2 (20.1) < .0001b Continued bleeding 1262 32.5 (18.4) Resolved bleeding (n = 2493)a Male 813 30.9 (21.6) < .0001b Female 1678 37.3 (19.0) Continued bleeding (n = 1263)a Male 213 29.2 (22.9) .0096b Female 1049 33.1 (17.3) Single bleed sites (n = 642) Male 153 26.1 (20.8) < .0001b Female 489 34.0 (18.0) Multiple bleed sites (n = 805) Male 132 27.5 (24.0) .0986 Female 673 30.3 (16.1) SD, standard deviation; VWD, von Willebrand disease. aTwo patients were missing data on age, and one patient on sex. bStatistically significant (P < .05). ‘Resolved bleeding’ and ‘continued bleeding’ refer to absence or presence of claims for bleeds in the post-VWD diagnosis period, respectively. ‘Single bleed sites’ and ‘multiple bleed sites’ refer to patients with one type of bleed claim or at least two types of bleed claim in the pre-VWD diagnosis period, respectively. 3.3 Treating physician specialty

Overall, hospital medicine specialists (hospitalists) were most commonly consulted for a bleeding event in both the pre- and post-diagnosis periods (with visits from 21.8% and 14.0% of patients, respectively), followed by primary care physicians (PCPs; 13.7% and 7.9%, respectively) and obstetrician-gynaecologists (OBGYNs; 12.9% and 9.7%, respectively). Haematologist visits for bleeding events were documented for only 5.9% of patients before diagnosis and 2.6% after diagnosis.

The most common physicians consulted for women were hospitalists, OBGYNs and PCPs, for both pre-diagnosis bleeds in patients whose bleeding resolved (Figure 2A) and pre- and post-diagnosis bleeds in those with continued bleeding (Figure 2B). For men with resolved or continued bleeding, the most common physician types consulted for pre-diagnosis bleeds were hospitalists, PCPs and haematologists (Figure 2A, 2B), compared with hospitalists, PCPs and urgent-care physicians for post-diagnosis bleeds in patients with continued bleeding (Figure 2B). Thus, more men with continued bleeding interacted with urgent-care physicians post-diagnosis compared with pre-diagnosis.

Most common specialties of treating physicians for bleed claims. (A) Patients with resolved bleeding. (B) Patients with continued bleeding.

ENT, ear, nose and throat specialist; OBGYN, obstetrician-gynaecologist; PCP, primary care physician.

Data are percentage of patients visiting the physician specialty for a bleed claim; specialties visited by > 1% of patients are included.

a’Hospitalist’ category may have included haematologists. Data shown include visits to a specialist to address a bleed

3.4 Bleeding patterns and anaemia

Overall, bleed claims reduced following VWD diagnosis: 45.4% and 33.6% of patients had bleed claims during the pre- and post-diagnosis periods, respectively. In total, 59% of patients (61% of women and 49% of men) with continued bleeding had bleed-related claims before diagnosis compared with 38% (41% of women and 32% of men) whose bleeding subsequently resolved.

In total, 1420 (37.8%) patients (41.7% of women and 27.6% of men) had at least one claim for anaemia. Among both male and female patients with continued bleeding, the percentage of patients with an anaemia claim increased following VWD diagnosis (from 23% pre-diagnosis to 27% post-diagnosis in women, and from 15% to 20% in men). Among patients with resolved bleeding, the rate of anaemia claims decreased following diagnosis (from 18% to 14% in women, and 11% to 7% in men).

3.5 Bleed types

Pre-diagnosis bleed claims for HMB, but not other bleed types, were significantly more common among women with multiple (compared with single) bleed sites (Table 2). Conversely, coagulation defects complicating pregnancy, childbirth or the puerperium were significantly more common among patients with a single (vs multiple) bleed site (Table 2). HMB was positively associated with a multiple-site bleeding, and coagulation defects complicating pregnancy, childbirth or the puerperium were negatively associated with multiple-site bleeding (Table 3).

TABLE 2. Bleed type frequency and treatment use according to post-diagnosis bleeding status and pre-diagnosis bleeding phenotype Bleeding phenotype before VWD diagnosis Bleeding status after VWD diagnosis Single bleed site (n = 642) Multiple bleed site (n = 805) P (Chi-square test) Continued (n = 1263) Resolved (n = 2493) P (Chi-square test) Bleed type before VWD diagnosis, n (%) Gastrointestinal bleed 71 (11.1) 80 (9.9) .4882 67 (5.3) 84 (3.4) .0043a Heavy menstrual bleeding 261 (40.7) 521 (64.7) < .0001a 410 (32.5) 372 (14.9) < .0001a Mucosal bleed 60 (9.3) 77 (9.6) .8874 51 (4.0) 86 (3.4) .3635 Epistaxis 127 (19.8) 166 (20.6) .6931 132 (10.5) 161 (6.5) < .0001a Coagulation defects complicating pregnancy, childbirth or puerperium 22 (3.4) 12 (1.5) .0157a 17 (1.3) 17 (.7) .0423a Haemorrhage unspecified 139 (21.7) 150 (18.6) .1537 107 (8.5) 182 (7.3) .2031 Treatment type before VWD diagnosis Oral contraceptivesb 98 (20.0) 188 (27.9) .002a 238 (22.7) 244 (14.5) < .0001a Desmopressin 31 (4.8) 52 (6.5) .185 74 (5.9) 118 (4.7) .1389 Von Willebrand factor 12 (1.9) 8 (1.0) .1565 15 (1.2) 30 (1.2) .9666 Aminocaproic acid 23 (3.6) 21 (2.6) .2838 37 (2.9) 50 (2.0) .0753 Nasal cauterization 26 (4.0) 48 (6.0) .1008 35 (2.8) 42 (1.7) .0264a Treatment type after VWD diagnosis Oral contraceptivesb 107 (21.9) 182 (27.0) .0445a 303 (28.9) 251 (15.0) < .0001a Desmopressin 59 (9.2) 122 (15.2) .0007a 176 (13.9) 202 (8.1) < .0001a Von Willebrand factor 22 (3.4) 19 (2.4) .2245 63 (5.0) 40 (1.6) < .0001a Aminocaproic acid 30 (4.7) 67 (8.3) .0058a 90 (7.1) 112 (4.5) .0007a Nasal cauterization 12 (1.9) 21 (2.6) .3492 56 (4.4) 1 (.0) < .0001a VWD, von Willebrand disease. aStatistically significant (P < .05) for frequency in patients with continued bleeding compared with resolved bleeding, or in patients with multiple bleed sites compared with a single bleed site. ‘Resolved bleeding’ and ‘continued bleeding’ refer to absence or presence of claims for bleeds in the post-VWD diagnosis period, respectively. ‘Single bleed sites’ and ‘multiple bleed sites’ refer to patients with one type of bleed claim or at least two types of bleed claim in the pre-VWD diagnosis period, respectively. bOral contraceptive use was evaluated in female patients only (continued bleeding, n = 1050; resolved bleeding, n = 1679; single bleed site, n = 489; multiple bleed site, n = 673). TABLE 3. Association of bleed types and treatments with post-diagnosis bleeding status and pre-diagnosis bleeding phenotype Multiple (vs single) bleed sites before VWD diagnosis Continued (vs resolved) bleeding after VWD diagnosis Odds ratio (95% CI)a P Odds ratio (95% CI)b P Bleed type before VWD diagnosis Gastrointestinal bleed 1.01 (.71–1.44) .9397 1.71 (1.22–2.40) .0019c Heavy menstrual bleeding 2.87 (2.21-3.72) < .0001c 2.07 (1.74–2.46) < .0001c Mucosal bleed 1.18 (.82–1.71) .3693 1.27 (.88–1.82) .2 Epistaxis 1.26 (.95–1.68) .1055 1.97 (1.53–2.55) < .0001c Coagulation defects complicating pregnancy, childbirth or puerperium .40 (.20–.82) .0129c 1.64 (.83–3.26) .1546 Haemorrhage unspecified .87 (.66–1.14) .2988 1.16 (.90-1.50) .2534 Treatment type before VWD diagnosis Oral contraceptivesd 1.41 (1.06–1.89) .0193c 1.57 (1.28–1.93) < .0001c Desmopressin 1.37 (.86–2.17) .1864 1.18 (.87–1.61) .2828 Von Willebrand factor .59 (.24–1.48) .2621 1.09 (.57–2.07) .7926 Aminocaproic acid .72 (.39–1.33) .2893 1.57 (1.01-2.45) .0477a Nasal cauterization 1.86 (1.12-3.07) .0165c 2.07 (1.30-3.31) .0024a Treatment type after VWD diagnosis Oral contraceptivesd 1.17 (.88–1.58) .2848 2.21 (1.80-2.71) < .0001c Desmopressin 1.67 (1.20-2.33) .0027c 1.66 (1.33–2.07) < .0001c Von Willebrand factor .71 (.37–1.33) .2783 3.44 (2.27–5.22) < .0001c Aminocaproic acid 1.73 (1.10-2.72) .0177c 1.52 (1.13–2.04) .006c Nasal cauterization 1.65 (.80-3.41) .1798 171.93 (23.61 to > 999.99) < .0001c,e, c,e CI, confidence interval; VWD, von Willebrand disease. Multiple logistic regression analysis with age (exact), sex and haematologist visit history as control variables. aIf OR = 1, there is an equal likelihood of multiple or single site bleeding pre-diagnosis; if OR > 1, bleeding is more likely to be multiple-site, and if OR < 1, bleeding is more likely to be single site. bIf OR = 1, there is an equal likelihood of resolved or continued bleeding post-diagnosis; if OR > 1, bleeding is more likely to be continued, and if OR < 1, bleeding is more likely to be resolved. cSignificant association between bleed type or treatment with pre-diagnosis bleeding phenotype or post-diagnosis bleeding status. dOral contraceptive use was evaluated in female patients only. eOnly one patient (who had no claim for epistaxis) after diagnosis had nasal cauterization.

Among women with resolved and continued bleeding, the most common pre-diagnosis bleed claims were for HMB, haemorrhage (unspecified) and epistaxis (Figure 3A, 3B). The most common bleeds in the post-diagnosis period for women with continued bleeding were HMB, GI bleeds and mucosal bleeds (Figure 3B). In men with resolved bleeding, the most common pre-diagnosis bleed claims were for epistaxis, haemorrhage (unspecified) and mucosal bleeds (Figure 3A). For men with continued bleeding, the most common pre-diagnosis bleed claims were for epistaxis, haemorrhage (unspecified) and GI bleeds compared with epistaxis, GI bleeds and haemorrhage (unspecified) in the post-diagnosis period (Figure 3B). Among both men and women with continued bleeding, the frequency of claims for the majority of bleed types increased from the pre- to post-diagnosis period (Figure 3B).