Journal of Medical Economics Vol. 17, No.

11, 2014, 798–802

1369-6998 Article 0039.R2/953679

doi:10.3111/13696998.2014.953679 All rights reserved: reproduction in whole or part not permitted

Original article
Costs and utilization of hemophilia A and B
patients with and without inhibitors
Journal of Medical Economics Downloaded from informahealthcare.com by 180.214.232.82 on 11/03/14

Edward P. Armstrong Abstract

Daniel C. Malone Objective:
Strategic Therapeutics, Tucson, AZ, USA, and College
of Pharmacy, University of Arizona, Tucson, AZ, USA To evaluate the health system costs among patients with hemophilia A and B with and without inhibitors over
5 years.
Sangeeta Krishnan
Biogen Idec, Cambridge, MA, USA
Methods:
Maj Jacob Wessler This was a retrospective, observational study utilizing medical and pharmacy electronic medical records and
Department of Pediatrics, Naval Medical Center administrative encounters/claims data tracking US patients between 2006–2011. Patients with diagnosis
Portsmouth, Portsmouth, VA, USA codes for hemophilia A and B were identified. Patients with inhibitors were characterized by utilization of
For personal use only.

Address for correspondence:
Edward P. Armstrong, Strategic Therapeutics, LLC,
11020 N Canada Ridge Dr, Tucson, AZ 85737, USA.
ed.armstrong@strategictherapeutics.com
Keywords:
Hemophilia – Medication adherence – Healthcare
cost – Hospitalization
Accepted: 7 August 2014; published online: 20 August 2014
Citation: J Med Econ 2014; 17:798–802
bypassing agents activated prothrombin complex concentrate or factor VIIa on two or more distinct dates.
Severity was classified as mild, moderate, or severe based on laboratory tests of clotting factor.
Results:
There were 160 hemophilia A patients and 54 hemophilia B patients identified. From this group, seven were
designated as patients with inhibitors (five with hemophilia A and two with hemophilia B). Hemophilia A
patients without inhibitors reported 65 (41.9%) as being severe, 19 (12.3%) as moderate, and 71 (45.8%)
as mild. Hemophilia B patients without inhibitors reported nine (17.3%) had severe, 13 (25.0%) had
moderate, and 30 (57.7%) had mild hemophilia. All patients with inhibitors had been hospitalized in the
previous 5 years compared to 64 (41.3%) with hemophilia A without inhibitors and 22 (42.3%) with
hemophilia B without inhibitors. The median aggregate cost per year (including factor and health
resource use) was $325,780 for patients with inhibitors compared to $98,334 for hemophilia A patients
without inhibitors and $23,265 for hemophilia B patients without inhibitors.

Conclusions:
The results suggest that, while the frequency of inhibitors within the hemophilia cohort was low, there was a
higher frequency of hospitalizations, and the associated median aggregate costs per year were 3-fold higher
than those patients without inhibitors. In contrast, hemophilia B patients experience less severe disease and
account for lower aggregate yearly costs compared to either patients with hemophilia A or patients with
inhibitors.

Introduction
Hemophilia is a congenital bleeding disorder resulting from clotting factor defi-
ciency, which leads to bleeding complications, joint damage, and requires the
use of lifelong clotting factor replacement therapy1. Hemophilia A results from
alterations in the gene of clotting factor VIII leading to lowered Factor VIII
activity that involves 1 in 5000 male births2. Hemophilia B results from lowered
Factor IX activity that impacts 1 in 30,000 males around the world2,3. People
categorized with severe hemophilia experience spontaneous bleeding into the
joints and soft tissue that may be recurrent and have complications including
joint damage and severe disability4,5. The joint damage may lead to reduced

798 Hemophilia cost with and without inhibitors Armstrong et al. www.informahealthcare.com/jme ! 2014 Informa UK Ltd

joint mobility, muscle atrophy, and chronic pain that may
require orthopedic surgery. Only a few joint bleeds may
result in joint damage6,7. Adult patients with hemophilia
may have more joint damage and reduced physical func-
tioning compared to pediatric patients with hemophilia8.
The ground-breaking clinical trial conducted by Manco-
Johnson et al.9 found that use of Factor VIII prophylaxis in
children reduced joint bleeding in boys.
In addition, some patients with hemophilia develop
inhibitors (alloantibodies) to replacement clotting factors,
which renders the treatment ineffective and, therefore,
requires a different treatment strategy. It is estimated
that inhibitors occur in 25–30% of severe hemophilia A
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patients and 3–5% of hemophilia B10. The presence of
inhibitors may make standard hemophilia replacement
therapy ineffective11–14. Patients with inhibitors are
often managed by using bypassing agents such as activated
prothrombin complex concentrate or factor VIIa10. The
activated prothrombin complex concentrate Factor Eight
Inhibitor Bypassing Agent (FEIBA) is often administered
as 50–100 IU/kg every 8–24 h to decrease the risk of bleed-
ing. The usual dose of factor VIIa ranges from 90–120 mcg/
kg. Higher dose regimens of factor VIIa have also been
evaluated. Another treatment option is immune tolerance
For personal use only.
induction which involves using very high doses of clotting
factor to sensitize the patient to the novel protein. This
strategy may be able to eradicate persistent inhibitors in
severe hemophilia A patients10. When hemophilia
patients have inhibitors, the need for bypassing agents
and immune tolerance induction further increases the
costs for patients and the healthcare organizations respon-
sible for covering these expenditures15. Since hemophilia
is an uncommon disease with an even smaller sub-set of
patients with inhibitors, there is limited data describing
the resources and costs required to care for these patients.
Therefore, the purpose of this study was to evaluate the
characteristics and health system costs among patients
with hemophilia A and B with and without inhibitors
over a 5-year period within the US Department of
Defense (DOD) database for military servicemen/women
and their families.
Methods
This study was a retrospective, observational study utiliz-
ing electronic medical records and administrative encoun-
ters/claims data tracking US patients between 2006–2011
for up to 5 years. These databases were searched and
patients with International Classification of Diseases, Ninth
Revision (ICD-9) diagnosis codes for hemophilia (ICD-9
code 286.0 for hemophilia A [factor VIII deficiency] and
286.1 for hemophilia B [factor IX deficiency]) were iden-
tified. Eligible patients must have received clotting factors
during the study period and had at least 6 months of
! 2014 Informa UK Ltd www.informahealthcare.com/jme
Journal of Medical Economics Volume 17, Number 11 November 2014
continuous enrolment in the worldwide DOD healthcare
system. Once the data were collected, administrative and
record review data were stripped of patient identifiers and
integrated into the analytical data-set. These research data
were derived from an approved Naval Medical Center,
Portsmouth, VA IRB protocol (IRB NMCP.2012.0016).
Patients were excluded if they had von Willebrand dis-
ease. These persons were categorized as the following: (1)
one or more prescriptions/claims for Humate-P or Wilate;
(2) young persons (less than 50 years of age) receiving
Alphanate or Koate; (3) one or more healthcare encoun-
ters with a diagnosis code specific to von Willebrand dis-
ease; or (4) older persons (age greater than 50) receiving
desmopressin therapy.
Patients with inhibitors were characterized by the util-
ization of at least one of two bypassing agents: activated
prothrombin complex concentrate or factor VIIa, on two
or more distinct dates16. Hemophilia severity was classified
as mild (5–40% normal factor activity), moderate (1–5%
normal factor activity), or severe (51% normal factor
activity). A review of the electronic medical records was
conducted by a trained nurse using a standardized data
collection instrument. Factor level documented in the
electronic medical record was used to categorize the hemo-
philia severity. Bleeding events were identified by ICD-9
codes. Hospitalizations were identified using the inpatient
DOD database. Aggregate costs included factor and health
resource use for each patient. Statistical analyses were con-
ducted using Stata 12.1. Due to the limited sample size of
patients with inhibitors, statistical analyses were restricted
to descriptive analyses.
Results
There were a total of 214 patients that met the study inclu-
sion criteria. Of this group, seven (3.3%) patients were
categorized as patients with inhibitors (Table 1). Of the
hemophilia A patients without inhibitors, 65 (41.9%) had
severe, 19 (12.3%) had moderate, and 71 (45.8%) had
mild hemophilia. Of the patients with hemophilia B with-
out inhibitors, nine (17.3%) had severe, 13 (25.0%) had
Table 1. Demographic and baseline characteristics.
Characteristic Number (%) of patients (N ¼ 214)
Hemophilia type
A 160 (74.8)
B 54 (25.2)
Patients with inhibitors
Hemophilia A 5 (3.1)
Hemophilia B 2 (3.7)
Age, median (range), years
Patients with inhibitors 2.0 (51–11)
Hemophilia A without inhibitors 6.0 (51–43)
Hemophilia B without inhibitors 8.5 (51–61)
Hemophilia cost with and without inhibitors Armstrong et al. 799
 Journal of Medical Economics Volume 17, Number 11 November 2014

moderate, and 30 (57.7%) had mild hemophilia. Patients inhibitors (Figure 2). For the seven patients identified
with inhibitors were children younger (median [range] with inhibitors, the median overall aggregate healthcare
age ¼ 2.0 [51 – 11] years) than those patients without cost per year was $325,780. Individuals with hemophilia A
inhibitors (Table 1). without inhibitors had considerably lower yearly total
Patients with inhibitors had a median (range) of 1.4 (0– healthcare costs (median ¼ $98,334). Patients with hemo-
3.8) bleeding events per year compared with 0.3 (0–5.0) philia B without inhibitors had the lowest total healthcare
for mild, 0.4 (0–4.0) for moderate, and 0.2 (0–3.3) for costs (median ¼ $23,265).
severe patients without inhibitors. A key finding in this
analysis is that all patients with inhibitors had at least one
hospitalization in the previous 5 years. In contrast, less
than 50% of patients with either hemophilia A or B with- Discussion
out inhibitors had a hospitalization within the same time This analysis found that a small proportion of patients with
Journal of Medical Economics Downloaded from informahealthcare.com by 180.214.232.82 on 11/03/14

period (Figure 1). hemophilia (3.3% in this study) develop inhibitors to

Median aggregate overall healthcare costs per year were replacement clotting factor products and required treat-
substantially higher for patients with inhibitors than ment with bypassing agents. However, these patients are
patients with hemophilia A or hemophilia B without very important in accounting for additional health

100

90
Paents with ≥1 hospitalization (%)

80

70
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60

50

40

30

20

10

0
Paents with inhibitors (n=7) Paents with hemophilia A Paents with hemophilia B
without inhibitors (n=155) without inhibitors (n=52)

Figure 1. Percentage of patients with at least one hospitalization within 5 years by inhibitor status.

$3,50,000

$3,00,000
Median healthcare costs ($)

$2,50,000

$2,00,000

$1,50,000

$1,00,000

$50,000

$-
Paents with inhibitors Paents with hemophilia A Paents with hemophilia B
(n=7) without inhibitors (n=155) without inhibitors (n=52)

Figure 2. Median aggregate overall healthcare costs per year by inhibitor status.

800 Hemophilia cost with and without inhibitors Armstrong et al. www.informahealthcare.com/jme ! 2014 Informa UK Ltd

resource utilization to a health system secondary to the
increased costs associated with their management. The
proportion of patients with inhibitors in this study
(3.3%) is slightly lower than the proportion identified
by Valentino et al.16 (6%). Wight and Paisley13 found
that the prevalence of inhibitors among hemophilia A
patients was 5–7%, and that the cumulative incidence
may be up to 39%. Thus, the proportion of patients with
inhibitors in the present study was slightly below the
values noted by Valentino et al.16 and Wight and Paisley13.
This analysis found that every patient with inhibitors
had at least one hospitalization in the previous 5 years
compared to less than 50% for other patients with either
Journal of Medical Economics Downloaded from informahealthcare.com by 180.214.232.82 on 11/03/14
hemophilia A or B. This suggests that treatment of patients
with inhibitors is more challenging as their morbidities
can be more severe.
In addition, patients with inhibitors accounted for more
than 3-times the annual cost of hemophilia A patients and
6-times the cost of hemophilia B patients. Difficult control
and frequent utilization of inpatient and outpatient ser-
vices lead to higher costs associated with these patients.
These results suggest that health systems should devote
attention to ensure optimal management to minimize
complications and hospitalizations in patients with inhibi-
For personal use only.
tors. Patients on prophylaxis or immune tolerance induc-
tion would also have higher costs due to increased factor
consumption. In addition, it should be kept in mind that
these costs and patients are specific to the Department
of Defense healthcare system and are not generalizable to
the general US hemophilia population.
It should be noted that patients with inhibitors in this
study were children and, therefore, the results cannot be
extrapolated to the adult hemophilia population. Older,
larger patients with inhibitors would be expected to
require larger doses and have higher factor costs than the
costs identified with these seven children with inhibitors.
The age data suggest that health systems work closely
with the parents and caregivers of younger patients with
inhibitors to optimize care and monitoring.
It is difficult to find other cost data to compare these
results. Globe et al.17,18 conducted a medical record review
at three California hemophilia treatment centers. These
previous studies also found that patients with inhibitors
had higher costs than patients with moderate hemophilia.
However, the authors were not able to measure actual costs
paid for factor and had to impute costs based on average
wholesale price. In contrast, this study measured actual
costs paid by the DOD.
There are three important limitations to this analysis.
The first is that hemophilia is a rare disease and uncom-
mon in many healthcare databases. The large DOD data-
base used in this study found only 214 patients with
hemophilia out of more than 9 million beneficiaries. It is
possible that this analysis under-estimated the number of
patients with inhibitors. However, this does not reduce the
! 2014 Informa UK Ltd www.informahealthcare.com/jme
Journal of Medical Economics Volume 17, Number 11 November 2014
importance of the frequent hospitalizations and very high
healthcare costs in patients with hemophilia inhibitors.
The second limitation is that claims in this analysis were
limited to services from a hospital, outpatient, or pharmacy
settings, and that other resources consumed in homecare
for breakthrough bleeding not requiring a clinic visit were
not captured. The third limitation is that this study may
have under-estimated the number of patients with inhibi-
tors. Some patients could have been referred to outside
Hemophilia Treatment Centers, although it should be
kept in mind that the DOD database covers care of
DOD members and their families around the world,
not just within the US. It is also possible that patients
with inhibitors could have been released from military ser-
vice, but, noting the age of patients in this study, the popu-
lation appears to largely be children of military members,
not the military members themselves. It is also possible
that using ICD-9 codes 286.52, 286.53, and 286.59 may
have identified additional patients with inhibitors, but
these codes are not specific to patients with inhibitors
and may also have included patients with other comorbid-
ities as well.
Conclusions
The results of this analysis suggest that, while the fre-
quency of inhibitors within the hemophilia cohort was
low, there was a higher frequency of hospitalizations and
the associated median aggregate costs per year are 3-fold
higher than those patients without inhibitors. Hemophilia
B patients experience less severe disease and account for
lower aggregate yearly costs compared with either patients
with hemophilia A or patients with inhibitors.
Transparency
Declaration of funding
This project was funded by Biogen Idec.
Declaration of interest
EA and DM were consultants to Biogen Idec through Strategic
Therapeutics, LLC for this project. SK is an employee of and
holds equity in Biogen Idec. MW has no interests which might
be perceived as posing a conflict or bias. JME peer reviewers on
this manuscript have no relevant financial or other relationships
to disclose. The views expressed in this article are those of the
authors and do not necessarily reflect the official policy or pos-
ition of the Department of the Navy, Department of Defense, or
the US Government.
Acknowledgments
EA, DM, SK, and MW were all involved in the design of the
research and writing and editing the manuscript. EA and DM
were responsible for the analysis of the data.
Hemophilia cost with and without inhibitors Armstrong et al. 801
 Journal of Medical Economics Volume 17, Number 11 November 2014
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