The relationship between target joints and direct resource use in severe haemophilia
O'Hara et al. Health Economics Review
The relationship between target joints and direct resource use in severe haemophilia
Jamie O'Hara 2
Shaun Walsh 0
Charlotte Camp 0
Giuseppe Mazza 1
Liz Carroll 4
Christina Hoxer 3
Lars Wilkinson 3
0 HCD Economics, The Innovation Centre , Daresbury WA4 4FS , UK
1 UCL Institute for Liver and Digestive Health, Royal Free Hospital, University College London , London , UK
2 Faculty of Health and Social Care, University of Chester , Chester , UK
3 Novo Nordisk A/S , Vandtårnsvej 114, -2860 Søborg, DK , Denmark
4 The Haemophilia Society , London , UK
Objectives: Target joints are a common complication of severe haemophilia. While factor replacement therapy constitutes the majority of costs in haemophilia, the relationship between target joints and non drug-related direct costs (NDDCs) has not been studied. Methods: Data on haemophilia patients without inhibitors was drawn from the 'Cost of Haemophilia across Europe - a Socioeconomic Survey' (CHESS) study, a cost assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the United Kingdom) in which 139 haemophilia specialists provided demographic and clinical information for 1285 adult patients. NDDCs were calculated using publicly available cost data, including 12-month ambulatory and secondary care activity: haematologist and other specialist consultant consultations, medical tests and examinations, bleed-related hospital admissions, and payments to professional care providers. A generalized linear model was developed to investigate the relationship between NDDCs and target joints (areas of chronic synovitis), adjusted for patient covariates. Results: Five hundred and thirteen patients (42% of the sample) had no diagnosed target joints; a total of 1376 target joints (range 1-10) were recorded in the remaining 714 patients. Mean adjusted NDDCs for persons with no target joints were EUR 3134 (standard error (SE) EUR 158); for persons with one or more target joints, mean adjusted NDDCs were EUR 3913 (SE EUR 157; average mean effect EUR 779; p < 0.001). Conclusions: Our analysis suggests that the presence of one or more target joints has a significant impact on NDDCs for patients with severe haemophilia, ceteris paribus. Prevention and management of target joints should be an important consideration of managing haemophilia patients.
Haemophilia; Cost of illness; Target joints; Burden of disease; Arthropathy; Synovitis
Haemophilia is an inherited, lifelong bleeding disorder
characterised by prolonged traumatic or spontaneous
bleeding due to a lack of clotting factor in the body.
Haemophilia is a recessive X-linked disorder and
primarily affects males; symptoms are present from infancy [
The two most common forms of the condition are
Haemophilia A (Factor VIII deficiency) and Haemophilia
B (Factor IX deficiency). Global incidence of haemophilia
A is approximately 1 in every 5000 male births;
haemophilia B is approximately six times rarer than
haemophilia A [
Bleed events may be musculoskeletal or mucosal in
nature but are most commonly observed in the joints of
the body. In the absence of preventative ‘prophylaxis’
factor replacement therapy, most persons with severe
haemophilia (<1% of normal factor level) will develop a
first haemarthrosis between the ages of 1 and 5 years.
Approximately four-fifths of bleed events occur in the
knees, elbows, and ankles; arthroses in the hip, shoulder,
carpus, or small hand or foot joints are less frequently
Repeat intra-articular bleed events within a short
timeframe (3–6 months) are associated with chronic synovial
inflammation and in the longer term induce haemophilic
]. Such joints, known as target joints,
exhibit continuous swelling and reduced range of motion;
repeat acute and subacute haemarthoses lead to
irreversible degradation of the joint, resulting in chronic pain
and poor physical function and requiring orthopaedic
intervention, ranging from removal of the synovium to
replacement or fusion of the joint [
]. Bleed frequency,
as well as age, body mass index, and inhibitor formation
are known drivers of joint disease and functional
limitation in persons with severe haemophilia [
economic burden of frequent hospitalisations and palliative
joint surgeries is reinforced by the psychosocial impact
of chronic pain and disability, including limited
employment opportunities, decreased social participation, and
poor mental health [
Prophylaxis regimens initiated at a young age (≤4 years
of age) are shown to reduce bleed frequency and joint
deterioration later into adulthood [
], and are therefore
considered the benchmark in care for severe haemophilia
]. However, introduction of universal prophylaxis has
been protracted in many developed countries, due to a
lack of evidence regarding clinical benefits of prophylaxis
initiation later into adolescence and adulthood, as well as
the substantial per-capita costs associated with
replacement therapy [
]. Prophylaxis replacement therapy
has recently undergone tentative economic evaluation by
several European organisations. There is a need for greater
clarity regarding the economic impact of care for persons
with severe haemophilia in Europe, specifically regarding
the cost of management of individuals with
musculoskeletal complications, and in particular those patients
receiving suboptimal therapy protocols.
The objective of this paper is to explore the relationship
between target joints and direct medical costs for persons
with severe haemophilia, and the extent to which health
resource utilisation and direct medical costs (excluding
replacement therapy) in severe haemophilia are driven
by long-term clinical complications of the disease. While
this topic has been explored to some detail within
singlecountry studies [
], this is the first to take a universal
methodology across several European countries in
assessing resource use and cost burden among persons
with severe haemophilia.
Resource and cost data were gathered as part of the
“Cost of Haemophilia across Europe – a Socioeconomic
Survey (CHESS)”, a prospective observational study in
severe haemophilia A and B across five European
countries (France, Germany, Italy, Spain, and the United
Kingdom) undertaken in 2015 [
]. One hundred and
thirty-nine haemophilia specialists provided demographic
and clinical information for 1285 adults (≥18 years) via
a web-based survey. A corresponding questionnaire
covering indirect costs and health-related quality of life
(HRQOL) measures was completed by patients.
Non drug-related direct costs (NDDCs) were an
amalgam of 12-month ambulatory and secondary care costs
gathered within the CHESS study, specifically
incorporating: haematologist and other specialist consultant
consultations, medical tests and examinations, surgeries
relating to joint damage, bleed-related hospital
admissions, and payments to professional care providers [
A unit cost database was developed for each country using
publicly available information. A breakdown of individual
cost elements of NDDCs is presented in Table 1.
Study exclusion criteria was limited to patients diagnosed
with an inhibitor at the time of study capture (n = 52), due
to a differing risk profile for bleeds and subsequent target
joint development among these patients, and a higher
utilisation of medical resources [
A ‘target joint’ as defined in the CHESS study
encompasses any joint with known chronic synovitis; in contrast
to previous clinical studies [
], study investigators were
given discretion as to how this may be further defined
with respect to bleed frequency and period of observation.
In order to explore the differential impact of costs
associated with lower and upper body joint deterioration, target
joints were categorised into two groups based on their
location. ‘Upper body’ target joints were those in the
shoulders, elbows, wrists, neck, and spine; ‘lower body’
target joints consisted of hips, knees, and ankles. The
target joint variable was assessed in three ways: as a
binary 0/1 variable; as a binary 0/1 variable split into
upper and lower body joints; and as a discrete variable.
Demographic and resource use data were compared
between the sample of patients with no reported target
joints and those with one or more reported target joints.
Means were used to describe continuous variables;
categorical variables are described as frequencies and
proportions. Standard t-tests were conducted in order to test for
The marginal effect of the presence of one or more
target joints on NDDCs was assessed using a generalized
linear model (GLM). Medical cost data is often positively
skewed with a large volume of zero values (i.e. no medical
costs) and a long ‘tail’ from a select group of costly
‘outlier’ patients. The GLM is an extension of the linear
regression framework (Eq. 1) suitable for
nonparametric dependent variables [
]. The GLM requires a
link function relating the conditional mean to the
covariates, and a distribution ‘family’ to specify the relationship
between the variance and the mean . The log-link
function (Eq. 2) in combination with a gamma distribution
Note. Ranges presented where more than one price is possible; ICU: intensive care unit; IU: International Units
†Arthrocentesis, arthrodesis, arthroplasty, arthroscopy, synovectomy
aSources: Ameli, sante.gouv, ViDAL.fr, Catalogue Commun des actes médicaux
bSources: Kbv.de, meinpharmaversand.de, Einheitlicher Bewertungsmaßstab, rote-liste service
cSources: AIFA, agenziafarmaco.gov
dSources: Oblikue e-salud, Agencia Española de Medicamentos y Productos Sanitarios
eSources: National Schedule of Reference Costs, Electronic Medicines Compendium
(Eq. 3) is frequently used to estimate medical costs and
was employed for this analysis [
]. A confirmatory
analysis of the family and link functions was conducted using
the modified Park test [
NDDCs12mth ¼ α þ β1ðt arget jo intsÞ þ β2x1
þ ⋯ þ βnxn
Where i ¼ 1; …; n
E½yjx ¼ f x0 β
¼ exp x0 β In ðE½yjx Þ ¼ x0 β
y∼VarðyjxÞ ≈ ðE½yjx Þλ
A univariate estimate of the relationship between target
joint status and NDDCs was first modelled (Model 1),
followed by a multivariate estimate using country of
residence, patient age, use of prophylaxis therapy regimen at
the time of study capture, and number of
haemophiliarelated hospital admissions in the preceding 12 months as
additional model covariates, added using a stepwise
inclusion method (Model 2). Results are presented as average
mean effects (AME). All statistical analysis was conducted
using Stata 13 [
The average age of study patients was 36 years old; the
majority of patients in the study were receiving
treatment prophylactically (n = 708; 57.7%) (Table 2). A total
of 1376 target joints were recorded across the study
population (mean 1.2 target joints; SD 1.37; range 0–10).
Seven hundred and fourteen patients (58.2%) were
reported diagnosed with one or more target joints.
Target joints exclusively in the lower body were most
commonly reported (n = 371 patients (52.3%)). More than
four in ten patients with a reported target joint had
undergone one or more surgeries on a target joint in the
preceding 12 months, with joint aspiration
(arthrocentesis) the most common procedure (200 patients, 28% of
the target joint cohort).
Medical resource use
In all cases examined, patients with no target joints
consumed less medical resources compared to patients with
one or more target joints (Table 3). The largest
betweengroup differences were reported for scheduled nurse
consultations with 5.75 (SD 11.98) and 3.94 (SD 9.13) for the
“has target joint” and “no target joint” groups respectively
(p < 0.001). Physiotherapy visits were found to be lower in
the no target joint group 0.89 (SD = 3.75) compared with
patients with one or more target joints 3.14 (SD = 7.99)
(p < 0.001). Patients with target joints attended a greater
number of scheduled haemophilia consultations: 5.5
(SD = 4.36) and 4.7 (SD = 3.72) respectively (p = 0.001).
The target joint group recorded 1.91 GP visits (SD = 3.78),
with non-target joint patients reporting 1.35 visits (SD =
2.67; p = 0.003). Mean number of target joint surgeries in
the affected group was 0.70. Rates of bleed-related
hospital admissions were almost three times higher in
the target joint cohort (mean 0.97 versus 0.36).
Mean NDDCs were EUR 3641 (SD 6157); per-patient
NDDCs in the presence of one or more target joints –
regardless of number or location – was EUR 5046 (SD
7479) versus EUR 1684 for patients with no target joints.
The number of target joints are positively correlated
with NDDCs: individuals with one target joint reported
mean NDDCs of EUR 3468 (SD 5595; n = 332) (Fig. 1);
this increased to EUR 5585 (SD 7980; n = 242) for
patients with two target joints; for those with three target
joints mean NDDCs were EUR 7470 (SD 9396; n = 70).
Patients with at least one target joint in the upper body
recorded mean NDDCs of EUR 5610 (SD 7861) (Fig. 2);
patients with at least one lower body target joint reported
mean NDDCs of EUR 5186 (SD 7594). The highest
NDDCs were recorded among patients with both lower
and upper body target joints (mean EUR 6696; SD 8461).
The results of the multivariate analysis are presented in
Table 4. A significant difference in costs was observed
between the target joint and non-target joint cohorts:
mean adjusted NDDCs for the non-target joint cohort
were EUR 3134 (SE 158); for the target joint cohort,
mean adjusted NDDCs were EUR 3913 (SE 157; AME
EUR 779; p < 0.001). The mean average marginal effect
(AME) of one or more upper body target joints was EUR
2646 (standard error (SE) 454); AME was EUR 2626 (SE
367) for individuals with one or more lower body target
joints. When the analysis examined the impact of the
location of the target joint, the AME for a lower body
target joint was greater, at EUR 655 (SE 143). The AME
for a patient with an upper body target joint was EUR
624 (SE 191).
Patient age was a negligible – albeit significant –
driver of NDDCs: an additional year of life contributed
just EUR 13.52 extra in costs (SD 3.48; p < 0.001).
Somewhat unsurprisingly, an additional haemophilia-related
hospitalisation was the most substantial contributor to
NDDCs (AME 2681.52; SD 220.15; p < 0.001).
This study has sought to quantify the economic burden
associated with management and alleviation of
joint-related complications in severe haemophilia. NDDCs
represent a small proportion of total costs for persons with
severe haemophilia (between 2% and 5% in most
European studies) [
], and as a result their prioritisation for
Note. Values are average marginal effects (AMEs). Standard error shown in
brackets. *Denotes 95% significance. **Denotes 99% significance
aBase factor: France
research has until now been limited. Nevertheless, it is
critical to understand both physiological, psychosocial,
and economic impacts of inadequate bleed control within
haemophilia, and the longer-term repercussions of joint
deterioration associated with suboptimal therapy and
patient management. The results of this analysis suggest that
cost drivers are not limited to surgical interventions, but
in fact encompass more intensive ambulatory and
outpatient care, including a higher volume of specialist
visits, tests, and examinations among persons with
severe haemophilia exhibiting chronic joint inflammation.
The CHESS study was a cross-sectional survey of
clinicians and persons with severe haemophilia across five
European countries, which captured a large volume of
clinical and demographic information about consulting
patients. However, we are limited in our ability to
explore the causal relationship between management of
haemophilia in early life and subsequent outcomes.
Further work is required to understand the long-term
impact of switching from on-demand to prophylaxis in late
childhood and adulthood, when joint deterioration may
already be present. Presence of target joints in the
CHESS patient group is significantly higher among those
receiving prophylaxis; whilst initially counterintuitive, it
points to a large number of patients moving away from
on-demand regimens due to poor bleed control and joint
damage. As shown in previous work, this is particularly
pertinent for those patients over the age of 30 years for
whom prophylaxis in early childhood was not widely
available. While the outcomes observed in this study
population are not necessarily translatable to children
born with haemophilia in the current era, suggestions
of reducing access to prophylaxis give rise to a need to
highlight the economic burden arising from
conservative therapy among persons with severe haemophilia.
A target joint in this analysis is defined by the
presence of chronic synovitis, the physiological manifestation
of frequent intra-articular bleed events. In the more
oftobserved scenario, sufficient time between bleed events
(~3–4 weeks) allows for gradual alleviation of swelling
and restoration of joint motion, via intensive infusions
of replacement therapy and regular physiotherapy.
Frequent recurrence of bleeding, however, precludes the
reinstatement of a baseline level of motion, strength, and
physical appearance; inadequate resolution of trauma
arising from such events can in turn exacerbate bleed
frequency. This cyclical process results in the longer
term in a state of chronic synovitis and progressive
arthropathy, due to excessive volumes of synovium and blood
retained within the joint space and gradual deterioration of
the joint tissue [
Other definitions in literature focus instead on the
frequency of bleed events over a short-term (≤6 months)
period in order to propose a diagnosis of a target joint.
The most recent International Society of Thrombosis
and Hemostasis (ISTH) definition, for example, is one in
which three or more spontaneous bleeds into a single
joint occur within a consecutive 6-month period [
the case of the ISTH guidelines, however, the joint ceases
to be a target joint when there have been less than two
bleeds into the joint within 12 consecutive months. While
alternative definitions allow for more or less frequent
bleeds and shorter or longer observation periods [
their commonality is the use of short-term bleed rates as a
measure, and an observable follow-up period within which
a target joint may no longer be defined as such.
In combination, these rules present a definition that is
well-suited to clinical trials with finite follow-up periods
and observable improvements in outcomes, but which
lacks the consideration of the long-term complications
associated with persistent bleed events. A recent paper
published on behalf of the United Kingdom Haemophilia
Centres Doctors Organisation (UKHCDO) highlights the
long term changes effected to the soft tissue of the joint
as a result of frequent bleed events, and thus a need for
continuous, targeted monitoring of the afflicted joint
beyond the period in which synovitis is observed [
choice of definition, therefore, encompasses an
assumption of high bleed frequency via the identification of
synovitis, as well as considering the long-term,
irreversible changes to the joint tissue and structure that arise
from repeat haemorrhage. We acknowledge, however,
that there is substantial overlap between definitions.
Regardless of nuances in the definition of a target joint,
the results presented in this study suggest that chronic
synovitis in severe haemophilia is associated with greater
intensity of patient management, resulting in higher levels
of health resource use and direct medical costs.
Approaches to minimising the long-term risk of joint damage
and deterioration among these patients – beginning at a
young age with proactive therapy protocols to minimise
bleed frequency and severity – will serve to reduce future
burdens on hospital systems and are a justification for
continued access to preventative therapy protocols.
Further studies should seek to incorporate the health-related
quality of life impact of bleed events and joint disease, and
hence to quantify the cost effectiveness of current therapy
protocols among severe persons with haemophilia.
While non drug-related direct medical costs in severe
haemophilia are small in relation to the costs of
replacement therapy, our analysis demonstrates that the majority
of individuals with this disease experience medical
complications requiring substantial follow-up in the hospital
setting. Further, the presence of one or more target joint can
have a major impact on medical resource utilisation and
subsequent costs for patients with severe haemophilia.
AME: average mean effect; CHESS: ‘The Cost of Haemophilia – a
Socioeconomic Survey’; EUR: Euro; GLM: generalized linear model;
HRQOL: health-related quality of life; ICU: intensive care unit;
ISTH: International Society on Thrombosis and Haemostasis; IU: international
units; PWH: people with haemophilia; SD: standard deviation; SE: standard error
Kind thanks to Ian Jacob (HCD Economics) for reviewing the manuscript drafts.
This study was funded by Novo Nordisk. Publication was not contingent
upon study results.
Availability of data and materials
The datasets generated and/or analysed during the current study are held
under license by the University of Chester and are not publicly available, but
are available from the corresponding author on reasonable request.
JOH designed the study protocol. CC and SW analysed the data. JOH, SW,
and CC wrote the manuscript. LC and GM provided non-clinical perspective
for the analysis and manuscript. All authors reviewed the manuscript. All
authors read and approved the final manuscript.
LW and CH are employees of Novo Nordisk.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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