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The impact of factor infusion frequency on health-related quality of life in people with haemophilia



Background Some studies suggest that people with haemophilia (PwH) who use prophylaxis value low frequency of clotting factor administration more than a lower risk of bleeding. However, more frequent infusions offer the potential of reducing joint disease and pain, which in turn may improve functioning and quality of life. Aims To explore the impact on health-related quality of life (HRQoL) aspects of haemophilia associated with adherence and annual infusion rate in the context of factors influencing treatment that are important to patients, including prophylaxis, chronic pain, concomitant conditions and hospital admission. Materials and methods HRQoL was assessed in participants with severe haemophilia in the ‘Cost of Haemophilia in Europe: a Socioeconomic Survey’ (CHESS) study who were using prophylaxis. Patients using on-demand treatment were excluded. This multivariate analysis examined the interaction between factors potentially influencing treatment and HRQoL, and minor and major bleeds. Results From the total CHESS population (n=1,285), 338 (26%) participants provided responses for major and minor bleeds and target joints, and 145 (11%) provided EQ-5D-3L responses. Major and minor bleeds were associated with pain. Patients with severe chronic pain reported a substantial negative impact on HRQoL; but this was significantly improved by increases in the annual infusion rate. This was not apparent in participants with mild or moderate pain. Conclusion Increasing the frequency of prophylaxis infusions is associated with improved quality of life in PwH who have severe chronic pain. However, increasing the number of infusions per week in those with mild or moderate chronic pain with the intention of improving prophylactic effect may not have the same effect.
J Haem Pract 2020; 7(1). doi: 10.17225/jhp00158102
The impact of factor infusion frequency
on health-related quality of life in people
with haemophilia
Gabriel Pedra, Pia Christoersen, Kate Khair, Xin Ying Lee, Sonia O’Hara, Jamie O’Hara, John Pasi
Background: Some studies suggest that people with
haemophilia (PwH) who use prophylaxis value low
frequency of clotting factor administration more than
a lower risk of bleeding. However, more frequent
infusions oer the potential of reducing joint disease
and pain, which in turn may improve functioning and
quality of life. Aims: To explore the impact on health-
related quality of life (HRQoL) aspects of haemophilia
associated with adherence and annual infusion rate
in the context of factors influencing treatment that
are important to patients, including prophylaxis,
chronic pain, concomitant conditions and hospital
admission. Materials and methods: HRQoL was
assessed in participants with severe haemophilia in
the ‘Cost of Haemophilia in Europe: a Socioeconomic
Survey’ (CHESS) study who were using prophylaxis.
Patients using on-demand treatment were excluded.
This multivariate analysis examined the interaction
between factors potentially influencing treatment
and HRQoL, and minor and major bleeds. Results:
From the total CHESS population (n=1,285), 338
(26%) participants provided responses for major and
minor bleeds and target joints, and 145 (11%) provided
EQ-5D-3L responses. Major and minor bleeds were
associated with pain. Patients with severe chronic pain
reported a substantial negative impact on HRQoL;
but this was significantly improved by increases in
the annual infusion rate. This was not apparent in
HCD Economics, Daresbury, UK. Email: gabriel.pedra@
Novo Nordisk A/S, Søborg, Denmark
Centre for Outcomes and Experience Research in
Children’s Health Illness and Disability (ORCHID), Great
Ormond Street Hospital, London; Haemnet, UK
Novo Nordisk A/S, Søborg, Denmark
HCD Economics, Daresbury, UK
Faculty of Health and Social Care, University of Chester, UK
Haemophilia Centre, Royal London Hospital, UK
The impact of infusion frequency on health-related quality of
life in people with haemophilia is variable, with influencing
factors including haemophilia severity and experience of pain.
A recent study indicates a need to balance burden of treatment
with protection against bleeds.
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J Haem Pract 2020; 7(1). doi: 10.17225/jhp00158 103
participants with mild or moderate pain. Conclusion:
Increasing the frequency of prophylaxis infusions is
associated with improved quality of life in PwH who
have severe chronic pain. However, increasing the
number of infusions per week in those with mild or
moderate chronic pain with the intention of improving
prophylactic eect may not have the same eect.
Keywords: Haemophilia, quality of life, infusion
frequency, chronic pain, CHESS study
Recommendations from the World Federation for
Hemophilia for the management of haemophilia
state that prophylaxis with factor replacement
therapy should maintain trough factor levels of
>1%, with the aim of minimising bleeds and reducing the
long-term risk of joint damage due to haemarthrosis [1].
However, the advent of extended half-life factors and
non-factor products such as emicizumab has raised
expectations among clinicians of improved quality of
life through a reduction in infusion frequency, greater
convenience and better tailored treatment [2].
The infusion frequency required to achieve trough
factor VIII (FVIII) levels of >1% ranges from once a
week to alternate days among most people with
haemophiliaA. However, even these dose regimens
do not prevent all spontaneous bleeds despite high
adherence [3], and the residual joint arthropathy continues
to develop, so that young men in their 20s and 30s
report increased pain and limitation of function [4,5]. Some
European countries are now seeing as many as 14–16%
of patients using daily intravenous infusions [6].
Extended half-life (EHL) products have already
changed clinical practice in economically developed
countries, but standard half-life products still dominate
prescribing elsewhere. EHL FVIII can maintain target
trough levels with a reduced infusion frequency
whereas EHL factor IX (FIX) oers higher trough levels
and a lower frequency of infusions [7]. It is clear that
maintenance of higher trough levels reduces the
risk of bleeds [8]. The choice between fewer infusions
or higher trough levels is likely to be influenced by
patient preference, available resources and cost, and
may not be exclusively one pathway or the other but
a compromise representing a balance somewhere in
between. When considering the best outcome from
the patient’s perspective, it is important to understand
the likely impact on clinical endpoints and quality of
life. Patient preference studies suggest that patients
value low frequency of administration more than a
lower risk of bleeding [9,10] and this was the commonest
reason cited for considering a switch from a traditional
standard half-life (SHL) product to an EHL factor [11].
However, joint disease and pain also impair health-
related quality of life (HRQoL) and daily functioning [12,13],
and these studies may not fully represent the potential
benefits available to patients from maintaining higher
trough factor levels.
The aim of this study was to test the hypothesis that
HRQoL in people with haemophilia (PwH) is influenced
by factors that are important to them, including
prophylaxis, chronic pain, concomitant conditions and
hospital admission.
The CHESS study
The ‘Cost of Haemophilia in Europe: a Socioeconomic
Survey’ (CHESS) study was a cross-sectional,
retrospective study carried out in 2015, where patients
aged ≥18 years with severe haemophilia in five European
countries (France, Germany, Italy, Spain and the UK) were
invited to participate [14]. 1,285 patients were recruited
by 139 haematologists and haemophilia care providers
based in hospitals and clinics. Data were collected
using two questionnaire forms: the patient record form
(PRF) was completed by physicians and a Patient and
Public Involvement and Engagement form (PPIE) was
completed by individual patients. Full details of the
methodology for data collection have been published [14].
Physicians reported the number of comorbidities
diagnosed at the time of consultation, hospital
admissions in the previous year, the presence of a target
joint (binary variable), level of adherence to prescribed
factor replacement therapy (high or low/medium, based
on the physician’s records) and the severity of chronic
pain (according to clinical assessment). In CHESS,
primary prophylaxis was defined as receiving prophylaxis
since the start of treatment for haemophilia; secondary
prophylaxis was defined as switching to prophylaxis
from on-demand treatment[15]. We included only
patients taking a prophylaxis dose of ≥10 IU/kg, which is
the minimum eective dose [16]. Patients currently
receiving on-demand treatment were not included due
to their infrequent use and dierent requirements for
adherence. Patients with a history of inhibitors or
currently with inhibitors were also excluded.
Additionally, patients were excluded when the ratio of
factor dose to body weight exceeded 1.2 (calculated as
FVIII: IU per infusion/body weight x 2; FIX: IU per
infusion/body weight) because this suggested the
possibility of an increased risk of thrombosis or of error
in completing the questionnaire.
J Haem Pract 2020; 7(1). doi: 10.17225/jhp00158104
Joint bleeds were defined as episodes of bleeding
into joints diagnosed by the physician which were
recorded as major and minor bleeds. Minor bleeds
were defined as those with mild pain, minimal swelling,
minimal restrictions of motion and resolution within 24
hours of treatment. Major bleeds were defined as pain,
eusion, limitation of motion and failure to respond to
treatment within 24 hours. The presence and number
of target joints was defined as joints aected by chronic
synovitis diagnosed by the physician. This definition,
originally proposed in 2004 [17], was adopted following
discussion with an expert advisory group.
All participants in the CHESS study provided informed
consent. The CHESS protocol was approved by the
Research Ethics Sub Committee of the Faculty of Health
and Social Care within the University of Chester. The
approval stipulated that the study was to be carried out
in correspondence with regional and relevant guidelines.
Health-related quality of life assessment
HRQoL was assessed using the validated tool
EQ-5D-3L[18,19]. This involves patient self-reporting
of their health status in five dimensions: mobility,
self-care, usual activities, pain and discomfort,
anxiety and depression. EQ-5D-3L index values are
normally confined to the range -0.594 to 1.0, where
1.0 represents ‘perfect health’, zero represents ‘dead’,
and values less than zero are health states ‘worse
than dead’. We were unable to utilise predictive
methodologies confined to a 0–1 range (e.g. logistic
regression, beta regression) without transforming
the data EQ-5D-3L values in the sample at zero. The
distribution of EQ-5D-3L values was therefore shifted
so that, in this analysis, EQ-5D-3L values ranges from
zero to 1.594 (as zero meaning worse than dead and
1.594 perfect health). Shifting EQ-5D-3L values does
not change their distribution and will facilitate the use
of a more appropriated statistical method given the
complex distribution. Other techniques have been
proposed, such as adding a threshold in the upper level
of the EQ-5D-3L scale range (Tobit models), but the
values obtained from this study are very close to the
threshold which would bias the results [20].
Statistical analysis
Descriptive analysis was conducted to summarise
patient characteristics. Means were used to describe
continuous variables and frequency and proportions
to describe categorical variables. Independent sample
t-tests and chi squared for independence tests were
conducted to test for between-group dierences.
Multivariate analysis was carried out using
generalised linear regression models. The analyses
were performed using R software and the function
glm(). Three models were generated with a single
set of candidate covariates: the first examined the
eect of the covariates on quality of life, the others
examined their eect on minor and major bleeds. A
gamma distribution with log link function was assumed
for a quality of life model whereas a Poisson with
log link function was used for the major and minor
bleeds regression models. For each model, a selection
approach was applied to identify the best model given
its complexity and goodness of fit. Candidate covariates
included all potentially important determinants of
the outcomes. The model selection was based on a
top-down selection, which consists of having a model
with all candidate covariates and removing each
covariate sequentially to see the improvement of the
fit. Likelihood ratio test was the test used in the model
selection process.
The set of candidate covariates were:
y = age + target joint + subtype + treatment
strategy + number of hospital admissions + number
of comorbidities + chronic pain + adherence +
infusion +(infusion rate * chronic pain)
where y is the dependent variable for each model.
Correlation matrix was obtained between explanatory
variables in order to identify any issues regarding
multicollinearity of the variables.
Patient characteristics
Patient characteristics are summarised in Table 1.
From the CHESS population (n=1,285), excluding
58 with a current inhibitor, of 1,227 patients with
severe haemophilia, 338 (26%) provided responses
for major and minor bleeds and target joints and 145
(11%) provided an EQ-5D-3L response. Most patients
had haemophilia A. The other participants were not
included in the analysis as described in the materials
and methods section.
The majority of participants were young adults
(<30 years old) and the mean level of comorbidity
was correspondingly low, though there was marked
variation in the number of concomitant conditions;
this was matched by variation in admission frequency.
Prophylaxis was secondary in almost two thirds of
patients; the number of infusions weekly ranged
J Haem Pract 2020; 7(1). doi: 10.17225/jhp00158 105
Table 1. Demographics of the study group (n=48)
SUBSET N=338 CHESS DATA 1,285
Age mean (SD)
median (range)
30.86 (12.07)
27 (18–67)
35.94 (14.70)
32 (18–88)
Haemophilia type A
283 (84%)
55 (16%)
996 (77.5%)
289 (22.5%)
Number of patients with target joint Yes
200 (59.2%)
138 (40.8%)
768 (59.8%)
517 (40.2%)
Number of comorbidities mean (SD)
0.80 (1.28)
0 (0–12)
0.94 (1.33)
1 (0–12)
Number of admissions mean (SD)
0.61 (1.43)
0 (0–15)
0.76 (1.46)
0 (0–15)
Treatment strategy primary PPX
secondary PPX
123 (36%)
215 (64%)
217 (16.9%)
1068 (83.1%)
Number of prescribed infusions per year mean (SD)
134.45 (42.40)
156 (52–364)
124.30 (50.05)
136.71 (52–364)
Weekly infusion rate†† 1
30 (9%)
6 (2%)
97 (29%)
179 (53%)
19 (6%)
5 (1%)
1 (<1%)
1 (<1%)
145 (21%)
10 (1%)
198 (29%)
276 (40%)
35 (5%)
20 (3%)
4 (1%)
1 (<1%)
Adherence high
117 (35%)
221 (65%)
773 (60.2%)
512 (39.8%)
Chronic pain rating none
121 (36%)
139 (41%)
71 (21%)
7 (2%)
461 (35.9%)
474 (36.9%)
301 (23.4%)
49 (3.8%)
PPX Prophylaxis (see Materials and Methods for definition).
†† Numbers of patients using prophylaxis and % of total using prophylaxis
from1–7. Physicians reported that almost two thirds
had a rating of low adherence (on a Likert scale of
1–2 vs 3–4) to their prophylaxis regimen. Physicians
reported pain in 64% of patients. This was rated mild in
most cases but considered to be moderate in one in
five patients, with few having severe pain.
Compared with the CHESS population as a whole,
the subset included in this analysis were slightly
younger, more likely to be using primary prophylaxis,
and fewer had high adherence. However, both had
more people on three times weekly administration and
the distribution of pain severity was similar.
Infusion rate on major bleeds
The coecients from the generalised models were
exponentiated (exp{β}) to represent the proportional
change in the response variable (EQ-5D-3L score,
number of major and minor bleeds). The generalised
model for major bleeds showed that using primary
(rather than secondary) prophylaxis, number of
comorbidities, infusion rate and having mild or severe
chronic pain were not statistically significant variables
(Table 2). Similarly, the interaction between infusion
rate and pain was not significant. In the model of best
fit, major bleeds were positively associated with age
(i.e. higher number of bleeds were more frequent with
higher age), having a target joint and hospital admissions
whereas high prophylaxis adherence was associated with
less events of major bleeds. Pain at every level of severity
was positively associated with number of major bleeds.
Infusion rate and minor bleeds
In the case of minor bleeds, the generalised model
also showed no significant association with primary
prophylaxis vs secondary prophylaxis, comorbidities,
mild pain, the interactions of infusion rate and pain,
J Haem Pract 2020; 7(1). doi: 10.17225/jhp00158106
and also with age or haemophilia subtype. In the
model of best fit, the presence of target joints and
admissions were positively associated with minor
bleeds whereas high adherence and higher infusion rate
were associated with fewer minor bleed events. The
association was also positive for chronic moderate and
severe pain, but not mild pain, and for the interaction
between infusion rate and severe pain.
Health-related quality of life
There was no significant association in the generalised
model between HRQoL and age, target joints,
comorbidities, haemophilia subtype, adherence,
infusion rate, or mild or moderate pain. The model of
best fit showed that HRQoL was positively associated
with using lifelong prophylaxis but negatively associated
with number of hospital admissions. Patients with
severe chronic pain reported a substantial negative
impact on HRQoL; this was slightly but significantly
improved by increases in the annual infusion rate.
Analysis of the impact of infusion rate on HRQoL
shows a trend to incremental decrease in EQ-5D-3L
score with each additional infusion per week (equivalent
to 52 per year) by approximately 2%, increasing to 10%
reduction with daily infusions.
Prophylactic clotting factor replacement reduces
major or minor bleeding, with patients on primary
prophylaxis reporting significantly increased HRQoL
[21]. There is a clear relationship between bleeding
and hospital admission: patients with higher bleeding
frequency are more likely to be admitted, with greater
impact on their day-to-day life and a reduced HRQoL.
The same can be said for the impact of bleeding on
increasing levels of pain and HRQoL. The absence
of an association between minor bleeding and the
use of primary vs secondary prophylaxis appears
counter-intuitive; possible explanatory factors include
the relatively low age of CHESS participants, a lower
perceived relative impact of minor bleeds by adults,
and a small dierence in eect size between primary
and secondary prophylaxis.
As shown in Table 2, a high adherence rate is
significantly associated with fewer major and minor
bleeds, with a corresponding decreasing trend in
HRQoL. However, adherence to a lifelong prophylaxis
regimen is associated with a treatment burden that
imposes reductions in HRQoL. This study shows that
a trend toward increasing infusion frequency per
week to increase protection from bleeding may have
some ceiling eects and may be associated with some
decreases in HRQoL scores. It is informative to consider
the additional annual treatment burden arising from
two to seven infusions per week: with a median infusion
frequency of three per week, this would entail up to
an extra 208 infusions per year (or higher for patients
currently using fewer infusions per week). It is this
substantial increase in the number of infusions annually
that underlies the impact on HRQoL. This dilemma
could be resolved with EHL factors, which have the
potential to increase trough levels with no increase or
even a reduction in weekly infusions [22].
The regression analysis further shows that an
increase in the annual infusion rate in patients with
severe pain is associated with a significant improvement
in HRQoL score. This possibly reflects higher trough
levels preventing frequent re-bleeding in damaged
joints, and subsequent joint deterioration and chronic
pain. This was not the case for mild or moderate levels
of pain, for which the reduction in HRQoL score had
little eect. This may suggest that, in PwH with more
severe pain, having higher trough levels may have a
greater benefit than those with less chronic pain and
could be considered as part of the balance of risk and
benefit of treatment.
The current generation of PwH in the CHESS study
who have received lifelong prophylaxis are ageing
with mild or moderate pain rather than the severe pain
associated with less intense therapy options in older
regimens [23]. This study shows that, in patients with mild
or moderate pain, as with those with severe chronic
pain, increasing infusion rate and adherence do not
have the same impact on HRQoL or bleeds.
This study suggests that having fewer weekly
infusions is more than just ‘a convenience’. The burden
of prophylaxis has a day-to-day impact on HRQoL.
Clinical management depends on raising trough factor
levels to provide greater protection against bleeds and
arthropathy. These findings show that increasing the
treatment burden (infusion frequency) is associated
with a negative impact on HRQoL; further research is
needed to determine whether it is also associated with
lower adherence and compromised treatment gains.
We relied on physician reporting of pain. There
is evidence that physician- and patient-reported
assessments and treatment of haemophilia-related
pain may not correlate well, and physicians tend to
underestimate pain compared with patients [24-26].
In this study, physicians reported that almost two
thirds of patients had pain, which was moderate in
21% and severe in 2%; there were seven patients with
J Haem Pract 2020; 7(1). doi: 10.17225/jhp00158 107
severe pain. For comparison, the HERO study found
the prevalence of haemophilia-related pain was 27%
(n=230) when reported by patients in an online survey,
whereas six reported extreme pain/discomfort [12,27]. This
suggests that, although pain is an important challenge
for PwH, the prevalence of severe pain is low and it is
dicult to recruit large numbers of aected patients
in a population-based study. However, the regression
analysis showed a statistically strong relationship
between chronic severe pain and major bleeds. Further
study in a larger group of patients is therefore warranted.
Adherence was assessed from physicians’ records.
Self-reported assessment has been shown to correlate
well with objective measures of adherence such as
pharmacy records [28], though there is also evidence
that patients may overestimate their adherence[29].
Assessment by a health provider has also been shown to
correlate significantly with self assessment, though slightly
less well with a patient-completed questionnaire [30].
The mean number of infusions prescribed was
approximately three per week, with a range of once
weekly to once daily, but the actual number of
infusions received by patients could be lower due
to the level of adherence to treatment. We cannot
exclude the possibility that the inverse relationship
between HRQoL and infusion frequency may be due
to inverse causality – i.e. that worse HRQoL may be
the deciding factor when considering the option of
a higher infusion frequency for a person with severe
pain. However, this does not alter the observation
that increasing infusion frequency does not appear to
benefit people with mild or moderate pain (in terms of
HRQoL). It appears that patients are willing to accept
chronic mild pain (which has a negative impact on
HRQOL) rather than increase infusion frequency.
Therefore, infusion frequency may have both a direct
and indirect eect on HRQoL. This underlines the
point that optimising management is a process of
balancing the burden of treatment with protection
against bleeds and quality of life.
This study strengthens the evidence that pain,
availability of prophylaxis and bleeding rate influence
HRQoL in people with severe haemophilia. It shows
that the impact of severe pain on HRQoL is mitigated
by increasing protection through raising trough factor
levels and subsequently requiring increased weekly
infusion rates. However, improvement in HRQoL in
patients with mild or moderate chronic pain may
be masked by the negative impact of the increased
treatment burden. Further studies are needed to
evaluate the implications for factor usage, cost-benefit
relationship and impact on HRQoL of new treatment
strategies that oer a lower infusion frequency while
maintaining higher factor levels.
The study reported in this paper was funded by Novo
GP, KK, JO, PC, XYL and SO contributed to the
analysis, preparation and interpretation of the data.
JP contributed to insights and interpretation of
the data. The authors would like to thank Declan
Noone (HCD Economics) for his contribution to the
manuscript preparation and Steve Chaplin (Haemnet)
for drafting the paper and incorporating authors’
Informed consent has been obtained from
participants in the CHESS study, on which the study
reported in this paper is based.
Declaration of interests
SO is a trustee of the Haemophilia Society and currently
consulting for World Federation of Haemophilia
(financial support). PC and XYL are currently employed
by Novo Nordisk. JP has received grants, honoraria and
non-financial support from Alnylam, Biomarin, Catalyst
Bio, SOBI, Shire/Takeda, Octapharma, Sanofi and Pfizer
and honoraria from Apcintex, Bayer, Novo Nordisk and
Roche. KK is an employee of Haemnet and a trustee
of the Haemophilia Society, and has received research
funding and honoraria from Bayer, CSL Behring, Novo
Nordisk, Pfizer, Roche, Sobi and Takeda. JO is a Trustee
of Haemnet.
Gabriel Pedra
Pia Christoersen
Kate Khair
Xin Ying Lee
Sonia O’Hara
Jamie O’Hara
John Pasi
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J Haem Pract 2020; 7(1). doi: 10.17225/jhp00158 109
Table 2. Results of the regression analysis (coecients, 95% confidence intervals)
Values >1.0 represent positive associations (e.g. having a target joint is strongly associated with major bleeds); values <1.0 represent
negative associations (e.g. having haemophilia B is negatively associated with major bleeds)
(Intercept) 1.6536***
Age 0.9981
— 0.9984
— 1.0199***
Having a target joint 0.9679
— 1.6486***
Primary prophylaxis
— 0.9992
Number of concomitant
— 1.0298
— 1.0356
Number of
High adherence 0.9917
— 0.8554*
Having haemophilia B 0.9996
— 1.0222
— 0.6977
Increasing infusion rate/
Mild chronic pain 0.9271
Moderate chronic pain 0.8994
Severe chronic pain 0.1826***
Infusion rate/year * mild
chronic pain
Infusion rate/year *
moderate chronic pain
Infusion rate/year *
severe chronic pain
* P <0.05, ** P<0.01, *** P<0.001
... Longer-acting FVIII substitutes and nonfactor replacement therapies allow less frequent (intravenous) administrations increasing patient mobility and quality-of-life. 5 The latest innovation in HA-treatment is the emergence of gene therapies. 6 The promise of one-time treatments inducing prolonged or sustained near-normal FVIII is considered a potential transformative innovation and creates high expectations among patients and physicians. ...
... 23 However, patients without inhibitors are expected to have a higher quality of life; therefore our utilities may be underestimated. 5 Also, our approach to use FVIII to simulate bleeding rates in the gene therapy arm was done to incorporate treatment durability as well overcome the limitation that valrox and prophylactic FVIII benefits are FVIII-level driven, and emicizumab is not. 72 The last limitation is that we did not take into account the costs and burden of administration of FVIII (intravenously) and emicizumab (subcutaneously) by the patients at home 3 times a week (around 1500 times and 250 times over 10 years, respectively), which may mean we underestimated societal costs and burden. ...
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The objective was to undertake an early cost-effectiveness assessment of valoctocogene roxaparvovec (valrox; Roctavian) compared to factor (F)VIII prophylaxis or emicizumab (Hemlibra; Roche HQ, Bazel, Switzerland) in patients with severe Hemophilia A (HA) without FVIII-antibodies. We also aimed to incorporate and quantify novel measures of value such as treatment durability, maximum value-based price (MVBP) and break-even time (ie, time until benefits begin to offset upfront payment). We constructed a Markov model to model bleeds over time which were linked to costs and quality-of-life decrements. In the valrox arm, FVIII over time was estimated combining initial effect and treatment waning and then linked to bleeds. In FVIII and emicizumab arms, bleeds were based on trial evidence. Evidence and assumptions were validated using expert elicitation. Model robustness was tested via sensitivity analyses. A Dutch societal perspective was applied with a 10-year time horizon. Valrox in comparison to FVIII, and emicizumab showed small increases in quality-adjusted life years at lower costs, and were therefore dominant. Valrox’ base case MVBP was estimated at €2.65 million/treatment compared to FVIII and €3.5 million/treatment versus emicizumab. Mean break-even time was 8.03 years compared to FVIII and 5.68 years to emicizumab. Early modeling of patients with HA in The Netherlands treated with valrox resulted in estimated improved health and lower cost compared to prophylactic FVIII and emicizumab. We also demonstrated feasibility of incorporation of treatment durability and novel outcomes such as value-based pricing scenarios and break-even time. Future work should aim to better characterize uncertainties and increase translation of early modeling to direct research efforts.
... The presence of the disability paradox among people with hemophilia has been recently described, with people with hemophilia reporting higher health states than the general population when assessed with the EQ-5D. 36 Other important factors such as pain, joint disease, and ability to perform ADLs also impact on HRQoL, 37,38 ...
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Introduction In 2017, all people with severe hemophilia B in Ireland switched to recombinant factor IX Fc fusion protein concentrate (rFIXFc) prophylaxis. Patient-reported outcomes (PROs) and health-related quality of life (HRQoL) are important to evaluate with new treatments. Aims To assess HRQoL in people with severe hemophilia B and their experience after switching to rFIXFc prophylaxis. Methods Participants completed a Patient Reported Outcomes Burden and Experience (PROBE) questionnaire on initiation and following two years of rFIXFc prophylaxis. The PROBE questionnaire has four domains: demographics, general health, haemophilia-specific, and European Quality of Life 5-Dimensions (EQ-5D-5L) questionnaire. Results Twenty-three participants completed the questionnaire at both time points. The number of activities where chronic pain occurred and interfered with the activity was reduced by 25% and 33%, respectively (P < .001), following two years of rFIXFc prophylaxis. There was a 9% decrease in chronic pain during the second year of rFIXFc prophylaxis compared to baseline, but the rate remained high, at 74%. A 25% reduction in the number of affected activities of daily living (ADLs) was reported following 2 years of rFIXFc prophylaxis (P = .007). The most common health problems were arthritis, hypertension, anxiety/depression, and gingivitis. The median EQ-5D-5L score was similar following two years of rFIXFc prophylaxis, 0.76 (range, −0.01 to 0.95), compared to 0.77 (range, 0.36-1) at baseline. Conclusion This study of real-world patient experience using PROs demonstrates a reduction in chronic pain and improvement in ADLs in participants after switching to rFIXFc prophylaxis. It provides important insights into patient-identified health care needs and living with severe hemophilia B.
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Factor replacement is currently the standard of care to prevent or treat bleeding episodes in haemophilia patients. This study examined current prescribing practices of factor therapy for patients at haemophilia treatment centres (HTCs) in the United States. Aims The aims were to evaluate the driving forces for prescribing factor products, to evaluate current attitudes and knowledge toward factor product and industry, and to discuss the implications for health care providers in practice. Methods An anonymous electronic survey was distributed to 744 HTC health care providers (HCPs); 118 responses were analysed. Results The most common driving force for HCPs to change a patient's factor product was poor response to current therapy, while the most common perception of patients’ motivation to switch products was the potential for fewer infusions. HCPs with strong influence over the prescribed therapy identified inadequate pharmacokinetic (PK) studies as an important driving force; patients/caregivers perceived as having a strong influence over which therapy is prescribed selected less frequent dosing as an important motivator. HCPs who allow patients/caregivers to have a strong influence over which factor is prescribed were more likely to cite patient/caregiver request as a significant driving force for change in therapy. Conclusion The haemophilia treatment landscape continues to evolve and is becoming increasingly complex. The multitude of treatment options available now offer choices, presenting a need to focus on patient-centric prophylaxis.
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Background N8‐GP is an extended half‐life recombinant factor VIII developed for prophylaxis and treatment of bleeds in patients with hemophilia A. Objective To assess pharmacokinetic (PK) characteristics of N8‐GP in previously treated patients with severe hemophilia A, model the time spent at hemophilia thresholds of ≥1 and ≤5 IU/dL (moderate) or >5 IU/dL (mild) FVIII levels during N8‐GP prophylaxis, and investigate the relationship between N8‐GP half‐life and von Willebrand factor (vWF). Methods PK assessments were obtained from patients with severe hemophilia A (FVIII < 1 IU/dL) participating in 4 clinical trials: pathfinder 1 (20‐60 years); pathfinder 2 (12‐17 and ≥18 years); pathfinder 5 (0‐11 years), and pathfinder 7 (25‐71 years). All PK profiles were assessed after washout and considered single‐dose PK profiles. Pre‐ and postdose FVIII activity at steady state was measured at all visits. Results From 69 patients, 108 PK profiles of N8‐GP 50 IU/kg were assessed. Adults/adolescents received 50 IU/kg every 4 days, achieving mean trough levels of 3.0 IU/dL (95% confidence interval, 2.6‐3.5, adults) and 2.7 IU/dL (1.8‐4.0, adolescents). Children received 60 IU/kg twice weekly, leading to mean trough levels of 1.2 IU/dL (0.8‐1.6, 0‐ to 5‐year‐olds) and 2.0 IU/dL (1.5‐2.7, 6‐ to 11‐year‐olds). PK modeling predicted children dosed every 3 days and adults/adolescents dosed every 3 to 4 days would maintain FVIII levels >5 and >1 IU/dL for >80% and 100% of the time, respectively. N8‐GP half‐life correlated linearly with von Willebrand factor levels in adults/adolescents, less in children. Conclusions Prophylaxis with fixed intervals (Q4D/twice weekly) and fixed weight‐based dosing (50/60 IU/kg) ensured >1 IU/dL FVIII trough levels in both adults and children.
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Introduction Therapeutic advances over the past 30 years have led to longer life expectancy and improved quality of life (QOL) for persons with hemophilia. Access to innovative therapy may be compromised if treatment decisions are driven solely by cost. New strategies are needed to assess true therapeutic values, along with financial cost, as physicians, policymakers, payers and manufacturers work together to improve patient care. Aim To provide an evidence‐based assessment of the value of prophylaxis vs on‐demand therapy for hemophilia, based on a widely recognized three‐tiered value framework approach for assessing a range of therapeutic interventions. Methods Data from six randomized clinical trials (ESPRIT, Joint Outcomes Study, SPINART, LEOPOLD II, ADVATE and POTTER) and four observational studies comparing primary and secondary prophylaxis vs on‐demand therapy were applied to a hemophilia value framework. Results Both primary and secondary prophylaxis showed advantages in Tier 1 “Degree of health/recovery” outcomes, including measures of bleeding, musculoskeletal complications, pain, function/activity and QOL. Tier 2 “Process of Recovery” outcomes, also favoured prophylaxis, including measures of recovery time, return to normal activities, orthopaedic intervention and venous access. In Tier 3 “Sustainability of Health Recovery,” measures of breakthrough bleeds, joint preservation, sustained productivity and QOL showed significant improvement with prophylaxis. Conclusion The hemophilia value framework affirmed value of primary and secondary prophylaxis vs on‐demand therapy, with clinical benefit demonstrated in all three tiers. This analysis also demonstrates clinical utility of the value framework process in the determination of optimal and cost‐effective hemophilia care for all stakeholders.
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Haemophilia therapy has undergone very rapid evolution in the last 10 years. The major limitation of current replacement therapy is the short half-life of factors VIII and IX. These half-lives have been extended by the addition of various moieties, allowing less frequent infusion regimens. Entirely novel approaches have also entered the clinic, including a bispecific antibody that mimics factor VIII and strategies that rebalance the haemostatic mechanism by reducing antithrombin through inhibition of synthesis. These two treatments are available by subcutaneous injection at infrequent intervals and both can be used in patients with neutralising antibodies (inhibitors). Finally, a cure may be on the horizon with preliminary evidence of success for gene therapy in haemophilia B and A.
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Introduction: Clinical trials have shown promising results for extended half-life factor VIII concentrates but little is known about individuals' valuation of haemophilia treatment attributes. Aim: To assess patient/caregiver and population valuation of treatment attributes of prophylactic regimens for people with severe haemophilia A. Methods: Members ≥16 years of the Swedish Haemophilia Society (FBIS) and of a web-panel representative of the Swedish population were invited to participate in a web-survey investigating preferences for haemophilia treatment attributes using the Time Trade-Off methodology which ranks health states on a scale 0 (dead) to 1 (full health). All respondents assessed the same four treatment scenarios for severe haemophilia A, each described by three stylized attributes: injection interval (every 2nd or 5th day); participation in physical activity (Y/N); annual risk of bleed (1-2 or 5-6 bleeds). Results: The survey had 1657 respondents (68% complete responses; 184/1233 from FBIS/web-panel gave informed consent; mean age 52 years, 51% men). Respondents from FBIS and from the web-panel had the same preference ranking of the four treatment scenarios, but members of FBIS consistently rated significantly higher health utilities; range 0.67-0.73 vs 0.54-0.60. Participation in physical activity implied +0.023 (95% confidence interval 0.015-0.030); a longer injection interval implied +0.038 (0.03; 0.45); and fewer bleeds implied +0.022 (0.015-0.029) utility points. Conclusions: Patient/caregiver and population preferences indicate that treatment attributes such as frequency of injections and the possibility of participating in physical activity are important attributes impacting quality of life in addition to the control and prevention of bleeding episodes.
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Introduction: Recurrent bleeding and associated pain are critical components in the management of bleeding disorders, yet scant data describe perceptions of pain in this patient population. Objective: This study assessed perceptions of pain and pain management in adolescents and young adults (AYAs) with haemophilia or von Willebrand disease (VWD) to determine agreement/disagreement between patients, caregivers and health care providers. Methods: Using an online questionnaire, AYA patients (N=89), their caregivers (N=77), and providers (N=54) reported on pain perception, pain treatment and pain control. Acute and chronic pain was measured in patients via the Faces Pain Scale-Revised (FPS-R). Questionnaires queried about pharmacologic and non-pharmacologic pain management methods and how well providers and caregivers helped to manage pain. Results: Poor agreement existed between patients and caregivers across all pain levels, perception of pain control and effectiveness of pain management. Specifically for chronic pain, poor agreement was noted between patients and caregivers (kappa=0.04; 29% agreement) and patients and providers (kappa=-0.07; 21.4% agreement). Among patients reporting acute or chronic pain, only 67% and 43%, respectively, utilized medication for their specific pain. Patients used more opioid medications than expected by their providers. On average, AYAs reported initial use of pain medications for chronic pain at 11.5 years. Conclusions: Ongoing research is needed in haemophilia and VWD pain management, and on the differences in pain perception between patients, caregivers and providers. As chronic pain often begins at an early age, optimal pain management should include acknowledging patient complaints, exploring pharmacologic and non-pharmacologic options, and optimizing prophylaxis.
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Background Severe haemophilia is associated with major psychological and economic burden for patients, caregivers, and the wider health care system. This burden has been quantified and documented for a number of European countries in recent years. However, few studies have taken a standardised methodology across multiple countries simultaneously, and sought to amalgamate all three levels of burden for severe disease. The overall aim of the ‘Cost of Haemophilia in Europe: a Socioeconomic Survey’ (CHESS) study was to capture the annualised economic and psychosocial burden of severe haemophilia in five European countries. A cross-section of haemophilia specialists (surveyed between January and April 2015) provided demographic and clinical information and 12-month ambulatory and secondary care activity for patients via an online survey. In turn, patients provided corresponding direct and indirect non-medical cost information, including work loss and out-of-pocket expenses, as well as information on quality of life and adherence. The direct and indirect costs for the patient sample were calculated and extrapolated to population level. Results Clinical reports for a total of 1,285 patients were received. Five hundred and fifty-two patients (43% of the sample) provided information on indirect costs and health-related quality of life via the PSC. The total annual cost of severe haemophilia across the five countries for 2014 was estimated at EUR 1.4 billion, or just under EUR 200,000 per patient. The highest per-patient costs were in Germany (mean EUR 319,024) and the lowest were in the United Kingdom (mean EUR 129,365), with a study average of EUR 199,541. As expected, consumption of clotting factor replacement therapy represented the vast majority of costs (up to 99%). Indirect costs are driven by patient and caregiver work loss. Conclusions The results of the CHESS study reflect previous research findings suggesting that costs of factor replacement therapy account for the vast majority of the cost burden in severe haemophilia. However, the importance of the indirect impact of haemophilia on the patient and family should not be overlooked. The CHESS study highlights the benefits of observational study methodologies in capturing a ‘snapshot’ of information for patients with rare diseases.
Aim: To compare subjective and objective measures of adherence to prophylaxis in haemophilia. Methods: In this cross-sectional study, we compared participants' self-perceived adherence and their estimate of the number of clotting factor concentrates (CFCs) that had been missed over the last period of CFC dispensation with an objective measure of adherence based on counts of CFC vials returned by participants. Results: We included 29 out of 31 eligible patients in the study. There was no significant correlation between self-perceived degree of adherence and the objective classification of adherence (Rho: 0.10, 95% CI: -028 to 0.46, P: 0.61) and between the classification of adherence based on the proportion of missed CFC doses assessed by participants' self-report and objectively (Rho: 0.32, 95% CI: -0.01 to 0.59, P: 0.11). Conversely, we found evidence of moderate correlation between the proportion of missed CFC doses as assessed by participants' self-report and objectively (Rho: 0.56, 95% CI: 0.24 to 0.77, P: 0.003). Participants' self-perceived adherence was 3 times more likely to be rated as very good or good than it was for the objective assessment to be classified as adherent or suboptimally adherent. Conclusion: Our results showed significant discrepancies between subjective and objective measures of adherence, which likely reflect the influence of social desirability bias in self-reported measures and different concepts of adherence between patients/caregivers and haemophilia experts. Additionally, our results allow us to hypothesize that studies on adherence to prophylaxis in haemophilia relying exclusively on information from self-reports and questionnaires may substantially overestimate adherence levels.
Introduction Prospectively collected real‐world data on bleeds, haemophilia treatment and safety in persons with haemophilia A (PwHA) without factor VIII (FVIII) inhibitors are limited. A global, non‐interventional study (NIS; NCT02476942) prospectively collected real‐world data in PwHA who were treated per local routine clinical practice. Aim Assess annualized bleeding rate (ABR), haemophilia treatment practices and adverse events (AEs) in adult/adolescent PwHA without inhibitors. Methods Eligible participants aged ≥12 years with severe HA without history of inhibitors prospectively collected bleeding and treatment information. Results Ninety‐four participants were enrolled (median [range] age, 34 [12‐76] years) and monitored for a median (range) of 29.8 (12.4‐47.7) weeks. In the episodic (n = 45) and prophylactic (n = 49) treatment groups, respectively, 872/1066 (81.8%) and 151/189 (79.9%), bleeds were treated; ABRs (95% confidence interval) were 36.1 (30.8‐42.3) and 5.0 (3.3‐7.5), respectively, for treated bleeds and 43.1 (36.5‐50.9) and 6.2 (4.2‐9.2), respectively, for all bleeds, and median (interquartile range) ABRs were 31.1 (19.8‐51.6) and 1.9 (0.0‐8.2), respectively, for treated bleeds and 35.3 (21.7‐62.9) and 2.7 (0.0‐9.4), respectively, for all bleeds. Half of the participants on FVIII prophylaxis had relatively high adherence to treatment, using 2.9 and 2.1 median doses/wk of standard and extended half‐life FVIII, respectively. Serious AEs included gastrointestinal polyp haemorrhage and haemarthrosis; the most common AE was viral upper respiratory tract infection. Conclusion PwHA without inhibitors continue to bleed on prophylaxis, consistent with the literature, and require treatment for breakthrough bleeds. This prospective NIS demonstrates the need for more efficacious haemostatic approaches.
Introduction Persons with haemophilia (PWH) experience recurrent joint bleeding which leads from early synovitis to irreversible joint damage. Pain strongly affects patients’ quality of life, as PWH suffer from acute pain associated with haemarthroses and chronic pain due to arthritic and degenerative complications. Aim To investigate pain issues among PWH and their treaters in Italy. Methods Persons with haemophilia and specialist physicians responded to a survey focused on pain characteristics, assessment, and management by phone call and online, respectively. Results One hundred and nineteen patients (76% severe haemophilia, 61% ≥18 years) and 44 physicians were involved. Pain was reported by 61% of PWH; among those who did not experience pain, 70% were children on prophylaxis. Patients described pain as chronic (71%), acute (69%) or postoperative (8%), and rated it as severe in 65% of cases. Clinicians reported lower percentages of patients with pain (46%), classified as chronic (58%), acute (33%) or postoperative (21%), half using specific scales. Pain was systematically investigated by treaters according to 36% of patients. Paracetamol was largely the most prescribed first‐line pain therapy (89%), as well the most employed analgesic by PWH (51%), who also used non‐steroidal anti‐inflammatory drugs (24%), cyclo‐oxygenase‐2 inhibitors (21%) or opioids (26%). To manage pain, 61% of clinicians stated to collaborate with other specialists. Physiotherapy was often suggested but less frequently used by PWH. Conclusions Pain is under‐recognized and unsatisfactorily addressed by haemophilia treatment centre (HTC) clinicians, with discrepant management compared to PWH responses. Education in systematic pain assessment and multidisciplinary treatment and development of management guidelines are highly needed.
Introduction: Health-related quality of life (HRQoL) is reduced among persons with haemophilia. Little is known about how HRQoL varies with complications of haemophilia such as inhibitors and joint disease. Estimates of preference-based HRQoL measures are needed to model the cost-effectiveness of prevention strategies. Aim: We examined the characteristics of a national sample of persons with severe haemophilia A for associations with two preference-based measures of HRQoL. Methods: We analysed utility weights converted from EuroQol 5 Dimensions (EQ-5D) and the Short Form 6 Dimensions (SF-6D) scores from 1859 males aged ≥14 years with severe haemophilia A treated at 135 US haemophilia treatment centres in 2005-2011. Bivariate and regression analyses examined age-group-specific associations of HRQoL with inhibitor status, overweight/obesity, number of bleeds, viral infections, indicators of liver and joint disease, and severe bleeding at the time of the first HRQoL measurement. Results: Overall mean HRQoL utility weight values were 0.71 using the SF-6D and 0.78 using the EQ-5D. All studied patient characteristics except for overweight/obesity were significantly associated with HRQoL in bivariate analyses. In a multivariate analysis, only joint disease was significantly associated with utility weights from both HRQoL measures and across all age groups. After adjustment for joint disease and other variables, the presence of an inhibitor was not significantly associated with HRQoL scores from either of the standardized assessment tools. Conclusion: Clinically significant complications of haemophilia, especially joint disease, are strongly associated with HRQoL and should be accounted for in studies of preference-based health utilities for people with haemophilia.