Keywords haemophilia A - severe haemophilia - emicizumab - mental health - work productivity
- health-related quality of life - patient-reported outcomes - prophylaxis - burden
of illness
Introduction
Haemophilia A (HA) is an X-linked bleeding disorder caused by mutations in the F8 gene that codes for factor VIII (FVIII) protein, an essential cofactor in the coagulation
pathway. The clinical phenotype of people with HA (PwHA) is largely governed by the
level of residual FVIII expression, where severe HA is classified as FVIII activity
less than 1% of wild-type (<1 IU/dL), moderate disease comprises 1 to 5% of wild-type
activity, and the mild form is 5 to 40% activity.[1 ]
[2 ] HA affects approximately 1 in 4,000 to 5,000 males across severities, with severe
HA prevalence estimated to be approximately 9.5 cases per 100,000 males.[1 ]
[2 ]
The clinical burden of HA is characterised in particular by irreversible joint damage,
with acute presentation characterised by recurrent haemorrhages, typically in major
joints (knees, ankles and elbows) associated with acute pain and swelling.[3 ]
[4 ]
[5 ] Repeated bleeding into the articular space can cause chronic synovial inflammation
and, over time, progressive joint deterioration.[4 ]
[5 ] This, in turn, may cause substantial chronic pain, movement restrictions and disability
with an increased risk of recurrent bleeding, all of which can greatly impact daily
functioning and quality of life for PwHA.[6 ]
The primary treatment goals for severe HA are to decrease mortality and minimise clinical
sequelae by preventing bleeding episodes with a prophylactic treatment regimen.[7 ]
[8 ] Replacement clotting factor prophylaxis has historically been the cornerstone treatment
for preventing bleeding events; however, standard half-life recombinant and plasma-derived
replacement factor prophylaxis requires frequent infusions to be effective, imposing
a substantial treatment burden on PwHA.[7 ]
[8 ]
[9 ]
[10 ]
[11 ]
Recent innovations in HA treatment, such as the introduction of extended half-life
(EHL) factor replacement therapies, have sought to ease the treatment burden and to
increase protection against bleeds.[8 ]
[10 ]
[11 ] Emicizumab, a subcutaneously administered activated FVIII mimetic, is a prophylactic
treatment for PwHA that has shown effective bleed control in paediatric and adult
populations with HA.[12 ]
[13 ]
[14 ]
[15 ]
[16 ] These newer therapeutic options have offered greater personalised treatment regimens
by increasing choice and flexibility in prophylactic coverage, though FVIII treatment
for breakthrough bleeding events may still be needed. Traditional EHL FVIII products,
however, require ongoing twice or thrice weekly infusions, and effective medical management
is still complicated by the potential development of inhibitors to FVIII in up to
30% of PwHA.[17 ]
[18 ] Ultralong half-life FVIII products allowing for once-weekly infusions have also
become available recently; however, wide access remains limited at this time.[19 ]
[20 ]
[21 ]
Despite improvements in adherence, convenience, and clinical outcomes observed with
therapeutic advances,[22 ]
[23 ] long-standing challenges remain, such as the management of long-term joint health,
along with opportunities to further improve clinical outcomes and health-related quality
of life (HRQoL) for people with this lifelong condition.[24 ] To this end, it is particularly important to consider humanistic outcomes along
with patient characteristics, real-world treatment patterns and clinical outcomes
in order to refine our understanding of how specific treatment attributes may align
with the needs of specific subgroups of PwHA. These considerations include, at a minimum,
how treatment regimens impact the performance of daily activities, work productivity,
and outcomes deemed most important by PwHA. This analysis explored HRQoL, work productivity
and other patient-reported outcomes (PROs) among people with severe haemophilia A
(PwSHA) in Europe on emicizumab or FVIII prophylaxis.
Methods
Data Source and Analysis Population
The “Cost of Haemophilia: a Socio-economic Survey” (CHESS) study is a 12-month retrospective
burden-of-illness study of adult men (aged ≥18 years) with congenital HA or haemophilia
B of any severity, with or without inhibitors, who were not participating in a clinical
trial at the time of data collection or during the preceding 12 months.
Study design, methodology and previous findings have been reported previously.[25 ]
[26 ]
[27 ] Briefly, the CHESS study is a retrospective burden of illness study that is carried
out periodically with information provided by both people with haemophilia (PwH) and
health care providers (HCP). Treating health care providers completed a specifically
designed clinical report form (CRF) reporting on demographics, clinical characteristics,
treatment patterns and health resource utilisation based on the PwH's medical history,
comprising the total population (with CRF data). PwH completed voluntary questionnaire
forms reporting on socioeconomic information, as well as their health status, HRQoL,
labour market and productivity outcomes, financial and daily life burden information,
as well as other PRO measures, comprising the ‘PRO cohort’. Data collection was carried
out periodically across five European countries (EU5; France, Germany, Italy, Spain
and the United Kingdom) and the United States, with a subsample of participants followed
over time and all data anonymised at the source to ensure protection of personal information.[27 ] Participating HCPs recruit the next eligible 8 to 16 patients they consult with,
regardless of consultation reason in order to minimise selection bias.[28 ] Not all PwHA for whom clinical data were available completed a questionnaire; that
is, not all PwSHA in the CRF sample were included in the PRO cohort. All participants
provided informed consent and the study protocol was approved by the Research Ethics
Sub-committee of the Faculty of Health and Social Care of the University of Chester
and received US exemption after review by WIRB-Copernicus Group. The study was carried
out in accordance with regional and relevant guidelines.
This analysis used data on CHESS participants from the EU5 with severe HA and no inhibitor
diagnosis in the 12 months preceding data collection who were receiving prophylactic
treatment (emicizumab or FVIII replacement therapy) from the 2022 (April–November
2022) and 2024 (October 2023–April 2024) study cohorts and specifically the subsample
of eligible PwH completing a patient questionnaire. The entire sample, consisting
of PwSHA and no inhibitors who had a completed CRF (regardless of patient questionnaire
completion), was also evaluated to identify any potential differences in demographic
characteristics or clinical outcomes that may have arisen from selective completion
of the patient questionnaires by a subset of PwSHA. As individuals participating in
clinical trials were not included in this study, no participants were treated with
efanesoctocog alfa at the time of data collection.
Patient Characteristics
Demographic and clinical characteristics of PwSHA, including age, body mass index
(BMI), HA treatment regimens and employment status, were collected by the HCPs. HCPs
also registered bleeding events, use of on-demand FVIII infusions, joint health and
chronic pain for their PwSHA as reported by the PwSHA during routine clinical care
visits in the 12 months prior to data collection. Bleeding events included all spontaneous/traumatic
joint and non-joint injuries. Annual bleeding rate (ABR) was calculated based on the
sum of all bleeding events. Annual spontaneous bleeding rate (ASBR) and annual joint
bleeding rate (AJBR) were also calculated as the sum of all spontaneous and joint
bleeding events, respectively. On-demand FVIII infusions to treat breakthrough bleeding
events were defined as infusions outside the normal prophylaxis treatment schedule
that were used to treat an actual or suspected bleeding event. Joint health was captured
as Problem Joints[25 ] (defined as joints with chronic pain and/or limited range of movement due to chronic
synovitis or arthropathy, with or without persistent bleeding) and Target Joints.[29 ] Problem joints were also captured from the point of view of the patient within the
patient form, recording the specific symptom affecting them and the relative intensity.
Location and magnitude of HA-related chronic pain were classified by the treating
HCP using a 4-point scale (0, no pain; 4, severe pain), accounting for functional
deficits, interference with activities of daily living, and use of analgesics/narcotics.[30 ]
Health-Related Quality of Life, Work Productivity and Mental Health
HRQoL data were collected from PwSHA using the validated, historical standard for
patient-reported HRQoL EQ-5D-5L instrument, comprising five dimensions evaluating
mobility, self-care, usual activities, pain/discomfort and anxiety/depression.[31 ] Additionally, specific HRQoL-related outcomes were also collected as described below.
For this analysis, the United Kingdom's EQ-5D crosswalk was applied using the mapping
algorithm developed by Hernandez Alava and colleagues, allowing for observations from
all countries to be assessed in aggregation.[32 ]
The impact of SHA on work productivity and activity impairment (WPAI) was captured
via the Work Productivity and Activity Impairment Specific Health Problem instrument.[33 ] Raw scores from the six questions in the tool allow for estimation of an overall
impairment, presenteeism, absenteeism and activity impairment percentages.[33 ] Additional work productivity outcomes included the proportion of each treatment
group that reported having missed work in the previous 3 months and the number of
workdays missed.
Self-reported mental health is assessed using the GAD-7[34 ] and the 8-item Patient Health Questionnaire (PHQ-8),[35 ] assessing symptoms of anxiety and depression over the previous 2 weeks.
The self-reported impact of HA on specific areas of daily life was also captured using
four custom-built questions focusing on social activities, physical activities, life
opportunities and feelings of frustration with HA's impact on lifestyle based on a
1- to 5-point Likert scale describing the level of compromise in the specific area.[27 ] Adaptation of treatment dosing and administration based on physical and social activities
was also captured in the patient questionnaire, inclusive of additional infusions
outside of the habitual treatment schedule that were not related to a specific bleeding
event. The requirement for assistance in daily activities was also reported by PwSHA.
Full definitions of the outcomes of interest are provided in [Supplementary Table S1 ].
Statistical Analysis
All findings were analysed descriptively. For continuous variables, both means (with
standard deviations [SDs]) and medians (with ranges) were reported. Between-group
differences in means in PRO measures and HRQoL variables were summarised using a two-sample
t -test with corresponding 95% confidence intervals (CIs), while differences in medians
were estimated using bootstrapping to generate 95% CIs. For binary categorical PRO/HRQoL
variables, frequencies and proportions were presented, with differences in proportions
and 95% CIs estimated using a two-proportion z -test. Consistent with the descriptive nature of the study, no formal hypothesis testing
was carried out, and no p -values are presented. All analyses were performed using STATA 18 (StataCorp LLC,
College Station, TX; www.stata.com ).
Results
Analysis Population
A total of 350 PwSHA met the eligibility criteria with information provided by their
health care providers in the CRF and were included in this analysis. The emicizumab
and FVIII prophylaxis groups had similar mean (SD) number of target joints (0.6 [1.0]
vs. 0.5 [0.7]) and problem joints (0.8 [1.1] vs. 1.0 [1.3]; [Supplementary Table S2 ]). All other characteristics of the total population are provided in [Supplementary Table S2 ].
Approximately one-quarter (27%, n = 94) of the total analysis population completed the patient questionnaires and were
included in the PRO cohort. Characteristics of the PRO cohort ([Table 1 ]) were generally consistent with those of the total analysis population ([Supplementary Table S2 ]), but a larger proportion of the PRO cohort was receiving emicizumab (68% and 55%,
respectively). The PRO cohort also appeared to be slightly older, with mean (SD) ages
of 38.8 (14.3) and 39.9 (16.1) for the emicizumab and FVIII groups, respectively,
in the PRO cohort, and 34.0 (13.2) and 36.1 (12.9) in the total population. Additionally,
albeit generally comparable, slightly less favourable clinical characteristics were
noted in the PRO cohort, such as a mean (SD) ABR of 1.6 (1.4) and 1.4 (1.1) in the
emicizumab and FVIII groups, respectively, compared with 1.3 (1.3) and 1.2 (1.0) in
the total population ([Table 1 ] and [Supplementary Table S2 ]).
Table 1
Demographic and clinical characteristics of people with severe haemophilia A in the
patient-reported outcome cohort (n = 94)
Emicizumab
(n = 64)
FVIII prophylaxis
(n = 30)
Age, years, mean (SD)
38.8 (14.3)
39.9 (16.1)
BMI, kg/m2 , mean (SD)
24.2 (3.8)
25.1 (2.9)
Country, n (%)
Italy
26 (40.6)
15 (50.0)
Spain
7 (10.9)
7 (23.3)
United Kingdom
11 (17.2)
2 (6.7)
France
14 (21.9)
0
Germany
6 (9.4)
6 (20.0)
Employment, n (%)
Employed
49 (76.6)
23 (76.7)
Student
4 (6.2)
2 (6.7)
Not employed
8 (12.5)
5 (16.7)
Physically unable to work due to HA
1 (1.6)
0
Unknown
2 (3.1)
0
Education, n (%)
None or primary schooling only
0 (0.0)
1 (3.3)
Secondary, Vocational, High School
39 (60.9)
16 (53.3)
University
23 (35.9)
12 (40.0)
Other or do not know
2 (3.1)
1 (3.3)
Ethnic origin, n (%)[a ]
White/Caucasian
47 (94.0)
29 (96.7)
Black/Afro-Caribbean
2 (4.0)
0 (0.0)
Middle Eastern
0 (0.0)
1 (3.3)
Asian–Indian subcontinent
1 (2.0)
0 (0.0)
FVIII treatment, n (%)
SHL/Plasma-derived
–
13 (43.3)
EHL
–
17 (56.7)
Previous treatment strategy, n (%)
Prophylaxis[b ]
40 (62.5)
23 (76.7)
High-dose FVIII prophylaxis[c ]
12 (30.0)
16 (69.6)
Intermediate-dose FVIII prophylaxis[d ]
6 (15.0)
5 (21.7)
Other[e ]
22 (55.0)
2 (8.7)
On-demand
24 (37.5)
7 (23.3)
Treatment class or strategy switch in 12 months prior, n (%)
19 (29.7)
6 (20.0)
Received ≥1 FVIII infusion for breakthrough bleeding events, n (%)
Mean (SD) number of infusions
22 (34.4)
0.5 (1.2)
10 (55.6)
2.7 (3.2)
Target joints, number, mean (SD)
0.6 (1.0)
0.4 (0.7)
Proportion with 1+ problem joints, n (%)
Problem joints, number, mean (SD)
29 (45.3%)
0.8 (1.1)
17 (56.7%)
1.0 (1.3)
PwSHA report of 1+ problem joint, n (%)
PwSHA-reported Problem Joint symptom, n (%)[f ]
Chronic pain
Chronic synovitis
Range of movement restriction
Recurrent bleeding
Haemophilic arthropathy
39 (60.9%)
30 (46.9%)
8 (12.5%)
17 (26.6%)
4 (6.2%)
3 (4.7%)
19 (63.3%)
16 (53.3%)
2 (6.7%)
11 (36.37%)
3 (10.0%)
1 (3.3%)
Chronic pain, n (%)
None
24 (37.5)
9 (30.0)
Mild
26 (40.6)
10 (33.3)
Moderate
13 (20.3)
11 (36.7)
Severe
1 (1.6)
0
ABR, mean (SD)
1.6 (1.4)
1.4 (1.1)
AJBR, mean (SD)
0.7 (1.0)
0.8 (1.0)
ASBR, mean (SD)
1.0 (1.2)
0.7 (0.8)
Treated annualised ABR (≥3 months on treatment), n , mean (SD)
n = 60, 0.6 (1.2)
n = 18, 0.8 (0.9)
Number of infusions to resolve bleeding episode, mean (SD)
n = 60, 0.6 (1.2)
n = 18, 2.7 (3.2)
Annualised ABR on previous treatment, n , mean (SD)
n = 56, 2.3 (2.5)
–
ABR difference (pre- vs. posttreatment), n , mean (SD)
n = 53, −0.6 (1.5)
–
Abbreviations: ABR, annual bleeding rate; AJBR, annual joint bleeding rate; ASBR,
annual spontaneous bleeding rate; BMI, body mass index; EHL, extended half-life; FVIII,
factor VIII; HA, haemophilia A; PwSHA, person with severe HA; SD, standard deviation;
SHL, standard half-life.
All variables reported by HCPs unless otherwise specified.
a Ethnic origin data were not available for 14 patients in the emicizumab group.
b May include any product type (standard half-life FVIII, extended half-life FVIII,
plasma-derived FVIII or emicizumab).
c High-dose prophylaxis is defined as >4,000 IU/kg/year.[8 ]
d Intermediate-dose prophylaxis is defined as 1,500 to 4,000 IU/kg/year;[8 ]
e Comprises low-dose prophylaxis (<1,500 IU/kg/year; n = 4, 6.4%),[8 ] PwSHA previously on a different frequency of emicizumab (n = 7, 11.1%) and PwSHA where the information was missing (n = 13, 20.6%).
f Proportion of people with haemophilia A reporting the specific symptom in at least
one of their reported problem joints.
Characteristics of the Patient-Reported Outcome Cohort
Of the PRO cohort, 68% (n = 64) were receiving emicizumab and 32% (n = 30) were receiving FVIII prophylaxis. Within the FVIII prophylaxis group, 57% (n = 17) were using EHL products. Overall, the greatest proportion of PwSHA were in
Italy (43%, n = 41), and the rest of the sample was generally evenly distributed across the other
four countries, ranging from 13% (n = 12) in Germany to 15% (n = 14) in Spain ([Table 1 ]). Greater proportions of the emicizumab group were in France and the United Kingdom,
and more of the FVIII group were in Italy and Spain. Mean (SD) ages of PwSHA were
38.8 (14.3) and 39.9 (16.1) years for the emicizumab and FVIII prophylaxis groups,
respectively. Mean BMI was 24.2 (3.8) and 25.1 (2.9) kg/m2 , with 59% and 57% of the emicizumab and FVIII treatment groups in the healthy weight
range, respectively. In both treatment groups, 77% of PwSHA were employed, with 36%
(n = 23) and 40% (n = 12) of the emicizumab and FVIII prophylaxis groups educated at the university level
([Table 1 ]).
The majority of PwSHA in both the emicizumab and FVIII prophylaxis groups reported
some level of chronic pain (63% vs. 70%, respectively). Chronic pain was also the
most commonly reported symptom among PwSHA who reported suffering from problem joints
in both the emicizumab (61%, n = 39) and FVIII prophylaxis groups (63%, n = 19; [Table 1 ]). Bleeding outcomes were largely equivalent between the treatment groups in terms
of ABR, AJBR, ASBR and treated bleeding events. On-demand infusions to treat breakthrough
bleeding events, however, were reported for 34% (n = 22) and 56% (n = 10) of PwSHA receiving emicizumab or FVIII prophylaxis who had available information
(the number of infusions to treat breakthrough bleeding events was only available
for 82 patients PwSHA in this sample; 18 in the FVIII prophylaxis group and 64 in
the emicizumab group). Mean (SD) number of on-demand infusions to achieve bleed resolution
was 0.6 (1.2) and 2.7 (3.2) for the emicizumab and FVIII prophylaxis groups. A greater
proportion of PwSHA in the emicizumab group were previously on an on-demand treatment
regimen (38% vs. 23%), with 30% versus 20% switching their treatment regimens in the
previous 12 months. Most patients with a history of prophylaxis treatment and available
information had received high-dose prophylaxis regimens ([Table 1 ]). Compared to previous treatments, PwSHA taking emicizumab experienced a decrease
of 0.6 bleeds per year ([Table 1 ]).
Mental Health
PwSHA in the emicizumab group reported less impact of SHA on their mental health than
those receiving FVIII prophylaxis ([Fig. 1 ] and [Table 2 ]). Specifically, GAD-7 anxiety scores were numerically lower in the emicizumab group
compared with the FVIII prophylaxis group (mean [SD], 6.0 [5.8] vs. 7.3 [5.2]; [Table 2 ]). Half (53%) of the emicizumab group reported no anxiety compared with 33% of the
FVIII prophylaxis group, and a smaller proportion self-reported their anxiety levels
as mild or worse (47%, n = 30) compared with 67% (n = 20) of the FVIII prophylaxis group. This observation remained when median scores
were analysed, showing a median score for the emicizumab group of 4.0 (range, 0–18)
and a median score for the FVIII prophylaxis group of 6.0 (range 0–19), where mild
scores for the GAD-7 range from 5 to 9, moderate scores from 10 to 14 and severe indicated
by a score of ≥15 ([Table 2 ]).
Fig. 1 Proportions of PwSHA reporting anxiety and depression. Proportions may not sum to
100% due to rounding. Maximum scores are 21 for the GAD-7 and 24 for the PHQ-8; both
characterise ‘moderate’ or worse anxiety or depression as scores ≥10.[34 ]
[35 ] GAD-7, 7-item General Anxiety Disorder questionnaire; PHQ-8, 8-item Patient Health
Questionnaire; PwSHA, people with severe haemophilia A.
Table 2
Health-related quality of life, work productivity and activity impairment and mental
health outcomes among people with severe haemophilia A
Emicizumab (n = 64)
FVIII prophylaxis (n = 30)
Delta
(95% CI)[c ]
EQ-5D-5L index score
Mean (SD)
Median (range)
0.71 (0.25)
0.72 (−0.1–1.0)
0.69 (0.29)
0.70 (−0.3–1.0)
−0.02 (−0.14–0.09)
−0.02 (−0.15–0.12)
Impact on work, previous 3 months
Missed ≥1 workday, n (%)
10 (15.6)
12 (40.0)
24.4 (4.7–44.0)
Number of days missed
Mean (SD)
Median (range)
n = 10
3.7 (2.1)
3.0 (2–8)
n = 12
4.2 (2.4)
4.5 (1–8)
0.6 (−1.5–2.6)
1.5 (−1.2–4.2)
Did not miss days but experienced issues in carrying out tasks, n (%)
22 (34.4)
6 (20.0)
−14.4 (−32.8–4.1)
WPAI[a ]
Overall work productivity loss[b ]
Mean (SD)
Median (range)
n = 51
31.3 (30.7)
26.2 (0–92)
n = 18
50.1 (24.3)
56.1 (0–83)
18.8 (2.8–34.8)
29.9 (9.6–50.3)
Absenteeism[b ]
Mean (SD)
Median (range)
n = 51
6.7 (12.5)
0.0 (0–60)
n = 18
16.5 (20.5)
8.3 (0–67)
9.9 (1.7–18.0)
8.3 (−2.4–19.1)
Presenteeism[b ]
Mean (SD)
Median (range)
n = 51
28.8 (28.5)
20.0 (0–90)
n = 18
41.1 (21.1)
45.0 (0–70)
12.3 (−2.4–27.0)
25.0 (6.0–44.0)
Activity impairment
Mean (SD)
Median (range)
39.8 (30.5)
40.0 (0–100)
48.7 (26.0)
55.0 (0–100)
8.8 (−4.0–21.6)
15.0 (−6.6–36.6)
GAD-7 score
Mean (SD)
Median (range)
6.0 (5.8)
4.0 (0–19)
7.3 (5.2)
6.0 (0–18)
1.3 (−1.2–3.8)
2.0 (−2.1–6.1)
GAD-7 anxiety severity category, n (%)[d ]
None (0–4)
Mild (5–9)
Moderate (10–14)
Severe (≥15)
34 (53.1)
13 (20.3)
10 (15.6)
7 (10.9)
10 (33.3)
10 (33.3)
6 (20.0)
4 (13.3)
–
PHQ-8 score
Mean (SD)
Median (range)
6.8 (6.0)
5.0 (0–22)
7.8 (5.7)
7.0 (0–21)
1.1 (−1.6–3.7)
2.0 (−2.0–6.0)
PHQ-8 depression severity category, n (%)[d ]
None (0–4)
Mild (5–9)
Moderate (10–14)
Moderately severe and above (≥15)
29 (45.3)
13 (20.3)
14 (21.9)
8 (12.5)
10 (33.3)
9 (30.0)
6 (20.0)
5 (16.7)
–
Abbreviations: CI, confidence interval; FVIII, factor VIII; GAD-7, 7-item General
Anxiety Disorder questionnaire; HA, haemophilia A; PHQ-8, 8-item Patient Health Questionnaire;
SD, standard d
eviation; WPAI, work productivity and activity impairment.
a Delta values were calculated as the difference between group means, medians and cohort
proportions (FVIII prophylaxis cohort minus emicizumab cohort); small discrepancies
(≤0.1) may be observed due to rounding of individual values. Delta values and corresponding
95% CIs for means, medians, and proportions were calculated using t -test, bootstrapping, and z -test, respectively.
b WPAI scores should be interpreted as the percentage of impairment in each category.
c Emicizumab group, n = 51; FVIII group, n = 18.
d Delta values and corresponding CIs were not computed for these variables due to the
small sample size within each subgroup and the absence of a strong clinical rationale
for further grouping.
A similar trend was observed for PHQ-8 depression scores, but with a slightly higher
level of burden for both groups and lower scores for the emicizumab group compared
with the FVIII prophylaxis group (mean [SD], 6.8 [6.1] vs. 7.8 [5.7]; [Fig. 1 ] and [Table 2 ]). This observation remained when median scores were analysed, showing a median score
in the emicizumab group of 5.0 (range, 0–22) and a median score in the FVIII prophylaxis
group of 6.0 (range 0–21; [Table 2 ]). As with the GAD-7, mild scores for the PHQ-8 range from 5 to 9, moderate scores
from 10 to 14 and moderately severe and above are indicated by a score of ≥15. A larger
proportion of PwSHA in the FVIII prophylaxis group (67%) reported some level of depression
(PHQ-8 score >4) compared with 55% of the emicizumab group ([Table 2 ]).
Health-Related Quality of Life and Work Productivity
Overall, HRQoL showed comparable EQ-5D-5L scores between the treatment groups, with
a marginally higher mean score in the emicizumab group (0.71 vs. 0.69) compared with
the FVIII prophylaxis group ([Table 2 ]). The emicizumab group also reported lower activity impairment, on average, when
compared with the FVIII prophylaxis group (39.8 vs. 48.7). A similar trend was observed
in treatment adaptation to physical and social activities, with a smaller proportion
of the emicizumab group looking to adapt their treatment (22%, n = 13) compared with the FVIII prophylaxis group (36%, n = 9). A smaller proportion of the emicizumab group also required assistance with
daily activities compared with the FVIII prophylaxis group (19% vs. 33%; [Fig. 2 ] and [Table 2 ]).
Fig. 2 Assistance requirement, treatment adaptation and areas of compromise among PwSHA.
a Missing responses in both the emicizumab and FVIII prophylaxis groups: n = 13/64 (22%) for emicizumab, n = 9/25 (36%) for FVIII prophylaxis. FVIII, factor VIII; PwSHA, people with severe
haemophilia A.
Substantial proportions of both treatment groups reported believing that haemophilia
had caused some level of compromise in their daily lives, however, this was a larger
proportion of the FVIII prophylaxis group (53%, n = 16) than the emicizumab group (44%, n = 28; [Fig. 2 ]). Approximately 45% of each group reported feeling frustrated with the impact of
haemophilia on their lifestyle and missing out on opportunities due to their haemophilia
([Fig. 2 ]). The FVIII prophylaxis group, however, reported feeling more impacted in the areas
of social activities (70% vs. 56%) and physical activity (57% vs. 44%) than the emicizumab
group, and a greater proportion had to give up exercise (57%) than in the emicizumab
group (44%; [Fig. 2 ]). Across all areas of compromise, however, the emicizumab cohort reported on average,
lower compromise ([Fig. 3 ]).
Fig. 3 Haemophilia-related compromises reported by PwSHA. Points further from the centre
indicate greater burden/compromise. PwSHA, people with severe haemophilia A.
The impact of haemophilia on employed PwSHA was lower for the emicizumab group, with
overall work impairment reported to be 31% versus 50% ([Table 2 ]). Specifically, lower rates of both mean (SD) absenteeism (6.7 [12.5] vs. 16.6 [20.5])
and presenteeism (28.8 [28.5] vs. 41.1 [21.1]) were reported with emicizumab compared
with the FVIII prophylaxis group. A smaller proportion of the emicizumab group also
reported having missed work in the preceding 3 months (16% vs. 40%), with a mean (SD)
of 3.7 (2.1) vs. 4.2 (2.4) missed workdays during that time ([Table 2 ]). Among those not reporting any missed work, however, substantial proportions of
PwSHA reported problems carrying out tasks at work due to their haemophilia, which
appeared higher in the emicizumab group (34% and 20% of the emicizumab and FVIII prophylaxis
groups, respectively; [Table 2 ]).
Discussion
This analysis of a cohort of PwSHA receiving prophylaxis in the CHESS III–IV study
showed a substantial burden of haemophilia on the mental health, work productivity
and HRQoL of PwSHA in Europe. Most PwSHA reported at least a mild degree of anxiety
and depression, which was numerically less of a burden for those on an emicizumab
compared to FVIII prophylaxis regimen. Among employed PwSHA, overall work productivity
impairment was notable and lower among those receiving emicizumab. Only 16% of PwSHA
receiving emicizumab had missed at least one day of work in the previous 3 months,
with a mean of 3.7 days missed, compared with 40% of those receiving FVIII prophylaxis
(mean, 4.2 days missed). Most PwSHA reported making compromises to their social lives,
ability to exercise and other life opportunities due to their SHA, which was again
reported more among those on an FVIII prophylaxis regimen than those taking emicizumab.
These trends were observed in the context of similar clinical outcomes, including
ABR, joint health and chronic pain between the treatment groups, despite evidence
suggesting PwSHA in the emicizumab group may have had more morbidity in their medical
and treatment history.
Overall, these data demonstrate the importance of treatment burden and good haemostatic
control on HRQoL, supporting the role of emicizumab as part of the standard of care
in clinical practice.[36 ] These findings are also consistent with previous reports of HRQoL improvements observed
with emicizumab among PwHA without inhibitors in the HAVEN clinical trial program,[37 ]
[38 ] including improvements in pain and pain-related HRQoL within 13 weeks of starting
treatment that were maintained through 78 weeks.[39 ]
In fact, the PROs suggested that emicizumab may provide distinct advantages in non-clinical
aspects of the lives of PwSHA. PwSHA receiving an emicizumab regimen also reported
less need for caregiver support compared with the FVIII prophylaxis group. PwSHA in
the emicizumab group appeared to have a more complex treatment history than their
counterparts in the FVIII prophylaxis group, with 38% versus 23% previously treated
with on-demand regimens, and 30% versus 20% having undergone a treatment switch in
the 12 months prior, consistent with a previous analysis of claims data, hypothesising
channelling bias in emicizumab patients.[40 ] This may suggest added benefits of emicizumab for PwSHA who have or have had treatment-related
challenges (e.g., venous access, needle phobia, adherence issues, unfavourable patient-specific
pharmacokinetics) or in balancing their condition with personal and professional engagements.
In these instances, emicizumab may provide an efficacious therapeutic option that
reduces treatment burden while providing appropriate protection from bleeding events
and supporting better mental health, work productivity and HRQoL.
Employed PwSHA in both treatment groups reported an impact of SHA on work productivity.
However, consistent with previous findings,[37 ] PwSHA taking emicizumab reported greater work productivity with fewer missed workdays
and lower rates of both presenteeism and absenteeism compared with the FVIII prophylaxis
group. In-line with this finding, PwSHA on emicizumab reported less impairment of
daily life activities than their counterparts taking FVIII factor prophylaxis. However,
approximately half of each treatment group reported missing out on life opportunities
due to their haemophilia and feeling frustrated with the impact of haemophilia on
their daily lives. More of the FVIII prophylaxis group, however, reported adapting
their treatment to account for physical and social activities, and reducing their
social and physical aspects of life due to their haemophilia, compared with those
taking emicizumab.
Lower levels of anxiety and depression were observed in the emicizumab group than
in the FVIII prophylaxis group, potentially reflecting the positive effect of a lower
treatment burden in the context of appropriate bleed control. Previous research has
linked frequent treatment administrations with reduced quality of life and treatment
burden to potential mental health impact on PwH, suggesting that a reduced treatment
burden may help to improve emotional well-being.[24 ]
[26 ]
[41 ]
[42 ] In contrast, Pedra and colleagues reported how more frequent FVIII treatment administration
may be beneficial in PwSHA who have adverse clinical situations, particularly those
with severe chronic pain, highlighting the importance of tailoring treatment to the
specific clinical situation of the PwSHA to achieve optimal outcomes.[43 ] Although mental health and HRQoL are critical components of the haemophilia care
pathway, and are not often captured quantitatively in routine practice, these data
advocate for the use of these simple tools as part of routine haemophilia management
provided by the multidisciplinary care team.[28 ] Assessments at least once every 12 to 24 months can prompt discussions between the
patient and their care team around aspects of management, including treatment burden
and treatment anxiety. All of these should be taken into consideration along with
lifestyle, social support, patient preferences and clinical considerations in a shared
decision-making process between PwSHA and their care team. Such a patient-centred
and holistic approach to haemophilia treatment can contribute to improving clinical,
quality of life and emotional well-being outcomes. Future research should continue
to explore the impact of different prophylactic treatments on both clinical and humanistic
outcomes and the impact of such assessments in changing these outcomes.
These findings should be considered in the context of certain limitations. This was
an analysis of secondary data that were not collected for the specific and sole purpose
of this analysis. The CHESS study was not designed a priori to detect statistically
significant differences between treatment groups. For this reason, we refrained from
performing any statistical tests and have only reported numerical differences. As
this was a secondary analysis of a study with no formal hypotheses or prespecified
power calculations, statistical power may be limited. Accordingly, and in-line with
the descriptive and exploratory nature of this analysis, no formal hypothesis testing
was conducted. Despite these limitations, these findings offer valuable insight into
the potential magnitude of differences between the two treatment groups and may provide
a foundation for hypothesis generation in future studies. Further, patient and clinician
participation in the CHESS studies was voluntary, and a degree of selection bias was
possible. Specifically, PwSHA with a more complicated clinical situation may be more
likely to visit the treatment centre, therefore increasing the likelihood of being
offered and completing the questionnaire, potentially contributing to selection bias.
It should also be noted that PwSHA taking emicizumab comprised a larger proportion
of the PRO cohort (68%) compared with the CRF sample (55%), which may have influenced
the direction of findings. A degree of recall bias was also possible, as well as potential
data entry errors or incomplete medical records, which may lead to underestimation
of clinical outcomes. The study's descriptive design does not account for potential
confounding factors due to differences in baseline characteristics between the treatment
groups. PwSHA taking emicizumab may generally have a more complicated treatment history,
which could influence the outcomes. Ideally, matching or weighting methods should
be used in future work to balance groups by their baseline characteristics for a robust
comparison. However, these methods were not adopted due to the small sample size.
As a result, while differences in ABR were observed between the groups, it was not
possible to infer whether these differences were driven by variations in activity
levels, joint health, or prior treatment efficacy. Additionally, variation in treatment
type (standard half-life vs. EHL) within the FVIII prophylaxis cohort may have introduced
further confounding; however, subgroup analyses to explore this were not feasible
due to the limited sample size. Furthermore, the primary focus of this analysis was
to assess WPAI, EQ-5D, anxiety and depression outcomes rather than to draw conclusions
on the drivers of bleeding rates. Finally, owing to the relatively small size of the
analysis sample, the generalisability of these results may be limited, and the results
may not be representative of the wider population of PwSHA. Therefore, caution is
warranted in the interpretation of results. Despite these limitations, this analysis
provides important preliminary evidence in the absence of extensive literature on
this topic, highlighting the need for further investigation and serving as a basis
for future research in this area. Future research is warranted to further explore
specific aspects of treatment on PwSHA, including how patients start and sustain prophylaxis
regimens in the context of emicizumab availability, and how the long-term effects
of different prophylactic regimens impact both clinical and PROs.
Conclusion
PwSHA receiving emicizumab prophylaxis regimens appeared to have more favourable mental
health, work productivity and HRQoL-related outcomes than those receiving FVIII prophylaxis.
These findings were observed in the context of comparable clinical characteristics
between emicizumab and FVIII prophylaxis despite evidence of a more complex treatment
history for the emicizumab group. Larger studies, accounting for potential confounding,
should compare HRQoL longitudinally across novel treatments.
Bibliographical Record
