Economic and Humanistic Burden of Moderate and Severe Hemophilia A and B in Spain: Real-World Evidence Insights from the CHESS II Study

Background: Hemophilia is a congenital disorder characterized by deficiency or absence of clotting factor VIII in hemophilia A (HA) or clotting factor IX in hemophilia B (HB), resulting in frequent, repeated, and prolonged spontaneous or traumatic bleeding into joints or soft tissue. Severity is classified by the patient’s baseline level of clotting factor activity as mild (>5%-40%), moderate (1%-5%), or severe (<1%). In Spain, there is limited information on the societal economic burden of disease. Objective: To estimate the economic and humanistic burden of disease in adult patients with non-inhibitor moderate and severe HA and HB in Spain. Methods: Spanish data from the CHESS II study (2018-2020) on patients’ clinical characteristics, health-related quality of life (HRQoL) and hemophilia-related healthcare resource utilization were analyzed. Economic burden was determined by estimating condition-related annual per-patient direct (medical and nonmedical) and indirect costs, stratified according to hemophilia type and severity and presented as 2022 Euros. HRQoL was assessed via the EQ-5D-5L. Results: Of 341 patients in the Spanish CHESS II cohort, 288 patients met the inclusion criteria: 181 had HA (37% [n = 66] moderate and 63% [n=115] severe) and 107 had HB (26% [n = 28] moderate and 74% [n = 79] severe). Mean annual direct cost was higher in HB than in HA, and higher in severe than in moderate patients, resulting in an annual cost/patient of €17 251 (moderate HA), €17 796 (moderate HB), €116 767 (severe HA) and €206 996 (severe HB). The main direct cost component in all groups except moderate HA was factor replacement therapy. Mean per-patient indirect cost was €4089 (moderate HA), €797 (moderate HB), €8633 (severe HA) and €8049 (severe HB). Finally, the mean total cost (direct and indirect) for moderate and severe patients were €91 017 (HA) and €163 924 (HB). EQ-5D-5L [SD] scores were lower in patients with severe HA (0.77 [0.18]) and severe HB (0.70 [0.22]) compared with patients with moderate HA (0.81 [0.15]) and moderate HB (0.86 [0.17]). Conclusions: Independently of the type of hemophilia, greater condition severity was associated with increased costs and a decrease in HRQoL.


INTRODUCTION
Hemophilia is an X-linked, recessive, congenital disorder characterized by a deficiency or absence of clotting factor VIII (FVIII) in the case of hemophilia A (HA) or clotting factor IX (FIX) in the case of hemophilia B (HB), which may lead to spontaneous acute bleeding or prolonged traumatic bleeding events. 1 Depending on the clotting factor activity level (reported as percentage of normal activity), the severity of hemophilia is classified as mild (40% to >5%), moderate (5% to 1%) or severe (<1%). 2,3emophilia mainly affects males, with HA being more prevalent than HB. 2,3According to data from the World Federation of patients with HA and 37 998 with HB were identified worldwide. 4he global prevalence, considering incidence and mortality rates, was estimated at 17.1 cases of HA and 3.8 cases of HB per 100 000 males, with prevalence of severe condition estimated as 3.8 for HA and 1.1 for HB. 4 In 2010, Spain had patient number estimates of a total of 2595 (86.7%)HA and 398 (13.3%)HB patients. 5In 2017, considering the ratios of HA to HB in the published data on hemophilia in Spain (HA/HB ratios of 6.5:1 6 and 5:1, 7 respectively), the number of patients with HB reported was 317 cases. 8The publication on Spanish hemophilia epidemiology from a registry in 2013, which included patients with moderate and severe hemophilia identified that the proportion of severe disease (HA, 80.8%; HB, 60.6%) was higher than moderate disease (HA, 19.2%; HB, 39.4%). 7he characteristic symptom of hemophilia is the manifestation of bleeding episodes; bleeds that occur at the intra-articular and muscular level, can lead to chronic inflammation, causing hemophilic arthropathy, generating long-term disability. 9,10Bleeding occurring in the central nervous system can result in severe complications leading to death. 9he clinical burden for people with hemophilia is, therefore, persistent and lifelong. 11,12][15] An improvement in treatment-related outcomes would help reduce the burden of disease.The standard of care for the patient includes prophylaxis and on-demand treatment with clotting factor replacement therapies (CFRT) or emicizumab (a monoclonal antibody indicated for routine prophylaxis of bleeding episodes in patients with HA). 9,16,17For prophylaxis with CFRT, standard half-life (SHL) intravenous infusion products (administered 2-3 times per week) are available; in addition, extended half-life (EHL) products have been developed.These EHL CFRTs reduce the frequency of dosing to 1-2 times per week, which may improve adherence and patient acceptance of prophylaxis. 9,16,17On the other hand, it is possible that the patient receiving CFRT may develop inhibitors (IgG antibodies) that neutralize CFRT, rendering treatment ineffective.Diagnosis and quantification of inhibitors should be performed in the laboratory when the presence of active inhibitors is suspected (ie, when a patient who normally responds to CFRT fails to respond. 9he available real-world evidence to establish optimal treatment strategies and utilization of healthcare resources in Spain is limited.In this regard, the aim of this study was to describe the sociodemographic and clinical characteristics identifying the economic and humanistic burden, from a social perspective, of adult patients with moderate and severe HA and HB in Spain, without inhibitor diagnosis, based on data from the Cost of Hemophilia in Europe: A Socioeconomic Survey II (CHESS II) study.

METHODS
Data for this analysis were drawn from the CHESS II study, a cross-sectional, retrospective, burden-of-illness study of 1337 men (≥18 years) with hereditary HA and HB of any severity from 8 European countries (Spain, France, Germany, Italy, United Kingdom, Denmark, Netherlands, and Romania); data were collected between November 2018 and October 2020. 18The design and methodology of the CHESS II study have been described in previous publications. 19,20he data collected in the CHESS study consisted of retrospective collection of patient data in the 12 months prior to the visit to the treating physician.In brief, data were provided by the physician (retrospective data from medical records) and by the patient (using the Patient Participation and Public Engagement Questionnaire [PPIE]).The physician entered data into an electronic case record form (CRF), while the patient filled out the PPIE.The CRFs had to be validated by the investigating physician or an authorized staff member to certify that the data contained in the CRFs had been correctly recorded.All data in the CRFs were anonymized and coded prior to analysis.Ethics approval was granted by the Research Ethics Subcommittee of the Faculty of Health and Social Care, University of Chester (UK) within the study, and all patients or their legal representatives provided signed informed consent to participate in the study. 18This analysis included people with moderate or severe HA or HB, not diagnosed with inhibitor, who were living in Spain at the time of data collection.

Patient Sociodemographic and Clinical Characteristics
Patient sociodemographic characteristics (education, home circumstances, and employment status) and clinical characteristics (age, weight, body mass index, baseline treatment patterns, and type of CFRT treatment used) were identified.Sociodemographic characteristics were reported by the patient in the PPIE questionnaire and clinical characteristics were extracted by the treating physician from the patients' medical records.

Clinical Outcomes
The main clinical outcomes included annual bleeding rate (ABR), target joints, problem joints, level of chronic pain, hospital admissions, and joint surgeries.ABR was calculated using the number of bleeding events experienced in the 12 months immediately prior to data collection. 20A target joint is defined as a joint in which at least 3 spontaneous bleeds have occurred within a consecutive 6-month period. 2 Where 2 or fewer bleeds have occurred into the joint within a consecutive 12-month period, the joint is no longer considered a target joint. 2The "problem joint" metric was developed in an exercise based on published expert consensus and was designed as a patient-relevant outcome for use in clinical practice and analysis of hemophilia. 21A problem joint is defined as a joint affected by chronic pain and/or limited range of motion due to compromised joint integrity (ie, suffering from chronic synovitis and/or hemophilic arthropathy), with or without recurrent bleeding. 21,22The level of hemophilia-related chronic pain was reported using a 1-to-4 scale ("no pain" to "severe pain") defined based on the use of analgesics and functional deficit.The absence of pain included no functional deficit and non-use of analgesic (except in case of acute hemarthrosis).Mild pain included a functional status where pain did not interfere with occupation or activities of daily living (ADL) and might require occasional non-narcotic analgesic.Moderate pain included a functional state where the pain partially or occasionally interfered with occupation or ADL and considered the use of non-narcotic medications.Severe pain was considered a functional state in which pain interfered with occupation or ADL and required frequent use of non-narcotic and narcotic medications.

Healthcare Resource Use and Costs
Economic outcomes included direct (medical and nonmedical) and indirect hemophilia-related costs in the 12 months prior to data collection.A societal perspective was considered.Direct medical costs were obtained from physician-reported health resource use through the CRF incorporating several cost components.The CFRT consumption (SHL, EHL, plasma-derived FVIII, and plasma-derived FIX), specialist consultations, laboratory tests, diagnostics, and hospitalizations (due to bleeding episodes and joint surgical procedures) were included.Hemophilia-related hospital admissions included information on length of Peral C, et al.

JOURNAL OF HEALTH ECONOMICS AND OUTCOMES RESEARCH
stay (day ward or ICU), both when due to a bleeding event or to a surgical joint procedure.The types of procedures included were arthrocentesis, arthrodesis, arthroplasty, arthroscopy, and synovectomy. 9,18,23In the case of direct nonmedical and indirect costs, resource consumption was obtained from the patient sample completing the PPIE questionnaire, whose data were extrapolated for the whole cohort.Nonmedical costs included patient-reported hemophilia-related expenses, such as driving expenses, formal care, out-of-pocket expenditure on medicines (over-the-counter or physician-prescribed), health devices and/or home alterations, additional alternative therapies as occupational therapist, swimming or yoga, and transfer payments (eg, disability allowance).Indirect costs included the patient's work productivity loss due to hemophilia and the loss of earnings by an informal caregiver.
Direct and indirect costs were calculated by first taking the mean quantity of the resource used and then multiplying that mean value by the source unit cost of the resource (Table S1).Each CFRT acquisition cost was calculated on the basis of the ex-factory price published by the General Council of Official Associations of Pharmacists (BotPlus), applying the deductions established by the Royal Decree-Law 8/2010 for Spanish National Health System. 24,25Unit costs of each resource consumed was obtained from the eSalud database and Spanish data sources (other unit costs were sourced from the literature). 18,19,26,27For the calculation of work productivity loss and informal caregiver cost, the labor costs (€7.82/hour) 28 and the minimum inter-professional salary (€16.35/hour) 29were applied respectively.All costs were expressed in euros valued for the year 2022 (€, 2022) (Table S1).

Health-Related Quality of Life
The assessment of humanistic outcomes was included in the PPIE and was based on the responses to the EQ-5D-5L 30 questionnaire (the index score was calculated using the EuroQol value set for Spain).Using the EQ-5D-5L questionnaire, 5 dimensions of health status (mobility, selfcare, usual activities, pain/discomfort and anxiety/depression) were assessed at 5 levels of severity (no problems, mild problems, moderate problems, severe problems, or extreme problems). 30According to the patients' responses to the dimensions, the EQ-5D-5L profiles or health states were determined.Subsequently, the EQ-5D-5L index (utility values) were calculated for the health states according to the Spanish valuation study estimates, 31 which were reported on a scale between 0 and 1, where death has a value of 0 and perfect health a value of 1.However, according to the valuation studies methodology based on time trade-off, negative values representing states worse than death were feasible.In addition, patients reported their satisfaction with the hemophilia healthcare received on a scale ranging from 1 (not at all satisfied) to 10 (very satisfied).

Patient Sociodemographic and Clinical Characteristics
Of the total 341 Spanish patients in the CHESS II data set, the cohort that met the inclusion criteria for the analysis (adult patients with moderate or severe HA and HB, with no current inhibitor diagnosis) consisted of 288 patients.The sociodemographic and clinical characteristics of the patients are presented in  (10.54) kg for the HA and HB cohort, respectively.The average body mass index (BMI) result was >25 kg/m 2 , between 24.79 (HA) and 24.71 (HB) kg/m 2 .In relation to education, home circumstances, and employment status, of the patients who met the inclusion criteria (n = 288), less than 35% (HA, n = 53; HB, n = 47) had completed college or had an advanced degree, 58% (HA, n = 114; HB, n = 53) had not completed college, and slightly more than 63% (HA, n = 110, HB, n = 70) were employed either part-time, full-time, or self-employed.Likewise, the three most frequent comorbidities among the total number of patients meeting the inclusion criteria were anxiety in 22% (HA, n = 45; HB, n = 17), osteoarthritis in 12% (HA, n = 26; HB, n = 9), and anemia in 10% (HA, n = 18; HB, n = 11).Regarding treatment strategy, there were no records (NR, not reported) of receiving prophylaxis in patients with moderate hemophilia (HA, n = NR; HB, n = NR).Prophylaxis (primary and secondary) was more frequently reported in patients with severe hemophilia, representing 41% (HA, n = 58; HB, n = 59) of the total number of patients meeting the inclusion criteria.The on-demand treatment strategy accounted for 38% (HA, n = 82; HB, n = 27) of the total group (N = 288).Of all target joints reported by physicians (HA, n = 84; HB, n = 29), the knee was the most commonly affected joint with 24% (HA, n = 58; HB, n = 12), also coinciding as the joint most reported as a problem joint (25%) (HA, n = 48; HB, n = 25) by patients.
Further details of the clinical outcomes of patients with HA and HB in Spain are presented in Table 2.

Healthcare Resource Use and Costs
Resource consumption for the management of HA and HB varied across condition severity (Table 3).In general, patients with severe hemophilia presented a higher mean number of specialist consultations than patients with moderate hemophilia during the 12 months prior to data collection.Among the specialties reported, visits to hematologists and specialist nurses were the most common.The mean (SD) annual number of visits (scheduled and unscheduled) to the treating hematologist was 8.73 (8.67)   were the data used to determine the cost of CFRTs.
Resource consumption of the nonmedical cost components obtained from the PPIE population (Table 4) reflects a higher number of hemophilia care-related visits to the treatment center hospital, or pharmacy for patients with severe disease.These visits were for medication pick-up, examination results, blood tests, or anything else related to hemophilia care.Of the 288 patients included, 153 (HA, n = 97; HB, n = 56) completed the PPIE, but not all patients completed data corresponding to all direct nonmedical cost components or indirect cost components.The mean (SD) number of visits in the previous 12 months reported among patients who completed the PPIE questionnaire was 32.66 (78.49) for patients with severe HA (completed PPIE, n = 65) and 21.97 (27.45) for patients with severe HB (completed PPIE, n = 39).The need for a formal caregiver ranged from a mean of 4.25 hours per week per patient with severe HB (n = 4) to 5.00 hours per week in the case for the patient with moderate HA (n = 4).Within the same population, the mean (SD) requirement for informal care was 7.84 (7.78) hours per week for patients with moderate or severe HA (n = 38) and 13.61 (9.86) for patients with moderate or severe hemophilia B (n = 18), respectively.
The economic burden increased substantially with increasing severity (Table 5; Figure 1).The mean annual per-patient direct cost was €83 505 for HA (€17 251 for moderate HA; €116 767 for severe HA) and €157 114 for HB (€17 796 for moderate HB; €206 996 for severe HB).According to the type of hemophilia, CFRT consumption represents 79% (€66 005) of the direct cost of HA and 95% (€148 521) of the direct cost of HB.The mean annual per-patient indirect cost ranged from €4089 (moderate HA) to €8049 (severe HB).The total annual per-patient cost (direct and indirect cost) was €21 340 to €125 400 for patients with moderate and severe HA, respectively; while in HB it ranged from €18 592 to €215 045 for moderate and severe condition, respectively.The average annual per-patient cost for HA and HB was €91 017 and €163 925, respectively.The average annual per-patient cost was €91 017 for HA and €163 924 for HB.It is assumed that the PPIE population data represent the total sample; this value is used for the extrapolation of costs using the proportions indicated.b Visits to the treatment center, hospital, or hospital pharmacy for any reason related to hemophilia care.c The data were provided by the patient related to an unpaid caregiver (friend or family member).

Health-Related Quality of Life
The data correspond to the number of hours lost in the last 3 months.Abbreviations: NA, not available due to sample size; NR, none reported; PPIE, Patient Public Involvement Engagement.
patient with severe hemophilia was the highest (HA, €116 767; HB, €206 996), with the cost of CFRT representing 86% and 95% for HA and HB, respectively.The economic burden of CFRT use was in line with the previous analysis of the CHESS study in patients with severe hemophilia, conducted in 5 countries in Europe, 19 which reflected that the economic burden of CFRT accounted for around 95% to 99% of the direct costs.
The study has the following limitations: first, the cost calculation methodology was performed using mean patient consumption data, which limits the ability to incorporate the variability (SD) of resource use collected in the CHESS II study, so the cost results lost this variability.However, this assumption would similarly affect all groups analyzed, since the objective was to determine costs between HA and HB, at the levels of moderate and severe severity.
For direct nonmedical and indirect costs, since data were not available for the total cohort, the mean per-patient cost was calculated for the PPIE sample, so that, from these costs, the costs of the entire population could be determined and divided into subgroups of hemophilia type and severity, thus avoiding overestimation or underestimation of costs and providing a representative estimate of the Spanish sample.
Finally, in relation to unit costs, data from public sources were used for the components related to direct medical costs, but nonmedical costs were reported directly by patients and calculated by pooling publicly available information and internal unit cost databases.

CONCLUSION
This descriptive analysis provides more information on the economic and humanistic burden of adult patients with moderate and severe HA and HB, without inhibitor diagnosis, in the Spanish setting.The results suggest that, regardless of the type of hemophilia, greater disease severity was associated with increased costs and a concomitant decrease in patient-reported HRQoL.Advances in hemophilia care are challenged to improve patient HRQoL while considering the sustainability of the system.Therefore, the descriptive data from the CHESS II observational study is a source of evidence for the knowledge of patients with a rare disease and useful for new therapies in the field of hemophilia.

Figure 1 .
Figure 1.Annual Direct Costs per Patient with Hemophilia A and Hemophilia B in Spain

Table 1 .
Sociodemographic and Clinical Characteristics of Patients with Hemophilia A and Hemophilia B in Spain HB). Finally, the mean annual consumption of all classes (EHL, SHL, and plasma-derived) per patient was 13 828 (moderate HA), 213 338

Table 1 .
Sociodemographic and Clinical Characteristics of Patients with Hemophilia A and Hemophilia B in Spain

Table 2 .
Clinical Outcomes of Patients with Hemophilia A and Hemophilia B in Spain

Table 2 .
Clinical Outcomes of Patients with Hemophilia A and Hemophilia B in Spain a Proportion of the sample that had at least 1 target joint.bProportion of the sample that had a surgical intervention in their joints in the past 12 months.cNumber of times a patient has required ward hospitalization (≥1 night) due to a bleeding event.dNumber of times a patient has required ward hospitalization (≥1 night) due to a joint procedure.Abbreviations: ABR, annual bleed rate; IU, international unit; NA, not available due to sample size; NR: none reported. .

Table 3 .
Resource Use and Direct Cost Components for Patients with Hemophilia A and Hemophilia B in Spain

Table 3 .
Resource Use and Direct Cost Components for Patients with Hemophilia A and Hemophilia B in Spain Abbreviations: EHL, extended half-life; ICU, intensive care unit; NA, not available due to sample size; NR, none reported; LOS, length of stay; SHL, standard half-life.

Table 4 .
Direct Nonmedical and Indirect Cost Components for Patients With Hemophilia and Hemophilia B in Spain (PPIE Population Only) a