ABSTRACT
Background and Aims
In Japan, about 6000 patients with hemophilia A (PwHA) are separately cared for at ~1000 clinics or hospitals. Interfacility collaboration (IFC) between hemophilia treatment centers and “satellite” medical facilities located closer to patients is necessary to eliminate care disparities. To facilitate IFC, the Japan Hemophilia Network Committee (JHNC) was approved in 2018 by the Japanese Society of Thrombosis and Hemostasis. However, it is unclear whether the JHNC is functioning effectively to provide comprehensive and specialized care to PwHA seen by doctors at non‐expert facilities. Therefore, we conducted a retrospective, longitudinal, observational study using the JMDC Claims Database to assess IFC for hemophilia A in Japan. Results are presented in adherence with the “Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)” guidelines.
Methods
PwHA were classified into those who were usually treated at non‐expert (N = 82) and expert (N = 97) facilities. Using descriptive statistics, we assessed hemophilia‐specific care using records of joint examinations and blood coagulation tests in the JMDC database from April 2013 to March 2023. The JMDC claims database has several limitations, including the number of elderly patients and the total number of health insurance associations providing data.
Results
Among patients who usually attended non‐expert facilities, the proportion who received hemophilia‐specific tests at expert facilities was persistently low during the observation period (6.9%–16.3% for joint examinations and 15.4%–32.6% for blood coagulation tests). The rate of visits to expert facilities among the non‐expert facilities group did not increase during the study period. The proportion of invasive procedures with bleeding risks performed at expert facilities was low (< 20%), and some procedures requiring specialist consultation were performed at non‐expert facilities.
Conclusion
These results suggest that IFC for the care of PwHA between non‐expert and expert hemophilia care medical facilities could be strengthened in Japan.
Keywords: blood coagulation tests, comprehensive health care, hemophilia A, hemophilic arthropathy, joint examinations, medical network
1. Introduction
Congenital hemophilia A (HA) is an X‐linked hereditary bleeding disorder resulting from deficiency or dysfunction of the factor VIII (FVIII) coagulation protein [1], with an estimated global prevalence of 17.1/100,000 males [2]. Severe, cmoderate, and mild HA are defined by plasma FVIII levels of < 1%, 1%–5%, and 5%– < 40% of normal levels, respectively [3]. In Japan, a 2023 survey reported an estimated 10,274 cases of coagulation disorders, of which 5869 involved HA [4]. The number of patients with HA (PwHA) who reported their disease severity was 1655 severe, 463 moderate, 632 mild, and 19 unknown [4]. PwHA in Japan are treated across ~1000 medical facilities, many without a hemophilia specialist on staff [4, 5, 6]. Interfacility collaboration (IFC) is required to provide comprehensive patient‐centered care.
Recent advancements in the care of PwHA include updates to treatment guidelines [3, 7] and the availability of new medications (e.g., emicizumab, which mimics FVIII function [8]) and other therapeutic options (e.g., gene therapy [9]). As the current standard therapy for HA is regular replacement of FVIII (prophylaxis) using recombinant FVIII or plasma‐derived clotting factor [3], care also involves patient education and facilitation of home treatment. Furthermore, PwHA may experience spontaneous and/or traumatic bleeding episodes, and recurrent bleeding into joints and muscles may lead to progressive musculoskeletal damage (hemophilic arthropathy) [10]. Thus, the needs of PwHA are best served by access to both local hospitals/clinics for acute care and hospitals/clinics with hemophilia specialists for ongoing health management, with IFC between the hospitals and clinics.
In Western countries, hemophilia centers provide specialized and comprehensive care in collaboration with local medical facilities [11, 12, 13]. The 2013 Japanese guidelines for PwHA include standards for IFC between hemophilia treatment centers (HTCs) with hemophilia specialists on staff and “satellite” medical facilities located closer to patients [6]. HTCs should provide comprehensive medical care, including physical therapy and surgery when required, manage home healthcare, partner with other hospitals and clinics to coordinate patient care, and implement patient‐centered hemophilia management [6]. To facilitate IFC between HTCs and local hospitals, the Japan Hemophilia Network Committee (JHNC) was approved in 2018 by the Japanese Society of Thrombosis and Hemostasis [5]. The JHNC comprises Hemophilia Comprehensive Care Centers (HCCCs), HTCs, and other medical institutions involved in hemophilia care. However, it is unclear whether the JHNC is working well to provide patients with comprehensive and specialized care.
The aim of this study was to assess the status of IFC for the care of PwHA in Japan. We assessed this by analyzing records of blood coagulation tests and diagnostic imaging of joints [3, 7], two tests commonly conducted in Japan as part of routine care for PwHA.
2. Materials and Methods
2.1. Study Design
This was a retrospective, longitudinal, observational database analysis using the JMDC Claims Database. The JMDC database is a payer‐based database of Japanese national healthcare insurance associations with data provided by multiple health insurance associations. Patients are tracked if they are members of the same health insurance association. Therefore, it is possible to track visits to multiple medical facilities within health insurance coverage for a single individual. Both inpatient and outpatient claims data are included in the JMDC database. As of September 2023, the JMDC cumulative data set included ~17 million individuals.
The total analysis period for this study was 10 years, from April 2013 to March 2023. Annual analyses were performed from April to March in each year (Figure 1).
Figure 1.
Study design schematic for primary and secondary objectives (annual analyses).
2.2. Ethics and Reporting Statement
As the study was based on anonymized secondary use data, informed consent and ethical review were not required according to local ethical guidelines, and ethical review was not performed. The results of this study are presented in adherence with the “Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)” guidelines [14].
2.3. Study Population
Patients in this database study had congenital HA without inhibitors (inhibitory antibodies to exogenous clotting factors) and were regularly prescribed medications for HA without inhibitors (i.e., FVIII agents or emicizumab). Patients were excluded if they received bypassing agents.
Population 1 comprised the population of PwHA without inhibitors who were regularly prescribed medications for HA as outpatients, that is, patients in the database with an HA diagnosis (International Classification of Diseases 10th Revision code: D66) with outpatient claims for ≥ 20 prescriptions of medications for HA (Anatomical Therapeutic Chemical Code: B02D1). Multiple prescriptions in the same month were counted as one prescription. For patients not observed for the full 10 years, the number of prescriptions was adjusted by years of observation (e.g., 10 prescriptions in 5 years was converted to 20 prescriptions in 10 years). Patients with prescription(s) of bypassing agents or who were not observable in the database for ≥ 5 years were excluded.
Patients in Population 1 were categorized into expert facilities or non‐expert facilities groups based on whether their outpatient claims (HA diagnosis and HA medications) were recorded by HCCCs or HTCs [15, 16]. The expert facilities group comprised PwHA with < 50% of outpatient claims recorded during the follow‐up period from non‐expert facilities. The non‐expert facilities group comprised PwHA with ≥ 50% of outpatient claims from non‐expert facilities.
Population 2 comprised patients in the non‐expert facilities group and was categorized by type of department—pediatric or adult. PwHA with ≥ 50% of outpatient claims recorded during the follow‐up period issued by “Pediatrics” or “Pediatric Surgery” were categorized as pediatric. All other PwHA were categorized as adult. Population 2a was defined as the annual population (every 12 months, April to the following March) of patients (1) having ≥ 50% of outpatient claims during the year issued by non‐expert facilities; (2) with an HA diagnosis as an outpatient during the year; and (3) with ≥ 2 HA medication prescriptions within the 12 months (multiple prescriptions within a single month were counted as one prescription). Patients were excluded from Population 2a if they had bypassing agent prescription(s) and/or were not observable throughout the year.
2.4. Outcome Measures
Patient demographics and clinical characteristics were recorded for patients in each of the expert and non‐expert facilities groups. The characteristics described are listed in Supporting Information S1: Supplementary Methods.
The primary outcome measure was the number of patients in the non‐expert facilities group (Population 2a) who had ≥ 1 record of an essential test for HA at an expert facility during the follow‐up period. Essential tests were defined as either joint examinations (by X‐ray, magnetic resonance imaging [MRI], or ultrasound) or blood coagulation tests (activated partial thromboplastin time [aPTT] test, FVIII activity test, or FVIII inhibitor test). Test claims codes are listed in Supporting Information S1: Table 1.
Secondary outcome measures included (1) the number of patients in the non‐expert facilities group (Population 2a) who visited expert facilities at least once per year and (2) the number of cases of invasive procedures with bleeding risks among patients in the non‐expert facilities group during the follow‐up period. Invasive procedures with bleeding risks included dental treatment, surgeries, and so forth, and were defined by a list of procedure claims codes.
Exploratory outcomes were the frequency of essential tests for HA (times/10 years) in each facility type for patients in each patient group (Population 1), and the frequency of visits to expert facilities and the frequency of essential tests for HA in expert facilities among patients who regularly visited non‐expert facilities (Population 2), stratified by type of department. Additional details regarding the outcome measures are provided in Supporting Information S1: Supplementary Methods.
2.5. Statistical Analysis
All patients who satisfied the eligibility criteria were included in each analysis set. For the annual analysis, the number of patients was determined as both a cumulative number for all years and a unique number (no duplicates) during the study period.
Primary and secondary outcome analyses were conducted on the analysis set of Population 2a. For each year, the number and percentage of patients who had essential tests for HA at expert facilities (the primary outcome) and who visited expert facilities at least once per year (a secondary outcome) were calculated. For invasive procedures with bleeding risks (a secondary outcome), the total number of invasive procedures and the number and percentage of procedures at expert facilities were calculated for each year. Exploratory outcomes were assessed over the full 10‐year study period as described in Supporting Information S1: Supplementary Methods. In all analyses, missing values were not imputed. All analyses were performed using Amazon Redshift version 1.0.61191, 1.0.61626, 1.0.63205 (Amazon Web Services, Seattle, WA, USA).
3. Results
3.1. Patient Disposition
From April 2013 to March 2023, 269 patients met the criteria for inclusion in the study (Figure 2). Excluding patients with bypassing agent prescriptions (n = 17) and patients not observable for ≥ 5 years (n = 77) left 179 outpatients with HA (without inhibitors) who were regularly prescribed medications for HA (Population 1), including 97 primarily treated at expert facilities (expert facilities group) and 82 primarily treated at non‐expert facilities (non‐expert facilities group; Population 2).
Figure 2.
Flow diagram of patient selection. ATC, Anatomical Therapeutic Chemical; HA, hemophilia A; ICD‐10, International Classification of Diseases 10th Revision.
The cumulative number of patients for all years in the annual analyses was 2248 (545 excluding duplicates; Figure 3). After excluding patients with bypassing agent prescriptions (n = 65), patients not observable throughout the year (n = 138), and patients with < 50% of all HA medications prescribed at non‐expert facilities (n = 1267), there were 912 (237 excluding duplicates) patients in the non‐expert facilities group for each year (Population 2a).
Figure 3.
Flow diagram of patient selection for annual analysis. †Cumulative number of patients for all years. ‡Cumulative number of patients for all years, excluding duplicates. ATC, Anatomical Therapeutic Chemical; HA, hemophilia A; ICD, International Classification of Diseases 10th Revision.
3.2. Demographic and Baseline Clinical Characteristics
The mean (standard deviation) age of patients was 27.0 (16.0) years in the non‐expert facilities group and 28.4 (16.8) years in the expert facilities group (Table 1). The proportion of patients aged ≥ 18 to < 40 years was higher in the non‐expert facilities group (40.2%) than in the expert facilities group (34.0%). The proportion of patients aged ≥ 40 to < 60 years was higher in the expert facilities group (27.8%) than in the non‐expert facilities group (18.3%). The proportion of patients with HA‐specific complications was higher in the expert versus non‐expert facilities group. Human immunodeficiency virus disease was more common in the expert versus non‐expert facilities group (10.3% vs. 4.9%, respectively). The proportion of patients receiving ≥ 4 prescriptions per year was higher in the non‐expert versus expert facilities group (FVIII products: 81.7% vs. 69.1%, respectively; non‐factor products: 13.4% vs. 8.2%, respectively).
Table 1.
Patient demographics and clinical characteristics (Population 1).
| Variable | Non‐expert facilities groupa (N = 82) | Expert facilities groupb (N = 97) | Total (N = 179) |
|---|---|---|---|
| Age, mean (SD), years | 27.0 (16.0) | 28.4 (16.8) | 27.8 (16.4) |
| Age category, years | |||
| < 12 | 15 (18.3) | 18 (18.6) | 33 (18.4) |
| ≥ 12 to < 18 | 15 (18.3) | 17 (17.5) | 32 (17.9) |
| ≥ 18 to < 40 | 33 (40.2) | 33 (34.0) | 66 (36.9) |
| ≥ 40 to < 60 | 15 (18.3) | 27 (27.8) | 42 (23.5) |
| ≥ 60 | 4 (4.9) | 2 (2.1) | 6 (3.4) |
| HA‐specific complications | |||
| Any complication | 65 (79.3) | 81 (83.5) | 146 (81.6) |
| Hemophilia bleeding | 26 (31.7) | 32 (33.0) | 58 (32.4) |
| Hemophilia arthritis | 50 (61.0) | 70 (72.2) | 120 (67.0) |
| Thrombotic disorder | 5 (6.1) | 5 (5.2) | 10 (5.6) |
| HIV disease | 4 (4.9) | 10 (10.3) | 14 (7.8) |
| Hepatitis C | 26 (31.7) | 31 (32.0) | 57 (31.8) |
| Prescriptions for HA treatment | |||
| FVIII product | |||
| Patients | 81 (98.8) | 97 (100) | 178 (99.4) |
| Prescription frequency, times/year | |||
| < 1 | 1 (1.2) | 2 (2.1) | 3 (1.7) |
| ≥ 1 to < 2 | 1 (1.2) | 5 (5.2) | 6 (3.4) |
| ≥ 2 to < 4 | 12 (14.6) | 23 (23.7) | 35 (19.6) |
| ≥ 4 | 67 (81.7) | 67 (69.1) | 134 (74.9) |
| Non‐factor product | |||
| Patients | 29 (35.4) | 39 (40.2) | 68 (38.0) |
| Prescription frequency, times/year | |||
| < 1 | 9 (11.0) | 8 (8.2) | 17 (9.5) |
| ≥ 1 to < 2 | 3 (3.7) | 1 (1.0) | 4 (2.2) |
| ≥ 2 to < 4 | 6 (7.3) | 22 (22.7) | 28 (15.6) |
| ≥ 4 | 11 (13.4) | 8 (8.2) | 19 (10.6) |
Note: Data are n (%) unless otherwise specified. Percentages are rounded to one decimal place; as a result, the sum of category percentages may be > 100%.
Abbreviations: FVIII, factor VIII; HA, hemophilia A; HIV, human immunodeficiency virus; SD, standard deviation.
Patients in the non‐expert facilities group had at least half of their claims from non‐expert facilities.
Patients in the expert facilities group had < 50% of their claims from facilities.
3.3. Primary Outcome: Patients in the Facilities Group Tested at Expert Facilities
The proportion of PwHA in the non‐expert facilities group who had essential tests at expert facilities did not tend to increase throughout the entire period (Figure 4). The proportion of patients in the non‐expert facilities group who had joint examinations at expert facilities ranged from 6.9% to 16.3% (Figure 4A). The proportion of X‐rays was higher than that of MRIs or ultrasounds in all years. The proportions of X‐rays and ultrasounds decreased from 2019 to 2020 but increased thereafter.
Figure 4.
Proportion of PwHA who received (A) joint examinations and (B) blood coagulation tests at expert facilities (Population 2a). Data in the table under the figure are n or n (%). aPTT, activated partial thromboplastin time; FVIII, factor VIII; MRI, magnetic resonance imaging; PwHA, patients with hemophilia A.
The proportion of patients in the non‐expert facilities group who underwent any blood test at expert facilities ranged from 15.4% to 32.6%, with a peak in 2014 and an overall decreasing trend thereafter (Figure 4B). There was a decreasing trend in FVIII activity and FVIII inhibitor monitoring from 2019 to 2022.
3.4. Secondary Outcomes
3.4.1. Visits to Expert Facilities by Patients Usually Treated at Non‐expert Facilities
Among patients usually treated at non‐expert facilities, the proportion of patients who visited an expert facility at least once per year did not show an overall increasing trend during the study period (Figure 5). The proportion of patients visiting expert facilities ranged from 17.9% to 37.2%, with a decrease from 2017 to 2020 and a slight increase in 2021 and 2022.
Figure 5.
Proportion of PwHA who visited expert facilities at least once per year (Population 2a). Data in the table under the figure are n or n (%). PwHA, patients with hemophilia A.
3.4.2. Invasive Procedures With Bleeding Risks
Among patients in the non‐expert facilities group, the total number of invasive procedures with bleeding risks tended to increase from 2013 to 2022, from 17 to 41 procedures, although only five procedures were recorded in 2015 (Figure 6). However, the proportion of invasive procedures with bleeding risks performed at expert facilities was low (< 20%, corresponding to no more than five procedures each year). The invasive procedures with bleeding risks recorded included a variety of medical and dental procedures (Supporting Information S2: Listing 1). In all years, most invasive procedures were performed in dental departments at non‐expert facilities. In addition, some invasive procedures with high bleeding risks that would require consultation with a hemophilia specialist, such as curettage for septic or tuberculous arthritis (knee) and endoscopic variceal ligation, were performed at non‐expert facilities (Supporting Information S2: Listing 1).
Figure 6.
Proportion of invasive procedures with bleeding risks in PwHA performed at expert facilities (Population 2a). Data in the table under the figure are n or n (%). PwHA, patients with hemophilia A.
3.5. Exploratory Outcomes
The percentage of patients in the expert facilities group who underwent joint examinations at high frequencies was higher at expert versus non‐expert facilities (≥ 3 to < 10 times in 10 years: 35.1% vs. 1.0%, respectively; ≥ 10 times in 10 years: 18.6% vs. 0%; Supporting Information S1: Table 2).
In the expert facilities group, the median (interquartile range [IQR]) frequency for any blood coagulation test at expert facilities was 21.00 (13.75–35.00) tests/10 years, and 88.7% of patients had ≥ 10 blood coagulation tests in expert facilities over 10 years (Supporting Information S1: Table 3). In the non‐expert facilities group, the median (IQR) frequency was 1.00 (0.00–8.25) tests/10 years at expert facilities, compared with 11.83 (6.35–18.00) tests/10 years at non‐expert facilities. In the non‐expert facilities group, median (IQR) frequency of aPTT, FVIII activity, and FVIII inhibitor testing was 10.00 (4.29–15.48), 9.62 (4.06–13.21), and 6.25 (1.48–10.28) tests/10 years in non‐expert facilities, and 0 (0–6.92), 0 (0–6.81), and 0 (0–6.00) tests/10 years in expert facilities, respectively. In the expert facilities group, median (IQR) frequency of aPTT, FVIII activity, and FVIII inhibitor tests was 0 (0–0) tests/10 years for all tests in non‐expert facilities, and 18.00 (10.63–32.86), 17.14 (10.00–31.30), and 15.00 (6.00–25.71) tests/10 years in expert facilities, respectively.
Within the non‐expert facilities group, the percentage of patients who visited expert facilities was higher in the pediatric (62.3%) versus the adult (52.2%) group (Supporting Information S1: Table 4). The percentage of patients who underwent ≥ 10 joint examinations in 10 years at expert facilities was 13.0% and 1.9% in adult and pediatric departments, respectively. The proportion of patients who underwent X‐rays was higher in the adult (39.1%) versus the pediatric (28.3%) group. For MRI joint examinations, a slightly higher percentage of patients were examined in the pediatric group (11.3%) than in the adult group (8.7%).
The percentage of patients in the non‐expert facilities group who had blood coagulation tests at expert facilities was higher in the pediatric (54.7%) versus the adult (47.8%) group (Supporting Information S1: Table 5). For all blood coagulation tests, the pediatric group had a higher percentage of patients with ≥ 10 tests at expert facilities over 10 years than the adult group (26.4% vs. 21.7%, respectively).
4. Discussion
This retrospective observational database study was the first to assess the status of collaborative care for HA in Japan. The study results demonstrate that many PwHA are not receiving regular treatment in expert medical facilities that specialize in hemophilia care and suggest that IFC for the care of PwHA may need strengthening in Japan.
In many Western countries, IFC between expert and non‐expert facilities has been the standard of care for decades [5, 12, 13]. Most patients in countries such as the United Kingdom, Canada, and the United States have access to a specialist hemophilia center at least once [5, 17]. Our study included many patients who regularly attended non‐expert facilities (82/179); among this group, < 40% of patients visited expert facilities in each year. This is consistent with an earlier study reporting that slightly less than half the PwHA in Japan surveyed (N = 2293) had visited a hemophilia center (or similar facility) at least once [5]. In other countries, better patient outcomes—including improvements in life expectancy, overall survival, and health‐related quality of life—have been associated with treatment at specialist hemophilia centers [5, 18, 19]. It is therefore important that IFC for the care of PwHA in Japan is strengthened and attendance at expert facilities is facilitated when needed.
Radiological evaluation of joints, along with physical examination, is used to monitor joint structure and function in PwHA [3]. In the 2013 World Federation of Hemophilia (WFH) treatment guidelines, annual radiological evaluation was recommended [7], although more recent guidelines are less proscriptive [3]. In our study, more pediatric than adult patients received regular joint examinations at expert facilities. However, the low (< 17% in all years) overall percentage of PwHA in the non‐expert facilities group receiving joint examinations in expert facilities indicates there is a need to promote expert joint examinations in Japan.
Most patients in the present study who received joint examinations had X‐ray examinations. Among patients in the non‐expert facilities group, MRI and ultrasound were performed very infrequently at expert facilities, in only 1.1%–3.4% and 0%–4.5% of patients, respectively. MRI and ultrasound are useful for detecting soft tissue and osteochondral changes in early hemophilic arthropathy, whereas X‐ray can detect only late arthropathy [20, 21, 22, 23, 24, 25]. Ultrasound may also be useful in clinical assessment to differentiate between painful joint bleeds and joint inflammation [26]. A recent real‐world study in the USA demonstrated that musculoskeletal ultrasound at the point of care was useful for informing treatment decisions, including physical therapy and referrals to orthopedists [27]. A similar study at an expert treatment facility in Japan found that musculoskeletal ultrasound every 6 months over the 3‐year study significantly improved hemophilic arthropathy scores, spontaneous annual joint bleeding rate, and Hemophilia Joint Health Scores [28]. For PwHA who routinely attend non‐expert facilities, MRI or ultrasound at expert facilities should be more routinely performed to detect and prevent future arthropathy and to better inform treatment decisions. Considering the long‐term impact of arthropathy on PwHA, it is preferable for joint examinations to be conducted at expert facilities where examination equipment is available and medical experts skilled in examination techniques are present. In non‐expert facilities, MRI/ultrasound equipment and skilled specialists are not necessarily available. In such cases, IFC with expert facilities can facilitate proper testing.
Blood coagulation tests are used for routine monitoring of PwHA who receive prophylactic FVIII therapy and are also indicated either when a bleeding incident occurs or prior to surgery [3, 7]. The WFH recommends that all testing for diagnosis and monitoring of hemophilia is conducted by experienced staff using appropriately validated equipment and reagents [3], that is, in laboratories in expert facilities. In the present study, the annual percentage of PwHA in the non‐expert facilities group who received blood coagulation tests at expert facilities ranged from 15.4% to 32.6%. As the rate of implementation of blood coagulation tests at expert facilities was < 33% in all years, it appears that collaboration between expert and non‐expert facilities for the clinical care of PwHA in Japan can be improved.
Interestingly, among PwHA in the non‐expert facilities group, a peak in both joint examinations and blood coagulation tests performed at expert medical facilities was observed in 2014. This may have been a response to the revision of Japanese guidelines for treatment of hemophilia in 2013, in which collaboration in clinical practice was specifically mentioned [6]. We also observed a decrease in blood coagulation tests at expert facilities from 2019 to 2022, which may have been due to a decrease in FVIII activity and inhibitor monitoring tests after the launch of emicizumab in Japan in 2018 [29]. In annual survey reports on people with coagulation disorders in Japan, the use of emicizumab among PwHA increased from 29 of 2993 cases in 2018 [30] to 744 of 3417 cases in 2022 [31], indicating rapid uptake of this medication.
When we compared monitoring in the non‐expert and expert facilities groups, the joint examination frequency was not regular among patients in the expert facilities group, with only 18.6% of patients having ≥ 10 joint examinations in 10 years. Blood coagulation testing of patients in both groups was generally more frequent than joint examinations. Among the non‐expert facilities group, 64.6% of patients had ≥ 10 blood coagulation tests in 10 years at non‐expert facilities, but only 23.2% had ≥ 10 blood coagulation tests in 10 years at expert facilities. There is therefore a possibility that patients in the non‐expert facilities group may have undergone appropriate tests but not had their tests interpreted by a hemophilia specialist.
In our study, the frequency of invasive procedures with bleeding risks that were performed at expert facilities was low (< 20%) in all years. Furthermore, the breakdown by department where invasive procedures with bleeding risks were performed showed that in most years, the proportion of procedures performed in expert facilities was lower than in non‐expert facilities for both medical and dental departments. WFH guidelines recommend that patients requiring surgery should be managed at or in consultation with a comprehensive HTC [3], and it is apparent that these guidelines are not necessarily being consistently followed in Japan. There was also evidence that higher bleeding risk procedures requiring consultation by a hemophilia specialist, such as curettage for septic or tuberculous arthritis (knee) and endoscopic variceal ligation, were sometimes performed at nonspecialized institutions. In Japan, primary physicians can easily transfer patients to nearby HCCCs/HTCs with hemophilia specialists on staff. Our results suggest there may be a lack of communication between primary physicians and specialists, despite the relative ease of patient transfer. There may be a need for further education of medical professionals in Japan about collaboration in the conduct of invasive procedures with bleeding risks for PwHA. If there is a regular communication system for joint examinations such as ultrasound between expert and non‐expert facilities, it would be helpful for developing IFC for highly invasive medical procedures to be performed at expert facilities, thereby achieving appropriate management of hemophilia.
Demographic and clinical differences were observed between patients who regularly attended non‐expert and expert facilities. The higher percentage of patients in the age group of 18–40 years in the non‐expert facilities group may be due to patients transitioning from pediatric care into a department of hematology in a non‐expert facility. The percentage of patients receiving ≥ 4 prescriptions per year was lower in the expert facilities group than in the non‐expert facilities group (for both FVIII and non‐factor products), indicating inconsistent implementation of prophylaxis of FVIII products (which is prescription based), even at expert facilities. This is potentially concerning because prophylaxis is a key component of hemophilia care and is recommended over acute episodic factor therapy for its role in maintaining hemostasis and preventing complications such as joint hemorrhages [3, 6, 7].
A strength of this study was that it used an objective database source, which enabled tracking of individuals across various expert and non‐expert medical hospitals and clinics. In addition, the study population included both pediatric and adult subgroups, and outcome measures included both regularly required testing (blood coagulation and inhibitor testing) and monitoring for longer‐term complications of HA (joint examinations).
Limitations included the small sample size, reflecting the rare nature of HA, and the low total number of tests performed in many years (e.g., the total number of joint examinations was < 10 in some years). The categorization of non‐expert and expert facilities groups according to the prescription of hemophilia agents may not fully reflect patients' attendance at expert facilities, nor whether the care was provided by hemophilia specialists or not. The use of medical insurance claims data may have led to missing details about patients (e.g., severity of HA) and/or their treatments. Furthermore, there were limitations associated with the JMDC database, including limited representation of elderly patients, no representation of patients from health insurance associations not contracted by JMDC, uncertainty regarding the accuracy of data from patients who change their health insurance association, absence of private practice data, and whether imaging tests other than for hemophilia‐associated joint examinations were included in the data set. Although we used the proportion of patients receiving essential monitoring tests as an indicator of the degree of collaborative medical care in the medical network, tests for acute symptoms (e.g., pain or bleeding) may also be included in our data set. This means the proportion of tests performed may not always reflect the degree of collaboration within the network. Lastly, the database may not have captured collaborative communication between healthcare providers (e.g., via telephone and not resulting in insurance claims).
In conclusion, the results of this retrospective observational database study suggest that IFC for the care of PwHA in Japan may need strengthening. By improving IFC between expert and non‐expert facilities, it is expected that PwHA will receive more appropriate medical care.
Author Contributions
Ei Kinai: methodology, writing – review and editing. Masako Yamaguchi: data curation, formal analysis, methodology, project administration, visualization, writing – review and editing. Akira Shirahata: methodology, writing – review and editing. All authors have read and approved the final version of the manuscript.
Disclosure
The corresponding author Masako Yamaguchi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Ethics Statement
As the study was based on anonymized secondary use data, ethical review was not required according to local ethical guidelines, and ethical review was not performed.
Consent
As the study was based on anonymized secondary use data, informed consent was not required.
Conflicts of Interest
Masako Yamaguchi is an employee and shareholder of Takeda Pharmaceutical Company Limited. Ei Kinai received research grants from Chugai Pharmaceutical Co. Ltd. and CSL Behring; honoraria from Chugai Pharmaceutical Co. Ltd., Sanofi, Bayer, Takeda Pharmaceutical Company Limited, Novo Nordisk, Fujimoto Pharmaceutical Corporation, and CSL Behring. Akira Shirahata has no conflicts of interest to report.
Supporting information
Table S1: Claims codes for essential tests. Table S2: Visit and joint examination frequencies in expert and non‐expert facilities among each patient group (analysis set: Population 1). Table S3: Blood coagulation test frequencies in expert and non‐expert facilities among each patient group (analysis set: Population 1). Table S4: Age at end of the study period and visit and joint examination frequencies in expert facilities among patients who regularly visited non‐expert facilities, stratified by type of department (analysis set: Population 2). Table S5: Blood coagulation test frequencies in expert facilities among patients who regularly visited non‐expert facilities, stratified by type of department (analysis set: Population 2).
IFC for hemophilia care in Japan Supplementary Listing 1: Invasive procedures with bleeding risks for each year that were included in Figure 6.
Acknowledgments
The authors acknowledge JMDC Inc. for their support of the data analysis. Medical writing assistance was provided by Koa Webster, PhD, CMPP, and Prudence Stanford, PhD, CMPP, of ProScribe—Envision Pharma Group, and was funded by Takeda Pharmaceutical Company Limited. ProScribe's services complied with international guidelines for Good Publication Practice.
Kinai E., Yamaguchi M., and Shirahata A., “Interfacility Collaboration for Hemophilia Care in Japan: A Retrospective Database Study Using a Japanese Healthcare Claims Database,” Health Science Reports 9 (2026): 1–10, 10.1002/hsr2.71643.
Data Availability Statement
The data that support the findings of this study are available from JMDC Inc. (https://www.jmdc.co.jp/en/). Restrictions apply to the availability of these data, which were used under license for this study. For inquiries about access to the data set used in this study, please contact JMDC (https://www.jmdc.co.jp//en/inquiry/). Masako Yamaguchi and the rest of the author team had full access to all of the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Claims codes for essential tests. Table S2: Visit and joint examination frequencies in expert and non‐expert facilities among each patient group (analysis set: Population 1). Table S3: Blood coagulation test frequencies in expert and non‐expert facilities among each patient group (analysis set: Population 1). Table S4: Age at end of the study period and visit and joint examination frequencies in expert facilities among patients who regularly visited non‐expert facilities, stratified by type of department (analysis set: Population 2). Table S5: Blood coagulation test frequencies in expert facilities among patients who regularly visited non‐expert facilities, stratified by type of department (analysis set: Population 2).
IFC for hemophilia care in Japan Supplementary Listing 1: Invasive procedures with bleeding risks for each year that were included in Figure 6.
Data Availability Statement
The data that support the findings of this study are available from JMDC Inc. (https://www.jmdc.co.jp/en/). Restrictions apply to the availability of these data, which were used under license for this study. For inquiries about access to the data set used in this study, please contact JMDC (https://www.jmdc.co.jp//en/inquiry/). Masako Yamaguchi and the rest of the author team had full access to all of the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis.