Bleeds and Resource Use in Hemophilia B: Retrospective Observational Study

ABSTRACT

Objectives: To describe people with hemophilia B (PWHB) in the US who experience bleeds despite factor replacement therapy and to quantify the associated burden from the third-party payer perspective.

Study Design: Observational study of adult male PWHB treated with factor IX replacement therapy identified from the PharMetrics Plus claims data from 2010 to 2019.

Methods: Patients with medically recorded bleeds (MRBs) were identified using diagnostic codes. Rates and rate ratios of inpatient admissions, emergency department (ED) visits, and outpatient visits among PWHB with and without MRBs were estimated. The presence of comorbidities was identified using diagnostic codes, and the analysis was stratified by age group.

Results: There were 345 PWHB with MRBs and 252 without MRBs. More than half of PWHB with MRBs (56.8%) had 1 or more comorbidity vs 39.3% of PWHB without MRBs. The prevalence of anxiety and depression was high in PWHB, regardless of bleed status and age group, whereas the prevalence of other comorbidities increased with age group. The rate of all-cause inpatient admissions for PWHB with MRBs was 14.8 per 100 person-years (95% CI, 12.8-17.1), 2.5 times higher than for PWHB without MRBs. The rate of all-cause ED visits for PWHB with MRBs was 67.6 per 100 person-years (95% CI, 63.2-72.3), 2.7 times higher than for those without MRBs.

Conclusions: This study reports significant resource use and clinical burden among PWHB who seek medical care. PWHB with MRBs had considerable all-cause resource use compared with PWHB without MRBs. The prevalence of mental illness was consistently high across all age groups.

Am J Manag Care. 2024;30(5):e157-e164. https://doi.org/10.37765/ajmc.2024.89543

Takeaway Points

• This retrospective observational study using PharMetrics Plus claims data demonstrates significant resource use and clinical burden among people with hemophilia B (PWHB) who, despite treatment, seek medical care associated with bleed-related and all-cause diagnoses.
• In all age groups, PWHB with medically recorded bleeds (MRBs) were consistently more likely to have inpatient admissions, emergency department visits, and outpatient visits compared with PWHB without MRBs.
• Although the prevalence of most comorbidities among PWHB increased with age, the prevalence of anxiety and depression were consistently high across all age groups.
• Efforts to assess the mental health of PWHB could be included in a comprehensive approach to management of the condition.

Hemophilia B is a rare, X-linked hereditary disorder that leads to deficiency of factor IX (FIX). It is characterized by bleeding manifestations, including spontaneous bleeding episodes in muscles and joints. People with hemophilia B (PWHB) are predominately male due to the disease’s X-linked recessive pattern of inheritance; approximately 1 in 25,000 males in the US have hemophilia B.¹ There were approximately 32,000 PWHB, regardless of disease severity level, worldwide in 2019.² Hemophilia involves many other clinical manifestations and is also linked to psychosocial challenges associated with increased emotional distress.^3,4

PWHB are typically treated with FIX replacement therapy or, when inhibitors are present, with bypassing agents. There is currently no cure for hemophilia, but significant treatment and management advances have been made since FIX concentrates first became available for treatment of episodic bleeding in the 1970s, followed by the implementation of recombinant products in the 1990s.^5,6 In most cases, the current standard of care in the US for individuals with severe and moderately severe hemophilia B is regular prophylactic clotting factor replacement therapy.⁶ The introduction of extended half-life clotting factor concentrates has allowed for less-frequent FIX administrations in some patients, but adherence to a routine intravenous infusion regimen is still regarded as crucial for patients requiring intravenous infusions.^5,6

Therefore, the optimal management of hemophilia B confers substantial treatment burden.⁷ Recurrent bleeding results in a progressive chronic synovitis, cartilage and bone destruction, and eventually a disabling arthropathy accompanied by muscle atrophy.⁷ The resulting musculoskeletal injuries are the major causes of morbidity and disability in PWHB and of reduced health-related quality of life (HRQOL) due to bleeding and joint damage.^8-10 Other critical bleeding sites include the bowel, brain, and soft tissues.^5,6

Despite advancements in care, some PWHB continue to experience bleeding episodes requiring health care intervention, which result in associated pain and disability.^6,11 A recent US real-world study reported a mean annual bleed rate of 1.73 in individuals with severe hemophilia B treated with FIX prophylaxis, and approximately 9% of patients with severe hemophilia had a bleed-related hospitalization in the previous 12 months.¹²

Hemophilia B–related morbidity results in substantial clinical and economic burden, even in those who are receiving active treatment.^5,12,13 There is an absence of literature quantifying real-world health care resource utilization (HCRU) specifically by PWHB experiencing bleeding events. The aim of this study was to describe PWHB in the US who experience bleeds despite having access to factor replacement therapy and to quantify the associated burden from the third-party payer perspective.

METHODS

This was a retrospective observational study using PharMetrics Plus medical and pharmacy claims data from January 1, 2010, to December 31, 2019. The health plans included in PharMetrics Plus encompass comprehensive geographic representation, and enrollees are generally representative of the US commercially insured population with respect to age and gender for individuals younger than 65 years.

The study population included adult male PWHB who received FIX replacement therapy. Those eligible for inclusion had to meet all the following criteria: male sex, aged 19 to 64 years, at least 1 inpatient or outpatient claim with a diagnosis of hemophilia B (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code or ICD, Tenth Revision, Clinical Modification [ICD-10-CM] code) in any diagnosis position, and at least 1 medical or outpatient pharmacy claim for FIX replacement therapy at any time in the study period during their continuous enrollment in the PharMetrics Plus database.^14,15 Although this case definition approach has not been validated for PWHB, a similar definition has previously been used and validated for individuals with hemophilia A.^14,15 Patients with evidence of bypassing agent use (likely indicating the presence of inhibitors to FIX) or with a diagnosis of moderate or severe liver disease at any point during the study period were excluded. Patients meeting all eligibility criteria were defined as PWHB and included in the study.¹⁶

The study period was from January 1, 2010, to December 31, 2019. PWHB were continuously enrolled from the date of enrollment or start of the study period (whichever was later) and until death, disenrollment, or end of the study period (whichever was earliest). Patients were required to have at least 1 day of observation following the date of the first medical or pharmacy claim for hemophilia B diagnosis or treatment. Because hemophilia B is a lifelong genetic disease commonly diagnosed in childhood, we described the clinical and economic burden of the patients in all available data (ie, from the later date of enrollment or start of the study until the earliest date of death, disenrollment, or end of the study).

PWHB were then segmented into 2 subgroups: (1) PWHB with medically recorded bleeds (MRBs) during the observational period and (2) PWHB without MRBs. MRBs were defined as bleeding events including hemarthrosis, intracerebral hemorrhage, gastrointestinal bleeding, and other bleeds identified using ICD diagnostic codes in any diagnosis position. MRBs were assumed to belong to the same event if they occurred within 7 days of each other, which has been reported as the average duration to treat a hemophilia-related bleed,¹⁶ to avoid double-counting for the same bleed. A similar approach using this 7-day period has been published in a study using US claims data.^6,16 PWHB with MRBs were defined as PWHB with any bleed-related diagnosis identified during the observational period. PWHB without MRBs were defined as PWHB with no bleed-related diagnoses at any point during the observational period.

Other variables of interest included demographic characteristics and recorded comorbidities. Individual comorbidities described in the Charlson Comorbidity Index and those considered particularly relevant for PWHB (hepatitis B, hepatitis C, depression, and anxiety) as reported in the literature were identified using ICD codes.^17-20

All-cause, bleeding-related, and arthropathy-related inpatient admissions, outpatient non–emergency department (ED) visits, and outpatient ED visits were measured. All-cause HCRU was defined as HCRU with any diagnosis during the observational period. Bleed-related HCRU was defined as HCRU with any diagnosis that occurred during a 7-day bleeding episode. Arthropathy-related HCRU was defined as HCRU with a diagnosis for joint disorders/arthropathy identified using ICD codes in any diagnosis position in the inpatient or outpatient setting and/or with a joint surgery identified using ICD-9/ICD-10 Procedure Coding System and Current Procedural Terminology codes. The length of stay per inpatient admission was defined as discharge date minus admission date. Pharmacy claims for pain relief medications were also counted during the entire observational period. The code lists used to identify hemophilia, comorbidities, hemophilia-related treatments, MRBs, and joint surgeries are included in eAppendix Table 1 (eAppendix available at ajmc.com).

Demographic and clinical characteristics were analyzed descriptively. Patients were categorized by numbers of individual comorbidities: 0, 1, 2, and more than 2. Poisson regression or negative binomial regression was used to estimate the rates and rate ratios (RRs) with 95% CI for comparisons of HCRU for PWHB with and without MRBs. The Pearson χ² goodness-of-fit test, deviance, and Akaike information criterion were used to assess model fit. Multivariable analyses were conducted with adjustment for age as a continuous variable, geographic region, year of the first medical or pharmacy claim for hemophilia B diagnosis or treatment, payer type, chronic pulmonary heart disease, mild chronic liver disease, diabetes without chronic complications, nonmetastatic cancer, hepatitis C, depression, anxiety, number of comorbidities, and length of observational period.

The analysis was also conducted in subgroups stratified by age group on the date of the first medical or pharmacy claim for hemophilia B diagnosis or treatment (ie, aged 19 to 30 years, 31 to 44 years, and 45 to 64 years). Data management and analysis were performed using SAS Enterprise Guide 7.1 (SAS Institute Inc).

RESULTS

There were 3949 PWHB during the study period, including 597 adult men who were treated with FIX replacement therapy. Of these, 345 (57.8%) were classified as PWHB with MRBs and 252 (42.2%) were classified as PWHB without MRBs (eAppendix Figure). The rate of MRBs was 1.0 per person-year (95% CI, 0.9-1.0) for PWHB overall and 1.4 per person-year (95% CI, 1.4-1.5) for PWHB with MRBs.

The median (IQR) length of the observational period was 33.0 (20.0-63.1) months for PWHB with MRBs and 22.0 (12.0-36.0) months for PWHB without MRBs. Table 1 shows the demographic and clinical characteristics of both cohorts. The median (IQR) age on the date of the first medical or pharmacy claim for hemophilia B diagnosis or treatment was 35.0 (26.0-50.0) years for PWHB with MRBs and 31.0 (25.5-45.0) years for PWHB without MRBs.

More than half of PWHB with MRBs (56.8%) had 1 or more comorbidity vs 39.3% of PWHB without MRBs (Table 1). The most common comorbidity in both cohorts (from a predefined list of the comorbidities captured in the Charlson Comorbidity Index plus hepatitis B, hepatitis C, depression, and anxiety) was mild chronic liver disease, followed by anxiety, chronic pulmonary heart disease, and depression (Figure 1). Most of the recorded comorbidities were numerically more common in PWHB with MRBs than in PWHB without MRBs (Figure 1).

The presence of comorbidities was also stratified by age group, and the top 4 comorbidities in PWHB with and without MRBs are shown in Figure 2. In both cohorts, the prevalence of mild chronic liver disease and chronic pulmonary heart disease increased consistently with age group (from 19-30 years to 45-64 years), demonstrating a higher comorbidity burden in older PWHB, regardless of bleed status. Prevalence estimates stratified by age for all other measured comorbidities generally aligned with these age-specific trends (eAppendix Table 2). However, the prevalence of anxiety and depression was the same, regardless of age group.

All-cause, bleed-related, and arthropathy-related HCRU by PWHB with MRBs vs those without MRBs are shown in Table 2. Nearly one-third (32.2%) of PWHB with MRBs had an all-cause inpatient admission compared with 9.9% of PWHB without MRBs. The rate of all-cause inpatient admissions for PWHB with MRBs was 14.8 per 100 person-years (95% CI, 12.8-17.1), 51.4% of which were bleed related, with a rate of bleed-related inpatient admissions of 7.6 per 100 person-years (95% CI, 6.2-9.3). The rate of all-cause inpatient admissions was more than 2 times higher for those with MRBs vs those without MRBs (adjusted RR, 2.5; 95% CI, 1.7-3.6). More than two-thirds (68.1%) of PWHB with MRBs had an all-cause ED visit compared with 34.5% of PWHB without MRBs. The rate of all-cause ED visits was nearly 3 times higher for PWHB with MRBs (67.6 per 100 person-years; 95% CI, 63.2-72.3) than for those without MRBs (23.5 per 100 person-years; 95% CI, 19.9-27.7) (adjusted RR, 2.7; 95% CI, 2.1-3.6).

Similar trends were evident when quantifying arthropathy-related HCRU; 11.9% of PWHB with MRBs had an arthropathy-related inpatient admission compared with 0.8% of PWHB without MRBs. The rate of arthropathy-related inpatient admissions was 4.6 per 100 person-years (95% CI, 3.5-5.9) for PWHB with MRBs, which was more than 14 times higher than for those without MRBs (adjusted RR, 14.3; 95% CI, 3.3-62.7). Further, the rate of joint surgeries was 7.1 per 100 person-years (95% CI, 5.7-8.7) for PWHB with MRBs, 2.8 times higher than for those without MRBs (2.5 per 100 person-years; 95% CI, 1.5-4.2) (adjusted RR, 2.8; 95% CI, 1.5-5.1). The number of pain relief medication prescriptions was 2.0 times higher for PWHB with MRBs (91.5 per 100 person-years; 95% CI, 86.3-97.0) than for those without MRBs (adjusted RR, 2.0; 95% CI, 1.3-3.3).

All-cause HCRU was also stratified by age, as illustrated in Figure 3. Across all age groups, HCRU rates were higher for PWHB with MRBs vs those without MRBs. However, age-specific patterns did vary according to HCRU category, which was especially evident in PWHB with MRBs. Although rates of inpatient admissions did not substantially differ across the 3 age groups, the rate of ED visits for PWHB with MRBs was highest in the youngest age group (19-30 years: 102.5 per 100 person-years; 95% CI, 92.7-113.3) and lowest in the oldest age group (45-64 years: 43.0 per 100 person-years; 95% CI, 37.8-48.9). The opposite trend was observed for non-ED outpatient visits; rates for PWHB with MRBs were highest in the oldest group (1996.6 per 100 person-years; 95% CI, 1959.2-2034.8) and lowest in the youngest group (1273.2 per 100 person-years; 95% CI, 1237.5-1310.2).

DISCUSSION

This study described the clinical and economic burden of male PWHB without inhibitors to FIX within the US health care setting who were stratified into 2 cohorts: those with concurrent bleeding (ie, with MRBs) and those without concurrent bleeding. The prevalence of most comorbidities increased with age in PWHB with and without MRBs, as would be expected.²¹ Prevalence rates of anxiety and depression were consistently high across all age groups, at 19.1% and 16.8%, respectively, among PWHB with MRBs and 10.7% and 7.5% among PWHB without MRBs. In contrast, 9.5%, 3.4%, and 2.7% of US adults (≥ 18 years) experienced mild, moderate, and severe symptoms of anxiety in 2019, respectively.²² From 2013 to 2016, the prevalence of depression in the general population (≥ 20 years) was 8.1% in the US.²³ The high prevalence rates of mental health issues in PWHB have been featured more prominently in recent literature; anxiety and depression can affect HRQOL, adherence to therapy, and motivation to self-manage chronic comorbid conditions.^17,24,25 One study reported that 18% of adult men in the US with mild to severe hemophilia A or B and a history of joint pain or bleeding reported at least moderate anxiety or depression, consistent with the prevalence estimates reported in the current study.²⁶ Our study did not assess HRQOL measures or the severity of anxiety or depression, but a recent European-based study found that only 1 in 7 individuals with hemophilia A or B who recorded problems with anxiety or depression classified it as extreme.¹⁷ The current study did not assess the underlying causes of differences in the prevalence of these mental health conditions, but a greater frequency of pain events resulting from MRBs and resulting arthropathy, joint disease, and disabilities is a potential explanation.^11,27 Accordingly, this study found that the number of pain relief prescriptions was significantly higher for PWHB with MRBs vs those without MRBs.

In all age groups, PWHB with MRBs were consistently more likely to have inpatient admissions, ED visits, and outpatient visits vs PWHB without MRBs. When PWHB with MRBs were stratified by age, the rate of ED visits was highest in the youngest group and lowest in the oldest group. The opposite was observed for all-cause outpatient visits. The underlying reason for such discrepancy by age groups should be further explored, and targeted care packages tailored to specific groups may be developed for better disease management.

This study provided an understanding of the characteristics of PWHB who, despite treatment, still experience potentially painful and debilitating bleeds, comorbidities, and high clinical burden. These results can help shape a comprehensive, patient-centered approach to care in the US across diverse patient types and health care systems, including mental health support.

Although this study did not assess treatment adherence, a US cross-sectional survey reported that adults with hemophilia A or B with moderate to severe depression were more likely to have lower treatment adherence than those without moderate to severe depression.⁴ This study found a numerically higher prevalence of comorbid depression and anxiety in PWHB with MRBs than PWHB without MRBs.⁴ Future research could explore the interactions among psychological comorbidities, treatment adherence, bleeds, and sequelae including HCRU.

Limitations

This retrospective observational analysis should be considered in the context of both its strengths and limitations. PWHB with MRBs may have greater opportunities for encounters with health care providers vs those without MRBs, which could introduce detection bias. The longer average length of enrollment time observed for PWHB with MRBs vs those without MRBs may also contribute to the increased prevalence of comorbidities. The reason for the difference in length of enrollment time is not known but may be due to variations in insurance coverage between the 2 groups; adults with severe hemophilia (who experience more bleeds) typically maintain continuous insurance coverage for extended periods, with limited switching between payers and insurance categories over time due to the high cost of switching plans for those with complex treatment needs.²⁸

Because it is recognized that minor bleeds may be managed at home and this was an observational study of claims data in which no patient diary was used to capture bleeding events, the true burden for patients likely will exceed the estimates presented herein.

More than half of the PWHB in the PharMetrics Plus database were excluded from the study population due to no recorded receipt of FIX replacement therapy. Although this proportion was high, it may exclude patients with mild disease not expected to be treated with FIX replacement therapy.¹⁶ Some excluded individuals could have received treatment in a different setting (eg, in specialty pharmacy) that was not captured in the data, potentially introducing misclassification bias; therefore, the findings from this study can be interpreted to be relevant only to interactions among PWHB and the health care system, the resulting burden on the health care system, and the patient burden of episodic bleeding in that context. In addition, information on the reason for factor replacement treatment (prophylactic or on demand) was not available in the PharMetrics Plus database.

Lastly, as is a common limitation across claims databases, PharMetrics Plus quantifies only the HCRU directly related to the covered interactions between enrollees and the third-party payer. There were no data on what ancillary products were covered by various insurance plans, and certain costs may have been shifted to enrollees, which could have led to less burden shouldered by the insurance plans and more by the enrollees. A more comprehensive assessment of the burden of hemophilia on the patient, health care system, and society should evaluate societal and economic costs, nonmedical resource use, and humanistic burden such as HRQOL and patient-reported outcomes.

CONCLUSIONS

This real-world study reports significant resource use and clinical burden among PWHB who seek medical care. PWHB with MRBs were more likely to have all-cause HCRU compared with PWHB without MRBs. The prevalence of anxiety and depression were consistently high across all age groups. Efforts to assess the mental health of PWHB could be included in a comprehensive approach to management of the condition.

Acknowledgments

The authors wish to acknowledge the significant contributions of Leona Markson in the design and evaluation of this research study. Editorial support was provided by Lu Ban, PhD, at Evidera and was funded by Pfizer.

Author Affiliations: Pfizer Ltd (LY), Tadworth, United Kingdom; PPD Ltd (LB), Beijing, China; Pfizer Inc (YC, PFF), Collegeville, PA.

Source of Funding: This study was sponsored by Pfizer.

Author Disclosures: Ms Young is an employee of Pfizer Ltd and owns stock in Pfizer, which manufactures therapies for the disease state discussed in this article. Dr Ban is an employee of Evidera, a PPD business unit, which received funding from Pfizer to participate in the study and the development of the manuscript. Drs Chen and Fogarty are employees of Pfizer Inc and own stock in Pfizer.

Authorship Information: Concept and design (LY, LB, YC, PFF); acquisition of data (YC); analysis and interpretation of data (LY, LB, YC, PFF); drafting of the manuscript (LY, LB, PFF); critical revision of the manuscript for important intellectual content (LY, YC, PFF); and administrative, technical, or logistic support (LB).

Address Correspondence to: Yong Chen, PhD, MHS, Pfizer Inc, 500 Arcola Rd, Collegeville, PA 19426. Email: yong.chen@pfizer.com.

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