Resource utilization and treatment costs of patients with severe hemophilia A: Real‐world data from the ATHNdataset

Abstract Hemophilia A is characterized by unpredictable spontaneous bleeds and chronic comorbidities. However, limited data exists at the national level into detailed management patterns related to patient clinical characteristics, representative real‐world dosing and treatment frequency, and costs. To assess and characterize the US severe hemophilia A (SHA) population, including subgroups of patients, in terms of clinical and demographic characteristics, healthcare resource utilization received at hemophilia treatment centers (HTCs), and projected annual costs of treatment utilizing data from the ATHNdataset of the American Thrombosis and Hemostasis Network (ATHN). Adult male people with SHA (PwSHA) (FVIII < 1%) were identified in the ATHNdataset between January 2013 and September 2019. This retrospective cohort study described patients’ demographic and clinical characteristics, clinical history, as well as the HTC‐related health resource utilization (HRU), treatment utilization, and projected annual treatment costs of US PwSHA received over the most recent year. Results are reported for the overall population and for three mutually exclusive subpopulations of patients: PwSHA with a history of and/or current inhibitors, PwSHA without a history of inhibitors but with (or a history of) one or more transfusion‐transmitted infections (hepatitis B virus [HBV], hepatitis C virus [HCV], or human immunodeficiency virus [HIV]), and PwSHA without a history of inhibitors or of transfusion‐transmitted infections (HBV, HCV, or HIV). Of the overall PwSHA cohort (N = 3677), there was a high prevalence of HCV (24.1%) and HIV (13.7%), while the prevalence of HBV (4.9%) was lower. Note that 20.5% of PwSHA overall currently or ever had FVIII inhibitors. On average, PwSHA had 2.8 total HTC visits per year, including 0.9 comprehensive care visits, 1.1 telephone contact visits, 0.5 office visits, and 0.1 surgeries or other procedures. However, 23.3% of PwSHA were not seen at an HTC, and 33.8% of PwSHA did not have a comprehensive care visit during their most recent year of data. HTC‐related HRU was similar between the overall cohort and across the patient subpopulations, although PwSHA and inhibitors had more frequent HTC visits (a mean of 3.6 visits annually vs. 2.5–2.8 in the other groups). Using reported treatment frequency and dosing, estimated mean annual hemophilia treatment costs varied by treatment and across the three subpopulations: extended half‐life factor product ($893,609–934,301 by subpopulation), standard half‐life factor product ($798,700–930,812), plasma‐derived factor product ($613,220–801,061), and non‐factor product treatment ($765,289—833,240). This study summarized recent sociodemographic and clinical characteristics, HTC‐related HRU, and HA treatments and projected costs among adult PwSHA, including among key subpopulations of PwSHA. PwSHA experience substantial clinical and resource burden on a chronic basis, despite the care coordination efforts of ATHN‐affiliated HTCs. These findings motivate further exploration of the drivers of resource utilization, observed differences across subpopulations and other disparities, and ongoing monitoring of clinical and treatment burden in the face of an evolving care landscape.


INTRODUCTION
Hemophilia A (HA) is an X-linked coagulation factor disorder primarily affecting males and caused by a deficiency of 40% or less than normal levels of the blood clotting factor VIII (FVIII) [1]. Because of insufficient endogenous levels of FVIII needed for normal blood clotting, patients with HA experience bleeds of varying severity (from clinically silent to life-threatening) occurring spontaneously or in response to minor injury [2]. HA is present in approximately one in 5000 live male births based on data from US hemophilia treatment centers (HTCs), or 400 infants newly diagnosed with HA in the United States annually [1][2][3][4][5], with global estimates of the birth prevalence of approximately one in 4000 live male births based on a recent meta-analysis [6]. Approximately, 22,000 PwHA have been treated at a US HTC between 2012 and 2021 [7].
Half to two-thirds of people diagnosed with HA have severe HA (SHA; i.e., FVIII activity < 1 percent of normal) and are at high risk of painful and potentially dangerous bleeding events, as well as joint and organ damage, need for surgeries, chronic arthropathy and other longterm complications, as well as lowered quality of life [2,8,9]. Routine management of HA involves prophylactic and acute (i.e., on-demand) administration of FVIII to levels permitting normal clotting [10]. FVIII replacement is effective in reducing bleeding and negative outcomes, permitting a more active life [11,12]. However, a major and common complication of FVIII replacement is the development of inhibitor antibodies in response to factor infusions, greatly reducing the ability of prophylactic or on-demand therapy to prevent or stop bleeding and increasing mortality risk [13]. In addition, treatment guidelines high-  [10]. The introduction of emicizumab in recent years, a recombinant, humanized, and bispecific monoclonal antibody, provided another treatment option for patients with or without FVIII inhibitors [10]. Understanding and describing the current SHA population is key to understanding the current burden of illness of SHA, and best approaches for management of the disease, as treatments evolve.
The economic burdens and impact on quality of life of FVIII replacement are also substantial due to the high costs of therapy, required treatment intensity and frequency, and monitoring over the span of a patient's entire life [14,15]. Recent estimates from registry studies and insurance claims analyses of the annual payer costs for patients receiving prophylactic therapies have ranged from $256,426 to 753,480 per year [16][17][18][19][20]. Based on Medicare spending in 2010, hemophilia treatments were the most costly drug on average per beneficiary [21]. Furthermore, some subpopulations of patients with HA, such as those with inhibitors or transfusion-transmitted infections, experience additional complications, worse clinical outcomes, and greater economic burden as FVIII therapy have reduced effectiveness. Finally, even with optimal management, breakthrough bleeds, lifestyle restriction, and high healthcare resource utilization (HRU) are still expected for patients with HA [22,23].
The treatment landscape for HA continues to evolve in response to the burden of treatment and the disease, with several new therapies in clinical development. For example, prophylactic FVIII replacement therapies include both standard half-life (SHL) and extended half-life formulations (EHL), with EHL formulations providing longer prophylactic benefits and decreased infusion frequency at higher up-front cost [16,24]. In a 2020 real-world study by Yan [25]. Additionally, nonfactor substitution product treatments such as emicizumab and hemostasis rebalancing therapies have been developed, featuring decreased treatment frequency, more convenient subcutaneous dosing, and the potential for improved outcomes relative to traditional intravenous FVIII prophylaxis therapies in patients both with and without inhibitors [26][27][28]. Gene therapies and other new breakthrough therapies being developed have the potential to further reduce treatment burden and improve patient outcomes for a subset of patients with HA.
This study aimed to characterize the US SHA population including subgroups of patients regarding clinical and demographic characteristics, HTC-related HRU, treatments, and projected annual costs of treatment utilizing data from the ATHNdataset derived from HTCs in the American Thrombosis and Hemostasis Network (ATHN). Along with the overall ATHN population with SHA, three mutually exclusive subpopulations, which may impact HRU, were described based on presence of inhibitors, transfusion-transmitted infections, without inhibitors, and no history of inhibitors or transfusion-transmitted infections.

Data source
The ATHNdataset is a HIPAA-compliant de-identified patient health dataset containing data from individuals with bleeding and clotting disorders receiving care through the US HTC Network. Individuals consent or opt-in to contribute their data in order to help establish a better understanding of bleeding and clotting disorders such as the complications of these disorders, the social and economic costs, and the effec-

Key variables and analyses
Sociodemographic and clinical characteristics were described based on the most recent activity in the ATHNdataset including age, weight, height, body mass index (BMI), geographic region, self-reported race/ethnicity, and education level. Clinical history was also summa-  prophylaxis were projected based on applying wholesale acquisition cost (WAC) prices for specific treatment [30] to the recorded dose, dose frequency for a patient/product, and aggregated for treatment class (EHL, SHL, plasma-derived, and non-factor products). Costs were estimated based on 2020 US dollar (USD) costs for a product.
Data were summarized using descriptive statistics in SAS 9.4.
Continuous variables were summarized using N, mean, SD, median, and interquartile range (IQR). Categorical variables were summarized using frequency and percentage. Where applicable, missing variables were presented as missing, with no imputation for missing data.
Unknown or missing data indicates that the data was not reported to the ATHNdataset during the reporting period [29].

Sample selection
The inclusion and exclusion criteria and the final SHA sample counts by subpopulation are presented in Figure 1.

Sociodemographic characteristics of PwSHA
Patients in the prespecified subpopulations were generally similar regarding demographic characteristics, with the exception of age (

Comorbid conditions
The overall cohort of PwSHA had high prevalence of HCV (24.1%) and HIV (13.7%), while the prevalence of HBV was lower at 4.9% (see Table 1

Annual HTC-related HRU
Annual HTC-related HRU among the overall study and subgroups is presented in  [31].
In addition to more visits overall, the patient subgroup with inhibitors had higher rates of all other HTC visit or contact types with the exception of surgeries or procedures. The annual incidence of any surgery/procedure was 3.9% in the overall cohort recorded in the dataset, with low rates of both specific surgeries/procedures (e.g., joint replacement surgeries) as well as patients undergoing multiple surgeries or other procedures.

Treatment characteristics
In the overall cohort, 8.1% used on-demand treatment, 76.4% used FVIII prophylaxis treatments, 12.1% used nonfactor substitution product treatments, and data concerning treatment type was missing in the remaining 3.4% of the cohort. The distribution of prophylaxis and other (i.e., on-demand and nonfactor products) HA treatments for the overall population and patient subgroups is presented in Table 3, along with mean dosing and frequency of treatments for each type of prophylaxis (i.e., SHL, EHL, plasma-derived) and nonfactor product treatments.
Among prophylaxis treatments, annual discontinuation rates were highest for patients treated with plasma-derived products (7.5% in the overall SHA population), followed by SHL product treatment (5.9%), and with EHL product treatment the lowest (2.6%). Observed discontinuation for nonfactor product treatment was very low (0.2% in the overall cohort). Patients with inhibitors had the highest rate of treatment discontinuation (9.0% of SHL and 4.6% of EHL), the most frequent prescribed dosing (2.6 and 3.6 days, respectively), the lowest use of prophylaxis (65.7%), and generally higher average doses.
Conversely, patients without inhibitors or transfusion-transmitted infections had lower rates of discontinuation, slightly less frequent prescribed dosing, and higher use of prophylaxis than in the overall cohort.

Estimated annual costs of prophylaxis treatment
The estimated costs of SHL, EHL, plasma-derived, and nonfactor products, based on observed HRU and treatment pricing assumptions, are presented in Table 4. For the overall cohort and the patient subgroups, the estimated mean annual treatment costs were highest for EHL products (ranging from $893,609 to 934,301 across the subgroups), followed by SHL and plasma-based treatments. The annual treatment costs with SHL products ranged from $798,700 to 930,812 across cohorts and plasma-derived costs ranged from $613,220 to 801,061.
The estimated mean annual treatment cost for nonfactor substitution products was comparable to that of SHL products ($821,567 vs. 802,746 in the overall population, respectively), with both annual cost estimates being lower than EHL products. One exception was in the subpopulation of PwSHA and inhibitors, where nonfactor products were estimated to have a lower mean annual treatment cost compared to each type of prophylaxis treatment.

DISCUSSION
The US hemophilia population has been clinically described as part of the centers for disease control and prevention  year, approximately 25% of PwSHA were not seen at an HTC during their most recent year of data, and 33% of PwSHA did not have a comprehensive care visit. This highlights the overall success of disease management actives at HTCs overall while also highlight the potential for improvement for individual PwSHA, particularly those who are not utilizing the HTC. Telephone contacts were only utilized in 20% of patients but may be an option to reach patients who are not being seen at the HTC annually. Relatedly, with the increased utilization of telemedicine and virtual appointments as the US healthcare system adapted to the COVID-19 pandemic, these virtual HTC visits may be another mechanism to reach PwSHA who are infrequently engaged with their HTC. The management of PwHA via telemedicine both before and during the pandemic has been assessed, finding that the disease is well suited for the benefits of telemedicine [41,42]. Personalization in management may also help to ensure that PwSHA are treated with appropriate hemostatic treatments and reduce the utilization of on-demand FVIII treatment regimens, which were still being utilized in 8% of PwSHA overall, including more than 10% of PwSHA and transfusion-transmitted infections, rather than prophylaxis, which is the standard of care for all patients with severe hemophilia [10] and has been demonstrated to reduce bleeding events and HRU [15,43]. Understanding individual patient factors in treatment decisions will likely be increasingly important as additional hemostatic treatment options are introduced.
One area of management where individualization already occurs is in prophylaxis regimens, as prophylaxis aims to take into considerations such as bleeding phenotype, joint status, patient preferences, and individual pharmacokinetics [10]. Due to this personalization, there has been limited description of real-world prophylaxis regimens currently utilized in the US, likely related to limitations of available datasets, which is a strength of the ATHNdataset. Detailed, accurate dosing information is not generally available from alternative data sources such as administrative claims analysis or patient surveys. Additionally, clinical trial-based reports do not accurately reflect typical dosing of prophylactic factor products commonly used in the US today as clinical practice has shifted from achieving a 1% trough level to adjusting dosing and dosing intervals sufficiently to prevent spontaneous and breakthrough bleeding and hemarthrosis [10]. Therefore, this analysis described current real-world dosing with prophylaxis regimens in the Finally, costs were estimated using prescription data and WAC prices, which may not reflect the costs paid by payers after manufacturer rebates and/or patient cost sharing. For nonfactor product treatments (e.g., emicizumab), the mean dose and dose frequency reported in this study may have combined the loading and maintenance phases; overall, observed data are consistent with the indicated dose and frequencies in the product label.

CONCLUSION
This study describes the adult US SHA population, along with sub-

ETHICS STATEMENT
The ATHNdataset is a certified, de-identified dataset. The ATHNdataset has undergone ethics review and was deemed non-human subjects research. Patient participation in the ATHNdataset is voluntary.