Clinical, humanistic, and economic burden of severe haemophilia B in adults receiving factor IX prophylaxis: findings from the CHESS II real-world burden of illness study in Europe

Haemophilia B is less prevalent than haemophilia A, with estimates of 3.8 and 17.1 cases per 100,000 males, respectively [1]. As such, the scientific literature tends to focus much more on burden and outcomes of patients with haemophilia A alone, or haemophilia at large (A and B, comprised mostly of patients with haemophilia A). However, patients with haemophilia B endure an ongoing clinical burden with substantial impairment of daily activities and health-related quality of life (HRQoL) [2‐4]. Patients with severe disease (factor IX level ≤ 1% IU/dL; FIX) experience frequent spontaneous and recurrent joint bleeds that, without appropriate treatment, lead to early arthritis, deformity, and other long-term complications [5‐7]. The burden of haemophilia B remains substantial and persistent [8‐11]. Improved outcomes also come with an inherent treatment burden, as treatments are administered 2–3 times per week for standard half-life (SHL) FIX or, more recently, every 1–2 weeks for extended half-life (EHL) FIX [12, 13].

Haemophilia B and its treatment also bear a notable economic burden on patients and society [14‐17]. The original CHESS study (known as CHESS I, “Cost of Haemophilia in Europe: a Socioeconomic Survey”) reported significant costs associated with severe haemophilia and its treatment, including reduced employment and lost wages among patients and their caregivers in Europe [18]. Since the data collection period of CHESS I in 2014–2015, haemophilia management and treatments have continued to evolve with the introduction and adoption of EHL and non-factor products into clinical practice. The CHESS II study, conducted in 2019–2020, sought to describe the comprehensive burden of haemophilia in Europe following these advances, including capturing real-world use of EHL treatment and up-to-date haemophilia care management practices. The holistic burden of haemophilia B among patients with severe disease, in particular, has been underserved in the literature. As these patients are likely to receive prophylactic therapy, we focused this analysis on patients with severe haemophilia B receiving prophylaxis. The development of inhibitors is also a rightful area for attention in the literature, and in keeping with our objective to address less developed areas of research, historically, we focused on patients without inhibitors for this analysis.

Here, we analyzed data from the recent CHESS II study to provide updated real-world findings on management practices, disease burden, and unmet needs of adults with severe haemophilia B receiving FIX prophylaxis in Europe.

A total of 132 CHESS II participants had severe haemophilia B, of whom 75 (57%) were on continuous FIX prophylaxis and were included in the analysis. Patient-reported data were available from 40 (53%) participants. The mean age was 36.2 years. Slightly fewer than half of the patients were receiving EHL prophylaxis (n = 33, 44%; Table 1). Overall, most patients 76% were receiving primary prophylaxis; mean (SD) duration of secondary prophylaxis was 4.5 (3.87) years. There was broad geographic distribution of patients with the United Kingdom contributing the highest proportion (29%), followed by Italy (23%) and Spain (20%). Demographic characteristics were generally similar between patients receiving SHL or EHL prophylaxis.

Most patients with severe haemophilia B on FIX prophylaxis had ≥ 2 bleeding events per year (70%) and the mean ABR was 2.4 (Table 2). Mean number of bleed-related hospitalisations overall was 0.67, and appeared lower among patients receiving EHL prophylaxis. Twenty-three percent of patients had ≥ 1 target joint and 40% had ≥ 1 problem joint. ABR was similar between patients receiving EHL or SHL prophylaxis. History of joint surgery was similar between patients receiving EHL prophylaxis (33%) or SHL (24%), likewise for problem joints, but a greater proportion of patients receiving EHL reported target joints (Table 2).

This analysis of the CHESS II real-world burden of illness study demonstrated the persistent negative impact of severe haemophilia B on patients in Europe. Patients averaged at least 2 bleeds per year, nearly half had at least 1 problem joint, and the majority reported mild or moderate chronic pain. Mean HRQoL was low for patients undergoing FIX prophylaxis, and indirect costs from early retirement/work stoppage and reduced work productivity for both patients and their caregivers were substantial. The direct costs associated with severe haemophilia B were substantial, driven almost entirely by FIX treatment.

This analysis of the recent CHESS II study provides a European perspective on real-world outcomes associated with FIX prophylaxis in patients with severe haemophilia B in the EU5. The study included a broad sample of patients receiving EHL or SHL treatment that was not limited to a single-center or a single-country analysis. These findings were even consistent with unmet needs reported prior to widespread use of EHL therapy for severe haemophilia B in Europe. Berntorp and colleagues reported real-world outcomes from haemophilia registries across 7 European countries where 57% of haemophilia B patients had severe disease (also 57% in CHESS II) [19]. Among patients with evaluable data for annual bleeds, Berntorp reported ≥ 1 bleed per year in 78% (57/73) of patients with severe haemophilia B (83% in CHESS II, 62/75) [19]. Other reports of the real-world clinical burden of severe haemophilia B in Europe included CHESS I, the predecessor of the current study [18, 20]. In this study, we observed a nearly identical distribution of ABR between patients receiving SHL or EHL treatment, but a greater proportion of EHL than SHL patients had at least one target joint (30% vs 17%, respectively). Physicians may have been more likely to prescribe EHL for their patients considered to have more severe joint complications, since switching to an EHL FIX product has been suggested to improve joint health outcomes [21], which has been discussed in the literature anecdotally but not quantified as of this writing [22, 23].

To our knowledge, CHESS II is the first multi-center study of EHL treatment use and costs among patients with severe haemophilia in the EU-5, specifically those with haemophilia B in this analysis. Though many patients had shifted to more expensive EHL therapy in CHESS II, the costs of haemophilia B in the EU5 were not substantially different from those observed with predominantly SHL therapy in CHESS I. Mean annual haemophilia-related direct medical costs for any FIX treatment were €232,000 in CHESS II, nearly identical to those reported with SHL treatment in CHESS I (€230,000) [18]. This may be due to changes in FIX unit cost associated with national tendering in EU, which varies with each country’s prioritization of prophylactic treatment in terms of both health policies and subsequent procurement. The proportional distribution of SHL and EHL treatment utilisation varied across countries in CHESS II, as did mean annual direct medical costs, which was likely due to differences in health system structures, policies, and reimbursement rates and was consistent with findings from CHESS I. The greatest proportion of EHL use and highest total costs were observed in Germany, which also showed the highest costs in the CHESS I analysis [18]. In general, we observed countries with lower proportions of EHL use to have lower total factor IX treatment costs, with the exception of Italy. This may have been due to health policies and/or procurement practices related to factor IX and EHL use specifically in this population.

Patients with severe haemophilia B in the CHESS II study showed substantial humanistic burden of disease and indirect costs despite FIX treatment. The majority of patients reported mild or moderate pain (76%) and impact of haemophilia on daily life (63%), consistent with published reports, particularly for patients with moderate to severe disease [4, 24]. The overall mean EQ-5D score among CHESS II patients with severe disease (mean 0.67) was slightly lower than that reported from severe haemophilia B patients in CHESS I (mean 0.76) [25]. This may be reflective of a persistent unmet need over time. We did not examine EQ-5D results by age due to the sample size of patients with severe disease; however, the mean overall EQ-5D score of 0.67 was substantially lower than published population norms for the participating countries (ranging from 0.86–0.92) [26]. The indirect costs of severe disease were observed to be similarly meaningful, comprised largely of early work stoppage or retirement (60%) followed by reduced productivity for caregivers (24%). The cost of lost productivity for patients was likely the smallest component of total indirect costs because early withdrawal from the workforce was the largest component, where severe haemophilia B may be more likely to keep working-age patients from working at all (mean age, 36 years in this cohort), rather than resulting primarily in absenteeism and presenteeism. Compromised employment due to severe haemophilia has been well established. Cutter and colleagues (2017) reported a negative impact of mild to severe haemophilia B on employment in the US as high as 95% among patients and 84–89% among caregivers and partners [27]. Patients who had left the workforce prematurely cited financial issues (59%), including healthcare expenses, and haemophilia-related issues (55%) most often.

Our analysis should be considered in the context of its strengths and limitations. The CHESS II study brings patient-reported outcomes and medical chart-extracted details to elucidate real-world encounters for patients with haemophilia B and is beholden to the expected limitations of any retrospective cross-sectional study, such as the potential for selection bias, recall bias, and data extraction errors. For example, patients who had sought physician care due to bleeding or joint health issues in the past 12 months were more likely to be included in the sample. The small sample sizes of patients with SHL or EHL prophylaxis precluded comparisons between these treatment groups, particularly for country-level and patient-reported outcomes. This analysis of the CHESS II data set focused on patients with severe haemophilia B without inhibitors with a record of consistent FIX prophylaxis over the past year. As such, our findings are not generalisable to patients with mild or moderate disease, those with inhibitors, and/or those receiving on-demand or less consistent prophylaxis therapy. Unmeasured variables may also impact the generalisability of our findings to other patient populations. Patient-reported outcomes (humanistic burden, indirect costs, and direct non-medical costs) were available from a subset of the overall study cohort (40/75 patients), which may have reflected a selection bias specific to those willing to complete the patient questionnaire. Our findings were from 5 large European countries, whereas recent studies of EHL costs across haemophilia types and subgroups have tended to be single-center, single-country, or more tightly focused regional analyses [28, 29].

These findings from an analysis of the CHESS II study demonstrate the substantial clinical and humanistic burden of severe haemophilia B, together with a consistent economic burden. Our analysis provides a comprehensive assessment of real-world outcomes among patients receiving SHL and EHL FIX prophylaxis in Europe currently, highlighting the persistent unmet needs for these patients, their caregivers, and society.