Real-world clinical and psychosocial outcomes among people with mild or moderate haemophilia A treated on-demand in the Italian CHESS II cohort: a real-world data analysis

We conducted a retrospective analysis of clinical and psychosocial outcomes among adults with mild or moderate HA living in Italy who participated in the CHESS II study. The design, methods and primary findings from the broader CHESS II study cohort have been reported previously ^[29]. The CHESS II study is a panel-based cross-sectional burden of illness study of male adults (≥18 years old) with congenital haemophilia A or B of any severity, with or without inhibitors, conducted between October 2018 and November 2020 in eight European countries (France, Germany, Italy, Spain, the United Kingdom, Romania, Denmark, and the Netherlands). The panel was composed by 173 haematologists (or haemophilia care providers, in France) treating at least eight PwH and practicing in one of the countries of interest. All demographic and clinical characteristics, as well as treatment patterns and health resource utilisation information, were reported by the treating physicians via a web-based form and abstracted from medical notes. Upon consenting to participate in the study, PwH were invited by their physician to complete a patient questionnaire with information relating to their health status (via the EQ-5D-5L) ^[30], work productivity and activity impairment (via the WPAI instrument) ^[31], and non-medical haemophilia-related costs, as well as information on the overall humanistic impact of haemophilia. People with severe HA or with haemophilia B and who were not living in Italy at the time of data collection were excluded from this analysis.

All participants who completed the patient questionnaire in the CHESS II study provided informed consent. The CHESS II study was approved by the Research Ethics Sub-Committee of the Faculty of Health and Social Care within the University of Chester, conducted in correspondence with regional and relevant guidelines and governed by an expert reference group. Participant consent for use of physician-reported clinical data was not required as per European Pharmaceutical Market Research Association (EPhMRA) guidelines. Participant consent was obtained via tick box selection from PwH wishing to also complete the patient questionnaire prior to the collection of any patient-reported data.

This study evaluated treatment patterns and corresponding clinical and psychosocial outcomes among a sample of people with mild or moderate HA in Italy stratified by HA severity. Data were collected from a physician-completed, web-based clinical record form (CRF) and a corresponding linked patient self-complete (PSC) questionnaire completed by the participating person with HA. The CRF contained information about the person’s medical history and consultations, and the PSC covered non-medical costs, psychosocial outcomes, HRQoL, and work impairment. This analysis focused on physician-reported clinical outcomes and on self-reported psychosocial outcomes from the PSC questionnaire.

Treatment patterns included the physician-reported treatment strategy for each person with HA including the number of on-demand FVIII infusions in the 12 months immediately prior to data collection. The number of on-demand FVIII infusions was estimated via the physician reported total 12-month yearly IU consumption and the reported IU/kg dosage.

Clinical endpoints of interest were reported by physicians and included annual bleeding rate (ABR) in the 12 months immediately preceding data capture, target joints, problem joints, chronic pain, and prevalence of anxiety and/or depression. A target joint was defined according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH) as “three or more spontaneous bleeds into a single joint within a consecutive 6-month period. Where there have been ≤ 2 bleeds into the joint within a consecutive 12-month period the joint is no longer considered a target joint” ^[3]. A problem joint was defined as “any joint that has been permanently damaged as a result of a bleeding disorder, with or without persistent bleeding, and may involve chronic pain and/or limited range of movement due to compromised joint integrity such as chronic synovitis and/or hemophilic arthropathy” ^[32]. The patientcentric ‘problem joint’ definition aims to characterise joint damage associated with chronic joint pain and/ or limited range of motion due to compromised joint integrity, as distinguished from the historical target joint definition of the ISTH ^[32]. Chronic pain was reported by the physician as part of the CRF, taken from clinical consultations including patient-reported pain, functional limitations due to pain and use of analgesics. The proportion of people with HA who experienced anxiety and/or depression was captured within the comorbidity section of the CRF from the physician-extracted medical records.

Psychosocial outcomes were captured in the PSC using a 5-point Likert scale. Participants reported having to ‘reduce or give up’ social activities or exercise, missing out on opportunities, and having feelings of frustration with the impact of HA on their lifestyle ranging from ‘strongly agree’ to ‘strongly disagree’.

Descriptive statistics were used to summarise participant characteristics, treatment patterns, and clinical and psychosocial outcomes. Means and standard deviations (SD) were used to describe continuous variables and frequency and proportions to describe categorical variables. All characteristics were reported by HA severity (mild or moderate). By assuming a 40 IU/kg dose (agreed as a relevant median dosage by the haemophilia clinical experts) and based on the physician-reported 12-month FVIII IU consumption, the number of on-demand infusions was estimated as (Total yearly IU consumption)/(weight×40). All analyses were conducted using STATA version 17.0 (StataCorp LLC, College Station, TX, SUA; www.stata.com).

Of the 1337 participants in the CHESS II study, 406 (30%) were residents of Italy at the time of data collection, of whom 278 (69%) had HA of any severity. The final study cohort comprised 113 people, of whom 34 (30%) had mild HA and 79 (70%) had moderate HA. People with moderate HA were slightly older than those with mild HA (mean age, 41.4 and 36.6 years, respectively), and a greater proportion were categorised as having a normal body mass index (61% and 53%, respectively) (Table 1).

No participants in this mild/moderate HA subsample of the Italian CHESS II cohort was receiving a prophylaxis treatment regimen at the time of data collection, with 29% and 30%, respectively, reporting any FVIII use (on-demand) in the 12 months preceding data collection (Table 1). Based on total physician-reported IU consumption in the 12 months prior to data collection, it was estimated that the mean (SD; median) number of on-demand FVIII infusions were 9.6 (8.1; 6.5) and 13.0 (13.0; 9) for those with mild or moderate HA, respectively.

Overall, the majority of those within the sample had ≥1 bleeding event in the 12 months preceding data collection (n=91/113, 81%). Compared with mild HA, people with moderate HA had a higher mean ABR (2.9 vs. 1.1, respectively), and a greater proportion of those with moderate vs. mild HA were reported to suffer from chronic pain (74% vs 35%), anxiety (20% vs 12%), and/or depression (15% vs 3%) (Table 1). The majority of people with mild (74%) or moderate (85%) HA had ≥1 bleeding event in the year immediately preceding data collection. While in the mild HA cohort all bleeding events were reported as post-traumatic, mean (SD) spontaneous ABR was 0.88 (0.93) in the moderate cohort, with 72% reported to have experienced spontaneous bleeding. Reported mean baseline FVIII levels were 21.0 (10.3) and 3.5 (1.2) for mild and moderate cohort, respectively. No relevant differences were found in baseline FVIII level between the cohort with ≥1 bleeding event and those with no bleeding, regardless of severity (Table 1). Approximately one-fifth (19%, n=21) of all people with mild or moderate HA in the cohort had ≥1 target joint, and more than one-third (39%, n=44) had ≥1 problem joint. Target joints were prevalent in 12% and 22% of those with mild or moderate HA, and problem joints in 12% and 51%, respectively.

Of the 113 CHESS II participants with mild or moderate HA living in Italy at the time of data collection, 44 (39%) completed the PSC (mild HA, n=19, 43%; moderate HA, n=25, 57%). A greater proportion of those with mild HA (n=19/34, 56%) completed the PSC than those with moderate HA (n=25/79, 32%). Similar to the overall cohort, people with moderate vs. mild HA had more annual bleeding events, greater joint morbidity and chronic pain (Supplementary Table S1).

Consistent with the clinical outcomes among the cohort completing the patient questionnaire, a greater proportion of people with moderate HA than mild HA reported having to compromise psychosocial aspects of life, including social activities, exercise, and opportunities, due to their HA (Figure 1). Overall, 40% vs. 10% of those with moderate vs mild HA, respectively, had to reduce or give up on social activities (‘Agree’ or ‘Strongly agree’), 44% vs. 21% had to reduce or give up exercise, 36% vs. 26% reported missing out on opportunities, and 48% vs. 26% felt frustrated by the influence of HA on their lifestyle.

Figure 1:

Results from this study should be considered in the context of certain strengths and limitations. To our knowledge, this is the first non-single-centre analysis of the clinical and psychosocial burden of HA specifically focused on Italian adults with mild or moderate condition. CHESS II is a cross-sectional population study using real-world data abstracted from medical charts and patient-reported outcomes, and as such is subject to the inherent limitations that characterise observational research and secondary data analysis. Therefore, despite efforts to minimise it, a degree of information and/or recall bias cannot be excluded which may have caused an underestimation of the clinical burden of people with mild haemophilia due to the potential lack of condition knowledge. Additionally, due to the observational nature of the CHESS II study, the use of convenience sampling, the characteristics of the population, and the rarity of the condition, a degree of selection bias cannot be excluded. Efforts to minimise this were, however, put in place by encouraging physicians to recruit the next eight PwH they consulted with, regardless of the reason for the consultation. While patient-reported information is essential to informed decision-making, it should be noted that only a subset of the cohort completed the PSC questionnaires. It is possible that unmeasured variables could have had an impact on these results, which is a known limitation of observational research. Efforts to minimise bias were put in place; however, the findings of this analysis should be interpreted with care, owing to the specificity of the subgroup and the small sample size, which may limit generalisability of results to the Italian mild/moderate HA population. Finally, as inclusion of clinical data in the study was contingent on having at least one consultation, there remains a lack of information on the people with mild or moderate HA who struggle to access care or have minimal contact with their treatment centres. Therefore, further research with more representative sample sizes is warranted to capture and fully evaluate condition burden of mild and moderate HA in the context of evolving treatment practices in Italy.