FormalPara Key Points

This survey was conducted among patients with haemophilia A in Slovenia to better understand patients’ treatment perceptions and preferences, particularly with regard to factor VIII (FVIII) product storage characteristics.

Patients were often non-compliant with prescribed FVIII treatment regimens, and many lacked understanding about key treatment aspects (e.g., the importance of pharmacokinetic testing and the correct storage requirements for FVIII products).

For many patients, the misconception that FVIII products must always be stored at temperatures ≤ 25 °C restricts daily activities and reduces treatment satisfaction.

Patient education and ongoing dialogue will be necessary to address patients’ concerns about their treatment, improve their understanding of disease management, and ultimately improve compliance and treatment outcomes.

Introduction

In today’s haemophilia A treatment landscape, replacement therapy with factor VIII (FVIII) concentrates—the gold standard of treatment—has evolved to allow for more effective disease management than was possible in the past [1, 2]. In large part, this is due to the broad availability of FVIII products (plasma-derived and recombinant products, along with standard and extended half-life concentrates), non-factor replacement therapies [1, 3], and, at least for patients in developed countries, access to regular FVIII prophylaxis [2, 4].

This pattern is reflected in Slovenia, where current treatment standards include prophylaxis for all patients with severe haemophilia A, switching from standard FVIII products to extended half-life FVIII concentrates or non-factor replacement therapy, and individualized treatment based on the patient’s lifestyle and pharmacokinetic (PK) data collected through the online WAPPS-Hemo tool (https://www.wapps-hemo.org/).

It has been well established that prophylaxis is effective in reducing bleeding rates and adverse joint outcomes (e.g., arthropathy) [5,6,7], at least in the clinical trial setting. However, from the patient’s perspective, regular prophylaxis is associated with various limitations, including inconvenience, the need for frequent infusions, venous access difficulties, the need for refrigerated product storage and considerable monetary costs, which together produce a high treatment burden [2, 3, 8,9,10]. This can adversely affect treatment adherence [8, 11], which can lead to poor clinical outcomes in real-world settings, such as high bleed rates [1, 5, 6, 12]. Therefore, efforts to improve treatment outcomes in haemophilia must address these limitations, which, in turn, necessitates understanding the patient’s perspective. Doing this in a way that incorporates patient preferences into treatment programmes not only enhances patient engagement with self-management, but also increases both treatment satisfaction and compliance [4, 13, 14]. Importantly, patients’ treatment preferences may differ from their physician’s clinical considerations, focusing more on product characteristics such as treatment convenience, product storage and portability [2, 13, 15, 16].

The aim of our study was to identify patient perspectives on treatment limitations and treatment satisfaction, particularly with regard to FVIII product storage characteristics, among patients with haemophilia A in Slovenia.

Materials and methods

Patients

Patients of all ages with haemophilia A (or their caregivers) were eligible for inclusion. All patients who were registered in one or both of two national patient organizations, or their caregivers, were invited to participate in the survey if they had provided informed consent for their information to be used for such purposes (N = 150). This study was exempt from requiring ethics approval in line with national guidelines (Ministry of Health, Commission for Medical Ethics).

Survey

All participants completed a self-administered, paper-based survey comprising 22 questions that collected information on demographic and clinical data, understanding of PK, compliance, FVIII product storage and treatment satisfaction (Online Resource 1, see electronic supplementary material [ESM]).The survey took approximately 10 min to complete. Before being sent to participants, the survey was assessed by a sample of five patients with haemophilia to ensure that the wording and language used was clear and understandable. Surveys were distributed to participants via mail in March 2020 by the two national patient organizations, and participants mailed their completed questionnaires back to the patient organizations. Between March and July 2020, two reminder emails were sent to remind participants to return their surveys. The first completed survey was returned at the end of March 2020, and the last was returned in July 2020. All survey responses were anonymized, and physicians did not discuss the surveys with respondents.

Analysis

Survey results are summarized using descriptive statistics. The minimum sample size was determined to be 44 patients (i.e., 20% of the 220 patients with haemophilia A in Slovenia identified by the Annual Global Survey 2019 from the World Federation of Hemophilia (WFH) [17]). Due to the limited sample size, responses from patients and caregivers were analysed together, and comparisons between participants’ responses are descriptive and illustrative only. There was variation in the number of patients who answered each question, as not all patients who returned the survey answered all the questions. This is reflected in the patient numbers and percentages reported in the Results section below.

The Kano model

The Kano model was used to evaluate patients’ satisfaction with storage conditions for FVIII products. This model is based on the concept of customer-defined quality and offers a simple way of ranking the attributes of a given product from the customer’s perspective [18, 19]. In other words, the model aims to identify product attributes that customers deem essential and those that are most likely to bring customer satisfaction, thus establishing the importance of individual product features to the customer [18]. The Kano model uses a simple, standardized two-question survey to assess patient requirements and preferences regarding product features: how do you feel if a particular product feature is present and how do you feel if that product feature is not present [18, 19]? For both questions, respondents can choose from the same five possible standardized responses: (1) I like it, it excites me; (2) I expect that to be the case; (3) I do not care; (4) I do not like it, but I can accept it; (5) I do not like it, it is unacceptable to me [18, 19]. In the questionnaire reported in this paper, this two-question Kano model survey and the standardized responses (questions 17 and 18 in Online Resource 1, see ESM) were used to identify how patients felt about FVIII products that can be stored at > 25 °C. These questions are shown in Table 1 along with the five standardized responses from which patients could choose. According to standard Kano model methodology [18, 19], participants’ responses to these two questions were combined in a standardized Kano evaluation table (Online Resource 2, see ESM) in order to classify the product attribute in question—namely, the ability to store FVIII products at > 25 °C—into one of six categories: (1) Must be; (2) Performance; (3) Attractive; (4) Indifferent; (5) Reverse; (6) Questionable [18, 19]. These categories are explained further in Table 1.

Table 1 Patient preferences regarding factor VIII product storage conditions: the Kano model [18, 19]
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Results

Demographic and clinical characteristics

Of the 150 patients and caregivers invited to participate, 63 completed the survey and were included in this analysis. Almost all respondents (61 [96.8%]) were patients; only two of the respondents (3.2%) were caregivers. Patients who did not respond to the invitation (N = 87) were not followed up, so their reasons for non-participation are not known.

Patient characteristics are summarized in Table 2. Most patients represented in the survey were > 18 years old (59/63 [93.6%]), had severe haemophilia A (43/63 [68.3%]) and received FVIII products prophylactically (45/61 [73.8%]) either three times per week (19/37 [51.4%]), twice per week (13/37 [35.1%]), every other day (4/37 [10.8%]) or once weekly (1/37 [2.7%]).The demographic data show that older patients (≥ 51 years; N = 35 [55.6%]) and patients with severe haemophilia (N = 43 [68.3%]) were heavily represented among the survey participants.

Table 2 Demographic and clinical characteristics of survey respondents
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Among the 61 patients who answered the question about bleeding frequency, the mean number of bleeds in the last 12 months was 4.9 (median, 3.0). The mean (median) number of bleeds was higher for patients with severe disease than for those with moderate or mild disease (6.3 [3.0], 4.0 [4.0] and 1.3 [1.0], respectively); additionally, patients on prophylaxis reported a higher mean (median) number of bleeds within the last 12 months (5.7 [3.0]) than those receiving on-demand treatment (2.3 [1.0]).

Understanding of pharmacokinetics

Twenty-nine patients, including 21 on prophylaxis, indicated that they had undergone PK testing. FVIII trough activity levels among these patients ranged between 0.1 and 24.0%, although evaluating PK based on patient answers was challenging as patients generally showed a lack of understanding of PK and PK testing, and patient responses about their PK levels may not have been accurate in all cases.

Compliance

Fifty-six respondents answered the questions about compliance, almost half of whom (26 [46.4%]) reported that they had missed, forgotten or delayed their scheduled doses at some point in the past. For the purposes of this report, these patients are referred to as ‘non-compliant.’ Bleeding frequency was affected by compliance, with non-compliant patients also reporting a higher number of bleeds within the last 12 months (mean, 5.9 [median, 4.0]) than those who were compliant (mean, 4.6 [median, 3.0]). Among 45 patients on prophylaxis, more than half (24 [53.3%]) reported being non-compliant at some point, and these had a higher mean (median) number of bleeds than compliant patients (6.3 [3.5] vs 5.0 [3.0] within the last 12 months). Non-compliance was also more common among patients aged ≤ 40 years (among 16 of 20 patients aged ≤ 40 years on prophylaxis, 12 [75.0%] reported non-compliance) than among patients aged > 40 years (29 of 43 patients aged > 40 years were on prophylaxis, and 14 [48.3%] of these patients were non-compliant) and among patients with severe haemophilia (57.5%) than among those with moderate disease (33.3%). However, compliance did not appear to be greatly affected by dosing frequency, with similar proportions of patients on twice-weekly and 3–4 times-weekly regimens reporting non-compliance.

FVIII product storage

Forty-two of 53 (79.2%) patients answering the questionnaire reported that they stored their FVIII products in a refrigerator. While 52/56 (92.9%) patients reported that they had been informed about product storage by a health care professional, the majority also believed that FVIII products should always be stored at temperatures ≤ 25 °C (49/54 [90.7%]), and 29/54 (53.7%) believed that FVIII products should always be stored in a refrigerator. Additionally, 25/56 (44.6%) patients were concerned or uncertain about whether their product had been exposed to temperatures > 25 °C, and 23/52 (44.2%) stated that they would like more information about FVIII product storage from their health care provider.

Fifty-five patients answered the question of how product storage affects their daily activities. Over two-thirds of these patients (42 [76.4%]) reported that their daily activities were limited to some degree by perceived storage requirements for FVIII products (i.e., the belief that all FVIII products must be stored in a refrigerator or at least at temperatures lower than 25 °C). Travel, including business and work trips, was the most frequently affected activity (Fig. 1).

Fig. 1
figure 1

Impact of perceived factor VIII storage conditions on daily activities. Percentages are rounded to the nearest whole number

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Treatment satisfaction

Overall, 46/63 (73.0%) patients indicated that treatment satisfaction would be improved by a FVIII product that could be stored at temperatures exceeding 25 °C; the greatest driver of this increased satisfaction would be improved convenience (Fig. 2). From the patients’ perspectives, the most important FVIII product characteristics were dosage frequency, shelf-life out of the refrigerator and method of product preparation/application (Fig. 3).

Fig. 2
figure 2

Expected advantages of a factor VIII product that can be stored at > 25 °C (n = 46 respondents). Percentages represent the proportion of respondents

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Fig. 3
figure 3

Importance of product characteristics from the patient’s perspective. Percentages are rounded to the nearest whole number

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Analysis of the survey results incorporated Kano model methodology to determine patients’ perspectives on FVIII products that can be stored at > 25 °C based on answers to two questions (questions 17 and 18 in Online Resource 1, see ESM). Sixty-one patients answered these questions. A FVIII product that could be stored at temperatures > 25 °C was ‘Attractive’ to 20 (32.8%) of these respondents; 23 (37.7%) indicated that the ability to store FVIII at > 25 °C would have no influence on their satisfaction; and only one patient (1.6%) was in the ‘Reverse’ category, indicating that the ability to store FVIII products at > 25 °C would negatively affect their satisfaction (Fig. 4). There was a relatively high proportion of responses (13 [21.3%]) that contained contradictions (‘Questionable’ category) and therefore could not be included in the analysis.

Fig. 4
figure 4

The Kano model: increase in satisfaction with factor VIII storage at > 25 °C (n = 61 respondents)

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Discussion

In Slovenia, patients with haemophilia A enjoy a relatively high standard of care [20]. In light of this, we conducted a survey to investigate patients’ perspectives and beliefs regarding treatment limitations and treatment satisfaction, particularly with regard to FVIII product storage characteristics. The patients predominantly represented in the survey were adults aged > 18 years with severe haemophilia A, most of whom were on prophylaxis, with a mean of 4.9 bleeds within the last 12 months. It is worth noting that patients on prophylaxis reported a higher number of bleeds within the last 12 months than those receiving on-demand treatment (5.7 and 2.3, respectively). This may be due to the presence of a more severe phenotype and/or joint disease in patients on prophylaxis, along with adherence issues or patients mistakenly attributing pain caused by chronic arthropathy to bleeding (as this was a self-administered patient survey, it was not possible to confirm whether a bleed had occurred or not using ultrasound).

The survey results indicated that almost half (46.4%) of patients had missed, forgotten or delayed their scheduled doses at some point, and it is not surprising that these patients also reported a higher frequency of bleeds. Furthermore, 53.3% of patients on prophylaxis reported non-compliance, and these patients had a higher bleeding rate than patients who were always compliant. However, as the group sizes in this study did not reach the minimum sample size, the data are only illustrative. The high rate of non-compliance was unexpected: in two other surveys recently conducted in Slovenia and Croatia, rates of non-compliance were just 17.0% [21, 22]. It is not possible to directly compare the non-compliance rates between the current survey and the previous two due to differences in methodology; however, the high rate of self-reported non-compliance in the present survey is interesting. It may just be a function of how information was elicited, as ‘non-compliance’ in the current survey did not distinguish between missed, delayed or forgotten doses. In contrast, previous surveys used the VERITAS-Pro questionnaire and thus allowed for more nuanced responses [21, 22].Further investigation may be warranted as numerous factors hinder compliance, including the presence of depressive symptoms [9, 21], and there may be a need to address these factors to improve compliance so that optimal health and quality of life outcomes can be pursued [22, 23].

Another important finding of the survey was that patients may lack understanding of certain key aspects of haemophilia treatment. For instance, there was typically a lack of understanding concerning PK testing, and this might account for the wide variability in trough levels that were reported (0.1–24.0%). This highlights the need to educate patients more effectively about PK parameters, including what they are, why they are measured and what the implications are for ensuring effective treatment and treatment monitoring. Our findings also support those from an earlier survey in which patients believed that FVIII products should always be stored in a refrigerator [16]. Most FVIII products can be exposed to higher temperatures for limited periods (Table 3) [24,25,26,27,28,29,30,31,32,33]; however, 90.7% of respondents believed that FVIII should always be stored below 25 °C, and approximately 93.0% reported that shelf-life (out of the refrigerator) is one of the most important product features. Furthermore, our survey results (including Kano model analysis) suggested that patients’ satisfaction with treatment would be improved by a FVIII product that could be stored at temperatures exceeding 25 °C. A large majority of respondents (92.9%) reported that they had been informed about product storage conditions by healthcare providers but many still trusted only refrigerated storage. This may be particularly true for older patients aged > 50 years (a patient group strongly represented in the survey), perhaps due to the emotional aspects of dealing with haemophilia treatment in the era of plasma-derived concentrates when home treatment was not as readily available as it is today. Furthermore, high treatment costs may also influence patients’ product storage behaviours by encouraging greater caution. While these circumstances all need to be explored further, it may be speculated that many patients generally are aware that FVIII products can be kept outside of the refrigerator for a limited time, but they are reluctant to accidentally expose their FVIII product to higher temperatures in case they compromise its efficacy.

Table 3 Factor VIII products that can be exposed to higher temperatures for limited periods
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The survey also supported previous studies which indicated that storing FVIII products at ≤ 25 °C imposes restrictions and limitations on daily activities, with travel being the most frequently restricted activity [15, 16]. For this reason, possible responses to the question evaluating the impact of product storage conditions on daily activities (question 20 in Online Resource 1, see ESM) were weighted towards travel: of 11 possible answers, six were related to some form of travel. However, this focus on travel in the possible responses may have skewed the findings, such that the association between product storage requirements and daily activities may not have been fully elucidated. Nonetheless, perceived limitations in daily activities may affect not only quality of life but also treatment compliance. In light of this, it is interesting to note that the survey indeed revealed a low compliance rate. While a potential link between these factors can be no more than speculation in the absence of further data, the survey’s findings support previous observations that patients prefer FVIII products with more convenient storage conditions [15].

This survey reveals some aspects of patients’ understanding about their treatment products that cannot be captured during regular clinical visits. The more we understand the patient’s perspectives, the more we can tailor treatment towards the individual’s preferences to improve compliance and overall outcomes [4, 15]. Our findings also highlight the ongoing need for patient education. In Slovenia, some patients—especially younger patients and those with mild-to-moderate disease—do not actively participate in educational initiatives provided by healthcare providers and patient associations, and it is essential to provide education to these patients as well.

A key limitation of our study is that a substantial amount of data was missing for some survey questions, as there was no requirement for respondents to answer all questions. It should also be noted that a substantial proportion of invited patients/caregivers (58%) declined to participate in the survey and therefore the sample size was only 63 respondents. However, these 63 patients represent a large proportion (approximately 29.0%) of the 220 patients with haemophilia A in Slovenia identified by the Annual Global Survey 2019 from the WFH [17]. Further, 52 respondents had severe or moderate haemophilia and thus represented approximately 47% of Slovenian haemophilia patients who have severe or moderate disease and who therefore require treatment. Another limitation of the study is the heterogeneous patient population (patients with both severe and non-severe haemophilia were included, and older patients outnumbered younger adults and adolescents). Together, these factors limit the generalizability of our findings, necessitate caution when interpreting the study data, and preclude proper statistical analysis of causality.

Conclusion

This survey provides further insight into patient perspectives regarding treatment satisfaction and limitations in haemophilia A, with a focus on product storage conditions. Dosing frequency, shelf-life and administration method were reported to be the most important FVIII product characteristics for patients, and many felt restricted in their daily activities (particularly travel) due to the perceived need to store FVIII products at ≤25 °C. As product storage conditions may affect overall treatment satisfaction, ongoing patient education about the correct storage of FVIII products could ultimately play a crucial role in improving compliance and overall health.