Clinical characteristics and burden of illness in patients with hereditary angioedema: findings from a multinational patient survey

Hereditary angioedema (HAE) is a rare genetic disease affecting 1.5 in 100,000 people [1]. It results from a deficiency in the level or function of the C1 inhibitor (C1-INH) protein (types 1 and 2, respectively) [2], and is characterized by debilitating attacks of angioedema affecting the skin and mucous membranes. Attacks most commonly affect the extremities, face, abdomen, and larynx; laryngeal attacks are of particular concern, as they are potentially fatal [3].

HAE attacks recur throughout life with unpredictable frequency and severity, and most last several days if untreated [3]. As such, HAE has an extensive short- and long-term impact on patients’ lives [4]. Daily function may be impaired, resulting in reduced productivity or lost days at work or school, which negatively affects advancement and overall well-being [5‐7]. Depression and anxiety were reported in a large proportion of patients with HAE [6]. Fear of future attacks often limits patients’ ability to socialize or travel, and many patients have concerns about their children inheriting HAE [8]. In addition, there is a heavy burden for the families and caregivers of patients [7, 8].

At the time of this study, treatments for HAE included on-demand medications to treat attacks after onset (such as icatibant, C1-INH inhibitor [Berinert® and Cinryze®], and ecallantide), and long- or short-term prophylactic therapy to prevent attacks (such as Cinryze®, androgens, and antifibrinolytics) [9]. However, despite improvements in the available HAE therapies, unmet needs remained; treatments require frequent dosing or intravenous administration, have limited efficacy, or are associated with poor tolerability [10].

While there has been increased interest in trying to better understand the burden of illness in HAE in recent years, key gaps in the literature remain, in particular a comprehensive, real-world understanding of the variability of HAE, its human and economic burdens, and its impact on quality of life directly from the patient’s perspective. A survey was thus conducted in Australia, Canada, and 6 European countries from July to October 2018 to gain this information. The findings from the survey are described herein and may help inform decision-making so that patients’ desired outcomes can be realized.

This study recruited the broadest international sample of patients with HAE from Europe, Australia, and Canada for a patient survey to date. Given the rarity of HAE, the sample size in this study was large and provided an expansive exploration of the burden of illness of HAE across a large geographical area. It is also the first known evaluation of quality of life in patients from Australia, Switzerland, and Austria. The findings in this survey are in agreement with those reported from the related US patient survey [19], and with other evaluations of disease characteristics, burden, and unmet needs in the management of HAE in Europe and Canada [4‐8, 20], confirming that issues faced by patients with HAE are not specific to a geographic region.

Patients reported an average of 25 HAE attacks in the past 12 months, and in almost half of patients, the most recent attack occurred within the last week. The majority of attack symptoms were moderate or severe, and approximately 42% of attacks lasted approximately 2 days or longer, indicating that disease activity remained high even after it was properly diagnosed and treatment was initiated. Notably, diagnosis was delayed by a mean of approximately 10 years across all countries after the first onset of symptoms, indicating a need for increased physician awareness of HAE.

The majority of patients carried on-demand medication at all times in accordance with international guidelines [21], and most attacks were treated with on-demand medication. However, some patients reported that they did not carry any on-demand medication in case of an attack, including patients who were using LTP. This reflects a gap in patient education, and patients should be made aware that breakthrough attacks may still occur during LTP use [22]. This could also result from limitations on the number of spare doses permitted by the patient’s health care system, leading patients to use their supply sparingly and only for more severe attacks [23].

Over half of patients were using LTP to control their attacks. LTP was generally effective, because many patients who used LTP reported few attacks compared with a high proportion of patients who reported many attacks and did not use LTP. Androgens were being used for LTP by over one-third of patients, despite well-documented side effects such as weight gain, virilization, menstrual abnormalities, headaches, and mood changes [24, 25], and tranexamic acid was used by almost 20% of patients, although its efficacy is not firmly established [26, 27]. Caution is recommended in deciding the appropriateness of androgens for LTP for individual patients [25], and guidelines do not support first-line use of tranexamic acid [9, 21]; thus, reasons for their continued use in HAE would be of interest to explore. In particular, the impact of convenience and dose frequency on adherence to oral versus intravenous treatments should be considered.

Interestingly, this survey also found that 20% of patients had used LTP in the past but discontinued. The proportion of past users was greater among patients who reported a high number of attacks in the past 6 months than those with few attacks. Sixteen patients (6.6%) reported using androgens as their most recent LTP, and of these, 3 (18.8%) discontinued based on physician recommendation. Given that almost half of patients reported in the AECT that they were “bothered” by the unpredictability of HAE attacks, and that scores were highest for the fears/shame domain of the AE-QoL (which includes a question about fear of the sudden onset of an attack), safe and effective LTP for prevention of attacks could be of significant benefit. Lower disease activity would also reduce the socioeconomic burden of HAE by decreasing the need for health care resource utilization and increasing work productivity.

Attack frequency was a major determinant of disease burden because quality of life, work productivity, and perception of disease control all worsened as attack frequency increased. Conversely, attack frequency did not affect the severity of anxiety and depression as measured by the HADS, the level of mental health impairment as measured by the SF-12v2, or fears/shame scores as measured by the AE-QoL. Anxiety and depression were, however, important factors contributing to the burden of HAE because patients with more severe anxiety or depression were more likely to show negative outcomes on all the other instruments administered. In particular, attack frequency, along with anxiety and depression, were drivers of poor disease control, as shown by the results from the AECT. Together, these data suggest that because of HAE, patients suffered from impaired mental health, particularly anxiety and depression, regardless of the severity of their disease as measured by the number of attacks. Even low HAE disease activity posed a burden, due to the perceived constant threat of an attack.

The unpredictable nature of HAE attacks may have been an important contributor to this mental health impairment [6], which in turn impacted other aspects of daily life. When asked about comorbidities, 26% of patients self-reported having anxiety, and 17% self-reported having depression. However, on the basis of the HADS subscale scores, 38% were classified as having moderate to severe anxiety and 17% were classified as having moderate to severe depression. This indicates that comorbid anxiety may have been underdiagnosed among patients with HAE.

Despite the clear burden of HAE, patients reported general satisfaction with their current HAE treatment: 73.2% were “satisfied,” “very satisfied,” or “extremely satisfied,” whereas 9.5% were “dissatisfied,” “very dissatisfied,” or “extremely dissatisfied.” Even among patients with ≥ 13 attacks in the past 6 months, 29.9% reported being satisfied to some degree. This response could have resulted from a sense of complacency, especially if resources were limited or other options were not readily available. Furthermore, patients may not have been aware of other treatments that are more tolerable and effective. This apparent discrepancy underlines the value of QoL assessment using validated tools for the management of HAE.

The survey also revealed gaps in patients’ understanding of HAE, as nearly one-third of patients that were screened out of the survey were unaware of which type of HAE they had. Furthermore, there remained some lack of adherence to international treatment guidelines; for example, approximately 5% of patients used tranexamic acid for the acute treatment of their most recent attack, even though guidelines state that such use is not recommended [9, 21].

Despite advances in HAE diagnostic strategies and the availability of more HAE treatment options, findings from this patient survey showed that many patients experienced frequent attacks of moderate to severe intensity, even with use of LTP. HAE imposed a substantial burden on patients in the countries included in this survey, including high levels of anxiety and depression and productivity impairment, even when patients were not having an attack. The findings from this study reflect the continuing need for improvements in care for patients with HAE. Keys to achieving this goal include better adherence to international guidelines, increased education for patients regarding compliance with and proper use of therapy, and more access to efficacious treatments.

This was a noninterventional, cross-sectional, web-based survey of patients with a self-reported diagnosis of HAE. The survey was conducted in Australia, Austria, Canada, France, Germany, Spain, Switzerland, and the United Kingdom. Patients were recruited through PAOs by member organizations of HAE International, an international umbrella organization for HAE patient groups. Local PAOs recruited patients with HAE within each of their respective countries using telephone, email, website advertisements, and social media postings. Patients contacted the PAO, which then provided a brief overview of the study and a link to the survey. The survey was available in each country’s target language. The survey began with screening questions, and patients who passed the screening were required to give consent through the web link before completing the rest of the survey. Patients were compensated with 30 USD by the PAO.

The survey targeted enrollment of 10–90 patients per participating country, as estimated by local PAOs. Patients were ≥ 18 years of age with HAE type 1 or 2, had experienced ≥ 1 HAE attack or instance of prodromal symptoms within the last year, had received HAE medication within the last 2 years to treat an attack, were able to provide consent, and were fluent in the target language. Patients with HAE with normal C1-INH were excluded.

The survey included questions on patients’ medical history of HAE, including time since diagnosis, comorbidities, their most recent angioedema attack, current and past treatments (including use of prophylaxis), and treatment satisfaction. The impact of HAE on health-related quality of life was measured using the AE-QoL [17] and SF-12v2 questionnaires [11, 12]. Four domains (function, fatigue/mood, fears/shame, and nutrition) and a total score were assessed in the AE-QoL; the scoring system ranges from 0 to 100, with higher scores indicating higher levels of impairment and lower quality of life. In the SF-12v2, higher scores indicate better functioning, and the physical and mental health composite scores are normalized to a mean (SD) score of 50 (10) for the general population on both scales. Perceived control of the disease was measured using the AECT [15]. Patients were asked how often they had angioedema, how their quality of life was affected by angioedema, how much the unpredictability of angioedema bothered them, and how well their angioedema had been controlled by therapy. Scores for the responses in the AECT range from 0 to 16, with higher scores indicating better disease control (≤ 9 poorly controlled; ≥ 10 well controlled). The ability to work and participate in regular activities was measured using the WPAI [18]; WPAI scores indicate the percentage of time the patient missed work or was less productive owing to HAE-related complications. Four domains were assessed: absenteeism, presenteeism, work productivity loss, and activity impairment. Mental health was measured using the HADS [13, 14], where total scores range from 0 to 42, with subscale scores ranging from 0 to 21 (0–7 is considered normal, 8–10 mild, 11–14 moderate, and 15–21 high for levels of anxiety or depression). General health and sociodemographic information were also collected.

All data were summarized using descriptive statistics. Subgroups that were analyzed included country, HAE type, number of angioedema attacks in the past 6 months (0 attacks, 1–3 attacks, 4–6 attacks, 7–12 attacks, ≥ 13 attacks), and HADS subscale scores for anxiety and depression (for each subscale, including normal, mild, moderate, and severe).