Use of a C1 Inhibitor Concentrate in Adults ≥65 Years of Age with Hereditary Angioedema: Findings from the International Berinert^® (C1-INH) Registry

Despite the lifelong nature of HAE and the growing number of individuals aged ≥65 years entering the healthcare system [20, 21], few published data are available on the treatment of HAE among patients ≥65 years [12]. Research focused specifically on the older adult population is important given that medical needs can differ from those of younger adults [11]. By generating a considerable volume of real-world data on the use of pnfC1-INH to treat HAE in 27 older adults through 1701 pnfC1-INH infusions, the findings from the Berinert Registry can help fill this knowledge gap. To our knowledge, the registry data described here are the first to specifically evaluate HAE attack characteristics and pnfC1-INH usage in patients aged ≥65 years.

In examining HAE attack patterns and characteristics, registry data for the older adult population generally paralleled those found among younger adults, with abdominal attacks reported most frequently. Abdominal attacks in the older adult population may be of particular interest, as other GI events that may present as an acute abdomen (e.g., diverticulitis, intestinal perforation) tend to occur more frequently in older individuals. Given the greater risk for anesthesia in this population, the differential diagnosis, inclusive of an abdominal HAE attack, is important. Fewer older adults reported ever having experienced a laryngeal attack. This may reflect a self-selection bias of this population, given the absence of effective, readily available HAE treatments decades ago and an ensuing higher likelihood of death from laryngeal attacks during younger years in this group. No triggering event was indicated for the majority of attacks in older adults. Previous research has identified similar attack patterns in general [22‐25], although the data reflected in the registry are limited to attacks treated with pnfC1-INH. While at least one severe attack was experienced by a majority (88.0 %) of older adults, mild attacks constituted the largest percentage of all documented attacks experienced within the older adult population.

Even in the absence of regulatory approval of pnfC1-INH for prophylactic treatment in the USA, half of older adult registry subjects used pnfC1-INH for this purpose, and two subjects received pnfC1-INH infusions exclusively for prophylaxis. These findings are not unexpected in light of consensus guidelines that recommend C1-INH for long- or short-term prophylaxis [1, 13, 14, 26, 27] and clinical data that support such use [28‐38].

Current dosing recommendations for pnfC1-INH suggest a dose of 20 IU/kg, regardless of patient age [39]. Prior to the current registry analysis, no known research has described pnfC1-INH dosing in older adults. Among older adult subjects in the registry, mean (8.8 IU/kg) and median (6.4 IU/kg) weight-based pnfC1-INH doses were notably lower than the recommended dose and also lower than the mean and median weight-based doses reported for 252 younger adults in the registry (12.9 and 12.5 IU/kg, respectively). Dosing patterns by geographic location identified a trend of lower mean weight-based pnfC1-INH doses for subjects in Europe relative to those in the USA, a pattern that was also demonstrated for the entire registry population, regardless of subject age [18]. Given that the older adult subgroup was skewed heavily toward European subjects, this presents another contributing factor to the relatively low mean pnfC1-INH doses observed in this subgroup as a whole.

Drug dosing in older adults is often approached conservatively given age-related physiologic changes that can influence the pharmacokinetics and pharmacodynamics of drug therapy [11, 40‐43]. Physical changes related to normal aging can be further complicated by the tendency of older adults to manifest comorbid medical conditions requiring concomitant therapy, as reflected by the majority of subjects in this study who were using a variety of medications along with pnfC1-INH. While there is no reason to suspect altered disposition of a naturally occurring therapeutic protein such as pnfC1-INH, the lower mean doses reflected in this subset of registry patients overall may reflect, at least in part, general attitudes about drug usage and conservative dosing strategies in older adults. These findings may also reveal consequences of long-term experience with pnfC1-INH and personalized dosage tailoring in these older patients, especially in European markets where Berinert has been marketed for several decades. Older adults are more likely to be retired and possibly have less stress and more time to focus on managing their disease.

Recent HAE consensus guidelines stress individualization of therapy [13, 14, 27, 44, 45]. The variation in dosing noted in the registry subjects seems to support an apparent lack of ‘one dose fits all’ mindset, regardless of the specific reasons for the lower doses reflected in this older adult subset. While attack treatment efficacy data were not captured as part of the registry, given this real-world setting for pnfC1-INH, it could be assumed that dosing was being tailored in these patients to maintain a satisfactory level of benefit.

Considering the possibly higher-risk status of older adults for drug-related problems due to the aforementioned age-related conditions, determining the safety of real-world use of pnfC1-INH in older patients is of particular interest, and data from the registry confirm the overall safety of pnfC1-INH within this population. Since retrospective data are not a reliable source of safety information, safety analyses in all age groups of the registry were conducted for prospectively recorded events only. In the older adult subgroup, the share of such data was 49.4 % (841 of 1701) of all recorded infusions in 23 of 25 older adults, which still constitutes a sizeable dataset. The observed AE rates for older adult registry subjects were very low, both as events per infusion and as events per subject, and were similar to corresponding rates noted in younger adults in the registry. None of the events were considered related to pnfC1-INH, and there were no reports of TEEs, hypersensitivity, or anaphylaxis. Viral transmission was not prospectively assessed, but there was no evidence that any patient was evaluated for suspected blood-borne viral illness during the registry. As previously noted, the majority of older adults were also receiving concomitant medications during the time of pnfC1-INH administration, thus highlighting safe use even in the presence of multiple concomitant therapies.

Regarding setting of pnfC1-INH administration, recent HAE expert guidelines consistently recommend training and equipping patients for self- or home-based administration of HAE medications, with treatment outside of a healthcare setting providing more timely symptom relief, mitigation of attack severity, lower healthcare costs, and improved quality of life [8, 46‐49]. For older adults, age-related changes in physical or mental capacity and the presence of medical comorbidities could be deterrents to self-administration of intravenous medication. Research has implicated several conditions, including osteoarthritis, vision difficulties, and cognitive impairment, that may negatively affect the elderly population’s self-management of various at-home therapies [12, 43, 50]. However, the registry findings support the safety and feasibility of pnfC1-INH administration outside of a healthcare setting in older adults with HAE. The vast majority (94.6 %) of infusions in older adult registry subjects were administered outside of the healthcare setting, and in 11 of the 27 older adult subjects, all pnfC1-INH administration occurred in a non-healthcare setting. Almost all pnfC1-INH infusions administered outside of a healthcare setting in older adults were reported as self-infusion; one infusion in one subject was documented as given by a caregiver.

Subjects within the group receiving pnfC1-INH outside of the healthcare setting had a wide range of number of infusions (from 1 to 612), suggesting achievability of self-administration regardless of attack frequency. This substantiates research identifying the skill of self-infusion as a long-term competency in patients with HAE, and time between attacks should not exclude patients from the option of self-administration [49]. While four older adults experienced at least one change in infusion setting from non-healthcare setting to healthcare setting, there were no recorded instances of difficulty with pnfC1-INH infusion being the reason for any of these instances. The rates of AEs remained low regardless of treatment setting and corroborate reports indicating the high safety profile of pnfC1-INH administration outside of a healthcare setting [51, 52]. While every patient should be assessed individually before being considered a candidate for home-based HAE treatment, the registry findings support the supposition that age itself should not preclude the option of self-managed intravenous pnfC1-INH therapy. Numerous studies have noted a marked increase in overall health and treatment adherence when care is patient driven [16, 41‐43, 49, 50, 53]. During a stage of life when independence is often threatened, the autonomy derived from medication self-administration can foster a sense of control in older adults, thereby improving morale and quality of life.

The data from this registry analysis are subject to several limitations. Inherent to the observational nature of the study, there was no control group (other than younger age groups) and no governance over pnfC1-INH usage or dosing patterns, all of which were determined by the treating physicians according to local standards of care. As such, patterns of individual usage varied widely, including the number of infusions per subject. Data were limited by what was gathered by the treating physician, and AEs for retrospective infusions were not reported. Furthermore, only HAE attacks treated with pnfC1-INH were recorded. The generalizability of the findings is limited by the racial homogeneity of the population, the relatively small sample size (although sizable for a rare disease subgroup), voluntary nature of participation. Finally, the nature of the registry data precluded analysis of attack treatment efficacy.