Survey Reveals Why Many Patients Skip Treatment for Dangerous Swelling Attacks

Hereditary angioedema, or HAE, is one of medicine’s most unpredictable rare diseases. Caused by genetic defects that unleash bradykinin-driven swelling episodes, it strikes without warning, producing painful and sometimes life-threatening attacks of edema in the limbs, face, abdomen, and, most dangerously, the larynx. Effective medications exist to both prevent attacks and stop them once they begin, yet a sweeping new real-world survey suggests that a striking gap has opened between what clinical guidelines recommend and what patients actually do when an attack arrives. The findings, drawn from more than a thousand patients across Europe, Japan, and the United States, expose persistent problems with adherence, convenience, and the quiet decisions patients make to simply endure an attack untreated.

The study, published in the journal Advances in Therapy, analyzed data from the Adelphi Real World HAE Disease Specific Programme, a cross-sectional survey conducted between January 2023 and January 2024. Physicians in France, Germany, Italy, Spain, the United Kingdom, Japan, and the United States completed detailed Patient Record Forms based on medical charts and their clinical judgment, while their patients were invited to fill out independent self-reported questionnaires. In total, 225 physicians provided information on 1,131 patients ranging in age from 3 to 82 years, and 279 adult patients completed the voluntary patient survey. The design allowed researchers to compare what doctors believed was happening with what patients themselves reported, a pairing that rarely exists in rare-disease research and one that revealed telling discrepancies.

The patient population reflected the classic epidemiology of the disease. Most patients in the physician-reported group had HAE type 1, accounting for 75 percent of cases, which stems from a deficiency of the C1 inhibitor protein that normally restrains bradykinin production. A smaller group had HAE with normal C1 inhibitor, a genetically heterogeneous form in which documented mutations appeared in the factor XII, plasminogen, and angiopoietin 1 genes. Roughly half of all patients, whether reported by physicians or by themselves, experienced only one or two attacks in the year before the survey, while about 11 percent of the physician-reported group endured five or more. Most patients were rated as having mild or moderate disease at the time of data collection, and the majority were female, consistent with the known demographics of the disorder.

Yet the survey’s most consequential finding concerned untreated attacks. More than three-quarters of patients were reported to have treated their most recent attack, but among those who did not, the dominant explanation in both groups was the perception that the attack was mild or not severe or limiting. Physicians cited this reason in 54 percent of cases and patients in 59 percent. This matters because current international guidelines, developed jointly by HAE experts and patient organizations, recommend that every attack be considered for on-demand treatment, and that patients carry at least two doses of rescue medication at all times. Swelling attacks can escalate rapidly, and laryngeal involvement, which 23 percent of surveyed patients reported experiencing in the previous year, can obstruct the airway with little warning. The researchers suggest that patients and physicians alike may come to view suboptimal treatment as good enough, a perception that quietly erodes guideline-based care.

Timing emerged as another critical variable. Patients reported waiting an average of 22.4 minutes before administering treatment for their most recent attack, though the range stretched from zero to a full 24 hours. Once treatment began, improvement typically followed within about 95 minutes according to physician reports, with most patients needing only one or two doses. The medications used were dominated by injectable therapies: icatibant, a bradykinin B2 receptor antagonist delivered by subcutaneous injection, accounted for 54 percent of treatments for the most recent attack, while C1 inhibitor concentrates, either plasma-derived or recombinant, accounted for 42 percent. Plasma kallikrein inhibitors made up a small fraction. Nearly all approved HAE therapies except one prophylactic and one on-demand agent require injection or infusion, a delivery burden that the survey identified as a persistent source of dissatisfaction.

Adherence to long-term prophylaxis, the preventive arm of HAE management, showed its own cracks. Forgetting to take medication was the leading reason for suboptimal adherence, cited by 45 percent of physicians and 51 percent of patients, followed by difficulty integrating the medication into daily routines and a reluctance to depend on treatment. Among patients not receiving prophylaxis at all, the main justifications were that attacks were well controlled with on-demand therapy alone or that attack frequency was low. The treatment landscape at the time of the survey was led by lanadelumab, a subcutaneous monoclonal antibody, as the most frequently used prophylactic, and branded icatibant as the most prescribed on-demand medication. Roughly a quarter of patients used prophylaxis only, about a third used on-demand treatment only, and 38 percent used both, while 4 percent had no prescribed treatment.

The unmet needs reported by both groups converged on a single theme: the route of administration. Physicians ranked a different route of administration as the top unmet need for both prophylactic and on-demand therapies, followed by frequent dosing schedules, discomfort upon administration, and injection site reactions. Patients echoed these concerns, with 19 percent disliking injections or experiencing pain, bruising, or burning at injection sites, and 17 percent disliking the need to inject medications in public places. Notably, 84 percent of patients said that, given the choice, they would prefer to take their on-demand medication by mouth. Dissatisfaction with portability outside the home and the inability to treat discreetly underscored how the logistics of injectable therapy shape day-to-day behavior, from adherence to the decision of whether to treat an attack at all.

These preferences are already reshaping the therapeutic pipeline. Berotralstat became the first oral prophylactic approved for HAE, and sebetralstat has emerged as the first oral on-demand treatment, with deucrictibant, an investigational oral bradykinin B2 receptor antagonist, showing promising results in clinical trials for both acute treatment and prevention. Further out, the field is exploring CRISPR/Cas9-based gene editing targeting the kallikrein pathway, short interfering RNAs, and long-acting subcutaneous monoclonal antibodies, all aimed at reducing treatment burden while maintaining or improving efficacy. Physicians surveyed in 2023 and 2024 predicted rising use of berotralstat and lanadelumab in the following months, though the authors caution that the landscape has since evolved rapidly, making those projections a snapshot of a moving target.

The burden data carried a surprising twist. Using validated instruments including the EQ-5D-5L and the Angioedema Quality of Life questionnaire, patients reported high overall quality of life, with a mean utility score of 0.94 and activity impairment of only 17 percent. This contrasts sharply with earlier burden-of-disease studies that documented moderate to severe impairment, and the authors attribute the discrepancy to selection effects: patients were recruited during physician visits and likely had good healthcare access, better-managed disease, and stronger support systems than the broader HAE population. Anxiety and depression were nonetheless the most common comorbidities, affecting 13 percent and 9 percent of patients respectively, with notably higher rates in the United States. A quarter of patients required caregiver assistance, primarily from partners or parents, for medication management, transportation, and household tasks.

The study’s limitations are acknowledged by its authors: the sample was not truly random, patients with poor healthcare access were likely underrepresented, some participating physicians were not HAE specialists, and recall bias may color reports of attacks occurring up to a year earlier. Even so, the central message stands with unusual clarity. Guidelines call for early treatment of every attack and consistent prophylaxis, but real-world behavior is governed by perceived severity, forgotten doses, and the physical and social friction of injections. Until therapies combine injectable-grade efficacy with the convenience of a pill, the gap between what medicine recommends and what patients living with HAE actually do will remain a defining challenge of this rare disease.

Subject of Research: Real-world patient and physician experiences with treatment of hereditary angioedema attacks

Article Title: Patient Experience with Treatment of HAE Attacks: Results from a Real-World Survey of Physicians and Their Patients

Article References: Patient Experience with Treatment of HAE Attacks: Results from a Real-World Survey of Physicians and Their Patients. (n.d.). https://doi.org/10.1007/s12325-026-03790-2

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03790-2

Keywords: hereditary angioedema, angioedema attacks, on-demand treatment, long-term prophylaxis, treatment adherence, patient survey, real-world evidence, bradykinin, icatibant, lanadelumab, oral therapy, rare disease