Contact System Activation and Bradykinin Generation in Angioedema: Laboratory Assessment and Biomarker Utilization.

The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1INH, plasma kallikrein activation, and cleavage of high-molecular-weight kininogen have each been associated with disease activity. More recently, HAE with normal levels of C1INH (HAE-nl-C1INH) has been recognized. Six genetic mutations have been identified which are linked to HAE-nl-C1INH phenotypes. The majority of individuals with HAE-nl-C1INH fall into the unknown category. There is substantial evidence that bradykinin generation underlies the recurrent attacks of swelling in some of these cohorts.

The Disease Burden of Hereditary Angioedema: Insights from a Survey in French-Canadians from Quebec.

Background: Limited data are available on the clinical profile and disease burden of hereditary angioedema (HAE) in Canadians. Objective: This study aimed to assess HAE disease characteristics and the burden of disease in Canadians with HAE types I, II, and normal levels of C1 inhibitor (nC1-INH). Materials and Methods: A 46-item patient survey evaluating clinical characteristics and burden of disease was developed and disseminated by the HAE patient organization Angio-oédeme héréditaire du Québec in Quebec, Canada, from May 2019 to February 2020. The survey received Research Review Board ethics approval. Results: In the 35 respondents, HAE type I was the most common (46%), followed by nC1-INH (43%). Female participants were significantly younger at first symptom presentation than males (p=0.04). Prior to diagnosis, 69% of participants underwent unnecessary treatments and procedures, with a 10-year delay between first symptoms and diagnosis. Before starting the current treatment, 42% of participants experienced weekly HAE attacks. Most participants identified experiencing attacks in the abdomen (89%), followed by the larynx (66%), feet (66%), hands (63%), and face (63%). Most attacks were severe or moderate, yet almost half of patients waited >1 hr before getting medical attention at their last emergency department (ED) visit. HAE was associated with decreased health-related quality of life, leading to significant functional impairment in personal and professional life. As compared to HAE type I/II, patients with HAE nC1-INH were treated more often with tranexamic acid for long-term prophylaxis, and their condition was less controlled, resulting in more attacks and ED visits. Conclusion: HAE manifests in this patient population as frequent moderate-to-severe attacks and a high disease burden; the HAE subtype may differentially affect care requirements. There is an urgent need for increased awareness and education on HAE among treating physicians.

Consequences of Insurance Coverage Delays and Denials for Patients With Hereditary Angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially fatal genetic disease associated with recurrent and unpredictable episodes of angioedema. Although modern therapies have dramatically increased quality of life, insurance changes, delays, and denials are becoming more common. OBJECTIVE: To examine the impact of insurance delays and denials on patient health and well-being. METHODS: A total of 20 patients with HAE (type 1 and 2) who recently experienced insurance delays or denials completed an online survey, and 19 participated in a follow-up focus group. The survey and focus group addressed the impact of insurance challenges on the use of health care services, work/school attendance, and anxiety. Three independent reviewers coded each focus group transcript using a thematic saturation approach. RESULTS: A total of 70% of participants reported an increased frequency of angioedema attacks resulting from insurance delays or denials. More than 50% missed work/school days because of increased attacks, and 90% reported greater anxiety. Twenty-five percent of respondents reported more urgent care or emergency department visits. In focus groups, participants identified specific ways that losing access to medication had a negative impact on their health, family, and work/school life. Insufficient notification of health insurance policy changes and the time and effort required to regain access to medications compounded patients' frustration and anxiety. CONCLUSION: Insurance delays and denials have significant impacts on individuals with HAE including (1) increased urgent care and emergency department visits, (2) missed work/school days, (3) higher levels of anxiety, and (4) a negative impact on family life.

Real-world changes in costs over time among patients in the United States with hereditary angioedema on long-term prophylaxis with lanadelumab.

AIMS: Investigate trends in paid lanadelumab costs over time in a population of patients persistent for 18 months, and to understand overall hereditary angioedema (HAE) treatment cost trends, including costs of acute medication/short-term prophylaxis and supportive care. Lastly, we sought to describe the proportion of lanadelumab patients with evidence of down titration via changes in total paid amounts for lanadelumab in a fixed time period. METHODS: Patients were identified in the Merative MarketScan Databases who had ≥1 claim for lanadelumab during 1/1/2018-6/30/2022 (index), a ≤ 60-d gap in days of supply over 18 months, and were enrolled for ≥6 months pre-index and 18 months post-index. Lanadelumab and HAE-specific costs were assessed during follow-up months 0-6, 7-12, and 13-18. Down titration was defined as a ≥ 25% decrease in lanadelumab costs from months 0-6 to months 7-12 or 13-18. Outcomes were compared between time periods using paired t-tests and McNemar's test. RESULTS: Fifty-four lanadelumab users were included; 25 (46%) had evidence of down titration. Lanadelumab costs decreased from $316,724 to $269,861 to $246,919 in months 0-6, 7-12, and 13-18, respectively (p < .01); total HAE treatment costs decreased from $377,076 to $329,855 to $286,074 in months 0-6, 7-12, and 13-18, respectively (p < .01). LIMITATIONS: Persistence was determined via days of supply on medication claims; use of the medication was not confirmed. Down titration was based on costs; the lanadelumab regimen could not be assessed. Results may not be generalizable to uninsured patients or those without commercial or Medicare insurance. CONCLUSIONS: Patients on long-term prophylaxis with lanadelumab experienced a significant reduction (24%) in HAE treatment costs over 18 months, driven by lower costs of acute medications and lanadelumab down titration. Down titration among appropriate patients with controlled HAE may lead to substantial savings in healthcare costs.

The Disease Burden and Societal Costs of Hereditary Angioedema.

BACKGROUND: According to the current treatment guidelines, the goals of treatment of patients with hereditary angioedema (HAE) are to achieve total control of the disease and to normalize patients' lives. OBJECTIVE: This study aims to establish the entire burden of HAE comprising disease control, treatment satisfaction, reductions in quality of life, and societal costs. METHODS: Adult patients with HAE under treatment at the Dutch national center of reference completed a cross-sectional survey in 2021. The survey consisted of different questionnaires: angioedema-specific questionnaires (4-week Angioedema Activity Score and Angioedema Control Test), quality of life questionnaires (Angioedema Quality of Life [AE-QoL] questionnaire and EQ-5D-5L), the Treatment Satisfaction Questionnaire for Medication (TSQM), and societal costs questionnaires (iMTA Medical Consumption Questionnaire and iMTA Productivity Cost Questionnaire). RESULTS: The response rate was 78% (69 of 88). The entire sample had a mean Angioedema Activity Score of 16.61, and 36% of participants had poorly controlled disease as expressed by the Angioedema Control Test. The mean quality of life in the entire sample was 30.99 as expressed by the AE-QoL and 0.873 as expressed by the EQ-5D-5L utility value. Utilities dropped by 0.320 points during an angioedema attack. TSQM scores ranged from 66.67 to 75.00 across its 4 domains. On average, total costs per year incurred €22,764, predominantly existing of HAE-medication costs. Total costs showed substantial variation between patients. CONCLUSIONS: This study describes the entire burden of HAE among Dutch patients comprising disease control, quality of life, treatment satisfaction, and societal costs. These results can inform cost-effectiveness analyses that can aid reimbursement decisions for HAE treatments.

Living With Hereditary Angioedema in Australia: Findings From a National Observational Study Using Short Message Service to Monitor the Burden of Disease.

BACKGROUND: To understand the impact and burden of disease experienced by patients with hereditary angioedema (HAE). OBJECTIVE: To determine whether the use of short message service (SMS) to communicate with patients with HAE facilitates the collection of attack rate, medication use, and quality of life measurements. METHODS: Patients aged 12 years and older with doctor-confirmed HAE C1-inhibitor deficiency types I and II were invited to participate. We devised a novel method for monitoring attacks by using questions weekly via SMS to gain a more accurate picture of the burden of HAE in Australian patients in real time. RESULTS: A total of 2,648 weekly SMS messages were sent to 47 participants; 1,892 responses were received (71%). Participants reported 463 attacks across all treatment groups. Sixty percent of attacks were treated. Icatibant and C1-inhibitor concentrate were administered IV for 210 and 67 attacks, respectively. Of the 463 recorded attacks, 23 necessitated presentation to the hospital (5%), predominantly for facial and/or throat swelling. Several participants reported attacks (n = 186), which they chose not to treat. Most of those attacks were rated mildly severe. Twenty-one participants reported lost days owing to HAE attacks (44.7%). Fifty-eight attacks (17%) resulted in time away from work or school, equating to a total of 85.5 days lost. CONCLUSIONS: This study was a first of its kind, real-world, prospective, observational study of Australian patients living with HAE. Despite the availability of effective on-demand therapies, HAE remains burdensome. Wider access to safe and effective prophylactic therapies is needed for patients living with HAE.

Challenges in the management of hereditary angioedema in urban and rural settings: Results of a United States survey.

BACKGROUND: Caring for patients with hereditary angioedema (HAE), especially rural patients, has challenges. OBJECTIVE: To confirm experiences of allergy and immunology health professionals in diagnosing and treating patients with HAE, including those living in rural settings. METHODS: An online survey of 2996 members of the American College of Allergy, Asthma, and Immunology was conducted in April 13 to May 3, 2022. Eligible participants were association members (physician, fellow, or allied health professional members) currently practicing allergy or immunology, in the United States, seeing or treating at least 1 patient with HAE yearly. RESULTS: A total of 138 responders saw an average of 9 patients with HAE yearly; 12% of the patients resided in a rural area. They reported that 66% of their patients with HAE had type I, 15% type II, and 19% HAE C1nl-INH. Misdiagnosis was the top diagnostic challenge reported (82%). Inability to afford treatment was the top treatment challenge (76%). Other observations include the sentiment that patients with HAE with government insurance are at a disadvantage because it is not accepted by many specialists who treat HAE (64%) and that better payments for drugs from Medicaid and Medicare (57%) and better payments to providers from Medicaid and Medicare (49%) could better support the treatment of patients in rural settings. Responders expressed a preference for therapies administered at home (72%). Since the coronavirus disease 2019 pandemic, 86% of the respondents used telehealth for appointments occasionally. CONCLUSION: Our findings illustrate the challenge of diagnosing HAE, especially HAE C1nl-INH, and the economic challenges of treatment, which can be compounded for those living in rural areas. We provide a call to action for addressing several of these real challenges.

Epidemiology, Management, and Treatment Access of Hereditary Angioedema in the Asia Pacific Region: Outcomes From an International Survey.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease with significant morbidity and mortality for which early diagnosis and effective therapy are critical. Many Asia Pacific (AP) countries still lack access to diagnostic tests and evidence-based therapies. Epidemiologic data from the AP is needed to formulate regional guidelines to improve standards of care for HAE. OBJECTIVE: To investigate the estimated minimal prevalence, needs, and potential interventions for the diagnosis and management of HAE in the AP. METHODS: A structured questionnaire was distributed to representative experts from member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology. Patient profiles and the presence of diagnostic facilities or tests, regional and national HAE guidelines, and patient support groups were reported and compared. RESULTS: Completed questionnaires were received from 14 representatives of 12 member countries and territories, representing 46% of the world population. Overall minimal prevalence of HAE in the AP region was 0.02/100,000 population, with significant heterogeneity across different centers. Only one-half and one-third had registered on-demand and prophylactic medications, respectively. Few had patient support groups (58%) or regional guidelines (33%), and their existence was associated with the availability of HAE-specific medications. Availability of C1-inhibitor level testing was associated with a lower age at HAE diagnosis (P = .017). CONCLUSIONS: Hereditary angioedema in the AP differs from that in Western countries. Hereditary angioedema-specific medications were registered in only a minority of countries and territories, but those with patient support groups or regional guidelines were more likely to have better access. Asia Pacific-specific consensus and guidelines are lacking and urgently needed.

Berotralstat en angioedema hereditario / Berotralstat in hereditary angioedema

INTRODUCCIÓN: El angioedema hereditario es un trastorno genético, de herencia autosómica dominante poco frecuente, que se manifiesta con episodios repentinos y recurrentes de edema cutáneo y mucoso. Cualquier parte del organismo puede verse afectada, sin embargo, los episodios que involucran a la orofaringe o laringe pueden provocar compromiso de las vías respiratorias, asfixia y conducir a la muerte. Los episodios suelen ser autolimitados, con una intensidad creciente durante las primeras 24 horas y posterior remisión espontánea durante los siguientes dos o tres días. Los episodios pueden ser espontáneos o desencadenados por diferentes estímulos, como por ejemplo procedimientos odontológicos. La expresión clínica o fenotipo es muy variable en cuanto a la frecuencia y gravedad de los episodios en distintas personas. Las formas hereditarias de la enfermedad se las dividen fenotípicamente en las que cursan con déficit del inhibidor del complemento 1 esterasa (C1-INH) y mutación en el gen SERPING1, y las que no presentan déficit. En ambas formas se puede observar un aumento en la producción de bradiquinina que se une al receptor de bradquininas tipo 2 de (RB2) que conduce a un aumento de permeabilidad vascular localizado y angioedema. El diagnostico de angioedema hereditario se basa en la sospecha clínica basada en episodios recurrentes de angioedema cutáneo, dolor abdominal o edema laríngeo recurrente, sobre todo si se añaden antecedentes familiares de síntomas similares, que se debe confirmar mediante determinaciones de laboratorio. Concentraciones bajas de C4 y del C1-INH, asociado una disminución de la actividad funcional de C1-INH, permiten diagnosticar el déficit de C1-INH con valores elevados de especificidad y valores predictivos positivos. El manejo terapéutico se divide en el tratamiento de la crisis y en la profilaxis a corto y largo plazo. El objetivo de la profilaxis a largo plazo es la disminución de la frecuencia, la gravedad y la duración de los ataques. No existe consenso sobre las indicaciones para iniciar profilaxis a largo plazo debiéndose considerar la frecuencia, gravedad y la calidad de vida de los pacientes ante los ataques. Un consenso internacional considera que estaría indicada cuando, a pesar de un tratamiento optimizado, el paciente presenta más de 12 episodios moderados o graves al año o está afectado por la enfermedad más de 24 días/año. Dentro de las recomendaciones enumeran diferentes medidas generales (como evitar la toma de estrógenos o fármacos con acción estrogénica e inhibidores de la enzima convertidora de angiotensina), y distintas opciones terapéuticas farmacológicas (andrógenos atenuados, antifibrinolíticos, etc.). TECNOLOGÍA: Berotralstat es un inhibidor de la enzima plasmática llamada calicreína. La calicreína es la encargada de la liberación de bradiquinina, un potente vasodilatador que aumenta la permeabilidad vascular. En los pacientes con angioedema hereditario por deficiencia o disfunción del C1-INH, la regulación normal de la actividad de la calicreína plasmática está alterada, lo que provoca aumentos de bradicinina que conduce a la crisis de angioedema. OBJETIV: O El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de berotralstat para el tratamiento de personas con angioedema hereditario. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. En PubMed se utilizó la estrategia de búsqueda que se detalla en el Anexo I. La fecha de búsqueda de información fue hasta el 28 de octubre de 2022. Para la búsqueda en Pubmed se utilizó la siguiente estrategia de búsqueda: (berotralstat [Supplementary Concept] OR berotralstat [tiab] OR BCX7353 [tiab]) AND ("Angioedemas, Hereditary" [MESH] OR "Angioedemas, Hereditary" [tiab] OR Hereditary Angioedema [tiab]). RECOMENDACIONES: En el Reino Unido el Instituto Nacional de Salud y Cuidados de Excelencia del Reino Unido (NICE, su sigla del inglés National Institute for Health and Care Excellence) recomienda el uso de berotralstat como una opción para prevenir ataques recurrentes de angioedema hereditario en personas de 12 años o más, solo si: tienen al menos 2 ataques por mes, y se continua solo si el número de ataques por mes se reduce en al menos un 50% después de 3 meses. Esta recomendación es solo si la empresa proporciona un descuento sobre el precio de lista a través de un acuerdo comercial.(8) En Canadá, la Agencia de Medicamentos y Tecnologías en Salud (CADTH, su sigla del inglés Canadian Agency for Drugs and Technologies in Health) se encuentra actualmente evaluando del medicamento. En referencia a las guías de practica clínicas y recomendaciones, un consenso argentino de expertos para el diagnóstico y tratamiento del angioedema hereditario publicado en el año 2021 no menciona la utilización de berotralstat dentro de las opciones terapéuticas. Las recomendaciones para profilaxis a largo plazo de las crisis de pacientes con AEH tipos I y II incluye el uso de lanadelumab, andrógenos atenuados o acido tranexámico, mientras que en pacientes con AEH nC1-INH menciona al acido tranexámico, las progestinas y los andrógenos atenuados. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización de berotralstat para el tratamiento de personas mayores de 12 años de edad con angioedema hereditario, se basa en un ensayo clínico aleatorizado con pocos participantes. Este estudio demostraría que su utilización, comparado con el uso de placebo, podría disminuir el número de ataques mensuales y su duración al corto plazo. Si embargo, no se observarían mejoras en la calidad de vida de las personas frente a placebo al corto plazo, y se han presentado discontinuaciones del tratamiento por eventos adversos. La seguridad y eficacia de berotralstat frente a otras opciones terapéuticas disponibles no puede ser establecida debido a que no se encontraron estudios que hayan evaluado estas comparaciones. Las agencias regulatorias relevadas han autorizado su comercialización en la indicación evaluada, advirtiendo que no se puede utilizar en el tratamiento de los ataques agudos de la enfermedad. Una recomendación actualizada para Argentina no menciona la tecnología entre las opciones terapéuticas disponibles en la indicación evaluada, mientras que Reino Unido la considera una opción cuando se cumpla el acuerdo de comercial con el productor, que incluye un descuento en el precio de venta. No se hallaron evaluaciones económicas publicadas, aunque el costo estimado del fármaco es muy elevado.

Eficacia y seguridad de ecalantida en el tratamiento de los ataques agudos en pacientes con angioedema hereditario / Efficacy and safety of ecalantide in the treatment of acute attacks in patients with hereditary angioedema

ANTECEDENTES El presente dictamen expone la evaluación de la eficacia y seguridad de ecalantida como tratamiento de los ataques agudos del angioedema hereditario (HAE, sigla del inglés hereditary angioedema). ASPECTOS GENERALES El HAE es una enfermedad genética rara (autosómica dominante), caracterizada por episodios recurrentes de angioedema sin urticaria, que afecta principalmente la piel y mucosas de las vías respiratorias superiores y tracto gastrointestinal (Zuraw 2008). Se desconoce cuál es la prevalencia de esta enfermedad en el Perú, pero a nivel mundial se reporta que el HAE afecta aproximadamente a una de cada 50,000 a 150,000 personas (Roche 2005; Zuraw 2008). TECNOLOGÍA SANITARIA DE INTERÉS: ECALANTIDA La ecalantida (KalbitorTM) es un inhibidor recombinante de la calicreína plasmática humana compuesto por una proteína de 60 aminoácidos que es producida en las células de la levadura Pichia pastoris mediante tecnología de ADN recombinante (Lehmann 2008). Se presenta como una solución isotónica incolora en un vial con una concentración de 10 mg/1 ml de ecalantida (FDA 2014). METODOLOGÍA: La búsqueda de la literatura científica se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de ecalantida en el tratamiento de los ataques agudos de HAE. La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, Cochrane Library y LILACS. Adicionalmente, se revisó la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como el National Institute for ealth and Care Excellence (NICE), la Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), la Scottish Intercollegiate Guidelines Network (SIGN), el Institute for Quality and Efficiency in Health Care (lOWiG), la European Society for Medical Oncology (ESMO), la European % Medicines Agency (EMA), y el Scottish Medicines Consortium (SMC). Finalmente, se TA ealizó una búsqueda manual en el portal ClinicalTrials.govdel National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que sus resultados no hayan sido publicados aún. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de la ecalantida como tratamiento de los ataques agudos del HAE. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). Debido al periodo corto de seguimiento de los ensayos clínicos y la naturaleza reincidente de los ataques agudos, se agregó información al respecto, procedente de dos estudios observacionales. CONCLUSIONES: En el presente dictamen, se evaluó la mejor evidencia científica disponible hasta la actualidad en relación con la eficacia y seguridad de ecalantida en el tratamiento de los ataques agudos de HAE. La ecalantida no tiene autorización de uso de Europa. El fabricante retiró su solicitud de aprobación en el 2011, luego que la EMA le solicitara mayor información. En un documento disponible en la página web de la EMA, se afirma que consideraba que el riesgo beneficio no era favorable. La FDA autorizó el uso de ecalantida, pero debido a la tasa de anafilaxia de 5 %, solicitó un estudio con mayor seguimiento (un año) con el objetivo de evaluar mejor el perfil de seguridad. Sin embargo, este estudio no fue completado y así no se cuenta con información recogida de manera sistemática y prospectiva. La tasa de anafilaxia asociada con el uso de ecalantida es alrededor del 4 %. Todos los pacientes fueron manejados exitosamente con epinefrina, corticoides, antihistamínicos y se resolvieron sin secuelas o fatalidades. Los datos provenientes de dos ECA de fase III comparados con placebo mostraron que ecalantida presentó mayores puntuaciones en las herramientas TOS y MSCS en el tratamiento de los ataques agudos de HAE. Un estudio observacional (DX-88/19) reportó similares resultados a los ensayos y no se observó alguna tendencia de disminución del efecto de la ecalantida, según un número creciente de episodios agudos. Comparado con placebo, la ecalantida ha mostrado beneficio en términos de resolución de síntomas, pero su uso está asociado con un riesgo de anafilaxia. No obstante, los ataques agudos de HAE imponen una carga importante en los pacientes con HAE y pueden poner en riesgo la vida del paciente debido al compromiso aérea en algunos casos. No se cuenta con una alternativa terapéutica en el contexto peruano y la literatura ha mostrado que las reacciones de anafilaxia se resolvieron sin dejar secuelas y usando recursos medicamentos accesibles disponibles, sin necesidad de procedimientos invasivos. Por lo expuesto, el ETS! aprueba el uso de ecalantida para el tratamiento de los ataques agudos en pacientes con HAE, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de dos años a partir de la fecha de publicación. La continuación de dicha aprobación está sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Addressing the individualized needs in hereditary angioedema: managed care strategies to optimize access to care.

Hereditary angioedema (HAE) is a serious, potentially fatal disease of recurrent swelling of various subcutaneous and submucosal tissues throughout the body. Swelling is mediated by uncontrolled regulation of bradykinin, making it pathologically distinct from other forms of angioedema. Diagnosis can be challenging, but distinctions in clinical presentation and laboratory studies can confirm clinical suspicion. Though the disease is rare, the socioeconomic burden of living with and treating HAE is significant for patients and healthcare systems. As a result, there has been a dramatic expansion of treatment options specifically designed for HAE in recent years. Novel treatments are effective in treating swelling attacks, preventing recurrence, and improving patient quality of life. However, significant differences in the risks, benefits, and cost of treatments must be weighed in the determination of clinical protocols to determine optimal utilization of healthcare resources.

Optimization of care for patients with hereditary angioedema living in rural areas.

BACKGROUND: People living in rural areas of the United States experience greater health inequality than individuals residing in urban or suburban locations and encounter several barriers to obtaining optimal health care. Health disparities are compounded for patients with rare diseases such as hereditary angioedema (HAE), an autosomal dominant genetic disorder characterized by recurrent, severe abdominal pain and life-threatening oropharyngeal or laryngeal swelling. OBJECTIVE: To explore the challenges of managing patients with HAE in rural areas and suggest possible improvements for optimizing care. DATA SOURCES: PubMed was searched for articles on patient care management, treatment challenges, rural health, and HAE. STUDY SELECTIONS: Relevant articles were selected and reviewed. RESULTS: Challenges in managing HAE in the rural setting were identified, including obtaining a diagnosis of HAE, easy access to a physician with expertise in HAE, continuity of care, availability of telemedicine services, access to approved HAE therapies, patient education, and economic barriers to treatment. Ways to improve HAE patient care in rural areas include health care provider recognition of the patient with undiagnosed HAE, development of individualized management plans, expansion of telemedicine, effective care at the local level, appropriate access to HAE medication, and increased awareness of patient support and advocacy groups. CONCLUSION: For patients with HAE living in rural areas, optimal care is complicated by health disparities. Given the scarcity with which these topics have been covered in the literature to date, it is intended that this article will serve as the impetus for a range of further initiatives focused on improving access to care.

Lanadelumabe para profilaxia de longo prazo em pacientes com angioedema hereditário / Lanadelumab for long-term prophylaxis in patients with hereditary angioedema

CONTEXTO: O angioedema hereditária (AEH) é uma doença genética, autossômica hereditária, que apresenta edema súbito e pronunciado da subderme ou das membranas mucosas, localizado, não inflamatório, assimétrico, desfigurante e autolimitado, decorrente da vasodilatação e aumento da permeabilidade vascular. Considerada uma doença rara com prevalência de 1:50.000 habitantes. O tratamento profilático de longo prazo, disponível no SUS, é o uso do danazol, mas devido aos efeitos colaterais e a ineficácia, 30%, em parte dos pacientes, um tratamento adicional é necessário. TECNOLOGIA: lanadelumabe (Takhzyro® ). PERGUNTA: A terapia com lanadelumabe é eficaz/efetiva e segura no tratamento profilático de pacientes com 12 anos de idade ou mais com angioedema hereditário após a falha com o uso do danazol? EVIDÊNCIAS CIENTÍFICAS: Foi encontrado um ensaio clínico randomizado, com alta qualidade metodológica, e mostrou que o uso do lanadelumabe diminuiu, significativamente, o número de ataques leves, moderados e graves, sendo em média de 1,97 ataques por mês (IC95% 1,64 a 2,36) para 0,14 a 0,77 ataques por mês dependendo da posologia. Os efeitos adversos foram frequentes, >90% dos pacientes, mas foram leve/moderados. Não houve eventos adversos graves ou morte nos estudos analisados. AVALIAÇÃO ECONÔMICA: Foi realizado uma análise de custo-utilidade (ACU), comparando o lanadelumabe com cuidado padrão (acompanhamento) com uma RCEI de R$ 5.129.661,00 por QALY. Dentre as limitações mais importantes está a descrição da metodologia utilizada para a ACU apresentada e o pressuposto dos dados de eficácia de populações com chance de resposta diferente ao proposto para a incorporação. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A avaliação do impacto orçamentário (AIO) foi apresentada um cenário base e mais dois cenários alternativos com difusão da tecnologia de forma mais rápida e mais lenta. Os valores da AIO variaram de R$205.653.639,50 até R$ 268.277.004,50, sendo a variação o resultado de mais ou menos pacientes fazendo uso da tecnologia a cada ano da projeção. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Após busca estruturada nas bases ClinicalTrials.gov e Cortellis foram detectados 3 tecnologias potenciais para indicação terapêutica em questão: garadacimab (CSL312) com administração via subcutânea, em fase 3 de estudo, vertralstat (BCX7353) com administração via oral, também em fase 3 de estudo e IONISPKK-LRx com administração subcutânea, em fase 2 de estudo. CONSIDERAÇÕES FINAIS: A evidência do uso do lanadelumabe para profilaxia de longo prazo em pacientes com angioedema hereditário, mostra eficácia significativa na diminuição de qualquer evento de angioedema. Os resultados são baseados em um único ensaio clínico randomizado, que tem alta qualidade metodológica, mas um pequeno tamanho de amostra e de curto seguimento, 26 semanas. No entanto, o ensaio clínico teve uma fase de extensão, aberta, incluindo todos os pacientes do ensaio clínico e uma coorte nova para uso do lanadelumabe por período mais longo, mostrando o uso por período mais longo e com efeitos adversos com perfil aceitável. A análise de custo-utilidade mostrou que a tecnologia não é custo-efetiva, com valor incremental muito elevado, e mesmo utilizando dados de eficácia com desfecho para diminuição de qualquer evento de angioedema, o custo do medicamento é elevado, no qual é possível observar o valor calculado do impacto orçamentário para o tratamento de um número pequeno de pacientes. RECOMENDAÇÃO PRELIMINAR: Considerou-se que após apreciação inicial do parecer técnico-científico, as evidências mostram que a tecnologia tem perfil de segurança, mas o benefício de melhora para qualquer evento não ficou entendido que é um desfecho relevante, que justifique a quantidade de recursos dispensada para esta tecnologia. Notavelmente, o modelo econômico apresentado pelo demandante reflete a relação do custo-efetividade da tecnologia. Assim, a Conitec em 08/04/2021, recomendou a não incorporação no SUS do lanadelumabe para profilaxia de longo prazo em pacientes com angioedema hereditário com 12 anos de idade ou mais, que falharam ao uso da profilaxia de longo prazo disponível no SUS. CONSULTA PÚBLICA: O relatório de recomendação inicial da Conitec foi disponibilizado para contribuições por meio da consulta pública nº 33 entre os dias 11/5/2021 e 31/5/2021. Foram recebidas 119 contribuições, sendo 25 contribuições de cunho técnico-científico e 94 contribuições de experiência pessoal ou opinião, que podem ser resumidas em 4 pontos: medo da crise/Angustia/Óbito, qualidade de vida, poucas opções de tratamento e efeitos colaterais do uso do danazol. As contribuições técnico-científica adicionaram informação de subgrupos de pacientes, relacionado a uso prévio de profilaxia de longo prazo ao experimento com lanadelumabe, além de nova proposta do valor de venda da tecnologia ao SUS. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 98ª Reunião Ordinária, no dia 09/06/2021, deliberaram, por unanimidade, recomendar a não incorporação do lanadelumabe para o tratamento profilático de longo prazo do angioedema hereditário em pacientes com 12 anos ou mais. Os membros da CONITEC consideraram que a adição de evidências de subgrupos de pacientes que experimentaram diferentes tratamentos profiláticos antes de serem submetidos ao uso de lanadelumabe não adiciona informação para a discussão de desfechos clinicamente relevantes, e mesmo com a nova proposta de redução de preço do frasco do lanadelumabe, o custo do tratamento em relação a eficácia alcançada mostrou-se com uma razão de custo-utilidade incremental expressiva, aquém das possibilidades de ser uma tecnologia eficiente para o SUS. Assim, foi assinado o Registro de Deliberação nº 628/2021. DECISÃO: Não incorporar o lanadelumabe para profilaxia de longo prazo em pacientes com angioedema hereditário, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 44, publicada no Diário Oficial da União nº 129, seção 1, página 81, em 12 de julho de 2021.

Lanadelumabe para profilaxia de longo prazo em pacientes com angioedema hereditário / Lanadelumab for long-term prophylaxis in patients with hereditary angioedema

CONTEXTO: O angioedema hereditária (AEH) é uma doença genética, autossômica hereditária, que apresenta edema súbito e pronunciado da subderme ou das membranas mucosas, localizado, não inflamatório, assimétrico, desfigurante e autolimitado, decorrente da vasodilatação e aumento da permeabilidade vascular. Considerada uma doença rara com prevalência de 1:50.000 habitantes. O tratamento profilático de longo prazo, disponível no SUS, é o uso do danazol, mas devido aos efeitos colaterais e a ineficácia, 30%, em parte dos pacientes, um tratamento adicional é necessário. TECNOLOGIA: lanadelumabe (Takhzyro®). PERGUNTA: A terapia com lanadelumabe é eficaz/efetiva e segura no tratamento profilático de pacientes com 12 anos de idade ou mais com angioedema hereditário após a falha com o uso do danazol? EVIDÊNCIAS CIENTÍFICAS: Foi encontrado um ensaio clínico randomizado, com alta qualidade metodológica, e mostrou que o uso do lanadelumabe diminuiu, significativamente, o número de ataques leves, moderados e graves, sendo em média de 1,97 ataques por mês (IC95% 1,64 a 2,36) para 0,14 a 0,77 ataques por mês dependendo da posologia. Os efeitos adversos foram frequentes, >90% dos pacientes, mas foram leve/moderados. Não houve eventos adversos graves ou morte nos estudos analisados. AVALIAÇÃO ECONÔMICA: Foi realizado uma análise de custo-utilidade (ACU), comparando o lanadelumabe com cuidado padrão (acompanhamento) com uma RCEI de R$ 5.129.661,00 por QALY. Dentre as limitações mais importantes está a descrição da metodologia utilizada para a ACU apresentada e o pressuposto dos dados de eficácia de populações com chance de resposta diferente ao proposto para a incorporação. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A avaliação do impacto orçamentário (AIO) foi apresentada um cenário base e mais dois cenários alternativos com difusão da tecnologia de forma mais rápida e mais lenta. Os valores da AIO variaram de R$205.653.639,50 até R$ 268.277.004,50, sendo a variação o resultado de mais ou menos pacientes fazendo uso da tecnologia a cada ano da projeção. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Após busca estruturada nas bases ClinicalTrials.gov e Cortellis foram detectados 3 tecnologias potenciais para indicação terapêutica em questão: garadacimab (CSL312) com administração via subcutânea, em fase 3 de estudo, vertralstat (BCX7353) com administração via oral, também em fase 3 de estudo e IONISPKK-LRx com administração subcutânea, em fase 2 de estudo. CONSIDERAÇÕES FINAIS: A evidência do uso do lanadelumabe para profilaxia de longo prazo em pacientes com angioedema hereditário, mostra eficácia significativa na diminuição de qualquer evento de angioedema. Os resultados são baseados em um único ensaio clínico randomizado, que tem alta qualidade metodológica, mas um pequeno tamanho de amostra e de curto seguimento, 26 semanas. No entanto, o ensaio clínico teve uma fase de extensão, aberta, incluindo todos os pacientes do ensaio clínico e uma coorte nova para uso do lanadelumabe por período mais longo, mostrando o uso por período mais longo e com efeitos adversos com perfil aceitável. A análise de custo-utilidade mostrou que a tecnologia não é custo-efetiva, com valor incremental muito elevado, e mesmo utilizando dados de eficácia com desfecho para diminuição de qualquer evento de angioedema, o custo do medicamento é elevado, no qual é possível observar o valor calculado do impacto orçamentário para o tratamento de um número pequeno de pacientes. RECOMENDAÇÃO PRELIMINAR: Considerou-se que após apreciação inicial do parecer técnico-científico, as evidências mostram que a tecnologia tem perfil de segurança, mas o benefício de melhora para qualquer evento não ficou entendido que é um desfecho relevante, que justifique a quantidade de recursos dispensada para esta tecnologia. Notavelmente, o modelo econômico apresentado pelo demandante reflete a relação do custo-efetividade da tecnologia. Assim, a Conitec em 08/04/2021, recomendou a não incorporação no SUS do lanadelumabe para profilaxia de longo prazo em pacientes com angioedema hereditário com 12 anos de idade ou mais, que falharam ao uso da profilaxia de longo prazo disponível no SUS. CONSULTA PÚBLICA: O relatório de recomendação inicial da Conitec foi disponibilizado para contribuições por meio da consulta pública nº 33 entre os dias 11/5/2021 e 31/5/2021. Foram recebidas 119 contribuições, sendo 25 contribuições de cunho técnico-científico e 94 contribuições de experiência pessoal ou opinião, que podem ser resumidas em 4 pontos: medo da crise/Angustia/Óbito, qualidade de vida, poucas opções de tratamento e efeitos colaterais do uso do danazol. As contribuições técnico-científica adicionaram informação de subgrupos de pacientes, relacionado a uso prévio de profilaxia de longo prazo ao experimento com lanadelumabe, além de nova proposta do valor de venda da tecnologia ao SUS. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 98ª Reunião Ordinária, no dia 09/06/2021, deliberaram, por unanimidade, recomendar a não incorporação do lanadelumabe para o tratamento profilático de longo prazo do angioedema hereditário em pacientes com 12 anos ou mais. Os membros da CONITEC consideraram que a adição de evidências de subgrupos de pacientes que experimentaram diferentes tratamentos profiláticos antes de serem submetidos ao uso de lanadelumabe não adiciona informação para a discussão de desfechos clinicamente relevantes, e mesmo com a nova proposta de redução de preço do frasco do lanadelumabe, o custo do tratamento em relação a eficácia alcançada mostrou-se com uma razão de custo-utilidade incremental expressiva, aquém das possibilidades de ser uma tecnologia eficiente para o SUS. Assim, foi assinado o Registro de Deliberação nº 628/2021. DECISÃO: Não incorporar o lanadelumabe para profilaxia de longo prazo em pacientes com angioedema hereditário, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 44, publicada no Diário Oficial da União nº 129, seção 1, página 81, em 12 de julho de 2021.

Caregivers' role in managing hereditary angioedema and perceptions of treatment-related burden.

Hereditary angioedema (HAE) is a rare genetic disease that results in recurrent, debilitating, and potentially life-threatening swelling episodes in the extremities, genitals, gastrointestinal tract, and upper airway. Patients can experience significant burdens related to their disease. Informal or familial caregivers often support patients with HAE and likely share in the disease-related burdens, although there are limited HAE caregiver-focused reports in the scientific literature. In the United States, we conducted an online survey of adults caring for an individual with HAE to better understand their experiences with the disease and identify psychosocial impacts of providing care for a patient with HAE. Thirty caregivers provided responses to the survey. Most caregivers were family members of the care recipient and many had HAE themselves. Caregivers reported participating in a number of medical-related tasks and experiencing some burdens as a result of caring for a person with HAE.

Indirect Comparison of Lanadelumab and Intravenous C1-INH Using Data from the HELP and CHANGE Studies: Bayesian and Frequentist Analyses.

BACKGROUND: Hereditary angioedema (HAE) with C1-esterase inhibitor (C1-INH) deficiency is a rare disease associated with painful, potentially fatal swelling episodes affecting subcutaneous or submucosal tissues. HAE attacks recur with unpredictable severity and frequency throughout patients' lives; long-term prophylaxis is essential for some patients. In the absence of head-to-head studies, indirect treatment comparison (ITC) of long-term prophylactic agents is a valid approach to evaluate comparative efficacy. METHODS: We conducted an ITC using data from the placebo-controlled HELP study (assessing patients receiving lanadelumab 300 mg every 2 or 4 weeks) and the 12-week, parallel arm, crossover CHANGE study (assessing intravenous C1-INH). Outcomes of interest were attack rate ratio (ARR) and time to attack after day 0 (TTA0) and after day 70 (TTA70). Two ITC methodologies were used: a Bayesian approach using study results to update non-informative prior distributions to posterior distributions on relative treatment effects, and a frequentist approach using patient-level data from HELP and CHANGE to generate Poisson regressions (for ARR) and Cox models (for TTA0 and TT70). RESULTS: Both Bayesian and frequentist analyses suggested that lanadelumab reduced HAE attack rate by 46-73% versus intravenous C1-INH. Relative to intravenous C1-INH, risk of first attack after day 0 was comparable between intravenous C1-INH and both lanadelumab doses; risk of first attack after day 70 was reduced by 81-83% with lanadelumab 300 mg every 2 weeks, compared with C1-INH. CONCLUSIONS: Findings from these two ITC methodologies support the favorable efficacy of lanadelumab in reducing the HAE attack rate and extending attack-free intervals in patients with HAE.

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

BACKGROUND: Hereditary angioedema (HAE) is a rare, debilitating, genetic disease characterized by unpredictable, recurrent, and potentially fatal swelling of the skin and mucous membranes. We conducted a noninterventional, cross-sectional, web-based survey of patients with a self-reported diagnosis of HAE type 1/2 in Australia, Austria, Canada, France, Germany, Spain, Switzerland, and the United Kingdom to gain a comprehensive real-world understanding of the characteristics of HAE and its burden from the perspective of the patient. The survey included questions on clinical and demographic characteristics, burden of disease, and treatment. Instruments used to measure patient-reported outcomes included the Angioedema Quality of Life questionnaire (AE-QoL), 12-Item Short-Form Health Survey (SF-12v2), Angioedema Control Test (AECT), Hospital Anxiety and Depression Scale (HADS), and Work Productivity and Impairment questionnaire (WPAI). Data were analyzed with descriptive statistics. RESULTS: A total of 242 patients (67.4% female; mean [range] age 43.8 [18-92] years) completed the survey. The mean (SD) age at first symptoms was 11.5 (8.9) years, while diagnosis occurred at 20.8 (13.2) years. Patients reported a mean (SD) of 12.5 (14.1) attacks in the past 6 months. The most recent attack occurred within the past month in 79.7% of patients; most were of moderate severity, 6.6% affected the larynx, 21.9% lasted ≥ 3 days, and 76.4% were treated with on-demand medication. Hospitalizations and emergency/urgent care visits were highest for patients with more attacks. At the time of the survey, 62.4% of patients were using long-term prophylaxis, including 34.4% using androgens. Moderate to severe anxiety and depression were reported in 38.0% and 17.4% of patients, respectively, as measured using the HADS. The severity of anxiety and depression was associated with poorer quality of life and productivity, measured using the AECT (mean overall score 8.00 [moderate perceived disease control]), AE-QoL, WPAI, and SF-12v2. Scores for AECT, AE-QoL, and WPAI were also worse with a higher number of attacks. CONCLUSIONS: This survey study of a broad international sample of patients with HAE showed that despite the availability of on-demand treatment and long-term prophylaxis for the prevention of attacks, patients across a wide geographical area continue to have high disease activity, likely due to restrictions in the availability of medications or incorrect use. Subsequently, significant disease burden, including impaired quality of life and mental health and decreased productivity, was evident. Increased patient education and access to newer, more effective therapies are needed.

Assessing the cost and quality-of-life impact of on-demand-only medications for adults with hereditary angioedema.

Background: Novel subcutaneous (SC) prophylactic therapies are transforming the treatment landscape of hereditary angioedema (HAE). Although questions are being raised about their cost, little attention has been paid to the cost and quality of life (QoL) impact of using on-demand-only medications. Objective: We assessed the overall economic burden of on-demand-only treatment for HAE and compared patient QoL with patients who received novel SC prophylactic therapies. Methods: US Hereditary Angioedema Association members were invited to complete an anonymous online survey to profile attack frequency, treatment use, and the presence of comorbidities as well as economic and socioeconomic variables. We modeled on-demand treatment costs by using net pricing of medications in 2018, indirect patient and caregiver costs, and attack-related direct billed costs for emergency department admissions, physician office visits, and/or hospitalizations. QoL was assessed by using the Angioedema Quality of Life questionnaire. Results: A total of 1225 patients (31.4%) responded. Of these, 737 adults with HAE (type I or II) met the inclusion criteria and completed the survey. Per patient/year direct costs associated with modeled on-demand-only treatment totaled $363,795, with additional indirect socioeconomic costs of $52,576 per patient/year. The greatest improvement in QoL was seen in patients who used novel SC prophylactic therapies, with a 59.5% (p < 0.01) improvement in median impairment scores versus on-demand-only treatment. In addition, patients who used novel SC prophylactic therapies reported a 77% reduction in the number of attacks each year when compared with those who used on-demand-only treatment. Conclusion: Our real-world patient data showed the cost and QoL burden of HAE treatment with on-demand-only therapy. Use of novel SC prophylaxis can lead to sizeable reductions in attack frequency and statistically significant and clinically relevant improvements in QoL. These data could be useful to clinicians and patients as they consider therapy options for patients with HAE.

Prospective Analysis in Patients With HAE Under Prophylaxis With Lanadelumab: A Real-life Experience.

BACKGROUND AND OBJECTIVES: Patients with the rare disease hereditary angioedema (HAE) suffer from recurrent acute attacks of edema. There is no curative therapy, but the frequency of attacks and quality of life of severely affected patients can be improved by prophylactic therapy. The monoclonal antibody lanadelumab has been approved for routine prophylaxis in patients with HAE since November 2018. PATIENTS AND METHODS: In this prospective assessment, a long-term therapy with lanadelumab was initiated in 12 adult patients with HAE. We analyzed their course of disease 6 months after the start of long-term prophylactic therapy using a validated quality-of-life questionnaire and evaluated the frequency and severity of attacks as well as side effects. Furthermore, the therapy with lanadelumab was compared with the previous medication. RESULTS: To date, our study is the first prospective quality of life analysis in HAE patients under treatment with lanadelumab in real life conditions. Mean attack frequencies were reduced from 6.4 to 0.3 attacks per month and patient in our cohort (P<0.0001). No severe attacks occurred under lanadelumab prophylaxis. In all patients, quality of life increased significantly. CONCLUSIONS: Lanadelumab is an effective but expensive long-term prophylaxis for HAE patients. A favorable side-effect profile has been shown. J Drugs Dermatol. 2020;19(10):978-983. doi:10.36849/JDD.2020.5269.