The International/Canadian hereditary angioedema guideline

International/Canadian HAE guideline gro… · 2026 · international

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Authors: Stephen Betschel, Karen Binkley, Rozita Borici-Mazi et al.
Title: The International/Canadian hereditary angioedema guideline
Journal: Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology, 2026
DOI: 10.1186/s13223-025-00999-8
Licence: CC BY 4.0
Changes: Verbatim excerpts; formatting adapted

Full text retrieved 2026-10-27 from Europe PMC · PMC13123228

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This page reproduces excerpts of the original publication; the original is authoritative. It has not been reviewed by a physician, does not state a recommendation of Medelix and does not replace medical advice. The guideline may have been updated since.

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Recommendations

Verbatim, with grade of recommendation or strength of consensus where given.

Diagnosis of HAE due to C1INH deficiency

1. The diagnosis of HAE due to C1INH deficiency should be made by measuring plasma levels of C1INH antigen or C1INH functionLevel of evidence and strength of recommendation: High, Strong
2. All individuals with a positive family history of HAE should be considered to be at risk of HAE and should be screenedLevel of evidence and strength of recommendation: Consensus, Strong

Acute treatment of HAE due to C1INH deficiency

3. Effective therapies should be used for the acute treatment of attacks of angioedema to reduce duration and severity of attacks. Effective therapies include ecallantide, icatibant, intravenous C1INH (plasma-derived or recombinant), and sebetralstatLevel of evidence and strength of recommendation: High, Strong
4. Attenuated androgens and tranexamic acid should not be used for the acute treatment of attacksLevel of evidence and strength of recommendation: Low, Strong
5. Frozen plasma could be used for acute treatment of attacks if other recommended therapies are not availableLevel of evidence and strength of recommendation: Low, Strong
6. Attacks should be treated early to reduce morbidityLevel of evidence and strength of recommendation: Moderate, Strong
7. Attacks should be treated early to reduce mortalityLevel of evidence and strength of recommendation: Moderate, Strong
8. All attacks of angioedema involving the upper airway are medical emergencies and must be treated immediatelyLevel of evidence and strength of recommendation: Low, Strong

Acute treatment in pregnant, breastfeeding, or lactating patients with HAE

9. pdC1INH is the treatment of choice for angioedema attacks in pregnant patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: Low, Strong
10. rhC1INH can be used for treating angioedema attacks in pregnant patients with HAE due to C1INH deficiency if pdC1INH is not availableLevel of evidence and strength of recommendation: Low, Strong
11. Icatibant may be used to treat angioedema attacks in pregnant patients with HAE due to C1INH deficiency if no other treatment is available or there is no response to pdC1INHLevel of evidence and strength of recommendation: Low, Weak
12. Ecallantide should not be used to treat attacks in pregnant patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: Consensus, Strong
13. pdC1INH is the treatment of choice for angioedema attacks in breastfeeding/lactating patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: Consensus, Strong
14. rhC1INH may be considered for treating angioedema attacks in breastfeeding/lactating patients with HAE due to C1INH deficiency if pdC1INH is not availableLevel of evidence and strength of recommendation: Consensus, Strong
15. Icatibant can be used to treat angioedema attacks in breastfeeding/lactating patients with HAE due to C1INH deficiency, but breastfeeding/lactation should be avoided for 12 h after administrationLevel of evidence and strength of recommendation: Consensus, Strong

Acute treatment of HAE in pediatric patients with HAE due to C1INH deficiency

16. All pediatric patients diagnosed with HAE, including those who are symptom-free, should have access to acute treatmentLevel of evidence and strength of recommendation: Consensus, Strong
17. Intravenous pdC1INH is an effective therapy for the acute treatment of HAE attacks in pediatric patientsLevel of evidence and strength of recommendation: Moderate, Strong
18. Icatibant is an effective therapy for the acute treatment of HAE attacks in children and adolescent patientsLevel of evidence and strength of recommendation: Moderate, Strong
19. Intravenous rhC1INH is an effective therapy for the acute treatment of HAE attacks in children and adolescent patientsLevel of evidence and strength of recommendation: Moderate, Strong
20. Ecallantide is an effective therapy for the acute treatment of HAE attacks in adolescent patientsLevel of evidence and strength of recommendation: Moderate, Strong

Diagnosis of HAE with normal C1INH

21. If the diagnosis of HAE-nC1INH is suspected, a referral should be made to a physician who has expertise with this conditionLevel of evidence and strength of recommendation: Consensus, Strong

Acute treatment of HAE with normal C1INH

22. pdC1INH is an effective therapy for the acute treatment of attacks in patients with HAE-nC1INHLevel of evidence and strength of recommendation: Low, Strong
23. Icatibant is an effective therapy for the acute treatment of HAE attacks in patients with HAE-nC1INHLevel of evidence and strength of recommendation: Low, Strong

Short-term prophylaxis

24. Short-term prophylaxis should be considered prior to known patient-specific triggers and made available for any medical, surgical, or dental procedures in patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: Low, Strong
25. HAE-specific acute treatment should be available during and after any procedures in patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: Consensus, Strong
26. Intravenous pdC1INH or rhC1INH should be used for short-term prophylaxis in patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: Low, Strong
27. Short-term prophylaxis is recommended in the case of a cesarean delivery or intrapartum instrumentation in patients with HAE due to C1INH deficiency. Effective acute therapy should be immediately available for all deliveriesLevel of evidence and strength of recommendation: Consensus, Strong
28. Short-term prophylaxis should be considered prior to known patient-specific triggers and made available for any medical, dental, and surgical procedures for patients with HAE-nC1INHLevel of evidence and strength of recommendation: Consensus, Strong

Long-term prophylaxis in HAE due to C1INH deficiency

29. Long-term prophylaxis should be considered at every visit taking disease activity, burden, control, and patient preference into accountLevel of evidence and strength of recommendation: Consensus, Strong
30. All patients should have a management plan, including immediate access to effective treatment for attacks, even when on prophylaxisLevel of evidence and strength of recommendation: Low, Strong
31. Berotralstat, donidalorsen, garadacimab, lanadelumab, and pdC1INH are effective therapies for long-term prophylaxis in patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: High, Strong
32. Berotralstat, donidalorsen, garadacimab, lanadelumab, or pdC1INH could be used as first-line therapy for long-term prophylaxis in patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: Consensus, Strong

Long-term prophylaxis in pregnant, breastfeeding, or lactating patients with HAE

33. Long-term prophylaxis should be considered in pregnant patients with HAELevel of evidence and strength of recommendation: Consensus, Strong
34. pdC1INH is the treatment of choice for long-term prophylaxis in pregnant patients with HAELevel of evidence and strength of recommendation: Low, Strong
35. Attenuated androgens should not be used in patients with HAE during pregnancyLevel of evidence and strength of recommendation: Consensus, Strong
36. Long-term prophylaxis should be considered in patients with HAE during the breastfeeding/lactation periodLevel of evidence and strength of recommendation: Consensus, Strong
37. pdC1INH is the treatment of choice for long-term prophylaxis in breastfeeding/lactating patients with HAELevel of evidence and strength of recommendation: Consensus, Strong
38. Attenuated androgens should not be used in patients with HAE during the breastfeeding/lactating periodLevel of evidence and strength of recommendation: Consensus, Strong

Long-term prophylaxis in pediatric patients with HAE due to C1INH deficiency

39. When long-term prophylaxis is indicated in neonates and infants (aged 0–2 years), pdC1INH is the treatment of choiceLevel of evidence and strength of recommendation: Consensus, Strong
40. When long-term prophylaxis is indicated in children and adolescents, lanadelumab and pdC1INH are effective treatmentsLevel of evidence and strength of recommendation: Moderate, Strong
41. Berotralstat is an effective therapy for long-term prophylaxis in adolescent patients with HAE due to C1INH deficiencyLevel of evidence and strength of recommendation: Low, Strong
42. Androgens should not be used for long-term prophylaxis in pediatric patientsLevel of evidence and strength of recommendation: Moderate, Strong

Long-term prophylaxis treatment in HAE with normal C1INH

43. Long-term prophylaxis may be appropriate for some patients with HAE-nC1INH. The decision to start a patient on long-term prophylaxis should be individualized between an HAE specialist and the patientLevel of evidence and strength of recommendation: Low, Strong

Self-administration

44. All patients with HAE should be trained on self-administration of HAE-specific therapies if they are suitable candidates. If patients cannot self-administer therapy, provisions should be made to ensure timely access to all appropriate therapiesLevel of evidence and strength of recommendation: Consensus, Strong

Approach to individualized therapy

45. The decision to start or stop long-term prophylaxis depends on multiple factors and should be made by the patient and an HAE specialistLevel of evidence and strength of recommendation: Consensus, Strong

Quality of life

46. Healthcare providers should routinely assess disease control, disease activity, and quality of life in patients with HAE using validated instruments in order to optimize HAE managementLevel of evidence and strength of recommendation: Unable to reach consensus, Strong

Shared decision-making

47. Shared decision-making should be used to create a partnership between the physician and patient focused on individualized careLevel of evidence and strength of recommendation: Consensus, Strong
48. Payers must consider the opinion of the HAE specialist when evaluating reimbursement for treatment of patients with HAE, including HAE-nC1INHLevel of evidence and strength of recommendation: Consensus, Strong

Comprehensive care

49. Comprehensive care for all patients with HAE should be provided to optimize treatment and outcomesLevel of evidence and strength of recommendation: Low, Strong
50. All patients with HAE should be informed about HAE patient associationsLevel of evidence and strength of recommendation: Consensus, Strong

Registries

51. Physicians should actively participate and encourage patients to enrol in an HAE registryLevel of evidence and strength of recommendation: Consensus, Strong

Long-term prophylaxis in HAE due to C1INH deficiency

Recommendation 32Berotralstat, donidalorsen, garadacimab, lanadelumab, or pdC1INH could be used as first-line therapy for long-term prophylaxis in patients with HAE due to C1INH deficiency.Level of Evidence: Consensus (100% Agree) Strength of Recommendation: Strong (95.5% Agree, 4.5% Disagree)

Abstract

This update to the 2019 Canadian Hereditary Angioedema (HAE) Guideline broadens its focus to include the management of patients with HAE worldwide, building on its established international framework. It has been developed through a collaboration of Canadian and international HAE experts and patient groups, coordinated by the Canadian Hereditary Angioedema Network. The objective is to provide evidence-based recommendations, using the Grading of Recommendations Assessment, Development and Evaluation system, for the management of patients with HAE. These include recommendations for the treatment of attacks, short-term prophylaxis, and long-term prophylaxis, as well as recommendations for self-administration, individualized therapy, health-related quality of life, and comprehensive care. New to the 2024 edition are specific recommendations for the treatment of angioedema attacks in individuals with HAE who are breastfeeding/lactating, as well as a dedicated section on shared decision-making. HAE results in spontaneous and often unpredictable attacks of painful swelling, typically affecting the extremities, bowel mucosa, genitals, face, and upper airway. These attacks are associated with significant functional impairment, reduced health-related quality of life, and in the case of laryngeal attacks, a high risk of mortality. Managing HAE is complex, and patient care in Canada, similar to many other countries, remains inconsistent and suboptimal. Care delivery lags behind nations that have implemented more structured management models for HAE, and offer broader access to a wider range of approved therapies. This guideline is intended to be used to optimize HAE management, highlight the importance of individualized care, and provide guidance to healthcare providers, policymakers, patients, and advocates. Primary target users include healthcare providers who are managing patients with HAE, as well as emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, pediatricians, hematologists, dermatologists, and gynecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13223-025-00999-8.

Contents of the original publication

The section headings of the original.

Background
Scope and purpose
Intended audience
Methods
Committee Members, Guideline Authors, and Conference Participants
Identifying the evidence
Summarizing and evaluating the evidence
Recommendation development and approval
Guideline recommendations
Diagnosis of HAE due to C1INH deficiency
Acute treatment of HAE due to C1INH deficiency
Acute treatment in pregnant, breastfeeding, or lactating patients with HAE
Acute treatment of HAE in pediatric patients with HAE due to C1INH deficiency
Diagnosis of HAE with normal C1INH
Acute treatment of HAE with normal C1INH
Short-term prophylaxis
Long-term prophylaxis in HAE due to C1INH deficiency
Long-term prophylaxis in pregnant, breastfeeding, or lactating patients with HAE
Long-term prophylaxis in pediatric patients with HAE due to C1INH deficiency
Long-term prophylaxis treatment in HAE with normal C1INH
Self-administration
Approach to individualized therapy
Quality of life
Shared decision-making
Comprehensive care
Registries
Implementation and future directions
Conclusions

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