Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, 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.# Introduction
Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is an autosomal dominant condition with an estimated prevalence of approximately 1:50,000. It results in random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life (HRQoL), and mortality in the case of laryngeal attacks. The swelling in HAE is a result of impaired regulation of bradykinin synthesis. Bradykinin is a nonapeptide kinin formed from high molecular weight kininogen by the action of plasma kallikrein. Bradykinin is a very powerful vasodilator and increases capillary permeability, constricts smooth muscle and stimulates pain receptors.
HAE can be categorized into 3 different types depending on the level and function of C1inhibitor (C1-INH): type 1(HAE-1), type 2 (HAE-2), and HAE with normal C1-INH function (HAE-nC1INH) previously referred to as type 3 (Table 1). HAE-1 is the most prevalent, representing approximately 85% of cases and results from low antigenic and functional levels of C1-INH. HAE-2 accounts for approximately 15% of cases and is associated with a normal C1-INHprotein level but impaired C1-INH function. C4 is reduced in 98% of cases for both HAE-1 and HAE-2, and nearly 100% of the time during an attack.
HAE-nC1INH (previously referred to as type 3 HAE), is much less prevalent than HAE-1 and HAE-2. The true prevalence is not known as there are no reliable assays to screen for this condition. In about 20% to 25% of identified patients, causative mutations in the gene coding for the coagulation factor XII (F12) have been found (HAE-nC1INH-FXII) whereas in the remaining patients no genetic cause has been identified up to now (HAE-nC1INH-unknown). The exact pathogenesis, however, including the mode of action of the F12 gene mutations and the role of estrogens is still unknown. The lack of laboratory and genetic assays (with the exception of F12 gene mutations) to diagnose HAE-nC1INH, has made the identification of these patients more difficult than patients with HAE-1 or HAE-2. A recent international consensus group has published criteria to make the diagnosis of HAE-nC1INH. These included a history of recurrent angioedema in the absence of concomitant hives or use of medication known to cause angioedema; documented normal or near normal C4, C1-INH antigen and function; and either a F12gene mutation associated with the disease, or family history of angioedema and documented lack of efficacy of chronic high dose non-sedating antihistamine therapy.
Management of HAE can be divided into various approaches. The aim of treatment of acute attacks, also referred to as 'on demand therapy' is to minimize their severity, including potentially fatal upper airway edema, and associated impairment of Quality of Life (QoL). Short term prophylaxis (STP) refers to treatment meant to minimize the risk of attacks when avoidance of potential and known triggers is not possible. Long term prophylaxis (LTP) refers to ongoing treatment of HAE aimed at minimizing the overall number, frequency and/or severity of attacks. The details of specific therapies for these treatment approaches will be discussed in the sections that follow. In addition to the evidence behind the proposed recommendations, the clinical considerations for their implementation will also be discussed. The United States Preventive Services Task Force describes clinical considerations as statements that can help clinicians by offering practical information so they can tailor guideline recommendations to individual patients. This Clinical Consideration section following each recommendation is intended to help place the recommendation into a clinical context.

# Scope and purpose
The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE-1, HAE-2 and HAE-nC1INH. This includes the treatment of attacks, STP, LTP, and recommendations for self-administration, individualized therapy, QoL, and comprehensive care.
The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients.
It is not the intent of this guideline to provide a detailed description of the pathophysiology or nomenclature of HAE which can be found elsewhere. It is also not intended to be prescriptive in its recommendations, but rather to highlight issues that need to be considered when choosing treatments options for patients with a focus on the importance of individualized care.

# Intended audience
The primary target users of this guideline are healthcare providers who are managing patients with HAE-1, HAE-2 and HAE-nC1INH. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, 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.

# Committee members and consensus conference participants
The Canadian Hereditary Angioedema Guideline Committee is a working committee under the umbrella of the Canadian Hereditary Angioedema Network (CHAEN)/ Reseau Canadien d'angioedeme hereditaire (RCAH) http:// chaen-rcah.ca/. Members on this committee included members from CHAEN/RCAH across Canada as well as the President of the Canadian HAE Patient Organization -Hereditary Angioedema (HAE) Canada/Angioedeme Hereditaire (AEH) Canada. The Canadian Hereditary Angioedema Committee was responsible for defining the scope and purpose of the guideline and choosing the international participants. International participants were selected based on their contributions to the HAE literature, relating to HAE and its management, and their expertise in priority areas for this guideline including self-administration, individualized therapy, HRQoL, and comprehensive care. Those identified experts were asked to present a summary of the evidence related to these areas to all conference participants. Conference participants included the CHAEN/RCAH Guideline Committee, international experts, all currently registered members of CHAEN who were able to attend the meeting, the President of HAE/AEH Canada and their designates, President of the international HAE patient group HAEi, Hema-Quebec, and industry representatives. An invitation was extended to representatives of the Provincial/Territorial Blood Coordinating offices.
Representatives from Industry, who manufacture products for the treatment of HAE, were also invited to provide information on their products if required during the meeting. Only medical personnel and general managers were invited but were not present during times when decisions were made. Marketing representatives were excluded.

# Funding and support
Funding for the CHAEN/RCAH Guideline Conference was done through the CHAEN/RCAH. This organization received equal support from 3 companies, who manufacture products for the treatment of hereditary angioedema (CSL Behring, Shire, and ViroPharma -Viropharma was acquired by Shire between the time of the guideline meeting and publication of the Guideline). Requests to procure funding from Provincial and National Government and Blood Agencies were not successful. Funding was used to support rental of the conference facilities, audio-taping, facilitation by an external facilitator, travel to the meeting, accommodation, and foods for all participants except for government agency representatives and patient representatives who were supported by their own agencies. No industry participants were funded by CHAEN/RCAH. No participants at the meeting were compensated for their time except for the Guideline meeting methodologist and facilitator from the Centre of Effective Practice.
The guideline meeting process was aided by a methodologist and a guideline facilitator from the Centre for Effective Practice and supported by HAE/AEH Canada.