Methods
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)/Réseau Canadien d'angioédème héréditaire (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/Angioédème Héréditaire (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.
Conflict of interest
Details of potential conflicts of interest were elicited using the standardized International Committee of Medical Journal Editors Form for Disclosure of Potential Conflicts of Interest (Additional file
1). COI forms were distributed to attendees prior to their reviewing the manuscript, and were mandatory for all contributing authors.
Identifying the evidence
A systematic search of Ovid MEDLINE was conducted by a librarian from the Centre for Effective Practice (KLR) on October 10, 2013, in order to identify clinical trials addressing long-and short-term prophylaxis and treatment of acute attacks in patients of any age diagnosed with HAE-1, HAE-2, or HAE-nC1INH. Outcomes of interest included frequency or severity of attacks, symptom relief and QoL measures as reported or measured by the affected subject or investigator. Studies were limited to English language publications, and there were no limits on the publication date of study other than those imposed by the database (1946-October week 1, 2013). After duplicates were removed, 416 results were found, the abstracts of which were reviewed to determine if they met the inclusion criteria. If unclear from the abstract whether the paper met these criteria, the full-text document was reviewed. One hundred and thirty two results were retrieved and reviewed in full text, and from this, 11 relevant randomized control trials and 34 lower-quality comparative studies without blinding or randomization were identified and included. No studies which met the inclusion criteria were identified for HAE-nC1INH. The full search strategy is available in Additional file
2.
Summarizing and evaluating the evidence
Key information from the included studies such as study design, number of patients, outcome measures, side effects and funding source was extracted into evidence tables for each intervention (see Additional file
3). Evidence tables were provided to the Committee Members and were available for reference at the meeting.
Criteria for determining Levels of Evidence and Strength of Recommendation were adapted from the GRADE system, [
16‐
18] and the process was based primarily on the Journal of Clinical Epidemiology’s 2011–2013 series of articles describing the GRADE methodology. GRADE is considered “outcome centric,” and traditionally recommends a single rating for each outcome across the full body of evidence. The method applied here involved evaluating the quality of each study individually, and then looking at the studies together to assign a Level of Evidence based on the collection of studies.
Each identified randomized control trial was assessed by two reviewers (KL-R, VP) for quality using the Cochrane Risk of Bias Tool [
19]. Any disagreements were resolved by a third reviewer (SB). Randomized trials were initially rated as High quality levels of evidence, with quality being downgraded for evidence of bias on the Cochrane tool and if there was evidence of inconsistency (Additional file
3: Table S1). Non-randomized, non-blinded trials were considered to be Low quality evidence.
Multiple factors were considered when assigning the Strength of Recommendation, including quality of evidence, balance between desirable and undesirable effects, values and preferences, and costs (Additional file
3: Table S2).
Additional file
3 describes additional detail how quality was assessed and the criteria used to determine the Strength of Recommendation. The quality ratings were presented at the meeting during the discussion of draft recommendations. Additional files
4 and
5 list the HAE RCT evidence tables and the lower quality comparison study evidence respectively.
Recommendation development and approval
The Chair (SB) developed draft recommendations based on the identified literature, and presented them to the Committee Members who approved them in draft. Invited Committee Members were assigned specific topic areas and were asked to review the evidence relevant to their topic and present the body of evidence for consideration at the Guideline meeting. After the summary was presented, the Consensus Conference Participants were provided an opportunity to discuss the literature. Following this discussion, the draft recommendation was presented and the group discussed the specific wording of the recommendation before voting anonymously via electronic voting to agree or disagree with the recommendation, or abstain. If 80% consensus was not reached, there was additional group discussion, the recommendation was rephrased, and a new vote conducted. This process was conducted a maximum of 3 times. If 80% consensus was not reached, it was considered that the committee was unable to reach consensus.
Once the phrasing of a recommendation was approved by the group, the proposed Level of Evidence was presented by the methodologist guideline facilitator (High, Moderate, Low, Very Low, or Consensus). The Level of Evidence was then discussed, revised if necessary, and similarly voted on as outlined above.
The suggested Strength of Recommendation (Strong or Weak) was then presented to the group. The methodologist guideline facilitator proposed a Strength of Recommendation based on the Level of Evidence, the balance between desirable and undesirable effects, values and preferences. These factors were discussed amongst the group before voting to accept the proposed Strength of Recommendation. All votes were recorded and presented in real time with the recommendations. Table
2 is a summary of all the recommendations, the level of evidence supporting each recommendation, and the strength of each recommendation.
Table 2
Summary of recommendations
Recommendation
|
Level of Evidence and Strength of Recommendation
|
Treatment of Acute Angioedema Attacks
|
1. Effective therapy should be used to treat acute attacks of angioedema to reduce duration and severity of attacks. | High, Strong |
2. pdC1-INH is an effective therapy for the treatment of acute attacks. | High, Strong |
3. Icatibant is an effective therapy for the treatment of acute attacks. | High, Strong |
4. Ecallantide is an effective therapy for the treatment of acute attacks. | High, Strong |
5. rhC1-INH is an effective therapy for the treatment of acute attacks. | High, Strong |
6. Attenuated androgens should not be used to treat acute attacks. | Low, Strong |
7. Tranexamic acid should not be used to treat acute attacks. | Low, Strong |
8. Frozen plasma could be used for treatment of acute attacks if other recommended therapies are not available. | Low, Strong |
9. We recommend early treatment of attacks to reduce morbidity (Level of Evidence: Moderate) and mortality (Level of Evidence: Expert Opinion). | Moderate, Strong/Expert Opinion, Strong |
10. All attacks of angioedema involving the upper airway are medical emergencies and must be treated immediately. (Level of Evidence: Low) In addition, we recommend emergency department assessment. (Level of Evidence: Expert Opinion). | Low/Expert Opinion, Strong |
Acute Treatment of HAE with Normal C1-INH
|
11. There is insufficient evidence to make a recommendation for or against the use of HAE-specific therapies in the treatment of acute attacks in patients with HAE with normal C1-INH. | Very Low / Insufficient Evidence |
Short-Term Prophylaxis
|
12. Short-term prophylaxis should be considered prior to known patient-specific triggers and for any medical, surgical or dental procedures. | Low, Strong |
13. HAE-specific acute treatment should be available during and after any procedure. | Low, Strong |
Long-Term Prophylaxis In HAE 1 & 2
|
14. Long-term prophylaxis may be appropriate for some patients to reduce frequency, duration and severity of attacks. | High, Strong |
15. Attenuated androgens are effective for long-term prophylaxis in some patients. | Moderate, Strong |
16. Plasma-derived C1-INH is effective for long-term prophylaxis in some patients. | High, Strong |
17. Anti-fibrinolytics are effective for long-term prophylaxis in some patients. | Moderate, Strong |
18. It is not necessary to fail other long-term prophylaxis therapies before use of C1-INH for long-term prophylaxis is considered. | Expert Opinion, Strong |
19. There is insufficient evidence to make a recommendation for or against long-term prophylaxis for patients with HAE with normal C1-INH. | Very Low/Insufficient Evidence |
Self-Administration
|
20. All patients 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 therapies. | Low, Strong |
Approach to Individualized Therapy
|
21. The decision to start or stop long-term prophylaxis depends on multiple factors and should be made by the patient and an HAE specialist. | Expert Opinion, Strong |
Quality of Life
|
22. Health care providers should specifically address factors known to affect quality of life with HAE patients. Management of HAE should aim to improve patients’ quality of life. | Low, Strong |
Comprehensive Care
|
23. Comprehensive care should be available for all patients with HAE. | Low, Strong |
For each topic area, group discussions were captured on audiotape, and used to inform the clinical considerations for each recommendation.
To mitigate any real or perceived bias that may have influenced the outcomes, industry representatives at the meeting were asked to leave the room after the scientific presentations and were not present during any discussion either of the data, wording of the recommendations, levels of evidence, strength of recommendations, or the voting process.
Prior to the in-person meeting, the Committee Members determined that open discussion amongst conference participants regarding an approach to individualized therapy would be beneficial. For this topic, small round table discussions were facilitated prior to recommendation review and voting, and additional clinical considerations were.
Competing interests
Dr. Betschel reports personal fees from CSL, Shire, ViroPharma, Baxter, Novartis, and Canadian Blood Services unrelated to the submitted work.
Ms. Badiou has no reported conflict.
Dr. Binkley reports consultation fees from Advisory Boards with Dyax, Shire, ViroPharma, and CSL Behring unrelated to the submitted work.
Dr. Hébert reports Advisory Board a consulting fee and clinical research from Shire and CSL Behring unrelated to the submitted work.
Dr. Kanani reports Advisory Boards from ViroPharma and speakers’ honorarium and CME sponsorship from CSL Behring unrelated to the submitted work.
Dr. Keith reports grants and personal fees from CSL Behring, personal fees from ViroPharma unrelated to the submitted work.
Dr. Lacuesta reports grants from CSL Behring, ViroPharma, and Shire; personal fees CSL Behring, ViroPharma, and Shire unrelated to the submitted work.
Dr. Yang reports research grants, Advisory Board activity, unrestricted educational grants, lectures from CSL Behring and Global/National Advisory Boards, unrestricted educational grants, lectures from Shire and ViroPharma unrelated to the submitted work.
Dr. Aygören-Pürsün reports grants and personal fees from CSL Behring, Shire, ViroPharma; personal fees from Sobi; grants from BioCryst unrelated to the submitted work.
Dr. Bernstein reports grants and personal fees from CSL Behring, ViroPharma, Shire, Dyax, and Pharming/Santarus unrelated to the submitted work.
Dr. Bork reports personal fees from CSL Behring and Shire unrelated to the submitted work.
Dr. Caballero reports personal fees from Sobi, ViroPharma, Shire, Novartis, MSD, and other funding from Shire for assistance for IOS manuscripts, Dyax, and Shire for writing assistance for manuscripts unrelated to the submitted work.
Dr. Ciccardi reports personal fees from CSL Behring, ViroPharma, Shire, Dyax, Sobi, Pharming, BioCryst, Sigma Tau; and grants from ViroPharma, Shire, and Dyax unrelated to the submitted work.
Dr. Craig describes payments for lectures including service on speakers bureaus from ViroPharma, CSL Behring, Dyax, Merck, Novartis, Genentech, and Teva; consultancy with CSL Behring, Dyax, ViroPharma, Shire, and Merck; grants from ViroPharma, CSL Behring, Shire, Dyax, Pharming, Forrest, Genentech, Biota, GSK, Grifols, Novartis, Sanofi Aventis, and Boehringer Ingelheim; and payment for development of educational presentations, Vietnam Education Foundation. All unrelated to the submitted work.
Dr. Farkas reports personal fees from Shire, Sobi, ViroPharma, and CSL Behring unrelated to the submitted work.
Dr. Longhurst describes grants, personal fees, and educational support from CSL Behring; personal fees and research collaboration from BioCryst; grants, personal fees, and educational support from Shire; personal fees and research collaboration from Sobi; and personal fees and research collaboration from ViroPharma unrelated to the submitted work.
Dr. Zuraw reports personal fees from Shire, CSL Behring, Dyax, BioCryst, ISIS, RMEI, and WebMD unrelated to the submitted work.
Mr. Boysen reports grants from ViroPharma, Shire, Dyax, and CSL Behring unrelated to the submitted work.
Dr. Rozita Borici-Mazi reports grants from CSL Behring; personal fees from ViroPharma and CSL Behring for Advisory Board work unrelated to the submitted work.
Dr. Bowen reports Advisory Board for CSL Behring, Advisory Board and travel grants from Shire and ViroPharma unrelated to the submitted work.
Dr. Dallas reports Advisory Board funding from Shire unrelated to the submitted work.
Dr. Dean reports no conflict of interest.
Dr. Laramée reports no conflict of interest.
Dr. Leith reports no conflict of interest.
Dr. Mace reports no conflict of interest.
Dr. McCusker reports no conflict of interest.
Dr. Moote reports consulting fees from CSL Behring, ViroPharma, and Grifols unrelated to the submitted works.
Dr. Poon reports personal fees and Advisory Board activity with ViroPharma, Advisory Board activity with CSL Behring; and travel support from Shire unrelated to the submitted work.
Dr. Bruce Ritchie reports no conflict of interest.
Dr. Stark reports funding from multiple pharmaceutical industries unrelated to the submitted work.
Dr. Sussman reports consultancy fees from Shire and CSL Behring unrelated to the submitted work.
Dr. Wasserman reports personal fees from CSL Behring, Shire, and ViroPharma unrelated to the submitted work.