UBC Faculty Research and Publications

Canadian hereditary angioedema guideline Betschel, Stephen; Badiou, Jacquie; Binkley, Karen; Hébert, Jacques; Kanani, Amin; Keith, Paul; Lacuesta, Gina; Yang, Bill; Aygören-Pürsün, Emel; Bernstein, Jonathan; Bork, Konrad; Caballero, Teresa; Cicardi, Marco; Craig, Timothy; Farkas, Henriette; Longhurst, Hilary; Zuraw, Bruce; Boysen, Henrik; Borici-Mazi, Rozita; Bowen, Tom; Dallas, Karen; Dean, John; Lang-Robertson, Kelly; Laramée, Benoît; Leith, Eric; Mace, Sean; McCusker, Christine; Moote, Bill; Poon, Man-Chiu; Ritchie, Bruce; Stark, Donald; Sussman, Gordon; Waserman, Susan Oct 24, 2014

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POSITION ARTICLE AND GUIDELINES Open AccessCanadian hereditary angioStephen Betschel1*, Jacquie Badiou2, Karen Binkley1, Jacques Hébert3, Amin Kanani4, Paul Keith5, Gina Lacuesta6,Bill Yang7, Emel Aygören-Pürsün8, Jonathan Bernstein9, Konrad Bork10, Teresa Caballero11, Marco Cicardi12,Timothy Craig13, Henriette Farkas14, Hilary Longhurst15, Bruce Zuraw16, Henrik Boysen17, Rozita Borici-Mazi18,Tom Bowen19, Karen Dallas20, John Dean21, Kelly Lang-Robertson1, Benoît Laramée22, Eric Leith23, Sean Mace1,Christine McCusker24, Bill Moote25, Man-Chiu Poon26, Bruce Ritchie27, Donald Stark4, Gordon Sussman1and Susan Waserman5ALLERGY, ASTHMA & CLINICAL IMMUNOLOGYBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50http://www.aacijournal.com/content/10/1/501University of Toronto, Toronto, Ontario, CanadaFull list of author information is available at the end of the article* Correspondence: betschels@smh.caAbstractHereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks ofpainful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks areassociated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the caseof laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The careof patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countrieswhere there are more organized models for HAE management, and where additional therapeutic options arelicensed and available for use. The objective of this guideline is to provide graded recommendations for themanagement 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, andcomprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and theiradvocates, that there will be an improved understanding of the current recommendations regarding managementof HAE and the factors that need to be considered when choosing therapies and treatment plans for individualpatients. 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 andotolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospitaladministrators, insurers and policy makers may also find this guideline helpful.Keywords: Hereditary angioedema, Guideline, Recommendations, Acute attacks, Short-term prophylaxis, Long-termprophylaxis, Self-administration, Individualized therapy, Quality of life, Comprehensive care, GRADE© 2014 Betschel et al.; licensee BioMed CentraCommons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.edema guidelinel Ltd. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,IntroductionBackgroundHereditary angioedema due to C1 inhibitor deficiency(C1-INH-HAE) is an autosomal dominant condition withan estimated prevalence of approximately 1:50,000 [1,2].It results in random and often unpredictable attacks ofpainful swelling typically affecting the extremities, bowelBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 2 of 18http://www.aacijournal.com/content/10/1/50mucosa, genitals, face and upper airway [3]. Attacks areassociated with significant functional impairment, de-creased Health Related Quality of Life (HRQoL), and mor-tality in the case of laryngeal attacks [4,5]. The swelling inHAE is a result of impaired regulation of bradykinin syn-thesis [6]. Bradykinin is a nonapeptide kinin formed fromhigh molecular weight kininogen by the action of plasmakallikrein. Bradykinin is a very powerful vasodilator andincreases capillary permeability, constricts smooth muscleand stimulates pain receptors [1].HAE can be categorized into 3 different types depend-ing on the level and function of C1inhibitor (C1-INH):type 1(HAE-1), type 2 (HAE-2), and HAE with normalC1-INH function (HAE-nC1INH) previously referred toas type 3 (Table 1). HAE-1 is the most prevalent, repre-senting approximately 85% of cases and results from lowantigenic and functional levels of C1-INH. HAE-2 ac-counts for approximately 15% of cases and is associatedwith a normal C1-INHprotein level but impaired C1-INH function [7,8]. C4 is reduced in 98% of cases forboth HAE-1 and HAE-2, and nearly 100% of the timeduring an attack [7].HAE-nC1INH (previously referred to as type 3 HAE), ismuch less prevalent than HAE-1 and HAE-2. The trueprevalence is not known as there are no reliable assays toscreen for this condition. In about 20% to 25% of identifiedpatients, causative mutations in the gene coding for the co-agulation factor XII (F12) have been found (HAE-nC1INH-FXII) whereas in the remaining patients no genetic causehas been identified up to now (HAE-nC1INH-unknown)[11-13]. The exact pathogenesis, however, including themode of action of the F12 gene mutations and the role ofestrogens is still unknown. The lack of laboratory and gen-etic assays (with the exception of F12 gene mutations) todiagnose HAE-nC1INH, has made the identification ofthese patients more difficult than patients with HAE-1or HAE-2. A recent international consensus group hasTable 1 Laboratory findings in hereditary angioedemaC4 C1-INHAntigen C1INH FunctionHAE - 1 ↓ ↓ ↓HAE - 2 ↓ Normal or ↑ ↓HAE - nC1INH-FXII mutation Normal Normal Normal-UnknownCause Normal Normal NormalReferences [9,10].published criteria to make the diagnosis of HAE-nC1INH[13]. These included a history of recurrent angioedema inthe absence of concomitant hives or use of medicationknown to cause angioedema; documented normal or nearnormal C4, C1-INH antigen and function; and either aF12gene mutation associated with the disease, or familyhistory of angioedema and documented lack of efficacy ofchronic high dose non-sedating antihistamine therapy [13].Management of HAE can be divided into various ap-proaches. The aim of treatment of acute attacks, also re-ferred to as ‘on demand therapy’ is to minimize theirseverity, including potentially fatal upper airway edema,and associated impairment of Quality of Life (QoL). Shortterm prophylaxis (STP) refers to treatment meant tominimize the risk of attacks when avoidance of potentialand known triggers is not possible. Long term prophylaxis(LTP) refers to ongoing treatment of HAE aimed at min-imizing the overall number, frequency and/or severity ofattacks. The details of specific therapies for these treat-ment approaches will be discussed in the sections that fol-low. In addition to the evidence behind the proposedrecommendations, the clinical considerations for their im-plementation will also be discussed. The United StatesPreventive Services Task Force describes clinical consider-ations as statements that can help clinicians by offeringpractical information so they can tailor guideline recom-mendations to individual patients [14]. This Clinical Con-sideration section following each recommendation isintended to help place the recommendation into a clinicalcontext.Scope and purposeThe objective of this guideline is to provide graded recom-mendations for the management of patients in Canadawith HAE-1, HAE-2 and HAE-nC1INH. This includes thetreatment of attacks, STP, LTP, and recommendations forself-administration, individualized therapy, QoL, and com-prehensive care.The care of patients with HAE in Canada is neitheroptimal nor uniform across the country. It lags behindother countries where there are more organized modelsfor HAE management, and where additional therapeuticoptions are licensed and available for use [15]. It is antic-ipated that by providing this guideline to caregivers, pol-icy makers, patients and their advocates, that there willbe an improved understanding of the current recom-mendations regarding management of HAE and the fac-tors that need to be considered when choosing therapiesand treatment plans for individual patients.It is not the intent of this guideline to provide a detaileddescription of the pathophysiology or nomenclature ofHAE which can be found elsewhere [13]. It is also notintended to be prescriptive in its recommendations, butrather to highlight issues that need to be considered whenthe standardized International Committee of Medicalby a librarian from the Centre for Effective PracticeBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 3 of 18http://www.aacijournal.com/content/10/1/50choosing treatments options for patients with a focus onthe importance of individualized care.Intended audienceThe primary target users of this guideline are healthcareproviders who are managing patients with HAE-1, HAE-2and HAE-nC1INH. Other healthcare providers who mayuse this guideline are emergency physicians, gastroenterol-ogists, dentists and otolaryngologists, who will encounterpatients with HAE and need to be aware of this condition.Hospital administrators, insurers and policy makers mayalso find this guideline helpful.MethodsCommittee members and consensus conferenceparticipantsThe Canadian Hereditary Angioedema Guideline Commit-tee is a working committee under the umbrella of theCanadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d'angioédème héréditaire (RCAH) http://chaen-rcah.ca/. Members on this committee includedmembers from CHAEN/RCAH across Canada as well asthe President of the Canadian HAE Patient Organization –Hereditary Angioedema (HAE) Canada/AngioédèmeHéréditaire (AEH) Canada. The Canadian HereditaryAngioedema Committee was responsible for defining thescope and purpose of the guideline and choosing the inter-national participants. International participants were se-lected based on their contributions to the HAE literature,relating to HAE and its management, and their ex-pertise in priority areas for this guideline includingself-administration, individualized therapy, HRQoL, andcomprehensive care. Those identified experts were askedto present a summary of the evidence related to theseareas to all conference participants.Conference participants included the CHAEN/RCAHGuideline Committee, international experts, all currentlyregistered members of CHAEN who were able to attendthe meeting, the President of HAE/AEH Canada andtheir designates, President of the international HAE pa-tient group HAEi, Hema-Quebec, and industry represen-tatives. An invitation was extended to representatives ofthe Provincial/Territorial Blood Coordinating offices.Representatives from Industry, who manufacture prod-ucts for the treatment of HAE, were also invited to pro-vide information on their products if required duringthe meeting. Only medical personnel and general man-agers were invited but were not present during timeswhen decisions were made. Marketing representativeswere excluded.Funding and supportFunding for the CHAEN/RCAH Guideline Conference wasdone through the CHAEN/RCAH. This organization(KLR) on October 10, 2013, in order to identify clinicaltrials addressing long-and short-term prophylaxis andtreatment of acute attacks in patients of any age diag-nosed with HAE-1, HAE-2, or HAE-nC1INH. Out-comes of interest included frequency or severity ofattacks, symptom relief and QoL measures as reportedor measured by the affected subject or investigator.Studies were limited to English language publications,and there were no limits on the publication date ofstudy other than those imposed by the database (1946-October week 1, 2013). After duplicates were removed,416 results were found, the abstracts of which werereviewed to determine if they met the inclusion criteria.If unclear from the abstract whether the paper metthese criteria, the full-text document was reviewed. Onehundred and thirty two results were retrieved andreviewed in full text, and from this, 11 relevant random-ized control trials and 34 lower-quality comparativestudies without blinding or randomization were identi-fied and included. No studies which met the inclusionJournal Editors Form for Disclosure of Potential Conflictsof Interest (Additional file 1). COI forms were distributedto attendees prior to their reviewing the manuscript, andwere mandatory for all contributing authors.Identifying the evidenceA systematic search of Ovid MEDLINE was conductedreceived equal support from 3 companies, who manufac-ture products for the treatment of hereditary angioedema(CSL Behring, Shire, and ViroPharma - Viropharma was ac-quired by Shire between the time of the guideline meetingand publication of the Guideline). Requests to procurefunding from Provincial and National Government andBlood Agencies were not successful. Funding was used tosupport rental of the conference facilities, audio-taping, fa-cilitation by an external facilitator, travel to the meeting,accommodation, and foods for all participants except forgovernment agency representatives and patient represen-tatives who were supported by their own agencies. No in-dustry participants were funded by CHAEN/RCAH. Noparticipants at the meeting were compensated for theirtime except for the Guideline meeting methodologist andfacilitator from the Centre of Effective Practice.The guideline meeting process was aided by a method-ologist and a guideline facilitator from the Centre forEffective Practice and supported by HAE/AEH Canada.Conflict of interestDetails of potential conflicts of interest were elicited usingcriteria were identified for HAE-nC1INH. The fullsearch strategy is available in Additional file 2.Betschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 4 of 18http://www.aacijournal.com/content/10/1/50Summarizing and evaluating the evidenceKey information from the included studies such as studydesign, number of patients, outcome measures, side effectsand funding source was extracted into evidence tables foreach intervention (see Additional file 3). Evidence tableswere provided to the Committee Members and were avail-able for reference at the meeting.Criteria for determining Levels of Evidence and Strengthof Recommendation were adapted from the GRADE sys-tem, [16-18] and the process was based primarily on theJournal of Clinical Epidemiology’s 2011–2013 series of ar-ticles describing the GRADE methodology. GRADE isconsidered “outcome centric,” and traditionally recom-mends a single rating for each outcome across the fullbody of evidence. The method applied here involvedevaluating the quality of each study individually, and thenlooking at the studies together to assign a Level ofEvidence based on the collection of studies.Each identified randomized control trial was assessed bytwo reviewers (KL-R, VP) for quality using the CochraneRisk of Bias Tool [19]. Any disagreements were resolvedby a third reviewer (SB). Randomized trials were initiallyrated as High quality levels of evidence, with quality beingdowngraded for evidence of bias on the Cochrane tool andif there was evidence of inconsistency (Additional file 3:Table S1). Non-randomized, non-blinded trials were con-sidered to be Low quality evidence.Multiple factors were considered when assigning theStrength of Recommendation, including quality of evidence,balance between desirable and undesirable effects, valuesand preferences, and costs (Additional file 3: Table S2).Additional file 3 describes additional detail how qualitywas assessed and the criteria used to determinethe Strength of Recommendation. The quality ratings werepresented at the meeting during the discussion of draft rec-ommendations. Additional files 4 and 5 list the HAE RCTevidence tables and the lower quality comparison study evi-dence respectively.Recommendation development and approvalThe Chair (SB) developed draft recommendations basedon the identified literature, and presented them to theCommittee Members who approved them in draft. In-vited Committee Members were assigned specific topicareas and were asked to review the evidence relevant totheir topic and present the body of evidence for consid-eration at the Guideline meeting. After the summarywas presented, the Consensus Conference Participantswere provided an opportunity to discuss the literature.Following this discussion, the draft recommendation waspresented and the group discussed the specific wordingof the recommendation before voting anonymously viaelectronic voting to agree or disagree with the recommen-dation, or abstain. If 80% consensus was not reached, therewas additional group discussion, the recommendation wasrephrased, and a new vote conducted. This process wasconducted a maximum of 3 times. If 80% consensus wasnot reached, it was considered that the committee was un-able to reach consensus.Once the phrasing of a recommendation was approvedby the group, the proposed Level of Evidence was pre-sented by the methodologist guideline facilitator (High,Moderate, Low, Very Low, or Consensus). The Level ofEvidence was then discussed, revised if necessary, andsimilarly voted on as outlined above.The suggested Strength of Recommendation (Strong orWeak) was then presented to the group. The methodologistguideline facilitator proposed a Strength of Recommenda-tion based on the Level of Evidence, the balance betweendesirable and undesirable effects, values and preferences.These factors were discussed amongst the group before vot-ing to accept the proposed Strength of Recommendation.All votes were recorded and presented in real time with therecommendations. Table 2 is a summary of all the recom-mendations, the level of evidence supporting each recom-mendation, and the strength of each recommendation.For each topic area, group discussions were capturedon audiotape, and used to inform the clinical consider-ations for each recommendation.To mitigate any real or perceived bias that may have influ-enced the outcomes, industry representatives at the meetingwere asked to leave the room after the scientific presenta-tions and were not present during any discussion either ofthe data, wording of the recommendations, levels of evi-dence, strength of recommendations, or the voting process.Prior to the in-person meeting, the Committee Membersdetermined that open discussion amongst conference par-ticipants regarding an approach to individualized therapywould be beneficial. For this topic, small round table discus-sions were facilitated prior to recommendation review andvoting, and additional clinical considerations were.Guideline recommendationsTreatment of acute attacks of HAE types 1 and 2BackgroundAcute attacks of HAE may be spontaneous or precipi-tated by an external stimulus and range from mild tolife-threatening. The decision to treat an attack dependson many variables and the severity of an attack cannotalways be predicted by its earliest manifestations. Theaim of treating acute attacks is to reduce the durationand severity of an attack, to minimize the impact of anattack on the functional ability of the patient, and reducemorbidity and potential mortality.Despite the increase in available beneficial therapies,some therapies which have not been shown to be effect-ive in trials continue to be used in acute attacks due toeither historical precedent or lack of awareness.Betschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 5 of 18http://www.aacijournal.com/content/10/1/50Table 2 Summary of recommendationsNine randomized trials were identified which demon-strated improvement in duration and severity of acuteattacks of HAE types 1 and 2 [20-29]. The therapiesRecommendationTreatment of Acute Angioedema Attacks1. Effective therapy should be used to treat acute attacks of angioedema to redattacks.2. pdC1-INH is an effective therapy for the treatment of acute attacks.3. Icatibant is an effective therapy for the treatment of acute attacks.4. Ecallantide is an effective therapy for the treatment of acute attacks.5. rhC1-INH is an effective therapy for the treatment of acute attacks.6. Attenuated androgens should not be used to treat acute attacks.7. Tranexamic acid should not be used to treat acute attacks.8. Frozen plasma could be used for treatment of acute attacks if other recomavailable.9. We recommend early treatment of attacks to reduce morbidity (Level of Emortality (Level of Evidence: Expert Opinion).10. All attacks of angioedema involving the upper airway are medical emergimmediately. (Level of Evidence: Low) In addition, we recommend emerg(Level of Evidence: Expert Opinion).Acute Treatment of HAE with Normal C1-INH11. There is insufficient evidence to make a recommendation for or against ttherapies in the treatment of acute attacks in patients with HAE with norShort-Term Prophylaxis12. Short-term prophylaxis should be considered prior to known patient-specmedical, surgical or dental procedures.13. HAE-specific acute treatment should be available during and after any prLong-Term Prophylaxis In HAE 1 & 214. Long-term prophylaxis may be appropriate for some patients to reduce fseverity of attacks.15. Attenuated androgens are effective for long-term prophylaxis in some pa16. Plasma-derived C1-INH is effective for long-term prophylaxis in some pati17. Anti-fibrinolytics are effective for long-term prophylaxis in some patients.18. It is not necessary to fail other long-term prophylaxis therapies before useprophylaxis is considered.19. There is insufficient evidence to make a recommendation for or against lpatients with HAE with normal C1-INH.Self-Administration20. All patients should be trained on self-administration of HAE-specific theracandidates. If patients cannot self-administer therapy, provisions should baccess to all appropriate therapies.Approach to Individualized Therapy21. The decision to start or stop long-term prophylaxis depends on multipleby the patient and an HAE specialist.Quality of Life22. Health care providers should specifically address factors known to affect qpatients. Management of HAE should aim to improve patients’ quality ofComprehensive Care23. Comprehensive care should be available for all patients with HAE.studied were plasma derived C1-INH (pdC1-INH), re-combinant human C1-INH (rhC1-INH), icatibant andecallantide. Table 3 lists the specific agents, theirLevel of Evidence and Strength ofRecommendationuce duration and severity of High, StrongHigh, StrongHigh, StrongHigh, StrongHigh, StrongLow, StrongLow, Strongmended therapies are not Low, Strongvidence: Moderate) and Moderate, Strong/Expert Opinion,Strongencies and must be treatedency department assessment.Low/Expert Opinion, Stronghe use of HAE-specificmal C1-INH.Very Low / Insufficient Evidenceific triggers and for any Low, Strongocedure. Low, Strongrequency, duration and High, Strongtients. Moderate, Strongents. High, StrongModerate, Strongof C1-INH for long-term Expert Opinion, Strongong-term prophylaxis for Very Low/Insufficient Evidencepies if they are suitablee made to ensure timelyLow, Strongfactors and should be made Expert Opinion, Stronguality of life with HAElife.Low, StrongLow, StrongncedionntrmlaxinsnsntBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 6 of 18http://www.aacijournal.com/content/10/1/50mechanism of action, their licensed indications inCanada, the recommended dosages, and importantpotential adverse reactions. The quality of individualstudies is described under the drug-specific recom-mendations which follow. Based on the rating ofeach study using the Cochrane Risk of Bias Tool(see Additional file 4), as well as the overall consistenteffect of therapy on the relevant outcomes (reduction ofduration and severity of acute attacks), and effect size, thisbody of evidence determined by the conference partici-pants to be of High quality.Based on the Level of Evidence, the potential severityof the outcomes and the low risk of adverse effects, thepanel voted for a Strong Recommendation in favour ofthe use of effective therapies in the treatment of acuteattacks.Recommendation 1Effective therapy should be used to treat acuteattacks of angioedema to reduce duration andTable 3 Therapies for HAE supported by high level of evideHAE specifictreatmentProduct name andcompanyMechanism ofActionApprovIndicatCanadaC1-INH– PlasmaBerinert® (CSL) Replaces CI-INH AcutetreatmeCinryze® (Shire) Replaces CI-INH Long teProphy– Recombinant Rhucin® (Pharming) Replaces CI-INH Not liceEcallantide Kalbitor® (Dyax) Inhibits plasmakallikreinNot liceIcatibant Firazyr® (Shire) Blocks bradykinin 2receptorAcutetreatmeseverity of attacks.Level of Evidence: High (96% Agree, 4% Disagree)Strength of Recommendation: Strong (100% Agree)Clinical considerationsThe panel emphasized the importance of changingpractice towards the use of effective therapies basedon evidence based data, and specifically not usingtherapies which were not supported by evidence, suchas antihistamines, corticosteroids and epinephrinewhich are directed at treating histamine mediatedangioedema.Recommendation 2pdC1-INH is an effective therapy for the treatmentof acute attacks.Level of Evidence: High (100% Agree)Strength of Recommendation: Strong (100% Agree)Clinical considerationsThe pdC1-INH is a human blood product. Treatment withpdC1-INHreplaces the deficient protein in patients withHAE-1 and HAE-2.Berinert® (CSL Canada) is the only li-censed product in Canada for the treatment of acute attacksof HAE-1 and HAE-2. It has been licensed since 2010, andis available throughout Canada, through Canadian BloodServices or Hema-Quebec. It can be used to treat all attacksof HAE-1 and HAE-2 in adults and children. The recom-mended dosage is 20 U/kg administered intravenously ei-ther by healthcare professionals or by patients and theircaregivers who have been trained in its administration. Ithas been shown to effectively treat acute attacks in pediatricand adult patients with HAE-1 and HAE-2 [22].Although not currently licensed in Canada for thetreatment of acute attacks, Cinryze® (Shire) is licensed inEurope for treatment of acute attacks in adolescent andadult patients with HAE-1 and HAE-2at a dose of 1000units intravenously initially and another 1000 units if noresponse. It has been shown to reduce the median timees InDose Adverse Events20 IU/Kg intravenous Anaphylaxis/Thrombosis (rare);Transmissionof infectious agents (theoretical)s1000 IU q3-4 daysintravenousAnaphylaxis/Thrombosis (rare);Transmissionof infectious agents (theoretical)ed 50 U/Kg Intravenous Anaphylaxis (rare)ed 30 mg subcutaneousinjectionAnaphylaxis (uncommon)30 mg subcutaneousinjectionPain, swelling, pruritis at injection site(common)Exacerbation of coronary artery disease(theoretical)to onset of unequivocal relief of symptoms compared toplacebo group [29].The dose derived for treatment of acute attacks comesfrom clinical trials. There have been no head to head trialscomparing products so it cannot be concluded that differ-ent doses of different products were equally effective.There is some evidence that efficacy is dose dependant,but this has not been confirmed with rigorous dose find-ing trials [30]. The pdC1-INH products are safe and welltolerated when used as indicated with no documentedtransmission of infectious agents.Recommendation 3Icatibant is an effective therapy for the treatmentof acute attacks.Level of Evidence: High (97% Agree, 3% Disagree)Strength of Recommendation: Strong (96% Agree/4% Disagree)Betschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 7 of 18http://www.aacijournal.com/content/10/1/50Clinical considerationsBradykinin is a key mediator in inducing angioedemathrough activation of the bradykinin B2 receptor [6]. Icati-bant is a synthetic 10-amino acid peptide and acts as aselective bradykinin B2 receptor antagonist. It is adminis-tered as a single 30 mg subcutaneous injection. It has beenshown to effectively treat acute attacks in adult patientswith HAE-1 and HAE-2 [20,25]. Icatibant is licensed inEurope and the USA for self-administration for the treat-ment of HAE attacks. (Addendum: Icatibant was licensedby Health Canada July 16, 2014). It is generally well-tolerated, although 90% of patients experience transientlocal pain, swelling, and erythema at the injection site.Recommendation 4Ecallantide is an effective therapy for the treatmentof acute attacks.Level of Evidence: High (94% Agree, 6% Disagree)Strength of Recommendation: Strong (94% Agree,6% Disagree)Clinical considerationsPlasma kallikrein generates bradykinin through cleavageof high-molecular-weight kininogen [6,31,32]. Ecallantideis a 60-amino acid recombinant protein that acts as an in-hibitor of kallikrein. It is administered as three 10 mg sub-cutaneous injections for a total dose of 30 mg. It has beenshown to effectively treat acute attacks in adolescent andadult patients with HAE-1 and HAE-2 [26]. Martinez-Saguer et al. [33] ecallantide (is not currently licensed inCanada but access can be requested through) the SpecialAccess Program of Health Canada. Hypersensitivity andsometimes anaphylactic-type reactions have been de-scribed with this agent in 5% or administrations, of whichapproximately 50% were possible anaphylactic reactions.Subcutaneous administration is associated with fewerof these episodes (1.6%), but is still a concern [32]. In theUSA, ecallantide is approved for treatment of acute at-tacks, but must only be administered by healthcare profes-sionals who are trained and are prepared to treat adversereactions.Recommendation 5rhC1-INH is an effective therapy for the treatmentof acute attacks.Level of Evidence: High (100% Agree)Strength of Recommendation: Strong (97% Agree,3% Abstain)Clinical considerationsThe rhC1-INH (conestat-alpha) is generated in themammary glands of transgenic rabbits and is identical topdC1-INH except for the degree of protein glycosylation[34]. This difference in glycosylation results in shorterplasma mean half-life of the recombinant product[33,35], however the effect this has on physiologic activ-ity is not known [30]. It has been shown to effectivelytreat acute attacks in adult patients with HAE-1 andHAE-2 [28]. It is administered intravenously at a dose of50 U/kg in people up to 84 Kg and at a dose of 4200 Ufor people above 84 Kg. Because of an isolated anaphyl-actic reaction after administration of rhC1-INH to arabbit allergic person, those with anti-rabbit IgE shouldbe excluded before prescribing. It is not currently li-censed in Canada but access can be requested throughthe Special Access Program of Health Canada.Recommendation 6Attenuated androgens should not be used to treatacute attacks.Level of Evidence: Low (97% Agree, 3% Abstain)Strength of Recommendation: Strong (100% Agree)Recommendation 7Tranexamic acid should not be used to treat acuteattacks.Level of Evidence: Low (93% Agree, 7% Disagree)Strength of Recommendation: Strong (83% Agree,10% Disagree, 7% Abstain)Clinical considerationsAttenuated androgens such as the 17 α-alkylated ana-bolic androgen danazol and anti-fibrinolytic drugs suchas tranexamic acid have not been shown to be effica-cious in the treatment of acute attacks of HAE-1 andHAE-2. Given the lack of evidence for these agents inthe acute treatment of HAE, the Committee stronglyagreed that they should not be used for the treatment ofacute HAE attacks as other agents with documented ef-ficacy are available in Canada.Recommendation 8Frozen plasma could be used for treatment of acuteattacks if other recommended therapies are notavailable.Level of Evidence: Low (96% Agree, 4% Abstain)Strength of Recommendation: Strong (100% Agree)Clinical considerationsFrozen plasma (FP) is a blood product which contains C1-INH in association with other plasma proteins. Frozenplasma (FP) is not as safe as solvent detergent plasma(SDP) with respect to pathogen inactivation, and the levelof evidence that frozen plasma is effective in the treatmentof acute attacks of HAE −1 and HAE-2 is low. It also con-tains potential substrates for the generation of additionalbradykinin and in theory could worsen attacks of angio-edema. Also, not all blood banks in Canada stock FP andBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 8 of 18http://www.aacijournal.com/content/10/1/50there are special requirements to enable access to SDP.Hence, there may be a significant delay in getting FP and/or SDP in a timely manner - in some cases up to 24 hours.Therefore, it was strongly felt by the Committee that frozenplasma products, although potentially beneficial, shouldonly be used if other recommended therapies are not avail-able and that every effort should be made to ensure timelyand appropriate therapy for acute attacks [36,37].Recommendation 9We recommend early treatment of attacks toreduce morbidity (Level of Evidence: Moderate)and mortality (Level of Evidence: Expert Opinion).Level of Evidence: Moderate (92% Agree, 8% Disagree)Strength of Recommendation: Expert Opinion/Strong (92% Agree, 4% Disagree, 4% Abstain)Clinical considerationsEarly treatment likely leads to more rapid symptom reso-lution. Observational studies have suggested that earlytreatment can be efficacious in reducing the duration of anattacking some patients [38-42]. Therefore, despite the ab-sence of a high level of evidence, expert opinion was strongendorsing early treatment in an attempt to reduce morbid-ity and likely mortality. Because of the potential barriers inaccessing therapy in a timely manner, patients should betrained on how to self-administer therapies appropriate forthe treatment of acute attacks of HAE. If patients are notable to self-administer their own therapy, efforts should bemade to ensure that this therapy is made available to themwithout a significant delay (see Recommendation #21).Recommendation 10All attacks of angioedema involving the upperairway are medical emergencies and must betreated immediately. (Level of Evidence: Low) Inaddition, we recommend emergency departmentassessment. (Level of Evidence: Expert Opinion).Level of Evidence: Low (96% Agree, 4% Disagree)Strength of Recommendation: Expert Opinion/Strong (100% Agree)Clinical considerationsAttacks of HAE are unpredictable and potentially life-threatening. Mortality due to laryngeal angioedema iswell recognized [3]. All attacks of laryngeal angioedemashould be considered medical emergencies, and therapiesthat have been shown to be effective in the treatment ofHAE should be readily available and given immediately. Itis also recommended that all patients with laryngealedema, even following self-therapy, be assessed in theemergency department in the event that the angioedemadoes not respond to therapy, and expertise in airway man-agement is required [43].Treatment of acute attacks of HAE with normal C1 INHfunctionBackgroundHAE-nC1INH is a rare disease that can be a challenge todiagnose with certainty as was discussed above. It has beensuggested, without confirmatory evidence that bradykininmay play a role in the pathogenesis of this disease whichhas led to speculation that therapies used for HAE-1 andHAE-2 may be beneficial [13]. There is also indirect evi-dence that anti-histamine therapy is not effective in this pa-tient group [44]. Owing to the difficulty in identifying thissubset of patients with HAE, and that there have been nei-ther significant case series nor controlled clinical trials withrespect to therapeutic intervention for acute attacks, wecannot recommend specific therapeutic interventions asthis time.Recommendation 11There is insufficient evidence to make arecommendation for or against the use of HAE-specific therapies in the treatment of acute attacksin patients with HAE with normal C1-INH.Level of Evidence: Very Low (96% Agree, 4% Disagree)Strength of Recommendation: InsufficientEvidence (N/A)Clinical considerationsThe committee felt that there was insufficient evidenceto make a specific recommendation regarding the use oftherapies that have been shown to be efficacious for theacute treatment of HAE-1 and HAE-2 in patients withHAE-nC1INH.However, in spite of this, if patients meet the clinical pro-file of HAE-nC1INH, a trial of HAE specific therapy couldstill be considered with the understanding that there is avery low level of evidence to support this and some reportsdemonstrate lack of efficacy for use of either pdC1INH oricatibant [45-48]. This may not be surprising given thatthere are neither abnormalities in C1-INH level or func-tion, nor any confirmatory evidence if a role for bradykinin.Short-term prophylaxisBackgroundSTP refers to the practice of treating patients to reducethe risk of associated and consequent morbidity andmortality during a period of time when there may be anincreased risk of having an attack of angioedema.It is well recognized that physical trauma, as can occurduring medical and dental procedures, can induce epi-sodes of angioedema [49,50]. Upper airway manipula-tion, including during dental surgery and intubation, isat particularly high risk due to its association with upperairway swelling. However, even minor procedures canprecipitate angioedema and the ability to predict whencentrates at 1,000 units, at least one additional treatmentBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 9 of 18http://www.aacijournal.com/content/10/1/50tal procedures; it was felt that STP should be consideredfor all medical, surgical and dental procedures. Onestudy assessed the risk of angioedema following surgerywithout prior pre-procedural prophylaxis as 5 – 30%, irre-spective of type and extent of surgery [53]. Based on this,and our inability to link the risk of an attack to a specificprocedure [49,53]; it was felt that STP should at least beconsidered for all procedures as well as known patient-specific triggers. This recommendation was intended toremain broad in its scope as the risk of appropriate STPwould likely be minimal compared to any real or perceivedrisk of not using STP when felt necessary. If the decisionis made not to administer STP, all patients should havetwo acute treatment doses of appropriate therapy immedi-ately available as per Recommendation 13. What is notknown from the current data is how many patients havebeen denied, or have chosen not to pursue necessary pro-cedures due to perceived risks, or not being offered STP.Ensuring access to STP may help mitigate the risk associ-Clinical considerationsThere was extensive discussion as to when STP shouldbe used and consideration was given to the developmentof a list of high and low risk procedures in this context.However, there is lack of data regarding the specific riskassociated with each of a wide range of medical and den-this may occur cannot be made with certainty. Attackscan occur anywhere from hours to several days after aprocedure [49].It is also suspected that other causes, such as emo-tional stressors can precipitate attacks. Individual pa-tients may also be aware of specific triggers that havebeen known to trigger their attacks.Despite these observations, there is a lack of controlledclinical trials in this area, and most data come fromretrospective reviews and surveys [49,51-53].Recommendation 12Short-term prophylaxis should be considered priorto known patient-specific triggers and for anymedical, surgical or dental procedures.Level of Evidence: Low(96% Agree, 4% Disagree)Strength of Recommendation: Strong (93% Agree,7% Disagree)Recommendation 13HAE-specific acute treatment should be availableduring and after any procedure.Level of Evidence: Low(92% Agree, 4% Disagree, 4%Abstain)Strength of Recommendation: Strong (100% Agree)ated with procedures and enable patients to seek and re-ceive the care they need [54].for acute attacks should be available. In Canada, pdC1-INHBerinert®is approved by Health Canada for acutetreatment and pdC1-INH Cinryze is approved by HealthCanada for long-term prophylaxis. In Europe, Cinryze islicensed to be given 1000 units within 24 hours of theprocedure, or Berinert1000 units within 6 hours of ananticipated procedure.Attenuated androgens may be considered for STP whensurgery-related risk is considered low and other HAE-specific acute treatments are not immediately available. Ifandrogens are chosen for STP, Danazol can be consideredstarting 5 days before the anticipated procedure or triggerand continuing 2–3 days after the anticipated trigger(Danazol 2.5 to 10 mg/kg/day, maximum 600 mg/day) [9].Disadvantages with androgen therapy include perceivedinferior efficacy to pdC1-INH concentrate and side effectssuch as emotional irritation and lability, menstrual dis-turbance, and vaginal dryness which can occur with shortterm use. Attenuated androgens areal so not suitable inpregnancy nor during breast feeding, and a pregnancy testshould be considered before initiation of therapy with an-drogens. Recurrent short-term uses may be associatedwith similar effects seen with long-term androgen use asdiscussed below.Anti-fibrinolytic agents such as tranexamic acid havebeen used for STP with suggested dosages of 25 mg/kg2–3 times daily to a maximum of 3–6 g per day, 5 daysbefore and 2–5 days after the procedure or anticipatedtrigger. The efficacy for prevention of attacks, however,is unknown and this agent should only be used if othertherapies are not available.Long-term prophylaxis in HAE types 1 and 2BackgroundLTP refers to the use of ongoing regular treatment toprevent attacks of HAE when on demand treatmentdoes not sufficiently meet patient treatment require-ments as discussed below in the Approach to Individual-ized Therapy section. Prophylactic therapy may beconsidered for patients with recurrent episodes of angio-edema to reduce the frequency, duration and severity ofIn the absence of rigorous data on specific dosing,pre-procedural prophylaxis with pdC1-INHconcentrateis recommended however there have not been controlleddose finding studies. Response however does appear tobe dose related. In one study patients had about a 30%risk with no prophylaxis, 15% risk with 500 units ofpdC1-INH which was reduced to about 5% risk at 1000units [49]. Furthermore, given that breakthrough attackshave occurred even with prophylactic pdC1-INH con-attacks. The specifics of when to consider and when toinitiate LTP are discussed below.Betschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 10 of 18http://www.aacijournal.com/content/10/1/50Recommendation 14Long-term prophylaxis may be appropriate forsome patients to reduce frequency, duration andseverity of attacks.Level of Evidence: High (100% Agree)Strength of Recommendation: Strong (100%)Clinical considerationsThe aim of LTP is to reduce the frequency and/or severityof attacks of HAE and minimize the impact of HAE ontheir QoL so as to enable patients to live normal lives.Some patients may be candidates for long-term therapyand the benefits and risks associated with such treatmentsshould be explored to optimize patient care. It is importantto remember that no prophylactic regimen has been associ-ated with the complete elimination of angioedema. There-fore, despite being on prophylaxis, all patients should beequipped to treat acute attacks in a manner consistent withRecommendation #1 and an acute treatment plan shouldbe agreed between patient and physician.Recommendation 15Attenuated androgens are effective for long-termprophylaxis in some patients.Level of Evidence: Moderate (92% Agree, 4%Disagree, 4% Abstain)Strength of Recommendation: Strong (90% Agree,6% Disagree, 4% Abstain)Clinical considerationsControlled trials and observational studies have demon-strated that treatment with 17-alpha-alkylated anabolicandrogens, such as danazol, reduces the frequency and se-verity of HAE attacks [55-60]. Although one of the trialswas a randomized controlled trial the level of evidence forthe trial was not considered High as there were insuffi-cient details on funding, sequence generation, and out-come reporting [55]. Historically, many patients have beencontrolled with androgen therapy and their use in somepatients may be acceptable provided that the lowest effect-ive dose is used to achieve efficacy and minimize adverseeffects. Expert opinion suggests the optimal dose for dana-zol, to minimize adverse effects, is ≤200 mg/day [9].Androgens can affect serum lipid levels, can be hep-atotoxic resulting in hepatitis and have been associatedwith hepatocellular adenoma and, in very rare cases,carcinoma [58,61,62]. It is recommended that all pa-tients on androgen therapy be monitored for hyperten-sion and have a complete blood count, liver enzymes,urinalysis, serum alpha-fetoprotein, creatine phosphoki-nase and lipid profile performed every 6 months, and anannual liver ultrasound [15].Virilising effects of androgen therapy can occur and in-clude menstrual irregularities, masculinization, irreversiblevoice alteration, and hirsutism. Psychological side effects in-clude emotional irritability and lability, aggressive behaviourand depression. Androgens are associated with interactionswith several medications. They are contraindicated in preg-nancy and during lactation, before puberty, and in patientswith androgen-dependent malignancy and hepatitis [61,62].Patients need to be made aware of these side effectswhen considering and while on androgen therapy andphysicians should carefully consider the risks and benefitsfor the particular patient.Recommendation 16Plasma-derived C1-INH is effective for long-termprophylaxis in some patients.Level of Evidence: High (100% Agree)Strength of Recommendation: Strong (100% Agree)Clinical considerationsControlled clinical trials have demonstrated that pdC1-INH used for prophylaxis in HAE-1 and HAE-2 reducesthe number, duration and severity of attacks of angio-edema [27,29]. Currently, Cinryze® (Shire) is the only ap-proved pdC1INH product for HAE prophylaxis inCanada. However, this product has not yet been distrib-uted in Canada. The dose of pdC1INH studied was 1000U once or twice weekly (usually every 3–4 days). No dosefinding studies have been done and at 1000 units twicea week the attacks are reduced by only 50%.Side effects reported in trials with pdC1-INH are min-imal. In the trial of Cinryze® for LTP, 21 of 24 subjects(88%) had one or more adverse events, however only threeadverse events (pruritus and rash, light-headedness, andfever) were classified as possibly related to the study drug.Two patients in that study demonstrated an increase in thenumber of attacks of HAE. A paper based on the FDAregistry of drug related adverse events, reported 10 cases ofsevere thrombosis related to the use of Cinryze® in threeyears between 2008 and 2011 [63]. The reason for thesethrombotic events has not been further elucidated. It hasbeen assumed to be related to the use of central lines. How-ever, the use of these should also be avoided due to the as-sociated risk of serious infection [63,64].On-going monitoring of a patients response to therapy isrecommended. In addition, as intravenous therapy requiresongoing venous access follow-up should ensure propertechnique is used to maximize the health of the veins.Recommendation 17Anti-fibrinolytics are effective for long-termprophylaxis in some patients.Level of Evidence: Moderate (96% Agree, 4%Disagree)Strength of Recommendation: Strong (86% Agree,14% Disagree)However, their role in current LTP was felt to be jus-Level of Evidence: Expert Opinion (100% Agree)Betschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 11 of 18http://www.aacijournal.com/content/10/1/50Strength of Recommendation: Strong (100% Agree)Clinical considerationsThe elements to consider when deciding to startprophylaxis are discussed below, in the approach toindividualized therapy section. However, there is norecommended order or hierarchy for which therapiesshould be chosen for LTP. This should be based onthe efficacy of the therapy, its side effects and safety,and the patient’s preference. The participants wereunanimous in their recommendation that should a pa-tient require long-term prophylaxis they can bestarted on prophylactic pdC1-INH without need to betried on other prophylactic therapies first.Long-term prophylaxis in HAE with normal C1-INHfunctionBackgroundPatients with HAE-nC1INH share similar clinical char-acteristics with HAE-1 and HAE-2 patients, includingthe risk of random unpredictable attacks of debilitatingand potentially life threatening angioedema [44]. Thesesimilarities have led to speculation that treatments usedfor LTP for HAE-1 and HAE-2 may be beneficial for pa-tients with HAE-nC1-INH; however, due to the lack oftified only in some patient groups due to the lack ofefficacy and the potential side effects at the dosagestudied. Although not specifically studied in paediat-ric patients, it was felt, due to the concern of usingattenuated androgens in this patient demographic,that anti-fibrinolytic agents could be considered. Therecommended dosage for tranexamic acid is 30–50 mg/kgdaily divided in 2 or 3 doses to a maximum of 6 g per day.Recommendation 18It is not necessary to fail other long-termprophylaxis therapies before use of pdC1-INH forlong-term prophylaxis is considered.Clinical considerationsThe benefit of the anti-fibrinolytic agent tranexamicacid was demonstrated in a randomized placebo con-trolled trial with 18 subjects aged 12 years and over-taking 1 g of tranexamic acid three times a day [65],and a double-blind crossover study of epsilon amino-caproic acid in 9 patients aged 7 to 40 years resultingin these agents being given a moderate level of evi-dence [66]. These data suggested that anti-fibrinolyticagents could be useful for LTP for HAE-1 and HAE-2.data a recommendation for this intervention could notbe made.Recommendation 19There is insufficient evidence to make arecommendation for or against long-term prophylaxisfor patients with HAE with normal C1-INH.Level of Evidence: Very Low (100% Agree)Strength of Recommendation: InsufficientEvidence (N/A)Clinical considerationsThe absence of good evidence in the LTP of HAE withnC1-INHpatients makes it difficult to make specific rec-ommendations regarding treatment. Patients shouldavoid known triggers of angioedema such as exogenousestrogen and angiotensin converting enzyme (ACE) in-hibitors. There is some evidence that progesterone,anti-fibrinolytics and attenuated androgens may be effi-cacious in patients with HAE-nC1INH [12]. However,the data were of low quality and uniform recommenda-tions could not be made regarding their use. The com-mittee felt strongly that more data are needed in thisarea and appropriate trials should be done to help guidefuture treatment recommendations.Self-administrationBackgroundSelf-administration refers to the treatment of patientsoutside of a health care facility either by the patient’sthemselves or by a trained caregiver. The recognitionand support of self-administration as treatment for HAEgo back to the first international consensus documenton HAE in 2003 and has been repeatedly recommendedin subsequent consensus statements and guidelines[9,15,67]. It has been shown to be a safe and convenientoption for patients, allows for early treatment, and mayreduce the overall treatment costs of this group whencompared to hospital-based therapy [68]. However, des-pite the demonstrated benefits of self-administration interms of efficacy and improved QoL, an online surveydone in the USA revealed that only 8.1% of treating phy-sicians had patients who self-treated and only 3.5% re-ceived home healthcare assisted administration [69,70].Although specific data in Canada is lacking, there is littlereason to think it would differ much from these findings.Self-administration of blood products for rare blood disor-ders is not without precedent and has been the corner-stone of effective therapy for hemophilia for more thanthree decades in Canada [71].Treatment is more efficacious when attacks are treatedearly [72]. Evidence has shown that the earlier an attackis treated the sooner it resolves [26,42,73,74]. The abilityto treat an attack early depends on reducing the numberof steps required between recognition of an attack thatrequires treatment and implementation of effective treat-ment. Obligating patients to travel to a health careBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 12 of 18http://www.aacijournal.com/content/10/1/50facility to receive a therapy which has been shown to beeffective when administered at home, or outside of ahealthcare facility, adds to the delay in receiving treat-ment, may result in many attacks not being treated.Patients may also face difficulties in accessing treatmentif local healthcare facilities are unfamiliar with this con-dition. The World Allergy Organization’s global guide-line emphasizes that all therapies should be available toall HAE patients worldwide and that home- and self-administration are preferred because they reduce morbidity,absenteeism, cost, disease burden and potentially mortality,as well as improveQoL [15,75].Carrying a personal supply of pdC1-INH by patientshas been shown to reduce the time spent waitingfor treatment [5]. Additionally, patients who self-administered or had on-demand therapy have beenshown to have reduced severity and duration of at-tacks, and an improved QoL.Recommendation 20All patients should be trained on self-administrationof HAE-specific therapies if they are suitablecandidates. If patients cannot self-administertherapy, provisions should be made to ensure timelyaccess to all appropriate therapies.Level of Evidence: Low (100% Agree)Strength of Recommendation: Strong (100%)Clinical considerationsAlthough the level of evidence was low for the recommen-dation that all patients should be trained on self-administration of HAE-specific therapies if they are suit-able candidates, it was considered a strong recommenda-tion unanimously. This is consistent with prior consensusstatements and guidelines [9,15,76]. The importance ofearly therapy should not be underestimated, and barriersthat affect its implementation should be removed. Cur-rently in Canada, pdC1INH is licensed for on demandtherapy (Berinert®) and for routine prophylaxis (Cinryze®).Because pdC1INH is a blood product and dispensed byblood banks in Canada, blood banks should adapt uniformoperating procedures to enable access to pdC1INH by allsuitable candidates and ensure uniform care for all pa-tients regardless of location. The Canada Health Act isintended to guarantee equal access to health services andhealth care. Geographic disparities in care are known toexist. Self-administration of therapy in HAE will removethese disparities. Although, pdC1INH is an intravenousproduct and requires special considerations includingproduct tracking and patient training, the use of intraven-ous blood products for self-administration is not unique.Hemophilia self-administration programs, which are simi-lar, have been widely implemented across Canada and havebeen shown to be effective [71,77].Treatments that do not require intravenous access foreither acute treatment or prophylaxis would simplify self-administered treatment. Ecallantide and icatibant are effi-cacious subcutaneous therapies which are administeredfor the treatment of acute attacks as discussed above. Ecal-lantide is not licensed in Canada but may be accessedthrough the special access program. Ecallantide shouldusually be administered only by a healthcare practitionerwith experience and facilities to treat anaphylactic reac-tions which occur in 3-8% of patients. Clinical trials arealso being conducted evaluating the use of subcutaneousC1INH for LTP therapy [78,79].Although not all patients will be suitable candidates forself-administered therapy, the option should be consideredin the overall care plan of HAE patients. If patients are con-sidered appropriate, and willing to learn self-administeredtherapy, they should agree to specific criteria as outlined inpreviously published international home-therapy guidelines[80,81]. With self-administered therapy, patients need to beregularly monitored to ensure appropriate control of theirsymptoms, compliance and competency. This is discussedfurther in the section on Individualized therapy.Approach to individualized therapyBackgroundHAE is a dynamic chronic disease and attacks of angio-edema can vary in frequency and severity over the pa-tient’s lifetime. This variability makes it important forpatients to be evaluated regularly to ensure that therapyis appropriate and is being used correctly, and that sideeffects of therapies are being minimized. A recently pub-lished document outlines an approach to monitoring at-tack frequency and severity [76].Perhaps one of the most challenging areas in patienttreatment is deciding when to start or stop LTP therapy.Although guidelines exist on which agents to use whenstarting LTP, there is no evidence comparing the use ofLTP to acute on-demand therapy regarding benefit andrisk. In the absence of such evidence, given the clinical im-portance of this therapeutic approach, the committeeattempted to determine which variables should be consid-ered when trying to decide when to start or stop LTP.Recommendation 21The decision to start or stop long-term prophylaxisdepends on multiple factors and should be made bythe patient and an HAE specialist.Level of Evidence: Expert Opinion (100% Agree)Strength of Recommendation: Strong (97% Agree,3% Disagree)Clinical considerationsLTP should be considered when on-demand therapydoes not allow HAE patients to lead healthy andBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 13 of 18http://www.aacijournal.com/content/10/1/50productive. There was considerable discussion regardingfactors that should be considered when deciding to startLTP. It was generally agreed that the key considerationsin making the decision included the efficacy of on-demand therapy to control the severity and frequency ofattacks. Although in the past some consensus docu-ments have tried to define the number and severity ofattacks as a reference point to consider when to startLTP [10], there was significant concern about the arbi-trary nature by which this would be defined. This ap-proach might lead to denying LTP to patients whose QoLis impacted, yet not meeting a specifically defined fre-quency of attacks. It was felt that, although the frequencyof attacks is important, it is only one among many factorsincluding severity of previous attacks, how readily patientscan access emergency treatment, and their ability to ad-minister on demand therapy, which should also beconsidered.Although the aim of LTP is to reduce the number andseverity of attacks, it does not eliminate the risk com-pletely. Patients must be aware that starting LTP does notmean that they will no longer have attacks and that thoseattacks can still be fatal. All patients must have a plan totreat attacks on demand despite being on LTP therapy. Allpatients must be monitored to ensure that LTP is effica-cious and that side effects are being recorded [76].When starting LTP it is important to understand andemphasize that LTP is not necessarily a lifelong therapyand that treatment needs ongoing re-evaluation. It maybe helpful to try to define what the expectations are asobjectively as possible when starting LTP. Part of themonitoring process should be to examine these goalsand ensure they are being met.The decision to stop LTP also generated significant dis-cussion. All participants felt LTP with androgens shouldbe stopped immediately if a patient became pregnant, wasbreast feeding or if the patient was less than Tanner stage5 development. Other factors that may lead to the consid-eration of stopping LTP is ongoing stable control withLTP therapy with no evidence of breakthrough attacks ofangioedema. If the decision to stop LTP is made, all pa-tients must ensure that they have access to the administra-tion of appropriate on-demand therapy of acute attacks asis consistent with Recommendation #20. All members ofthe patients comprehensive care team should be aware ofthe plan to stop LTP in case complications arise.When stopping LTP with attenuated androgens oranti-fibrinolytics, the majority of participants agreed thata gradual taper is recommended, if the patient is notpregnant, while monitoring the frequency of and the im-pact on the patient’s QoL. When stopping LTP withpdC1-INH it was felt it could either be stopped abruptlyor the frequency of administration decreased, whilemonitoring the patient’s response.The committee was unanimous that the decision to startor stop LTP should be made jointly by the patient and anHAE specialist. The patient needs to be informed of therisks and benefits of all therapies, as discussed in the rele-vant sections above, to enable making an informed deci-sion. Particular attention is needed when attenuatedandrogens are being considered for LTP in special popula-tions such as women of childbearing age and children.Additionally, long-term effects on vein health need to beconsidered when considering repeated IV infusions.Quality of lifeBackgroundThe Constitution of the World Health Organization(WHO) defines health as “A state of complete physical,mental, and social well-being not merely the absence ofdisease.” It follows that the measurement of health andthe effects of health care must include not only changesin the frequency and severity of diseases but also an esti-mation of wellbeing and HRQoL. The impact of HAE ona person’s HRQoL can be considerable. A survey donein the USA in 2004 revealed that 85% of patients wereafraid of sudden closure of their airway, 75% experiencedintolerable pain and 53% were concerned about trans-mitting HAE to their offspring [82]. A recent study of457 HAE patients from the USA reported significantlypoorer health-related QoL versus population norms,based on the SF-12 Physical Component Summary andMental Component Summary [83]. Productivity was alsomarkedly impaired in all Work Productivity and ActivityImpairment-General Health categories, including 34%overall work impairment. Because of their most recentHAE attack, workers lost a mean of 3.3 days; studentslost a mean of 1.9 days. In a Swedish registry of HAE pa-tients missed days from work and school were docu-mented [84]. In a multicenter European Studyabsenteeism from work and school as well as markedloss in productivity with the most recent attack and inbetween attacks were recognized [85].The Burden of Illness Study in Europe (Denmark,Germany, Spain) have shown that HAE had a high im-pact on daily activities during attacks and that HAE alsoimpacted patients’ daily activities between attacks[73,85,86]. In this study patients also reported substan-tial anxiety about future attacks, traveling, and passingHAE to their children [82]. Based on Hospital Anxietyand Depression Scale scores, 38 and 14% had clinicallymeaningful anxiety and depression, respectively [73].Moreover, 51% (n = 84) indicated that HAE had hin-dered their career/educational advancement [85].In Sweden and France, attack frequency was shown tohave a negative effect on HRQoL as measured by EQ5Dtoday [84] or SF-36 [87]. Attack severity was shown tobe related with absenteeism [84,85].additional factors that may have impact HAE patients’QoL.Comprehensive careBackgroundComprehensive care of patientsis based on integration ofthe organization, delivery, and management of services re-lated to diagnosis, treatment, care, rehabilitation andhealth promotion. The comprehensive care model hasbeen adopted by many rare disease groups and there isevidence in other rare diseases that this model results inbetter patient outcomes and reduced costs [71]. Haemo-philia has used this model for decades. HAE is similar toother rare blood disorders, including haemophilia, becauseit is a chronic condition that is potentially life threateningand requires a highly specialized, multidisciplinary team tomanage. However, although HAE is similar to other condi-tions, it is also different enough to require its own frame-work to meet the specific needs of these patients. Therecommendation to provide comprehensive care forTable 4 Requirements for comprehensive care in themanagement of hereditary angioedema patientsBest Clinical Treatment outcomes including:a. A comprehensive care team made up of nurse coordinator,clinician, social worker, data manager, pain managementspecialist, genetic counsellor, and administrative support;b. Access to specialized diagnostic testing;c. Access to home treatment;d. A networked Patient Information System to facilitate productrecalls - collect data on therapy outcome measures and safety,Betschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 14 of 18http://www.aacijournal.com/content/10/1/50HAE has a significant impact on QoL both during andbetween attacks and on absenteeism during attacks[73,84,85]. In aSpanish study assessing the developmentof a disease-specific QoL questionnaire for adult patientswith hereditary angioedema due to C1 inhibitor defi-ciency, the factors cited most often by both experts andpatients as affecting their QoL included potentially life-threatening attacks; the adverse side effects of medica-tion (in several cases associated with chronic treatment);the unavailability of acute specific treatment at severalhealth care centres; hereditary transmission; the lack of aknown trigger which could be avoided; and the fact thatit is a rare disease about which health care professionalsknow very little. The authors particularly noted that pa-tients and experts may not agree on what are the mostrelevant aspects of HAE [88]. Aesthetics was mentionedmore often by patients than by experts. On the otherhand, experts were more likely to mention the adverseside effects of treatment. This finding supports the gen-eral opinion that the clinician’s view of disease severitydoes not necessarily match with the patient’s perception.Recommendation 22Health care providers should specifically addressfactors known to affect quality of life with HAEpatients. Management of HAE should aim toimprove patients’ quality of life.Level of Evidence: Low (100% Agree)Strength of Recommendation: Strong (100% Agree)Clinical considerationsAssessment of HAE control as it relates to the frequency,duration and severity of attacks is not the only thing toconsider when monitoring patients. Data suggests that fac-tors which relate to a patients qualify of life are importantwhen following patients with HAE. An international spe-cific HRQoL questionnaire for adult patients with HAEdue to C1-inhibitor deficiency has been developed [89]and is available for its use in clinical practice. The factorsthat impact a patient’s QoL may be different than thoseanticipated by the healthcare providers. Modificationsshould be made to improve a patient’s QoL wherever pos-sible. A small study demonstrated that self-administrationof pdC1-INH improved QOL on both physical andpsychological parameters. Patients were able to resume anormal life without restriction [75]. Implementation ofself-administered therapy may lead to an improved QoLby reducing the suffering caused by treating attacks toolate or leaving them untreated altogether. It was reinforcedat the meeting by the patient representatives that there arestill significant barriers to getting timely and appropriatetherapy at centres across Canada, likely from the lack ofawareness of HAE and the appropriate therapies availablefor treatment. On-going research is required to determineand facilitate participation in clinical trialse. Access to clinical advances as they become available;f. Access to 24 hour support;g. Access to up-to-date standards of care, including standardizedwallet cards;h. Tracking and intermittent audit of quality outcomes includingbeneficial and adverse outcomes through secure, comprehensiveand networked data management.Education of patients and staff regarding:a. Responsible Self/Family Care (home care model) with home andself-infusion/administration instruction and support;b. Developments in the cause, diagnosis, treatment, outcomes, andprognosis of HAEc. Changes in the administrative management of the clinicAn environment conducive to research including:a. Access to and support for clinical trials of new treatments;b. Access to and support for translational research in diagnosis andprognosis;c. Access to and support for psychosocial research such as quality oflife studies.An advisory or oversight board with patient group representationfor each clinicReference [9].Dr. Bork reports personal fees from CSL Behring and Shire unrelated to thesubmitted work.Ingelheim; and payment for development of educational presentations,Vietnam Education Foundation. All unrelated to the submitted work.Dr. Zuraw reports personal fees from Shire, CSL Behring, Dyax, BioCryst, ISIS,Betschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 15 of 18http://www.aacijournal.com/content/10/1/50patients with HAE is not new and exists in previouslypublished guidelines. The specific elements of comprehen-sive care for HAE in Canada were published previouslyand are listed in Table 4.Recommendation 23Comprehensive care should be available for allpatients with HAE.Level of Evidence: Low (100% Agree)Strength of Recommendation: Strong (100% Agree)Clinical ConsiderationsAlthough the importance of the comprehensive caremodel in HAE was recognized by the committee unani-mously, and specific recommendations have existed withrespect to its requirements, this care model is not avail-able to all patients with HAE in Canada. The provincialand territorial model of health care funding makes im-plementation of nationally uniform HAE comprehensivecare clinics challenging. Despite this, the fundamentalsof comprehensive care should be uniform across thecountry and equally accessible across all geographic lo-cations. Support should be provided by provincial andterritorial governments to ensure that proper standardsof care are being met. Treatments for HAE can be ex-pensive; however inappropriate treatment of HAE maybe even more costly. It was recognised by the committeethat on-going monitoring of comprehensive care pro-grams is essential to measure their impact on patients’outcomes such as disease control, QoL and economiceffects.Special populationsThe committee recognized that management of HAE incertain populations were not specifically addressed inthis guideline. These include paediatric HAE patientsand HAE patients during lactation and menstruation.The recently published WAO document specifically ad-dressed recommendations for the management of HAE-1 and −2 in children [15]. An international consensusand practice guidelines on the gynaecologic and obstet-rical management of female patients with hereditary an-gioedema caused by C1 inhibitor deficiency was recentlypublished by Caballero et al. [90] and readers are re-ferred to those publications with the understanding thatthey are not specific to Canadians.Additional filesAdditional file 1: Conflict of Interest Form.Additional file 2: Search Strategy.Additional file 3: Levels of Evidence and Strength ofRecommendation.Dr. Farkas reports personal fees from Shire, Sobi, ViroPharma, and CSLBehring unrelated to the submitted work.Dr. Longhurst describes grants, personal fees, and educational support fromCSL Behring; personal fees and research collaboration from BioCryst; grants,personal fees, and educational support from Shire; personal fees andresearch collaboration from Sobi; and personal fees and researchcollaboration from ViroPharma 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 Shirefor 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, andDyax unrelated to the submitted work.Dr. Craig describes payments for lectures including service on speakersbureaus 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 BoehringerAdditional file 4: HAE RCT Evidence Tables. Includes data extraction,quality assessments, and study reference codes and citations forrandomized control trials.Additional file 5: HAE Lower Quality Comparison Study EvidenceTables. Includes data extraction, quality assessments, and study referencecodes and citations for lower quality comparison studies.AbbreviationsHAE: Hereditary Angioedema; C1-INH: C1 inhibitor; C1-INH-HAE: HereditaryAngioedema due to C1Inhibitor Deficiency; HRQoL: Health Related Quality ofLife; HAE-1: Hereditary Angioedema Type 1; HAE-2: Hereditary AngioedemaType 2; HAE-nC1INH: Hereditary Angioedema with Normal C1 Inhibitor;F12: Factor 12; HAE-nC1INH-FXII: Hereditary Angioedema due to Factor XIImutations; HAE-nC1INH-unknown: Hereditary Angioedema due to unknowncause; QoL: Quality of Life; STP: Short-term Prophylaxis; LTP: Long-termProphylaxis; CHAEN: Canadian Hereditary Angioedema Network;RCAH: Réseau Canadien d'angioédème héréditaire; pdC1-INH: PlasmaDerived C1-inhibitor; rhC1-INH: recombinant C1-inhibitor.Competing interestsDr. 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 fromShire and CSL Behring unrelated to the submitted work.Dr. Kanani reports Advisory Boards from ViroPharma and speakers’ honorariumand CME sponsorship from CSL Behring unrelated to the submitted work.Dr. Keith reports grants and personal fees from CSL Behring, personal feesfrom ViroPharma unrelated to the submitted work.Dr. Lacuesta reports grants from CSL Behring, ViroPharma, and Shire; personalfees CSL Behring, ViroPharma, and Shire unrelated to the submitted work.Dr. Yang reports research grants, Advisory Board activity, unrestrictededucational grants, lectures from CSL Behring and Global/National AdvisoryBoards, unrestricted educational grants, lectures from Shire and ViroPharmaunrelated 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 thesubmitted work.Dr. Bernstein reports grants and personal fees from CSL Behring, ViroPharma,Shire, Dyax, and Pharming/Santarus unrelated to the submitted work.RMEI, and WebMD unrelated to the submitted work.Mr. Boysen reports grants from ViroPharma, Shire, Dyax, and CSL Behringunrelated to the submitted work.Acknowledgements1University of Toronto, Toronto, Ontario, Canada. 2HAE Canada, Notre DameBetschel et al. Allergy, Asthma & Clinical Immunology 2014, 10:50 Page 16 of 18http://www.aacijournal.com/content/10/1/50des Lourdes, Manitoba, Canada. 3Department of Medicine, Laval University,Quebec City, Quebec, Canada. 4Department of Medicine, University of BritishColumbia, Vancouver, British Columbia, Canada. 5Department of Medicine,McMaster University, Hamilton, Ontario, Canada. 6Department of Medicine,Dalhousie University, Halifax, Nova Scotia, Canada. 7University of OttawaMedical School, Ottawa, Ontario, Canada. 8Goethe-Universität Frankfurt amMain, Frankfurt am Main, Germany. 9Department of Internal Medicine,University of Cincinnati, Cincinnati, Ohio, USA. 10Department of Dermatology,University Hospital of the Johannes Gutenberg-University of Mainz, Mainz,Germany. 11Hospital La Paz Health Research Institute, Madrid, Spain.12Department of Internal Medicine, UniversitadegliStudi di Milano, OspedaleL. Sacco, Milan, Italy. 13Departments of Medicine and Pediatrics, Penn StateUniversity, Hershey, Pennsylvania, USA. 143rd Department of InternalMedicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary.15Department of Immunology, Barts and the London NHS Trust, London,England, UK. 16University of California, San Diego, San Diego, California, USA.17HAE International, Skanderborg, Denmark. 18Department of Medicine,Queen’s University, Kingston, Ontario, Canada. 19Departments of Medicineand Paediatrics, University of Calgary, Calgary, Alberta, Canada. 20SaskatoonHealth Region, Saskatoon, Saskatchewan, Canada. 21BC Children’s Hospital,Vancouver, British Columbia, Canada. 22Centre hospitalier de l’université deMontréal, Montréal, Quebec, Canada. 23Department of Medicine, University ofToronto, Oakville, Ontario, Canada. 24Department of Immunology, McGillUniversity Health Centre, Montreal, Quebec, Canada. 25Department ofMedicine, Western University, London, Ontario, Canada. 26Southern AlbertaDr Valeria Palda and Ms Jess Rogers from the Center for Effective Practice fortheir part as facilitators for the development of these guidelines.Mr Peter Waite, Executive Director of CHAEN, for administrative support.Table 4, Requirements for Comprehensive Care in the Management ofHereditary Angioedema Patients, was reprinted from AACI with permission.Author detailsDr. Rozita Borici-Mazi reports grants from CSL Behring; personal fees fromViroPharma and CSL Behring for Advisory Board work unrelated to thesubmitted work.Dr. Bowen reports Advisory Board for CSL Behring, Advisory Board and travelgrants from Shire and ViroPharma unrelated to the submitted work.Dr. Dallas reports Advisory Board funding from Shire unrelated to thesubmitted 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 Grifolsunrelated 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 Shireunrelated to the submitted work.Dr. Bruce Ritchie reports no conflict of interest.Dr. Stark reports funding from multiple pharmaceutical industries unrelatedto the submitted work.Dr. Sussman reports consultancy fees from Shire and CSL Behring unrelatedto the submitted work.Dr. Wasserman reports personal fees from CSL Behring, Shire, andViroPharma unrelated to the submitted work.Authors’ contributionsSB prepared the manuscript. KLR developed the search strategy andprepared the evidence tables. All authors were involved in wording of therecommendations and reviewing and determining the level of evidence foreach recommendation. All authors have read, revised and approved themanuscript.Rare Blood and Bleeding Disorders Comprehensive Care Program, Calgary,Alberta, Canada. 27Departments of Medicine and Medical Oncology,University of Alberta, Edmonton, Alberta, Canada.Received: 28 August 2014 Accepted: 10 September 2014Published: 24 October 2014References1. Cicardi M, Agastoni A: Hereditary Angioedema. N Engl J Med 1996,334:1666–1667.2. Zuraw BL: Clinical practice. Hereditary angioedema. N Engl J Med 2008,359:1027–1036.3. Bork K, Hardt J, Witzke G: Fatal laryngeal attacks and mortality inhereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol2012, 130:692–697.4. 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