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. 2022 Nov 3;11(11):CD013403.
doi: 10.1002/14651858.CD013403.pub2.

Interventions for the long-term prevention of hereditary angioedema attacks

Nicole Beard  1 , Michael Frese  1 , Elena Smertina  1 , Peter Mere  2 , Constance Katelaris  3 , Kerry Mills  1
Affiliations

Interventions for the long-term prevention of hereditary angioedema attacks

Nicole Beard et al. Cochrane Database Syst Rev. .

Abstract

Background: Hereditary angioedema (HAE) is a serious and potentially life-threatening condition that causes acute attacks of swelling, pain and reduced quality of life. People with Type I HAE (approximately 80% of all HAE cases) have insufficient amounts of C1 esterase inhibitor (C1-INH) protein; people with Type II HAE (approximately 20% of all cases) may have normal C1-INH concentrations, but, due to genetic mutations, these do not function properly. A few people, predominantly females, experience HAE despite having normal C1-INH levels and C1-INH function (rare Type III HAE). Several new drugs have been developed to treat acute attacks and prevent recurrence of attacks. There is currently no systematic review and meta-analysis that included all preventive medications for HAE.

Objectives: To assess the benefits and harms of interventions for the long-term prevention of HAE attacks in people with Type I, Type II or Type III HAE.

Search methods: We used standard, extensive Cochrane search methods. The latest search date was 3 August 2021.

Selection criteria: We included randomised controlled trials in children or adults with HAE that used medications to prevent HAE attacks. The comparators could be placebo or active comparator, or both; approved and experimental drug trials were eligible for inclusion. There were no restrictions on dose, frequency or intensity of treatment. The minimum length of four weeks of treatment was required for inclusion; this criterion excluded the acute treatment of HAE attacks.

Data collection and analysis: We used standard Cochrane methods. Our primary outcomes were 1. HAE attacks (number of attacks per person, per population) and change in number of HAE attacks; 2. mortality and 3. serious adverse events (e.g. hepatic dysfunction, hepatic toxicity and deleterious changes in blood tests). Our secondary outcomes were 4. quality of life; 5. severity of breakthrough attacks; 6. disability and 7. adverse events (e.g. weight gain, mild psychological changes and body hair). We used GRADE to assess certainty of evidence for each outcome.

Main results: We identified 15 studies (912 participants) that met the inclusion criteria. The studies included people with Type I and II HAE. The studies investigated avoralstat, berotralstat, subcutaneous C1-INH, plasma-derived C1-INH, nanofiltered C1-INH, recombinant human C1-INH, danazol, and lanadelumab for the prevention of HAE attacks. We did not find any studies on the use of tranexamic acid for prevention of HAE attacks. All drugs except avoralstat reduced the number of HAE attacks compared with placebo. For breakthrough attacks that occurred despite prophylactic treatment, intravenous and subcutaneous forms of C1-INH and lanadelumab reduced attack severity. It is not known whether other drugs have a similar effect, as the severity of breakthrough attacks in people taking drugs other than C1-INH and lanadelumab was not reported. For quality of life, avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increased quality of life compared with placebo; there were no data for danazol. Four studies reported on changes in disability during treatment with C1-INH, berotralstat and lanadelumab; all three drugs decreased disability compared with placebo. Adverse events, including serious adverse events, did not occur at a rate higher than placebo. However, serious adverse event data and other adverse event data were not available for danazol, which prevented us from drawing conclusions about the absolute or relative safety of this drug. No deaths were reported in the included studies. The analysis was limited by the small number of studies, the small number of participants in each study and the lack of data on older drugs, therefore the certainty of the evidence is low. Given the rarity of HAE, it is not surprising that drugs were rarely directly compared, which does not allow conclusions on the comparative efficacy of the various drugs for people with HAE. Finally, we did not identify any studies that included people with Type III HAE. Therefore, we cannot draw any conclusions about the efficacy or safety of any drug in people with this form of HAE.

Authors' conclusions: The available data suggest that berotralstat, C1-INH (subcutaneous, plasma-derived, nanofiltered and recombinant), danazol and lanadelumab are effective in lowering the risk or incidence (or both) of HAE attacks. In addition, C1-INH and lanadelumab decrease the severity of breakthrough attacks (data for other drugs were not available). Avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increase quality of life and do not increase the risk of adverse events, including serious adverse events. It is possible that danazol, subcutaneous C1-INH and recombinant human C1-INH are more effective than berotralstat and lanadelumab in reducing the risk of breakthrough attacks, but the small number of studies and the small size of the studies means that the certainty of the evidence is low. This and the lack of head-to-head trials prevented us from drawing firm conclusions on the relative efficacy of the drugs.

Trial registration: ClinicalTrials.gov NCT02870972 NCT03485911 NCT03873116 NCT02586805 NCT01912456 NCT02316353 NCT01005888 NCT01756157 NCT02052141 NCT02247739 NCT01984788 NCT02303626 NCT02584959 NCT00462709 NCT03712228 NCT04656418.

PubMed Disclaimer

Conflict of interest statement

NB: none.

MF: none.

ES: none.

PM: none.

CK: has conducted original investigator‐led research in the field of hereditary angioedema (HAE) and has participated as a principal investigator in sponsored multinational randomised controlled trials (RCTs) of several therapies used for HAE management (acute and prophylactic therapies). She has participated actively in several global HAE meetings and has chaired advisory boards discussing HAE management in Australia. CK has declared that her institution has received payment for the conduct of multinational clinical trials from CSL Behring, KalVista Pharmaceuticals and BioCryst Pharmaceuticals Inc. She has received honoraria from CSL Behring and Takeda Pharmaceutical Company for serving on advisory boards and for lectures and presentations. She is a board member of HAE Australasia (patient organisation).

KM: has declared that she conducts comparative effectiveness work for TruDataRx Inc, which provides independent advice to employers based on the efficacy of pharmaceutical drugs. This company does not receive funds from the pharmaceutical industry or government.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Risk of hereditary angioedema attacks by drug (approved doses only).
5
5
Change in number of hereditary angioedema attacks per week by drug (approved doses only).
6
6
Risk of serious adverse events compared with placebo by drug.
7
7
Change in Angioedema Quality of Life (AE‐QoL) Questionnaire scores.
8
8
Change in quality of life (all scales) by drug.
9
9
Change in disability compared with placebo by drug (approved doses only) (standardised mean difference).
10
10
Risk of any adverse event compared with placebo by drug.
11
11
Change in number of hereditary angioedema attacks per week by drug (approved doses only).
12
12
Risk of any adverse event compared with placebo by drug.
1.1
1.1. Analysis
Comparison 1: Risk of hereditary angioedema (HAE) attacks, Outcome 1: Risk of HAE attacks by drug vs placebo
1.2
1.2. Analysis
Comparison 1: Risk of hereditary angioedema (HAE) attacks, Outcome 2: Risk of HAE attacks by drug (approved doses only)
1.3
1.3. Analysis
Comparison 1: Risk of hereditary angioedema (HAE) attacks, Outcome 3: Risk of HAE attacks by dose (avoralstat)
1.4
1.4. Analysis
Comparison 1: Risk of hereditary angioedema (HAE) attacks, Outcome 4: Risk of HAE attacks by dose (berotralstat)
1.5
1.5. Analysis
Comparison 1: Risk of hereditary angioedema (HAE) attacks, Outcome 5: Risk of HAE attacks by dose (C1‐INH(SC))
1.6
1.6. Analysis
Comparison 1: Risk of hereditary angioedema (HAE) attacks, Outcome 6: Risk of HAE attacks (C1‐INH) – head‐to‐head trials
2.1
2.1. Analysis
Comparison 2: Change in number of HAE attacks per week, Outcome 1: Change in number of HAE attacks per week by drug
2.2
2.2. Analysis
Comparison 2: Change in number of HAE attacks per week, Outcome 2: Change in number of HAE attacks per week by drug (approved doses only)
2.3
2.3. Analysis
Comparison 2: Change in number of HAE attacks per week, Outcome 3: Change in number of HAE attacks per week by dose (avoralstat)
2.4
2.4. Analysis
Comparison 2: Change in number of HAE attacks per week, Outcome 4: Change in number of HAE attacks per week by dose (berotralstat)
2.5
2.5. Analysis
Comparison 2: Change in number of HAE attacks per week, Outcome 5: Change in number of HAE attacks per week by dose (C1‐INH – all forms)
2.6
2.6. Analysis
Comparison 2: Change in number of HAE attacks per week, Outcome 6: Change in number of HAE attacks per week by dose (lanadelumab)
2.7
2.7. Analysis
Comparison 2: Change in number of HAE attacks per week, Outcome 7: Change in number of HAE attacks per week (C1‐INH) – head‐to‐head trials
2.8
2.8. Analysis
Comparison 2: Change in number of HAE attacks per week, Outcome 8: Change in number of HAE attacks per week (children and adolescents)
3.1
3.1. Analysis
Comparison 3: Serious adverse events, Outcome 1: Risk of serious adverse events compared with placebo by drug
3.2
3.2. Analysis
Comparison 3: Serious adverse events, Outcome 2: Risk of serious adverse events – head‐to‐head trials
4.1
4.1. Analysis
Comparison 4: Change in quality of life, Outcome 1: Change in Angioedema Quality of Life (AE‐QoL) Questionnaire scores
4.2
4.2. Analysis
Comparison 4: Change in quality of life, Outcome 2: Difference in EQ‐5D scale compared with placebo
4.3
4.3. Analysis
Comparison 4: Change in quality of life, Outcome 3: Change in SF‐36 compared with placebo
4.4
4.4. Analysis
Comparison 4: Change in quality of life, Outcome 4: Change in quality of life (all scales) by drug
4.5
4.5. Analysis
Comparison 4: Change in quality of life, Outcome 5: Change in AE‐QoL total score – head‐to‐head trials
5.1
5.1. Analysis
Comparison 5: Difference in HAE attack severity, Outcome 1: Difference in HAE attack severity by dose (C1‐INH)
5.2
5.2. Analysis
Comparison 5: Difference in HAE attack severity, Outcome 2: Difference in HAE attack severity – head‐to‐head trials (C1‐INH)
5.3
5.3. Analysis
Comparison 5: Difference in HAE attack severity, Outcome 3: Risk of a severe HAE attack by drug compared with placebo
5.4
5.4. Analysis
Comparison 5: Difference in HAE attack severity, Outcome 4: Risk of a moderate HAE attack compared with placebo
5.5
5.5. Analysis
Comparison 5: Difference in HAE attack severity, Outcome 5: Risk of a mild HAE attack compared with placebo
5.6
5.6. Analysis
Comparison 5: Difference in HAE attack severity, Outcome 6: Risk of no HAE attacks compared with placebo
6.1
6.1. Analysis
Comparison 6: Disability, Outcome 1: Change in disability compared with placebo by drug (approved doses only) – SF‐36 scale
6.2
6.2. Analysis
Comparison 6: Disability, Outcome 2: Change in disability compared with placebo by drug (approved doses only) – AE‐QoL physical functioning subscale
6.3
6.3. Analysis
Comparison 6: Disability, Outcome 3: Change in disability compared with placebo by drug (approved doses only) (standardised mean difference)
7.1
7.1. Analysis
Comparison 7: Risk of any adverse event compared with control, Outcome 1: Risk of any adverse event compared with placebo by drug
7.2
7.2. Analysis
Comparison 7: Risk of any adverse event compared with control, Outcome 2: Risk of any adverse event – head‐to‐head trials
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References

References to studies included in this review

APeX‐1 {published data only}
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APeX‐2 {published data only}
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APeX‐J {published data only}
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COMPACT {published data only}
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COMPACT extension {published data only}
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Gelfand 1976 {published data only}
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HELP {published data only}
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NCT01005888 {published data only}
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NCT01756157 {published data only}
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NCT02052141 {published data only}
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NCT02247739 {published data only}
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OPuS‐1 {published data only}
    1. Aygören-Pürsün E, Magerl M, Graff J, Martinez-Saguer I, Kreuz W, Longhurst H, et al. Efficacy correlates with plasma levels in OPuS-1, a proof-of-concept study of oral kallikrein inhibitor BCX4161 as a prophylaxis against attacks of hereditary angioedema (HAE). Journal of Allergy and Clinical Immunology 2015;135(Suppl 1):AB192.
    1. Aygören-Pürsün E, Magerl M, Graff J, Martinez-Saguer I, Kreuz W, Longhurst H, et al. Prophylaxis of hereditary angioedema attacks: a randomized trial of oral plasma kallikrein inhibition with avoralstat. Journal of Allergy and Clinical Immunology 2016;138(3):934-6.e5. - PubMed
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    1. Magerl M, Rae W, Aygoren-Pursun E, Bygum A, Panovska VG, Steiner UC, et al. Prophylactic therapy with BCX7353 improves anxiety and stress in hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) patients. Allergy 2018;73(Suppl 105):414.
OPuS‐2 {published data only}
    1. Riedl MA, Aygören-Pürsün E, Baker J, Farkas H, Anderson J, Bernstein JA, et al. Evaluation of avoralstat, an oral kallikrein inhibitor, in a phase 3 hereditary angioedema prophylaxis trial: the OPuS-2 study. Allergy 2018;73(9):1871-80. - PMC - PubMed
SAHARA {published data only}
    1. Farkas H, Martinez-Saguer I, Yang WH, Johnston D, Tang T, Vardi M, et al. Reduction of attack severity with fixed-dose subcutaneous (SC) C1 inhibitor liquid in hereditary angioedema patients: results from the phase 3 SAHARA study. Allergy 2018;73(Suppl 105):720-1.
    1. Lumry W, Bernstein JA, Jacobs J, Yang WH, Moldovan D, Riedl MA, et al. Fixed-dose subcutaneous (SC) C1 inhibitor liquid for prophylactic treatment of hereditary angioedema attacks: results from the phase 3 SAHARA study. Allergy 2018;73(Suppl 105):287.
    1. Lumry W, Bernstein JA, Jacobs J, Yang WH, Moldovan D, Riedl MA, et al. Fixed-dose subcutaneous (SC) C1 inhibitor liquid for prophylactic treatment of hereditary angioedema attacks: results from the phase 3 SAHARA study. Swiss Medical Weekly 2018;148(Suppl 231):26S-7S.
    1. Lumry WR, Martinez-Saguer I, Yang WH, Bernstein JA, Jacobs J, Moldovan D, et al. Fixed-dose subcutaneous C1-inhibitor liquid for prophylactic treatment of C1-INH-HAE: SAHARA randomized study. Journal of Allergy and Clinical Immunology. In Practice 2019;7(5):1610-18.e4. - PubMed

References to studies excluded from this review

Aabom 2015 {published data only}
    1. Aabom A, Andersen KE, Perez-Fernandez E, Caballero T, Bygum A. Health-related quality of life in Danish patients with hereditary angioedema. Acta Dermato-venereologica 2015;95(2):225-6. - PubMed
Aberer 2017 {published data only}
    1. Aberer W, Maurer M, Bouillet L, Zanichelli A, Caballero T, Longhurst HJ, et al. Breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis are responsive to icatibant: findings from the Icatibant Outcome Survey. Allergy, Asthma, and Clinical Immunology 2017;13:31. [DOI: 10.1186/s13223-017-0203-z] - DOI - PMC - PubMed
Agostoni 1978a {published data only}
    1. Agostoni A, Marasini B, Cicardi M, Martignoni GC. Intermittent therapy with danazol in hereditary angioedema. Lancet 1978;1(8061):453. - PubMed
Agostoni 1978b {published data only}
    1. Agostoni A, Marasini B, Cicardi M, Martignoni G, Uziel L, Pietrogrande M. Hepatic function and fibrinolysis in patients with hereditary angioedema undergoing long-term treatment with tranexamic acid. Allergy 1978;33(4):216-21. - PubMed
Agostoni 1980a {published data only}
    1. Agostoni A, Cicardi M, Martignoni GC, Bergamaschini L, Marasini B. Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema. Journal of Allergy and Clinical Immunology 1980;65(1):75-9. - PubMed
Agostoni 1983 {published data only}
    1. Agostoni A. The management of hereditary angioedema. Ricerca in Clinica e in Laboratorio 1983;13(1):55-9. - PubMed
Aygören‐Pürsün 2013 {published data only}
    1. Aygören-Pürsün E, Martinez Saguer I, Kreuz W, Klingebiel T, Schwabe D. Risk of angioedema following invasive or surgical procedures in HAE Type I and II – the natural history. Allergy 2013;68(8):1034-9. - PMC - PubMed
Baker 2013 {published data only}
    1. Baker JW, Craig TJ, Riedl MA, Banerji A, Fitts D, Kalfus IN, et al. Nanofiltered C1 esterase inhibitor (human) for hereditary angioedema attacks in pregnant women. Allergy and Asthma Proceedings 2013;34(2):162-9. - PubMed
Bernstein 2019 {published data only}
    1. Bernstein JA, Li HH, Craig TJ, Manning ME, Lawo JP, Machnig T, et al. Indirect comparison of intravenous vs. subcutaneous C1-inhibitor placebo-controlled trials for routine prevention of hereditary angioedema attacks. Allergy, Asthma, and Clinical Immunology 2019;15:13. [DOI: 10.1186/s13223-019-0328-3] - DOI - PMC - PubMed
Birjmohun 2008 {published data only}
    1. Birjmohun RS, Hovingh GK, Stroes ES, Hofstra JJ, Dallinga-Thie GM, Meijers JC, et al. Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary angioedema. Clinical Therapeutics 2008;30(12):2314-23. - PubMed
Blohmé 1972 {published data only}
    1. Blohmé G. Treatment of hereditary angioneurotic oedema with tranexamic acid. A random double-blind cross-over study. Acta Medica Scandinavica 1972;192:293-8. - PubMed
Bork 2008 {published data only}
    1. Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Annals of Allergy, Asthma & Immunology 2008;100(2):153-61. - PubMed
Bork 2011 {published data only}
    1. Bork K, Hardt J. Hereditary angioedema: long-term treatment with one or more injections of C1 inhibitor concentrate per week. International Archives of Allergy and Immunology 2011;154(1):81-8. - PubMed
Bork 2017 {published data only}
    1. Bork K, Wulff K, Witzke G, Hardt J. Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII). Allergy 2017;72(2):320-4. - PubMed
Busse 2017 {published data only}
    1. Busse P, Baker J, Martinez-Saguer I, Bernstein JA, Craig T, Magerl M, et al. Safety of C1-inhibitor concentrate use for hereditary angioedema in pediatric patients. Journal of Allergy and Clinical Immunology. In Practice 2017;5(4):1142-5. - PubMed
Chyung 2014 {published data only}
    1. Chyung Y, Vince B, Iarrobino R, Sexton D, TenHoor C, Kenniston J, et al. Results of a phase 1a, single ascending dose study of DX-2930, a human monoclonal antibody inhibitor of plasma kallikrein under investigation for long term prophylaxis of hereditary angioedema. Allergy 2014;69(S99):581.
Cicardi 1997 {published data only}
    1. Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. Journal of Allergy and Clinical Immunology 1997;2:194-6. - PubMed
Davis‐Lorton 2016 {published data only}
    1. Davis-Lorton MA, Busse PJ, Banerji A, Shennak M, Lumry WR, Wedner HJ, et al. Pharmacodynamic effect of DX-2930 on plasma kallikrein in hereditary angioedema patients. Journal of Allergy and Clinical Immunology 2016;137(2):AB252.
Drouet 2008 {published data only}
    1. Drouet C, Desormeaux A, Robillard J, Ponard D, Bouillet L, Martin L, et al. Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P. Journal of Allergy and Clinical Immunology 2008;121(2):429-33. - PMC - PubMed
EudraCT 2009‐010736‐18 {published data only}
    1. EudraCT 2009-010736-18. An open-label exploratory phase II study of the safety and prophylactic effect of a weekly 50 U/kg rC1INH treatment in asymptomatic patients with hereditary C1INH deficiency (HAE) – OPERA. clinicaltrialsregister.eu/ctr-search/trial/2009-010736-18/HU (first received 4 April 2009).
EudraCT 2010‐019670‐32 {published data only}
    1. EudraCT 2010-019670-32. Pharmacokinetics and safety of human pasteurised C1-inhibitor concentrate (Berinert/CE1145) in subjects with congenital C1-INH deficiency. clinicaltrialsregister.eu/ctr-search/trial/2010-019670-32/IT (first received 19 December 2012).
Farkas 2010 {published data only}
    1. Farkas H, Czaller I, Csuka D, Vas A, Valentin S, Varga L, et al. The effect of long-term danazol prophylaxis on liver function in hereditary angioedema – a longitudinal study. European Journal of Clinical Pharmacology 2010;66(4):419-26. - PubMed
Farkas 2013 {published data only}
    1. Farkas H, Csuka D, Zotter Z, Varga L, Fust G. Prophylactic therapy in children with hereditary angioedema. Journal of Allergy and Clinical Immunology 2013;131(2):579-82.e1-2. - PubMed
Füst 2011 {published data only}
    1. Füst G, Farkas H, Csuka D, Varga L, Bork K. Long-term efficacy of danazol treatment in hereditary angioedema. European Journal of Clinical Investigation 2011;41(3):256-62. - PubMed
Hofstra 2012 {published data only}
    1. Hofstra JJ, Kleine Budde I, Twuyver E, Choi G, Levi M, Leebeek FW, et al. Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor®): multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety. Clinical Immunology (Orlando, Fla.) 2012;142(3):280-90. - PubMed
NCT01108848 {published data only}
    1. NCT01108848. Patient registry study of Berinert® in normal clinical practice. clinicaltrials.gov/show/NCT01108848 (first received 22 April 2010).
NCT01467947 {published data only}
    1. NCT01467947. Postmarketing immunogenicity study in HAE subjects treated with Berinert. clinicaltrials.gov/show/NCT01467947 (first received 9 November 2011).
NCT01576523 {published data only}
    1. NCT01576523. A study to evaluate the clinical pharmacology and safety of C1-esterase inhibitor administered by the subcutaneous route. clinicaltrials.gov/show/NCT01576523 (first received 12 April 2012).
    1. Zuraw BL, Cicardi M, Longhurst HJ, Bernstein JA, Li HH, Magerl M, et al. Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate. Allergy 2015;70(10):1319-28. - PMC - PubMed
NCT01760343 {published data only}
    1. NCT01760343. A study to evaluate the safety and pharmacokinetics of two formulations of C1-esterase inhibitor. clinicaltrials.gov/show/NCT01760343 (first received 4 January 2013).
Sharma 2009 {published data only}
    1. Sharma K, Levy RJ, Wasserman RL, Jacobson KW, Laudadio C, Craig TJ. Evaluation of prodromal symptoms concurrent with hereditary angioedema therapy. Journal of Allergy and Clinical Immunology 2009;123(2 Suppl):S100.
Sweet 1980 {published data only}
    1. Sweet LC, Jackson CE, Yanari SS, Yott JB. Danazol therapy in hereditary angioedema. Henry Ford Hospital Medical Journal 1980;28(1):31-5. - PubMed
Szegedi 2008 {published data only}
    1. Szegedi R, Széplaki G, Varga L, Prohaszka Z, Szeplaki Z, Karadi I, et al. Long-term danazol prophylaxis does not lead to increased carotid intima-media thickness in hereditary angioedema patients. Atherosclerosis 2008;198(1):184-91. - PubMed
Széplaki 2005 {published data only}
    1. Széplaki G, Varga L, Valentin S, Kleiber M, Karadi I, Romics L, et al. Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema. Journal of Allergy and Clinical Immunology 2005;115(4):864-9. - PubMed
Wang 2017 {published data only}
    1. Wang Y, Martin P, Lu P, Schranz J. Pharmacokinetics (PK) and pharmacodynamics (PD) of c1 esterase inhibitor (c1-IHN) for prophylaxis of angioedema attacks in patients (PTS) with hereditary angioedema (HAE). Allergy 2017;72(Suppl 103):148.
Waytes 1996 {published data only}
    1. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. New England Journal of Medicine 1996;334(25):1630-4. - PubMed
Zotter 2013 {published data only}
    1. Zotter Z, Czaller I, Csuka D, Szabo E, Kohalmi KV, Varga L, et al. Adverse effects of danazol prophylaxis in female patients with hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). Allergy: European Journal of Allergy and Clinical Immunology 2013;97:430.

References to studies awaiting assessment

Zhang 1990 {published data only}
    1. Zhang H. Long-term therapy of hereditary angioedema. Chung-Hua i Hsueh Tsa Chih 1990;70(4):211-3. - PubMed

References to ongoing studies

NCT03712228 {published data only}
    1. NCT03712228. A study to investigate CSL312 in subjects with hereditary angioedema (HAE). clinicaltrials.gov/ct2/show/NCT03712228 (first received 19 October 2018).
NCT04656418 {published data only}
    1. NCT04656418. CSL312 (Garadacimab) in the prevention of hereditary angioedema attacks. clinicaltrials.gov/ct2/show/NCT04656418 (first received 7 December 2020).

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References to other published versions of this review

Beard 2019
    1. Beard N, Frese M, Mere P, Katelaris C, Mills K. Interventions for the long-term prevention of hereditary angioedema attacks. Cochrane Database of Systematic Reviews 2019, Issue 8. Art. No: CD013403. [DOI: 10.1002/14651858.CD013403] - DOI - PMC - PubMed

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