What is hereditary angioedema and how is it treated?
Hereditary angioedema (HAE) is a serious and potentially life-threatening condition that causes acute (sudden onset) attacks of swelling, pain and reduced quality of life. Several new medicines have been developed to treat acute attacks and prevent attacks from occurring. Some medicines are taken by mouth, whereas others are injected under the skin, or given by a vein directly into the blood.
The medicines currently given for preventing HAE attacks are human C1 esterase inhibitor (often abbreviated as C1-INH), berotralstat, lanadelumab, tranexamic acid, and danazol. In addition, we found a further medicine (avoralstat) that is currently being studied for its ability to prevent HAE attacks.
What did we want to find out?
We investigated whether these medicines reduce the number of HAE attacks, and if any attacks that do occur are less severe than they would otherwise be. We also looked at whether people taking the medicines experienced a better quality of life, and whether the medicines caused unwanted side effects.
What did we do?
We searched medical databases for clinical studies in children or adults with HAE that compared medications to prevent HAE attacks with placebo (a pretend treatment) or another medicine.
What did we find?
We found 15 studies with 912 participants. All medicines except avoralstat reduced the number of HAE attacks, and even when attacks did occur, they were less severe for C1-INH and lanadelumab (there were no results for the other medicines). We found that most medicines improved the quality of life of the people with HAE and were generally safe as they did not increase the number of serious and less serious side effects.
We found no studies that tested tranexamic acid, and only one study tested danazol. There were also no studies that compared one medicine directly with another. This means that we cannot say for sure whether one medicine is better than another.
Conclusions
C1-INH, berotralstat, lanadelumab and danazol appear to reduce the risk of HAE attacks and increase the quality of life in people with HAE. The medicines do not seem to result in an increase in side effects.
What are the limitations of the evidence?
Our findings are limited by the small number of studies and the small number of participants in each study. Therefore, our confidence in these findings is low.
How up to date is this evidence?
The evidence is current to 3 August 2021.
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.
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.
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.
We used standard, extensive Cochrane search methods. The latest search date was 3 August 2021.
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.
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.
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.