INTRODUCTION — Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare genetic disorder in which mutations in the SERPING1 gene result in deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1-INH) protein [1,2]. Terminology is evolving, and the abbreviations HAE-C1-INH and C1-INH-HAE are both used for this disorder in the literature [2,3]. HAE is characterized by recurrent episodes of angioedema without pruritus or urticaria, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although swelling resolves spontaneously in two to five days in the absence of treatment, angioedema is often temporarily debilitating, and laryngeal angioedema may cause fatal asphyxiation.
In patients with sufficiently frequent or severe episodes of angioedema, regularly administered prophylaxis is required to maintain an acceptable quality of life. This is referred to as long-term prophylaxis, in contrast to short-term prophylaxis, which is premedication given briefly before a specific medical or dental procedure. Short-term prophylaxis is discussed separately. (See "Hereditary angioedema: Short-term prophylaxis before procedures or stressful events to prevent angioedema episodes".)
The general management of adults and children with HAE-C1-INH and the various long-term prophylactic therapies that are used to prevent attacks will be reviewed here. The management of HAE attacks as well as the clinical manifestations, pathogenesis, and diagnosis of this condition are discussed separately:
●(See "Hereditary angioedema: Acute treatment of angioedema attacks".)
●(See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)
●(See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis".)
There is another form of HAE in which patients have normal complement studies called HAE with normal C1-INH. This disorder affects mainly women, while men are often asymptomatic carriers. Mutations in at least four genes (coding for coagulation factor XII, plasminogen, angiopoietin 1, and kininogen 1) have been associated with some patients with HAE with normal C1-INH. This disorder is also characterized by the tendency of estrogens in exacerbating the swelling. HAE with normal C1-INH is reviewed separately. (See "Hereditary angioedema with normal C1 inhibitor".)
GENERAL CARE — General care measures for HAE include education, testing of family members, identification and avoidance of possible triggers, and planning for HAE attacks. The first international consensus document was published in 2010 based upon the available literature and practices worldwide [4]. Two updated international consensus documents/guidelines have since been released [5,6]. Recommendations have also been published by an expert American group [7]. The approach in this review is consistent with these publications.
Education — The most important intervention for a patient who has been newly diagnosed with HAE is education about the disease. Both the affected individual and his/her family members should be involved. Patients can access detailed, patient-oriented information through the United States Hereditary Angioedema Association and HAE International. The ACARE (Angioedema Centers of Reference and Excellence) program has been launched for developing network for developing and accrediting an interactive network of HAE centers. Patients should be taught about attack triggers, potential risks, and the benefits of early treatment of HAE attacks. The genetics of HAE and the implications regarding family members should be discussed. Finally, the entire range of treatment options should be explained.
Testing of family members — First-degree relatives of the patient should be offered diagnostic testing for HAE. The disease is transmitted in an autosomal dominant fashion with variable but typically high penetrance. However, the patient may be the first affected member in the family, since approximately 25 percent of cases result from new mutations.
The importance of testing first-degree family members is illustrated by a cohort study that demonstrated that the risk of death from asphyxiation was greater in patients with undiagnosed HAE compared with those who had been formally diagnosed and educated about the condition [8]. It should be explained to patients that one-half of the children of a person with HAE can be expected to have the abnormal gene, although not everyone with the abnormal gene has symptoms. Some people with the abnormal gene have minimal or no symptoms, while others have symptoms of variable severity, and there is no way to predict how severely an individual will be affected. Another advantage of testing is that it may help avoid diagnostic confusion and inappropriate treatment if and when the person does develop symptoms.
Complement studies (C4, C1-INH level, and C1-INH function) are the recommended tests for screening family members. Additional issues surrounding testing are discussed separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis", section on 'Testing family members'.)
Trigger avoidance — Triggers vary among patients, although the following measures are important for most:
●Avoidance of trauma, particularly iatrogenic trauma to the face and upper respiratory tract
●Recognition and prompt treatment of upper airway and dental infections
●Avoidance of medications that can worsen the severity or frequency of angioedema episodes (estrogens, angiotensin-converting enzyme inhibitors, others)
Triggers are reviewed in more detail separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Triggers and exacerbating factors'.)
Planning for acute treatment — All patients should be equipped with the following:
●A medical information bracelet or necklace identifying the condition.
●A written plan for treatment of HAE attacks for use in emergency department care. This document (also available in a wallet card) should briefly explain the patient's diagnosis, outline the indicated treatment for HAE attacks, and provide contact information for the supervising clinician (form 1 and form 2). (See "Hereditary angioedema: Acute treatment of angioedema attacks".)
●Whenever possible, the ability to self-administer an effective drug outside of a medical facility. Patients should have a sufficient amount of medicine available and be trained in self-administration.
Baseline laboratory studies — Baseline studies are recommended to assess hepatic and other organ function (due to the potential need for chronic medications) and to screen for blood-borne illnesses (due to the possible need for blood products). The following tests are suggested: liver function tests (including alanine aminotransferase, total bilirubin); albumin; creatine kinase; blood urea nitrogen; creatinine; complete blood count and differential; pregnancy testing (if applicable); urinalysis; and screening tests for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C [4]. A cholesterol panel should be obtained if the patient may be treated with androgens.
Vaccinations — Patients should be vaccinated against hepatitis B in case they require blood-derived products in the future [4].
Gynecologic and obstetric care — An international expert panel produced guidelines on the gynecologic and obstetric care of women with HAE [9].
●Well-tolerated options for contraception include progesterone-based methods, such as progesterone-only oral contraceptives, other progesterone delivering methods, and intrauterine devices [10].
●The effect of pregnancy on a given patient's frequency and pattern of HAE attacks is difficult to predict, although abdominal attacks usually become more frequent [11]. Disease activity during one pregnancy does not necessarily predict disease activity during subsequent pregnancies [12]. C1-INH is the preferred agent for prophylaxis and acute treatment of HAE attacks during pregnancy.
●Labor and delivery generally do not precipitate HAE attacks, and the rate of cesarean deliveries is not elevated compared with the overall population. However, C1-INH concentrate should be available during delivery in case acute symptoms develop and for at least 48 hours afterward.
●Lactation can cause an increase in HAE attacks in some women. C1-INH concentrate is preferred during lactation because the side effects of lanadelumab, berotralstat, tranexamic acid, and androgens on infants are not known.
●The impact of menopause on HAE severity is variable.
●Other issues, such as the management of polycystic ovary syndrome, infertility, and breast, uterine, and cervical cancers, are also discussed in the guidelines [9].
ACCESS TO "ON-DEMAND" THERAPIES — All patients should have access to therapies to treat acute episodes of angioedema, irrespective of whether they are receiving long-term prophylactic treatment. Options for on-demand therapy include plasma-derived C1-INH concentrate (human), recombinant C1-INH concentrate (human), icatibant, and ecallantide, as reviewed in detail separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Overview'.)
APPROACH TO LONG-TERM PROPHYLAXIS — The consensus guidelines provide several options for long-term prophylaxis to prevent attacks of HAE-C1-INH, with which the authors agree, although practice differs somewhat around the world [1,4].
Overview of available therapies — The therapies used for long-term prophylaxis in patients with HAE-C1-INH are various preparations of C1 inhibitor concentrate, lanadelumab, berotralstat, antifibrinolytics, and attenuated androgens. Each has advantages and disadvantages, as summarized in the table (table 1). C1-INH concentrate, lanadelumab, and berotralstat are first-line therapies where available. Antifibrinolytics and attenuated androgens are alternatives that are less costly and are given orally, but these either have significant side effects (androgens) or are less effective (antifibrinolytics) than the first-line therapies.
●C1-INH concentrate – Regular injections of plasma-derived C1 inhibitor concentrate (pdC1-INH) are effective and well-tolerated by nearly all patients. pdC1-INH prophylaxis can be administered by intravenous or subcutaneous injection. When administered intravenously, repeated injections can lead to problems with venous access, and the placement of indwelling ports is discouraged because of risk of infection and thrombosis [13]. (See 'Intravenous plasma-derived C1 inhibitor' below.)
A subcutaneous preparation of pdC1-INH was approved for long-term prophylaxis in the United States in 2017 (Haegarda [brand name]). Subcutaneous administration provides more consistent plasma levels compared with intravenous (IV) administration. It is also helpful for patients with difficult venous access. It is anticipated to become available in other countries soon. (See 'Subcutaneous C1 inhibitor' below.)
Recombinant human C1 inhibitor (rhC1-INH) is not approved for long-term prophylaxis, although in a clinical trial, prophylaxis with rhC1-INH provided clinically relevant reductions in frequency of hereditary angioedema attacks and was well-tolerated [14]. If shortages of pdC1INH arise, rhC1INH could be used instead. The suggested dose is 50 international units (IU) per kilogram twice weekly initially, rounding up to use the whole vial and avoid wasting drug and subsequently adjusted up or down to achieve control of symptoms. Use of rhC1-INH for acute treatment of HAE attacks is reviewed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Recombinant C1 inhibitor'.)
●Lanadelumab – Lanadelumab is a fully human monoclonal antibody to kallikrein, which became available in the United States in 2018. It is injected at a dose of 300 mg subcutaneously every two weeks and was shown to be safe and effective. In patients who experience no attacks after six months of treatment with lanadelumab, the dose may be reduced to 300 mg every four weeks. (See 'Lanadelumab' below.)
●Berotralstat – Berotralstat is a synthetic small molecule developed to inhibit plasma kallikrein, which can be administered orally as once-daily capsules (150 mg). It is effective and safe for prophylaxis of HAE attacks and was approved in United States in 2020. (See 'Berotralstat' below.)
●Attenuated androgens – Long-term androgen therapy is usually effective but can have significant adverse effects. It is least problematic in postpubertal males, particularly when used at a low dose. It may be tolerated by women too, if the doses required to control symptoms are sufficiently low. It should not be used in growing children or pregnant or lactating women, unless there are extenuating circumstances. (See 'Attenuated androgens' below.)
●Antifibrinolytics – Antifibrinolytic agents include tranexamic acid (TA) and epsilon aminocaproic acid (also called aminocaproic acid). These are less predictably effective for preventing HAE episodes compared with pdC1-INH concentrate, lanadelumab, or androgens, and some patients have problems tolerating them. However, antifibrinolytics can be useful for long-term prophylaxis in growing children and possibly in women who are pregnant or planning to become pregnant in the near future in whom androgens should not be used and pdC1-INH is not available. Once a woman is pregnant or lactating, pdC1-INH concentrate is preferred for prophylaxis. Consensus guidelines do not emphasize the use of antifibrinolytics, but they remain an option [7]. (See 'Antifibrinolytics' below.)
Indications for long-term prophylaxis — The long‐term prophylaxis of HAE refers to the use of regular medication to reduce the burden of the disease by preventing/attenuating attacks in patients with confirmed HAE. Long-term prophylaxis is given to decrease the number, severity, and length of HAE attacks. Not all patients require it, and the decision to start a patient on long-term prophylaxis should be individualized based on maximizing quality of life [7]. Data are limited, but the authors estimate that from 20 (HF) to 70 percent (BZ) of their patient panels are on long-term prophylactic therapies. In contrast, in countries where on-demand therapies are less available, long-term prophylaxis is required by most symptomatic patients.
The decision to administer long-term prophylaxis to a specific patient should take into account the frequency and severity of attacks, access to emergency treatment, comorbid conditions, patient preference and experience, and failure to attain adequate control with appropriate on-demand therapies [5,15]. The therapeutic strategy should always be individualised. Patients should be evaluated for long‐term prophylaxis at every visit, or at least once a year. Patients receiving ongoing long‐term prophylaxis should be assessed regularly for efficacy and safety of the therapy, and dosage and/or treatment interval should be adapted according to the clinical response. Trigger avoidance should be reviewed periodically to see if patients can avoid exacerbating factors more effectively. All patients using long‐term prophylaxis should also have access to on‐demand medication. (See 'Access to "on-demand" therapies' above.)
The decision about when it is appropriate to initiate long-term prophylaxis is approached somewhat differently around the world:
●United States guidelines suggest that the decision to initiate long-term prophylaxis be individualized based upon multiple parameters, including attack frequency, comorbidities, patient preferences, and access to emergency care [7].
●In some countries, regulatory authorities have stipulated that patients are eligible for long-term prophylaxis with twice weekly injections of pdC1-INH if they are requiring four or more on-demand treatments per month, an approach that was adapted from hemophilia, where prophylactic injections of factor VIII are initiated when the number of on-demand approaches the number of prophylactic injections [16].
Goal of long-term prophylaxis — Long-term prophylaxis is deemed successful when symptoms are controlled to a level that is acceptable to that patient.
CHOICE OF AGENT IN SPECIFIC GROUPS — The options for long-term prophylaxis are intravenous (IV) or subcutaneous (SC) plasma-derived C1-INH (pdC1-INH) concentrate, lanadelumab (a monoclonal antibody to plasma kallikrein), berotralstat (an orally available plasma kallikrein inhibitor), attenuated androgens, and antifibrinolytics. Head-to-head trials are lacking. Within this group of therapies, pdC1-INH, lanadelumab, and berotralstat, which are all relatively costly, have either better efficacy or fewer adverse effects, and are thus considered preferable to androgens and antifibrinolytics. The choice of which long-term prophylactic agent to use is influenced both by patient characteristics (age, gender, pregnancy/lactation), as well as regulatory requirements in different countries (table 2).
Prepubescent children — Prepubertal children can usually be managed with on-demand therapies alone because HAE symptoms are generally less severe prior to puberty. The expanded availability of these therapies for HAE attacks has greatly reduced the number of children who require long-term prophylaxis. However, for those who do require preventative therapy, SC or IV pdC1-INH or oral tranexamic acid (TA) are commonly used. We suggest avoiding androgens in children who require long-term prophylaxis despite on-demand therapy. TA is easier to administer, while pdC1-INH is more effective. However, data reflecting the impact of modern therapies on the management of children are still limited.
Long-term prophylaxis with IV or SC pdC1-INH is approved down to the age of six. In many countries, access to long-term prophylaxis with pdC1-INH is limited.
One approach in this circumstance, based on clinical experience, is a trial of TA initially. If this does not control symptoms sufficiently, then it should be discontinued and regular injections of pdC1-INH given instead. These suggestions are based on clinical experience and may change as more information about the newer therapies becomes available. (See 'Dosing and efficacy' below.)
Before the newer therapies became available, management options in children consisted of TA and androgens, while C1-INH was usually reserved for life-threatening HAE attacks. The experience with these therapies remains relevant in resource-limited settings. One group published outcomes of a cohort of 48 children (23 boys and 25 girls) followed from diagnosis until age 18 in which TA was the initial agent given for long-term prophylaxis [17]. Overall, a relatively low percentage of children (19 percent) required long-term prophylaxis initially, compared with adult populations. However, by the age of 18 years, 43 percent required prophylaxis, with most needing to start long-term prophylaxis around the time of puberty. Some patients were adequately controlled with intermittent use of long-term prophylaxis during times when more attacks were anticipated (eg, during school exams, flu season, winter months, family crises, or puberty). If symptoms were not controlled by TA, it was stopped and replaced with low-dose danazol (starting at 100 mg every other day). Only 2 of 48 patients required significant use of pdC1-INH concentrate. Using this approach, serious side effects of danazol were avoided in children of both sexes. Androgen therapy should be administered in consultation with an endocrinology specialist.
Postpubescent and adult men — The options preferred for pubertal and adult male patients are regular injections of pdC1-INH, lanadelumab, berotralstat, androgens, or TA.
The approach of the American author (BZ) is to present all four treatment options, review the advantages and disadvantages of each, and make a joint decision about which therapy should be tried initially (table 1).
In more resource-limited settings, TA and androgens are commonly used and pdC1-INH is reserved for men with contraindications to or inadequate response to these therapies. If TA is chosen as an initial prophylactic agent, a trial of full-dose therapy is undertaken for a few weeks. If TA does not result in sufficient improvement, it should be stopped and androgen therapy initiated. Once attacks have subsided on androgens, most patients do not require high doses to keep the disease under control. Prophylaxis can also be given intermittently during times of anticipated stress, to reduce overall exposure.
Women not considering pregnancy in the near future — The agents that are preferred in women who are not considering pregnancy in the near future, and who require preventative therapy, are pdC1-INH, lanadelumab, berotralstat, and TA. Attenuated androgens can also be used, provided symptoms can be controlled with lower doses. (See 'Gynecologic and obstetric care' above.)
The approach of the American author (BZ) is to present all treatment options, review the advantages and disadvantages of each, and make a joint decision about which therapy should be tried initially. Androgens are generally avoided.
Pregnant and lactating women — If long-term prophylaxis is required in a pregnant or lactating woman, the best-studied approach is regular injections of pdC1-INH concentrate [9]. If pdC1-INH injections are not tolerated (rare) or not available, TA or fresh frozen plasma on-demand may be used instead [12]. Lanadelumab and berotralstat have not been studied in pregnancy. (See 'Adverse effects and safety' below.)
SPECIFIC AGENTS — The agents that can be used for long-term prophylaxis are reviewed here, with mechanisms of action, availability, efficacy, adverse effects, contraindications, and monitoring [18]. Monitoring C4 or C1-INH antigenic levels for the purpose of assessing disease control is not indicated or useful, except possibly in the case of subcutaneous (SC) plasma-derived C1-INH (pdC1-INH). (See 'Subcutaneous C1 inhibitor' below.)
Prophylactic treatments may be divided into targeted therapies (eg, various forms of C1-INH replacement therapy, lanadelumab, and berotralstat), which were specifically developed for use in HAE-C1-INH or related disorders and are generally more effective, and non-targeted therapies (eg, androgens and antifibrinolytics) that were originally developed for other disorders and have proven useful in the clinical management of HAE.
C1 inhibitor replacement therapies
Intravenous plasma-derived C1 inhibitor — Plasma-derived C1 inhibitor concentrate (pdC1-INH) can be injected intravenously (IV) at regular intervals (continuous replacement therapy) to prevent attacks of angioedema. Two human pdC1-INH are available: Cinryze (brand name) and Berinert (brand name). pdC1-INH concentrate is available throughout Europe, the United Kingdom, Canada, and Argentina [4,19].
Indications — Continuous replacement therapy with IV pdC1-INH is a first-line option for patients requiring long-term prophylaxis [20,21]. In the United States, pdC1-INH is a first-line long-term prophylactic agent for HAE-C1-INH without the need to have failed or experienced side effects from other medications such as androgens or antifibrinolytics. In some other countries, pdC1-INH may be restricted to patients who have had adverse effects to androgens or antifibrinolytics, were not adequately controlled on these agents, or who do not wish to take these agents. pdC1-INH concentrate is the treatment of choice for long-term prophylaxis during pregnancy [9]. (See 'Choice of agent in specific groups' above.)
Dosing and efficacy — Dosing of pdC1-INH Cinryze (brand name) for prophylaxis is 1000 units IV every three to four days. This dose may be adjusted over time to determine the lowest effective dose for each patient.
Small randomized trials and other studies have demonstrated that pdC1-INH concentrate is highly effective for long-term prophylaxis when given either on-demand or on a regular schedule [20-24]. Earlier estimates of efficacy may be understated, since the patients enrolled in these studies were refractory to other treatments and represented the severe end of the disease spectrum.
The first randomized controlled trial of pdC1-INH for long-term prophylaxis studied six severely affected HAE-C1-INH patients who demonstrated significant decreases in attack frequency when receiving pdC1-INH 25 units per kilogram every third day for 17 days compared to placebo in a crossover design [20]. The phase 3 trial included 24 patients randomized to pdC1-INH (1000 units every three to four days) or placebo injections for 12 weeks, after which the groups crossed over for another 12 weeks [21]. Subjects receiving pdC1-INH experienced approximately one-half as many attacks as those in the placebo group, and attacks were significantly shorter and less severe.
An open-label extension study of pdC1-INH (1000 units every three to four days) in 146 HAE patients for up to 2.6 years found an overall 93.7 percent reduction in the number of angioedema attacks compared with historical controls [24]. Just over one-third of patients experienced no attacks on prophylactic pdC1-INH. Another 7.5 percent of patients continued to experience frequent attacks, despite using the pdC1-INH, and no predictive marker for nonresponsiveness was found. No evidence for loss of effectiveness of the pdC1-INH over time was observed.
Adverse effects — Adverse effects of IV pdC1-INH are rare and include headache, fever, and anaphylaxis [25]. Other concerns are rare thrombotic events and the possibility of disease transmission.
●Rare thrombotic events have been reported in association with long-term prophylaxis with pdC1-INH, particularly in patients with indwelling injection ports or those receiving higher than usual doses. A retrospective analysis of the US Food and Drug Administration (FDA) event reporting system database identified an association between thrombotic events and use of Cinryze (brand name), especially in patients with ports, although no conclusions about causality or frequency could be made from the data [26]. In a registry of patients receiving Berinert (brand name), there was one thrombotic event considered related to pdC1-INH, although this patient also had an indwelling port [27]. However, there are no data to suggest that pdC1-INH at registered doses is associated with an increased risk of thromboembolism in patients without indwelling ports [28]. A retrospective study of patients treated for many years with pdC1-INH found no evidence for an increased risk of thromboembolism during treatment with pdC1-INH, even in patients with multiple predisposing factors [29]. In addition, animal studies suggest that high-dose C1-INH therapy is antithrombotic, rather than prothrombotic [30]. However, because of the uncertainty surrounding this issue, pdC1-INH product inserts include a warning that patients with risk factors for thromboembolic events (eg, ports, previous thrombosis, underlying atherosclerosis, oral contraceptives, androgens, morbid obesity, or immobility) should be monitored for thrombotic events. In addition, the use of ports should be avoided in patients with HAE.
●Treatment with any plasma-derived product, including pdC1-INH, confers some risk of disease transmission. Before the introduction of virucidal methods (from 1980 to 1985), a high percentage of HAE patients were infected with hepatitis C virus through a lyophilized preparation manufactured by Immuno Vienna (later Baxter). Production of the Baxter pdC1-INH product was subsequently discontinued in 2004. In response to this, pdC1-INH was subsequently vapor-heated to inactivate viruses, and the source of plasma was changed to carefully screened donors and continually monitored for pathogens [31]. Since vapor-heated pdC1-INH became standard, only hepatitis G transmission has been reported, and the pathogenic significance of hepatitis G infection is unclear [32]. (See "GB virus C (hepatitis G) infection".)
The preparations in use in most of the world are Berinert (brand name) and Cinryze (brand name), which are virus-inactivated by pasteurization and nanofiltered. Postmarketing surveillance for Berinert (brand name) since 1985 has revealed no case of viral transmission, despite the administration of hundreds of millions of units. Processing methods also remove prions [33]. Still, patients must be informed that there is a theoretical risk of transmission of unidentified pathogens.
Monitoring — The efficacy of pdC1-INH therapy should be assessed clinically by sufficient reduction of HAE attacks. Usefulness for monitoring C4 or C1-INH antigenic levels has not been tested. For patients receiving C1-INH concentrate, studies have not been undertaken to correlate successful therapy with specific C1-INH levels, and attacks may subside at levels of C1-INH that are still significantly below normal.
Periodic testing for hepatitis C and human immunodeficiency virus (HIV) is recommended for patients regularly receiving pdC1-INH.
Subcutaneous C1 inhibitor — The administration of a concentrated formulation of pdC1-INH subcutaneously (SC) is easier for most patients and also appears to be more effective for preventing attacks compared to IV administration. The SC formulation contains 1500 international units (IU) in 3 mL of water, compared with the IV formulation, which contains 500 IU in 10 mL. In addition, SC administration results in more consistent plasma levels between doses, compared to IV [34]. SC pdC1-INH is available for prophylaxis in the United States [Haegarda (brand name)] and in Europe [Sc Berinert 2000/3000 (brand name)] [35,36].
A SC formulation of Cinryze (brand name) is in development [37]. Although not yet available, this product would further expand options for SC therapy.
Dosing and efficacy — The dose of SC pdC1-INH for prophylaxis of HAE attacks in adolescents and adults is 60 IU per kilogram body weight twice weekly (every three or four days). It is injected SC into the abdominal area. Pending additional information about the use of higher doses, patients who do not achieve the desired level of control with the recommended dose should use the shortest interval between doses (ie, three days) to maximize efficacy.
Efficacy was demonstrated in a randomized, multicenter trial of 90 patients (12 years of age and older), in which participants self-administered one of two doses of SC pdC1-INH (40 IU or 60 IU per kilogram body weight) twice weekly or placebo for 16 weeks each in a crossover design [38]. The primary endpoint was number of episodes of angioedema, which was reduced 89 and 95 percent with the lower and higher dose, respectively, relative to placebo. For patients taking the higher dose, there were 3.51 fewer attacks per month compared with placebo (95% CI -4.21 to -2.81). The predominant adverse effect was mild injection site reactions that did not lead to discontinuation. Earlier studies of twice weekly injections of pdC1-INH demonstrated that SC injection resulted in higher and more sustained plasma levels relative to twice weekly IV administration [34,38]. Higher levels of plasma C1-INH function correlated with a lower risk of attacks, with a functional level of approximately 40 percent being an inflection point for the relative risk of attacks. The study also showed that postinjection functional C1-INH plasma levels varied among patients, such that individualized dose adjustment may be needed for optimal disease control. In the open-label extension trial, the mean C1-INH functional trough level was 66 percent, and 83 percent of the 23 subjects receiving pdC1-INH for 30 months were attack-free in the last 6 months [35]. Longer duration studies are needed to assess long-term safety.
Compared to IV — Although studies direction comparing SC to IV pdC1-INH are not available, SC administration provides the advantage of more consistent plasma levels, and preliminary evidence suggests it provides better symptom control. An analysis of a subset of patients from a larger study examined attack rates in individuals who changed from IV to a SC preparation of pdC1-INH [39]. Although the design was not optimized for this assessment, the majority of patients changing from various doses of IV to 40 IU/kg or 60 IU/kg of the SC preparation experienced clinically meaningful reductions in HAE attacks.
Adverse effects and monitoring — Adverse effects occurring in more than 4 percent of subjects treated with SC C1-INH in initial trials were injection site reactions, hypersensitivity, nasopharyngitis, and dizziness. SC C1-INH carries a similar theoretical risk for disease transmission as IV pdC1-INH concentrate. Thromboembolic events have not been reported.
Higher levels of functional C1-INH correlated with lower attack risk in patients receiving SC C1-INH, in contrast to IV C1-INH, which does not result in a sustained increase in plasma levels of C1-INH function at clinically effective doses. As with other C1-INH formulations, periodic testing for HIV and hepatitis C should be done. (See 'Monitoring' above.)
Plasma kallikrein inhibitors — Two agents are available that inhibit plasma kallikrein: lanadelumab and berotralstat.
Lanadelumab — A fully human monoclonal antibody to plasma kallikrein, lanadelumab (brand name Takhzyro), was approved by the United States FDA and European Medicines Agency (EMA) in 2018 for prophylaxis in patients 12 years of age and older [40,41]. This agent limits the production of excess bradykinin by reducing plasma kallikrein activity (figure 1). It is injected subcutaneously, and its duration of action, which is significantly longer than other prophylactic therapies, allows dosing once or twice a month.
Dosing and efficacy — The recommended initial dose of lanadelumab is 300 mg injected SC every two weeks.
In the study on which approval was based, patients discontinued other prophylactic therapies completely before starting lanadelumab, but in clinical practice, this may be less than ideal, as it takes over two months to reach a steady state of lanadelumab. A conservative empiric approach is to continue the patient's current therapy for at least two weeks and possibly longer for those with frequent or severe attacks and to gradually reduce the dose of the previous prophylactic agent over an additional two weeks for a total of one month of overlap.
●If a patient is stably attack-free (eg, for more than six months), especially in patients with lower body weights, the dosing interval can be lengthened to 300 mg every four weeks.
●The dose should not be increased, because higher doses have not been studied.
In a phase 1b study, two doses of lanadelumab given 14 days apart reduced attack rates by between 88 and 100 percent [42]. A phase 3 randomized trial involving 125 HAE patients showed a reduction in attacks ranging from 73 to 87 percent, depending on the dose and timing. Monthly attack rates were 1.64, 0.42, and 0.21 in subjects receiving placebo, 300 mg every four weeks, and 300 mg every two weeks, respectively [43].
Adverse effects and safety — Injection site reactions were the most common adverse effect with lanadelumab, occurring in 45 to 56 percent of subjects receiving active drug, compared with 34 percent of those receiving placebo. Increased aspartate and alanine transaminase levels occurred in 2 percent of active drug recipients versus 0 in the placebo group. These were asymptomatic and transient and did not require drug discontinuation. Lanadelumab can increase activated partial thromboplastin time but has not been associated with abnormal bleeding.
There are no known contraindications to use of lanadelumab. However, lanadelumab has not been studied in pregnant or lactating women, and although animal studies in pregnancy are reassuring, we would avoid use in pregnant or lactating women until more information is available [44].
Berotralstat — Berotralstat (BCX7353) is an orally-administered plasma kallikrein inhibitor that was approved by the United States FDA in late 2020 for prevention of HAE attacks in adult and pediatric patients 12 years of age and older (figure 1) [45,46]. The drug binds to plasma kallikrein and inhibits its proteolytic activity. The dose is 150 mg once daily, taken with food. It will likely become available in other countries in the near future.
Safety and drug interactions — Higher doses can increase the risk of QT prolongation and are not recommended. A lower strength capsule (110 mg) is also available and is indicated in patients with moderate-to-severe hepatic impairment (Child-Pugh B or C) and in those taking BCRP (breast cancer resistance protein; eg, cyclosporine) or P-glycoprotein (P-gp) inhibiting medications (table 3). Berotralstat should not be used in patients taking P-gp inducers. The most common side effects are gastrointestinal symptoms (abdominal pain, vomiting, diarrhea, and gastroesophageal reflux) and back pain, all of which occurred in ≥10 percent of patients but generally subsided with continued use [47]. No specific laboratory monitoring is recommended by the manufacturer. Berotralstat has not been studied in pregnancy or lactation, although animal studies are reassuring [47].
Efficacy — Several trials have addressed efficacy and safety of berotralstat (BCX7353).
●In the multicenter phase 2 Angioedema Prophylaxis 1 (APeX-1) trial, 77 patients with a history of at least two attacks per month were randomized to placebo or four different doses of active drug (62.5 mg, 125 mg, 250 mg, and 350 mg) once daily for 28 days [48,49]. Once-daily oral administration of a dose of 125 mg or more resulted in a significantly lower rate of HAE attacks compared with placebo.
●In a phase 3 trial of 121 adolescents and adults with HAE (APeX-2), patients were randomized to either berotralstat 150 mg or 110 mg, or placebo for 24 weeks to determine optimal dosing [50]. Patients had a median of 2.9 attacks per month after discontinuing other prophylactic medications. Response to berotralstat was defined as ≥50 percent reduction in that patient's HAE attack rate compared to baseline. Berotralstat demonstrated a significant reduction in attack rate at both 150 mg and 110 mg (1.31 and 1.65 attacks per month, respectively, compared with 2.35 in the placebo group). A response was seen in 58, 51, and 25 percent of patients receiving 150 mg, 110 mg, and placebo respectively. On the higher dose, 50 percent of patients achieved at least a 75 percent reduction in attacks and 23 percent had at least a 90 percent reduction.
●In a similar trial in Japan, APeX-J, orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated [51].
●APeX-S (NCT03472040) is a long-term safety study of BCX7353 being conducted simultaneously with the APeX-2 study to evaluate the long-term effects of the 110- and 150-mg doses over a 48-week period.
Non-targeted therapies — Non-targeted therapies refer to medications that were originally developed for other disorders and have proven useful in the clinical management of HAE.
Attenuated androgens — Synthetic 17-alpha-alkylated androgens ("attenuated" or anabolic androgens) include danazol, stanozolol, oxandrolone, tibolone, and methyltestosterone. The precise mechanism of action of attenuated androgens is unknown [52-54]. The choice of androgen is based largely upon availability, since differences among drugs have not been well-characterized. Danazol is widely available throughout the world. Stanozolol is not produced commercially in the United States, although it is available by prescription and can be compounded by individual pharmacies. Tibolone and oxandrolone may be less virilizing than other agents [55-57]. Methyltestosterone is another alternative [58].
Efficacy — In a double-blind, placebo-controlled study of nine patients, high doses of androgen therapy (danazol, 600 mg daily) dramatically reduced the risk of at least one acute episode during a one-month treatment period from 94 to 2 percent and reduced attack rates from monthly to 1 every 10 months [59]. Other small, controlled studies and multiple observational studies also concluded that androgens were effective at preventing attacks [57,60-66]. A retrospective survey of 650 HAE patients revealed substantial variability in the efficacy of androgens [67].
Dosing — Most patients with HAE are controlled with doses ranging from 50 to 200 mg of danazol, either daily or every other day (or an equivalent dose of another androgen, eg, stanozolol 1 to 2 mg daily or every other day). We suggest either of the following two ways of administering androgens for long-term prophylaxis: starting with a high dose and then tapering or starting with a low dose and gradually increasing (table 1) [4].
●Initial high dose – This protocol is based on the strategy of initiating androgen therapy with high doses that are subsequently tapered as tolerated. This approach is favored for rapid control of attacks. Using danazol as an example, therapy is begun with 400 to 600 mg daily until new attacks have ceased (usually a few weeks). The dose can then be tapered over several weeks to 200 mg daily, although the guidelines suggest tapering more slowly (eg, by 100 mg daily per month or by one-third of the dose per month if there are no breakthroughs). When 200 mg daily is attained, therapy is tapered by 50 mg every two months and by every three months when below 100 mg per day. The minimum dose is 50 mg daily for five days every week for most patients. For those in whom a breakthrough attack occurs, remission can be reinduced by resuming the last effective dose and then using a higher maintenance dose.
The equivalent dosing for stanozolol is 4 to 6 mg daily for the first month and then gradual tapering to the minimal effective dose, which is generally in the range of 0.5 to 2 mg daily.
●Initial low dose – This regimen involves the initiation of therapy with low doses, with increases in the dose as necessary. This approach minimizes medication side effects. Using danazol as an example, therapy is initiated at a dose of 100 mg daily for men and 50 mg daily for women. If there is no response after two weeks, the dose is increased to 200 mg daily (men)/100 mg daily (women) for two to four weeks.
General observations regarding the use of attenuated androgens for long-term prophylaxis include the following:
●In postpubertal females, androgenic effects may be troublesome, and regulation of periods and use of other hormones can become issues. We suggest that treatment decisions be made with the cooperation of the patient's obstetrician/gynecologist.
●Some patients have reported that increasing the dose of androgen in response to prodromal symptoms or at the first sign of swelling seems to help prevent progression to more severe symptoms. As an example, a patient taking 200 mg of danazol daily for prophylaxis could increase the dose to 400 mg three times daily and maintain the higher dose until there is some indication of clinical improvement or an attack ensues. Although there are anecdotal reports of efficacy, this intervention has not been studied, and opponents of the practice counter that androgens do not act quickly enough to be effective when used in this manner [4,68].
Adverse effects and contraindications — At the doses typically required (ie, 200 mg danazol daily or less), androgen therapy is usually tolerated by postpubertal males and by some female patients as well. However, most patients do experience some adverse effects, and there are important contraindications [67].
Adverse effects with long-term androgen administration may include weight gain, lipid abnormalities, arterial hypertension, virilization, abnormalities in serum transaminases, menstrual irregularities, postmenopausal bleeding, diminished libido, vasomotor symptoms, and depression [4,60,64,66-71]. These adverse effects can be controlled or minimized by using the lowest effective dose. Elevations of transaminases are most often seen with prolonged administration of higher doses (eg, danazol, 400 mg or more daily or stanozolol 4 to 16 mg daily). There are also rare reports of hepatocellular adenomas and carcinoma with years of use [72,73]. Because of these concerns, daily doses greater than 200 mg per day are not recommended for long-term use [12]. Although androgen-related adverse effects are more common with higher doses, they are not always dose-dependent, and some patients experience side effects at low doses [71]. A yearly measurement of alpha-fetoprotein and liver ultrasound was also suggested by the 2010 consensus guidelines as a possible means of detecting liver neoplasms, although not all experts agree that this is helpful.
Contraindications to long-term androgen use include childhood, pregnancy and lactation, liver disease, nephrotic syndrome, hypercholesterolemia, hypertension, mood disorders, and breast or prostate cancer, although rare exceptions are made.
Androgens should not be used in children prior to Tanner stage 5 (table 4). The main concern about androgen use in prepubertal children is the potential of these agents to cause premature epiphyseal closure and decreased growth [74]. However, findings of the only retrospective study conducted among pediatric patients suggest that treatment with the lowest effective doses of danazol does not influence growth [75].
Monitoring — The efficacy of androgen therapy should be assessed clinically by sufficient reduction of attacks. Monitoring C4 or C1-INH antigenic levels is not necessary or useful.
●Laboratory values – The 2010 consensus guidelines recommend obtaining a complete blood count, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lipid profile, and urinalysis (to detect hematuria that can result from androgen use) every six months in patients taking long-term androgen therapy [4]. A yearly measurement of alpha-fetoprotein was also suggested by the 2010 consensus guidelines as a possible means of detecting liver neoplasms, although not all experts agree that this is helpful.
●Ultrasonography – The risk of hepatic neoplasms may be increased with the long-term use of androgen therapy, both for patients with HAE and other diseases [73,76,77]. This risk appears to be small, although there are insufficient data to quantitate magnitude. In addition, it is not clear how best to detect focal neoplastic lesions, which may not necessarily result in elevations in serum transaminases [78]. As a result, not all of the authors of this review agree with the below suggestions.
In the absence of consensus, the 2010 guidelines suggest that ultrasonography of the liver be performed every six months for adult patients receiving more than 200 mg/day of danazol (or the equivalent of another androgen) and for all prepubertal patients receiving maintenance androgens [4]. Yearly screening may be sufficient for adults receiving 200 mg or less of danazol daily.
Antifibrinolytics — Antifibrinolytics interfere with the functions of plasminogen and plasmin, leading to decreased production of bradykinin, although the mechanism of action in angioedema remains poorly defined (figure 1) [79]. The only antifibrinolytic medication in widespread use for HAE is tranexamic acid (TA). Another agent, epsilon aminocaproic acid (EACA), was shown to reduce the frequency of HAE attacks in a randomized trial in the 1970s [80]. However, EACA is less potent and has more gastrointestinal side effects compared to TA, although some patients do well with it [81]. Antifibrinolytics effectively prevent attacks in a smaller proportion of patients, compared to pdC1-INH.
In settings in which C1-INH replacement therapy is not available or access is limited, antifibrinolytics are generally preferable to androgens for long-term prophylaxis in pregnant women, children, and patients who do not tolerate androgens. Androgens should be avoided in patients with increased risk for thrombosis. Because pregnancy itself is a relative risk factor for thrombosis, C1-INH replacement therapy is a better choice for prophylaxis in pregnancy. However, one of the authors (HF) has some experience with using TA successfully in pregnant women, particularly if the patient has taken the drug successfully before pregnancy, and it could be considered if C1-INH replacement therapy is not feasible. Of note, Cinryze (brand name) has been associated with a small number of cases of thrombosis as well. (See 'Adverse effects' above.)
Experience with TA is greatest in Europe and Asia, where it has been available for decades [17,82,83]. In the United States, EACA has been available for many years, and an oral preparation of TA became available in 2009 when it was approved by the FDA for the treatment of menorrhagia. Antifibrinolytics are not FDA-approved for HAE, although this does not preclude their use.
Dosing and efficacy — In both children and adults, TA is administered for long-term prophylaxis at a dose of 1 to 3 grams per day or at a total daily amount of 25 mg/kg, divided into two to three doses per day. It is available in a 500 mg dose in much of the world, and in a 650 mg dose in the United States.
●In children, we usually start with 250 mg twice daily for a few weeks, and gradually increase if tolerated to 500 mg twice or three times daily.
●In adolescent and adults, we start with 500 mg (or 650 mg of the United States preparation), two to three times daily for a few weeks, and gradually increase if tolerated to 1 gram three times daily. Only about one-third of patients will achieve adequate control with doses below 3 grams per day. However, the dose of TA must be reduced for patients with renal impairment.
In observational studies of TA, attack frequency and severity are reduced somewhat in approximately 70 percent of patients, although efficacy seems higher in some case series [81,84,85]. Overall, there is a general agreement that a sufficient response is seen in less than 30 percent. Still, TA has been used successfully for long-term prophylaxis in some pediatric patients [86]. (See 'Prepubescent children' above.)
The usual prophylactic dose of EACA in adults is 1 to 2 grams per dose, given three times per day (ie, 3 to 6 grams daily). For children, the suggested dose is 0.05 g/kg per dose, given two times per day.
Adverse effects and contraindications — Antifibrinolytics carry the potential risk of intravascular thrombosis, although the true prothrombotic effects of these medications have not been quantified [87,88]. These agents should not be used in patients with increased thrombotic risk or history of ischemic events.
Additional side effects associated with these agents include the following:
●TA uncommonly causes gastrointestinal distress (eg, nausea, vomiting, diarrhea), headache, hypotension, and anal pruritus, which can occur early in therapy [17,81]. There are also reports of retinal damage with prolonged use of higher doses of TA [89].
●EACA is associated with several adverse effects at higher doses than are indicated for HAE [80,84]. However, at the doses typically used in HAE patients, gastrointestinal distress is typically the main adverse effect, and some patients tolerate it quite well.
Monitoring — The therapeutic success of TA is determined clinically, and each patient should be maintained on the lowest dose that adequately prevents attacks.
●Laboratory values – Doses are adjusted for decreased renal function, so blood urea nitrogen and serum creatinine should be measured yearly. The 2010 consensus algorithm suggests that creatinine kinase, tests of liver and renal function, and urinalysis be performed every six months, although some experts believe yearly evaluation is sufficient.
●Ophthalmologic exam – Annual assessment of ocular pressure has been suggested for patients on long-term therapy, based on the theoretical concern that retinal thrombosis could block outflow of aqueous humor. Periodic ophthalmologic exams for patients on long-term therapy are suggested by some drug information databases because of early reports of ophthalmologic tumors in animals treated with high doses of TA, although this has never been reported in humans. The authors have not performed ophthalmologic exams as part of monitoring therapy.
INVESTIGATIONAL THERAPIES — Several additional drugs for long-term prophylaxis of HAE are in human trials.
●Garadacimab (previously known as CSL312) is a fully human, IgG4 type recombinant monoclonal antibody, which binds to the catalytic site of FXIIa, blocking its proteolytic activity (figure 1). Efficacy, pharmacokinetics, and safety of subcutaneously administered (SC) CSL312 as prophylaxis to prevent HAE attacks were investigated in a multicenter, phase 2 study. The number of attacks was reduced compared with placebo. Mean percentage reductions with three doses of garadacimab were 89, 99, and 91 versus placebo and the drug was well-tolerated [90].
●KVD824 is a small molecule that inhibits plasma kallikrein, limiting the generation of bradykinin. In a phase 1 trial, 84 healthy volunteers received KVD824 either as a single dose of up to 1280 mg or as multiple doses of up to 640 mg each. The trial investigated the safety, tolerability, and pharmacokinetics of the treatment at each of the doses and also studied the effect of food on pharmacokinetics. Participants tolerated all doses well. Another study is currently underway in the United Kingdom assessing single and multiple doses of KVD824 in healthy volunteers. Phase 2 Clinical Trial of KVD824 as an Oral Prophylactic Treatment for Hereditary Angioedema is in planning.
●IONIS-PKK-LRx (donidalorsen) is a ligand-conjugated antisense oligonucleotide designed to inhibit prekallikrein activity, which is under development as a prophylactic agent for bradykinin-mediated angioedema. It is intended for receptor-mediated delivery to hepatocytes. In a phase 1 study, IONIS-PKK-LRx was well tolerated and reduced plasma kallikrein activity and levels in a dose-dependent manner [91]. In a pilot compassionate use study, subcutaneous injections in two patients with different types of severe bradykinin-mediated angioedema over a several-month period was accompanied by a reduction in the angioedema attack rate [92]. In a small phase 2 study of 20 patients (14 received active drug) monthly attack rate was 0.23 (95% CI 0.08-0.39) among patients receiving donidalorsen and 2.21 (95% CI 0.58-3.85) among those receiving placebo [93]. The medication was administered as a monthly subcutaneous injection.
●ALN-F12 is a double-stranded small interfering RNA (siRNA) inhibitor of FXII conjugated to an N-acetylgalactosamine ligand, which suppresses the synthesis of the FXII protein and reduces vascular permeability. RNA interference-mediated reduction of FXII was shown to mitigate excess bradykinin stimulation in an animal model and in an ex vivo human plasma assay [94].
●PHA-022121 is a novel small-molecule antagonist of the bradykinin 2 (B2) receptor that is administered orally. PHA-022121 inhibited the bradykinin-induced changes in blood pressure at all doses tested (0.1, 0.3, 1, 3 and 10 mg/kg given orally) one hour after administration. Based on preclinical experimental data and modelling, this compound is predicted to be effective for prevention of HAE attacks [95].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary angioedema and other forms of nonhistaminergic angioedema".)
INFORMATION FOR PATIENTS — Patients can access detailed, patient-oriented information through the United States Hereditary Angioedema Association and the International Patient Organization for C1 Inhibitor Deficiencies.
SUMMARY AND RECOMMENDATIONS
●General care – General measures for patients with hereditary angioedema (HAE) include education, testing of family members, identification and avoidance of possible triggers, and planning for HAE attacks. Common triggers include dental and medical procedures, periods of stress, menstruation, pregnancy, infections, and certain medications, such as estrogens and angiotensin-converting enzyme inhibitors. (See 'General care' above.)
●Planning for angioedema attacks – Immediately upon diagnosis, clinicians should help construct a plan for emergency care, including how and where the patient will access treatment and education about the need to seek care in a medical facility for laryngeal attacks. In countries where on-demand therapies (ie, C1 inhibitor concentrate [C1-INH], icatibant, or ecallantide) are available, all patients should have access to these medications irrespective of whether they receive long-term prophylaxis. Patients should be offered a medical identification bracelet and a written plan for treatment of HAE attacks for use in emergency department care (form 1 and form 2). (See 'Planning for acute treatment' above and 'Access to "on-demand" therapies' above.)
●Indications for long-term prophylaxis – Long-term prophylaxis is indicated for patients who do not achieve adequate control of their disease with on-demand therapy alone. The decision to start long-term prophylactic treatment should be individualized and the approach may differ somewhat around the world. (See 'Approach to long-term prophylaxis' above.)
●Available medications – The options for long-term prophylaxis are regularly injected (intravenously or subcutaneously) plasma-derived C1-INH (pdC1-INH), lanadelumab (a monoclonal antibody to plasma kallikrein), berotralstat (an orally available plasma kallikrein inhibitor), attenuated androgens, and antifibrinolytics. Each agent has advantages and disadvantages (table 1). (See 'Overview of available therapies' above.)
•The choice of which long-term prophylactic agent to use is influenced both by patient characteristics (age, gender, pregnancy/lactation) as well as regulatory requirements in different countries (table 2). There are few studies directly comparing the different therapies to each other. (See 'Choice of agent in specific groups' above.)
•For patients requiring prophylaxis for severe disease (ie, laryngeal attacks or frequent attacks of other types) we recommend pdC1-INH, lanadelumab, or berotralstat over other agents (Grade 1B). (See 'Specific agents' above.)
-For patients receiving pdC1-INH, we suggest subcutaneous in preference to intravenous administration (Grade 2C). (See 'Compared to IV' above.)
-For pregnant and lactating women, we suggest pdC1-INH in preference to other agents (Grade 2C). If pdC1-INH is not available, we suggest tranexamic acid (Grade 2C). (See 'Pregnant and lactating women' above.)
•If pdC1-INH, lanadelumab, or berotralstat are not available, tranexamic acid or androgens are options. Androgens are more effective but are contraindicated in children younger than Tanner stage 5 (table 4), pregnant or lactating women, and patients with certain comorbidities. Tranexamic acid is less effective but has fewer side effects. (See 'Attenuated androgens' above and 'Antifibrinolytics' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marco Cicardi, MD, who contributed to earlier versions of this topic review.
