Hereditary angioedema: Acute treatment of angioedema attacks

INTRODUCTION — Hereditary angioedema (HAE) is a rare, autosomal dominant disorder characterized by recurrent episodes of well-demarcated angioedema without urticaria, which most often affects the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although swelling resolves spontaneously in two to four days in the absence of treatment, laryngeal edema may cause fatal asphyxiation, and the pain of gastrointestinal attacks may be incapacitating or lead to unnecessary abdominal surgery. The most common forms of HAE (types I and II) are caused by deficiency or dysfunction in C1 inhibitor (C1-INH) [1-3]. A more precise abbreviation is C1-INH-HAE, for hereditary angioedema due to C1-inhibitor deficiency/dysfunction. There are other forms of the disorder in which C1-INH is normal called "HAE with normal C1-INH," which are discussed separately. (See "Hereditary angioedema with normal C1 inhibitor".)

The evaluation and treatment of HAE attacks in adults and children will be reviewed here. Other aspects of these conditions are discussed separately:

●(See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis".)

●(See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

●(See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)

OVERVIEW — Attacks of HAE are commonly categorized as upper airway (commonly referred to as "laryngeal"), gastrointestinal, or cutaneous. Laryngeal attacks are the least common but most dangerous type of attack because airway obstruction can progress to asphyxiation and death. More than one-half of all HAE patients experience a laryngeal attack at some point [4]. Therefore, all patients should be educated about the early signs and symptoms of laryngeal attacks, even if the individual has never experienced one [5]. There should also be a specific plan for how the individual will access emergency treatment. (See 'Laryngeal attacks' below.)

Gastrointestinal attacks can range from mild to severe but usually resolve without serious complications, unless the patient undergoes unnecessary surgical interventions because the disorder is not recognized as HAE [6]. Cutaneous attacks are not associated with significant risk of serious complications or death, although they often cause substantial morbidity as patients' lives can be significantly disrupted by repeated episodes. In addition, cutaneous attacks of the face may extend to involve the larynx in 15 to 30 percent of cases [4].

In HAE, deficiency or dysfunction of C1 inhibitor (C1-INH) leads to excessive production of the vasoactive mediator bradykinin, which leads to episodic increases in vascular permeability and angioedema. The bradykinin-mediated angioedema of HAE is fundamentally different from the angioedema that occurs with allergic reactions (which is mediated by histamine and other mast cell mediators), and it does not respond to epinephrine, antihistamines, or glucocorticoids. Instead, first-line therapies for HAE act by replacing C1-INH or by blocking the production or function of bradykinin.

Equipping patients for emergency care — HAE is rare, and clinicians in emergency settings may not be familiar with the disease or its treatment. Therefore, as soon as a patient has been diagnosed with HAE, a plan for emergency care should be put in place, with particular focus on how the patient should seek care in the event of a laryngeal attack. Patients should be educated that any swelling involving the airway is potentially life threatening and should be treated as an emergency. An important concept that has arisen with the availability of effective on-demand therapies is that of a personalized care plan that takes into account the severity of disease, resources available, and the patient's values and preferences regarding the different therapies. All patients should have also have a plan in place for accessing treatment rapidly [7,8].

●Patients should be supplied with medication for acute treatment of at least two attacks.

●Patients should be made aware that they should carry their acute medicine with them at all times.

●Patients and caregivers should be educated about home treatment and self-administration.

●Patients should be equipped with a form that summarizes treatments for acute episodes of angioedema to assist in communication with emergency providers and ensure appropriate care (full-sized and wallet forms are provided) (form 1 and form 2).

●When possible, clinicians or their representatives should communicate with the hospitals nearest to the patient's home to ensure that acute therapies are available [7].

●In some countries (not the United States), national call centers have been established to provide 24-hour phone access to HAE expert clinicians who can be consulted for help with emergency treatment [9,10].

First-line therapies — There are several first-line therapies for acute treatment of episodes of angioedema in HAE with C1-INH deficiency, which are summarized in the table and discussed in more detail below (table 1) (see 'First-line agents: Dosing, efficacy, and adverse reactions' below):

●C1-INH concentrate, derived from human plasma (plasma-derived C1-INH or pdC1-INH) (see 'C1 inhibitor (plasma derived)' below)

●Recombinant human C1-INH (rhC1-INH, conestat alfa) (see 'Recombinant C1 inhibitor' below)

●Icatibant, a synthetic bradykinin B₂-receptor antagonist (see 'Bradykinin B2-receptor antagonist' below)

●Ecallantide, a recombinant plasma kallikrein inhibitor (see 'Kallikrein inhibitor (United States only)' below)

A clinical response should be evident within two hours after treatment with first-line therapies. No direct, head-to-head trials comparing these agents have been performed, and attempts to compare therapies indirectly are likely confounded by the multiple variables specific to each protocol [11]. Each medication is discussed in detail below, including mechanism of action, dosing, availability, efficacy data, and adverse effects. (See 'First-line agents: Dosing, efficacy, and adverse reactions' below.)

Initiating acute treatment of HAE attacks at home — Early treatment of HAE attacks has been shown to result in improved efficacy [12-14]. Initiating treatment at home (or other settings away from a medical environment) can decrease the delay between the onset of symptoms and time of treatment, and time to start of improvement and resolution of swelling are both significantly shorter when therapies can be given at home. All of the first-line therapies for HAE are likely to be effective if given in the first few hours of the angioedema attack (when the swelling is increasing). Most patients are willing and able to initiate acute treatment of edematous attacks at home. The medications that can be given at home by the patient or by a nursing service on demand are:

●C1-INH concentrate (plasma derived or recombinant), which may be self-administered or given by a caregiver or nurse through a peripheral intravenous line at the first sign of symptoms [15]. Practices regarding injection by the patient versus injection by a nurse in the home setting differ by country. (See 'C1 inhibitor (plasma derived)' below and 'Recombinant C1 inhibitor' below.)

●Icatibant, which may be self-administered as a subcutaneous injection. (See 'Bradykinin B2-receptor antagonist' below.)

●Ecallantide, which is only available in the United States and is given as three subcutaneous injections. Although it is not approved by the US Food and Drug Administration (FDA) for self-administration, because of a risk of hypersensitivity reactions, it can be given by a trained nurse in the patient's home. (See 'Kallikrein inhibitor (United States only)' below.)

While home treatment is preferred, the decision to prescribe therapies for acute treatment at home must be individualized. The clinician must consider each patient's situation, history of attacks, proximity to care, ability to self-administer medications, and preferences.

Second-line therapies — If none of the first-line therapies are available, other options for laryngeal and gastrointestinal attacks are solvent/detergent (S/D) treated plasma (preferred because of lower risk of transmission of infectious diseases) or fresh frozen plasma (FFP) (table 2). (See 'Plasma' below.)

MANAGEMENT ISSUES FOR SPECIFIC TYPES OF HAE ATTACKS

Laryngeal attacks — More than one-half of all HAE patients experience a laryngeal attack at some point [4]. Airway angioedema can present as a sensation of throat swelling, change in voice quality, difficulty swallowing secretions, or difficulty breathing. Angioedema usually progresses over hours, although it can escalate precipitously. Intubation may become very difficult due to distortion of the anatomy of the upper airway. Features of laryngeal attacks and patterns of progression are reviewed separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Upper airway attacks'.)

A first-line therapy (C1 inhibitor, icatibant, or ecallantide) should be administered as early as possible in the attack (table 1). Patients who have first-line therapies at home and self-administer an initial dose should still seek medical care promptly, in case further intervention is required. If first-line therapies are not available at the hospital, 2 units of plasma can be administered after reviewing the risk of disease transmission with the patient. Dosing and counseling are discussed below. (See 'Plasma' below.)

Airway management — Assessment and protection of the upper airway is the first and most important management issue in the patient with an attack involving any part of the airway because none of the available therapies, including first-line agents, can be considered universally effective in all cases. In addition, these agents take time to work, and the patient's airway must be protected in the interim.

Intubation should be attempted immediately if stridor and/or signs of respiratory arrest are present. A clinician trained in difficult airway management and able to perform tracheostomy should be summoned, if possible, because failed attempts can lead to fatal obstruction. Emergent cricothyroidotomy may be required at this stage. (See "Emergency cricothyrotomy (cricothyroidotomy) in adults".)

Once the patient is assessed and either intubated or deemed stable, additional treatment can be considered. Transfer to the intensive care unit should be arranged, unless the laryngeal angioedema responds promptly to treatment in a stable patient. Frequent and meticulous monitoring of airway status should continue throughout the course of the attack until complete resolution, and patients should not be discharged until all airway symptoms have resolved.

Gastrointestinal attacks — Gastrointestinal attacks present with varying degrees of gastrointestinal colic, nausea, vomiting, and/or diarrhea, which result from bowel wall edema. Gastrointestinal attacks can range from mild to severe but usually resolve without serious complications, unless patients undergo unnecessary surgical interventions because the disorder is not recognized [6,16]. The clinical presentation and evaluation of gastrointestinal attacks is reviewed in more detail separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Gastrointestinal attacks'.)

When a patient with known or suspected HAE presents with gastrointestinal colic, the clinician must determine if the abdominal symptoms are actually due to angioedema or to an unrelated process. Patients who have had previous gastrointestinal attacks lasting two to five days should be questioned carefully to ascertain if their current symptoms are similar to past episodes.

The clinical response to one of these first-line therapies can be valuable in distinguishing gastrointestinal attacks of HAE from other abdominal pathologies. With all of the first-line therapies, clinical response should be evident within two hours, keeping in mind that improvement is usually most prompt when the therapy is given in the first several hours of the episode (table 1). If given later in the attack, a slower, more gradual response may be seen. However, if there is no response at all two hours after the initial dose, then evaluation for other causes of abdominal symptoms should proceed.

If first-line therapies are not available, then management of gastrointestinal attacks is largely supportive (table 2). Alternatively, 2 units of plasma can be administered after reviewing the risk of disease transmission with the patient. Dosing is discussed below. (See 'Dosing' below.)

Rehydration and symptomatic therapy — Therapy to abort the attack is most important, but some patients with gastrointestinal attacks also require treatment for dehydration and pain, particularly if effective treatment was not given early in the attack. Agents such as scopolamine (hyoscine) butylbromide (not available in the United States), metoclopramide, or prochlorperazine can be helpful for cramping, nausea, and vomiting. Opioid pain relievers were previously used to treat the severe pain associated with gastrointestinal attacks; however, opioid addiction is a serious risk in patients treated with these drugs. Fortunately, the development of effective on-demand medications, when available, has removed the need to use opioid pain medications.

Cutaneous attacks — Cutaneous attacks may involve any part of the body, including the extremities, torso, neck, face, and genitalia. Many cutaneous attacks result in significant dysfunction, and patients may miss several days of school or work [17]. Thus, consideration of treating early rather than waiting until swelling becomes more severe should be given particularly in facial attacks, which may extend to involve upper airway mucosa. Acute therapies are less likely to provide relief when given late in an attack. However, the decision to treat obviously depends upon the availability of acute therapies (table 2).

Attacks involving multiple locations — HAE attacks can involve more than one location, with approximately 30 percent of severe attacks affecting multiple sites [18]. These attacks can involve any combination of laryngeal, gastrointestinal, or cutaneous locations. Symptoms at the individual locations typically parallel each other, although, in some cases, swelling can start at a new site while resolving at an earlier site. Management of multisite attacks is based on the management principles for each individual site. The response to effective treatment tends to be similar at the various sites.

FIRST-LINE AGENTS: DOSING, EFFICACY, AND ADVERSE REACTIONS — The medications used for acute treatment of episodes of angioedema in HAE are discussed in this section, with proposed mechanism of action, dosing, efficacy data, and side effects (table 1). An approach to using these medications to manage acute angioedema was presented previously. (See 'Overview' above.)

C1 inhibitor (plasma derived) — C1 esterase inhibitor (C1-INH), concentrate from human plasma, is referred to in this review as plasma-derived C1-INH or pdC1-INH. It is administered intravenously for acute treatment of HAE attacks. pdC1-INH is the best-studied first-line therapy for acute episodes of angioedema in patients with HAE [19,20]. It is also the preferred acute treatment for HAE attacks in pregnant individuals with HAE [21-24]. (See 'Pregnancy and lactation' below.)

C1-INH acts at several points in the pathways important in the generation of angioedema (figure 1). (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis", section on 'Pathogenesis'.)

Two pdC1-INH products are available for acute treatment: Cinryze (brand name) and Berinert (brand name), which are administered by intravenous injection. Other C1-INH products (ie, Haegarda [brand name] or Berinert 2000/3000 [brand name]) are administered by subcutaneous injection and approved only for prophylaxis. Prophylaxis is discussed in detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Subcutaneous C1 inhibitor'.)

Dosing — The dosing of pdC1-INH (Berinert) for treatment of acute episodes is based upon weight, and the recommended dose is 20 units/kg [25,26]. Each vial of drug contains 500 units of pdC1-INH. Thus, doses for patients of different weight ranges are:

●Administer 1000 units if weight is ≤50 kg (110 pounds)

●Administer 1500 units if weight is >50 kg (>110 pounds) and ≤75 kg (165 pounds)

●Administer 2000 units if weight is >75 kg (>165 pounds) and ≤100 kg (220 pounds)

●Administer 2500 units if weight is >100 kg (>220 pounds)

If the patient's weight-based dose falls between the amounts in a vial, we round up to the nearest whole vial. pdC1-INH should be reconstituted, warmed to body temperature before administration, and given through a peripheral vein by slow infusion (eg, 1000 units over 10 minutes). It can be administered at home by the patient, a caregiver, or a nurse or in a medical facility [27,28]. The solution must not be shaken, as this can cause denaturation of the protein. In an emergency, it can be given without prewarming. These therapies should be given as early as possible in the course of an attack. One study showed that patients treated within six hours of symptom onset had shorter times to relief and resolution of symptoms compared with those treated later [29].

Stabilization or improvement in symptoms is usually seen within 30 minutes in laryngeal or gastrointestinal attacks [30]. Fewer than 1 percent of attacks require a second dose [31,32]. However, if symptoms initially improve but then start to recur or only partially improve, a second dose can be given after the first. Similarly, if symptoms are still worsening after the initial dose of pdC1-INH, a second dose can be administered, particularly for attacks affecting the airway. Berinert (brand name) might be used as rescue therapy in patients not responding to icatibant appropriately [31].

The US Food and Drug Administration (FDA) has not approved Cinryze (brand name) for acute treatment of HAE attacks (only for prophylaxis). However, there is no empiric reason to suspect that Cinryze (brand name) would be less effective than other C1-INH products. The Cinryze (brand name) dose approved in the European Union for HAE attacks is 1000 units, with the possibility of another 1000 units if not improving. In the absence of trials to determine optimal dosing of Cinryze (brand name) in HAE attacks, either this dosing or weight-based dosing (described above) is acceptable.

Efficacy — The efficacy of pdC1-INH for acute treatment of HAE attacks has been well-demonstrated in randomized trials [25,33-38].

●A randomized trial of pdC1-INH (Cinryze [brand name]) for acute treatment of HAE attacks involved 68 patients assigned to either 1000 units of pdC1-INH (regardless of weight, with the possibility of another 1000 units after one hour based on clinician and patient assessment of need) or placebo for nonlaryngeal attacks [38]. The median time to onset of unequivocal relief (the primary endpoint) was two hours in the pdC1-INH group compared with over four hours in the placebo group.

●A subsequent randomized trial of 125 patients with acute gastrointestinal or facial cutaneous angioedema episodes compared pdC1-INH (Berinert [brand name]) at doses of 10 units/kg or 20 units/kg with placebo [25]. Patients were treated within five hours of the symptoms reaching moderate intensity. Median time to onset of relief was significantly shorter with the higher dose of pdC1-INH (0.5 hours), compared with the lower dose of pdC1-INH (1.2 hours) or placebo (1.5 hours).

●A retrospective comparison of data from 881 laryngeal attacks treated with any of the available first-line therapies found that weight-adjusted pdC1-INH appeared to give the best outcomes, with time to onset of relief ranging from 15 minutes to two hours and none of the 48 attacks requiring a second dose [11]. A subsequent nonrandomized trial also confirmed the efficacy of weight-based pdC1-INH (Berinert [brand name]; 20 units/kg) in patients with laryngeal edema [39].

Data from a multicenter registry found that the response could be improved when patients were able to self-administer pdC1-INH at home at the first sign of swelling (pdC1-INH "on demand") and that this practice was safe [40]. In a small study, 12 patients reported initiation of relief in a mean of approximately 40 minutes after the onset of symptoms when pdC1-INH was self-administered as compared with about 2.5 hours when the patients were dependent on a health care facility for administration [12].

Adverse effects — Adverse effects of pdC1-INH are reviewed in detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Adverse effects'.)

Recombinant C1 inhibitor — Recombinant human C1-INH (rhC1-INH, conestat alfa; Ruconest [brand name] in Europe and the United States, Rhucin [brand name] in other countries) became available in Europe in 2011 and in the United States in 2014 [41]. It is collected from the milk of transgenic rabbits [42-44]. Compared with the plasma product, rhC1-INH has a similar protease inhibitory activity but a shorter half-life. Thus, higher doses are required to achieve adequate plasma levels over a period of time sufficient to impact acute symptoms compared with the plasma-derived product.

Dose — The recommended dose of rhC1-INH for acute treatment of an HAE attack is 50 units/kg, rounded up to the nearest whole vial, and up to a maximum of 4200 units [45-47]. The medication is a lyophilized powder that is reconstituted in sterile water, warmed to body temperature before administration, and given through a peripheral vein over five minutes.

Patients generally respond within four hours and do not require repeat dosing, although a second identical dose can be given if there is no improvement for a maximum of 4200 international units given twice in 24 hours. Relapse may occur in 2 to 3 percent of patients [48].

Efficacy — The efficacy of rhC1-INH for acute treatment of HAE attacks has been demonstrated in several randomized trials [47,49-52].

●In two similar randomized trials, patients received rhC1-INH at doses of 100 units/kg, 50 units/kg, or placebo [47]. The primary endpoint was the time to initial relief of symptoms, which was a median of 66 minutes (95% CI 61-122) with the higher dose, 122 minutes (95% CI 72-136) with the lower dose, and 495 minutes (95% CI 245-520) with placebo. At both doses, rhC1-INH was well-tolerated.

●In another randomized trial, 75 patients were treated with rhC1-INH (50 international units/kg to a maximum of 4200 international units/treatment) or placebo [49]. Median time to the beginning of symptom relief was 90 minutes and 152 minutes in patients receiving rhC1-INH and placebo, respectively. Median time to minimal symptoms was 303 minutes in the rhC1-INH group.

●In a prospective study that analyzed the course of 544 HAE attacks experienced by 21 patients who received rhC1-INH, the time to the administration of rhC1-INH was 90 minutes (median) after the onset of symptoms [52]. Improvement began as early as 60 minutes after administration, and the attacks resolved in approximately 12 hours. As with other therapies for acute attacks, the more promptly the rhC1-INH was given, then shorter the time to onset of improvement and time to complete resolution. No local or serious systemic adverse events/effects were observed.

Recombinant and plasma-derived C1-INH have not been compared in head-to-head studies, and information about their relative risks and benefits is limited. A small series described the use of rhC1-INH in patients with disease that was not fully responsive to pdC1-INH and other therapies, with mixed results [53].

Adverse effects — Side effects with rhC1-INH were uncommon and included headache, nausea, and diarrhea [45]. No postexposure antibody responses against the product have been detected [54].

Allergy to rabbits is a contraindication to the use of rhC1-INH because anaphylaxis was reported during a phase-I study in a normal volunteer with preexisting rabbit allergy [55]. Patients can simply be asked about this. Formal testing for rabbit allergy is not necessary unless the patient reports allergy.

Thrombotic events were not seen in the randomized trials of Ruconest (brand name) mentioned above [45,47,49]. (See 'Adverse effects' above.)

Bradykinin B2-receptor antagonist — Icatibant (Firazyr or Sajijer [brand names]) is a synthetic bradykinin B2-receptor antagonist that has been available in the European Union since 2008 and became available in the United States in 2011, where it was approved for patients 18 years of age and older [56-58]. In the European Union, icatibant was approved for use in children as young as two years of age.

Icatibant is a synthetic polypeptide that is structurally analogous to bradykinin and acts by selectively and competitively antagonizing the bradykinin B2-receptor (figure 1). It is approved for acute treatment of HAE attacks in patients with hereditary C1-INH deficiency.

Icatibant dose and administration — The dose of icatibant in adults is 30 mg, given by slow subcutaneous injection because of the relatively large volume (3 mL) involved, preferably in the abdominal region [59]. It can be self-administered. The pediatric dose is dependent on the patient's weight as below (table 1):

●Administer 10 mg if weight is 12 to 25 kg

●Administer 15 mg if weight is 26 to 40 kg

●Administer 20 mg if weight is 41 to 50 kg

●Administer 25 mg if weight is 51 to 65 kg

●Administer 30 mg if weight is >65 kg

Most patients require only one dose to treat symptoms adequately [60-63]. If symptoms are gradually improving after the initial dose, no further doses are needed. However, if symptoms continue to worsen after the initial dose, a second dose can be given after six hours, and a third dose can be given, if needed, after an additional six hours. A maximum of three doses within 24 hours is recommended.

Efficacy studies — The "For Angioedema Subcutaneous Treatment" (FAST-1 and FAST-2) trials were randomized, multicenter, phase-III trials in which 130 adults with C1-INH deficiency were treated with icatibant for laryngeal, gastrointestinal, or cutaneous attacks of moderate-to-severe intensity [64]. FAST-1 compared icatibant with placebo, and FAST-2 compared icatibant with oral tranexamic acid. The primary endpoint was median time to onset of symptom relief. FAST-1 did not demonstrate a clear benefit of icatibant over placebo (2 hours versus 4.2 hours), but FAST-2 did (2 hours with icatibant versus 11 hours with tranexamic acid). In a pooled analysis of the two trials, significantly more patients receiving icatibant had symptom relief within four hours compared with placebo or tranexamic acid (73 versus 45 and 29 percent, respectively) [65]. In addition, median time to near-complete symptom relief was significantly shorter with icatibant compared with placebo or tranexamic acid (15, 21, and 36 hours, respectively).

In a third trial, FAST-3, 83 patients were randomly assigned to receive icatibant or placebo for moderate-to-severe attacks at any location [66]. Icatibant significantly reduced median times to ≥50 percent reduction in symptom severity (2 versus 19.8 hours, primary endpoint), onset of primary symptom relief (1.5 versus 18.5 hours, secondary endpoint), or near-complete symptom relief (8 versus 36 hours) and provided a shorter time to initial symptom relief (0.8 versus 3.5 hours). For laryngeal attacks, median times to ≥50 percent reduction in symptom severity were 2.5 and 3.2 hours for icatibant and placebo, respectively. None of the patients receiving icatibant required rescue therapy before symptom relief occurred.

The Icatibant Outcome Survey (IOS) was a phase-III study of 32 children and adolescents with HAE, ranging in age from 2 to 18 years, who were treated with 0.4 mg/kg of icatibant [60]. Among 11 children and 11 adolescents treated for attacks, the median time to symptom relief was one hour. Mild or moderate adverse events occurred in nine subjects and consisted predominantly of injection-site reactions and gastrointestinal complaints. Post-hoc analysis from the IOS confirmed in a real-world setting that early treatment of HAE attacks with icatibant in type I and II HAE subjects resulted in shortened times to symptom resolution and attack duration. Among the patients in both studies who were treated in medical facilities, median time from attack onset to treatment was 6.5 versus 2 hours, median time to symptom resolution was 8 versus 3.5 hours, and median attack duration was 16.9 versus 7.3 hours in IOS and FAST-3, respectively [67].

Adverse effects and precautions — Mild and transient pain at the injection site is the most common adverse reaction to icatibant. Other uncommon adverse effects include nausea, gastrointestinal colic, fever, asthenia, dizziness, increase in transaminases, and headache [68]. Icatibant should be used with caution in patients with acute ischemic heart disease or unstable angina since antagonism of the bradykinin B2-receptor can reduce coronary blood flow in animal models, and patients with these comorbidities were excluded from clinical trials [69]. HAE attacks may relapse in 10 percent of icatibant-treated cases [70].

Kallikrein inhibitor (United States only) — Ecallantide (Kalbitor [brand name]) is a genetically engineered recombinant plasma kallikrein inhibitor [71]. This drug blocks the production of bradykinin by inhibiting plasma kallikrein (figure 1) [56,72-76]. Ecallantide was approved by the US FDA in 2009 for the treatment of acute attacks of HAE in patients 12 years of age or older [77]. It is only available in the United States [78].

Like pdC1-INH, ecallantide is a first-line acute therapy for laryngeal angioedema (following airway protection) and for gastrointestinal attacks. It is occasionally used for severe cutaneous attacks. However, clinical experience with ecallantide is more limited.

While it can be administered in a nonmedical setting, ecallantide cannot be self-administered. Ecallantide should be administered by a health care provider in a setting equipped to manage anaphylaxis as well as severe angioedema related to HAE. Anaphylaxis and allergic reactions were reported in 2 to 3 percent of patients in clinical trials. (See 'Efficacy studies and safety' below.)

Ecallantide dosing and administration — Ecallantide is available in 1 mL vials of 10 mg each, and the adult dose is 30 mg. Injections should be given as three separate injections of 10 mg in the abdomen, upper arm, or thigh. The sites of injection should be anatomically distant from the area affected by the angioedema.

A second dose of 30 mg may be administered if symptoms persist. Based on limited information, the second dose could be given as early as 1 hour and up to 24 hours after the first dose. Relapse has been reported in less than 3 percent of patients [79].

Efficacy studies and safety — The efficacy of ecallantide was assessed in two randomized trials: EDEMA3 [80] and EDEMA4 [78]. In an analysis of the pooled data from these studies, 143 subjects were treated with either ecallantide or placebo [81]. All types of attacks occurred (gastrointestinal, laryngeal, and cutaneous), with gastrointestinal attacks being the most common. Change from baseline mean symptom complex score at four hours after dosing was significantly greater in the ecallantide group compared with the placebo group (-0.97±0.78 and -0.47±0.71, respectively). The percentages of ecallantide- and placebo-treated patients with meaningful improvement at four hours were 70 and 38, respectively.

Allergic reactions and anaphylaxis — The leading safety issue is a risk of allergic reactions and anaphylaxis, which have been reported in 3 to 4 percent of patients receiving it subcutaneously in the clinical trials [78,80,82]. For this reason, ecallantide should be administered in a supervised setting by a medically trained provider. Patients should be monitored carefully following administration because some symptoms of anaphylaxis overlap with those of HAE (ie, angioedema, throat discomfort), and recognition of an allergic reaction may be challenging. In the available reports, anaphylaxis presented within one hour of administration as flushing, urticaria, pruritus, rhinitis, chest discomfort, pharyngeal or laryngeal edema, wheezing, and/or hypotension. Anaphylaxis has not been reported with the first dose when the drug is given subcutaneously. All episodes have responded to epinephrine and other appropriate treatments with no fatalities [82]. Until more information is available, patients experiencing anaphylaxis or clear symptoms of hypersensitivity should not be given the drug again until evaluated by an allergy specialist. The mechanism responsible for these reactions has not been conclusively demonstrated, and the role of skin testing is not clear [82]. However, some patients with hypersensitivity reactions have tolerated the drug upon graded challenge [82].

Other adverse effects of ecallantide are generally mild and include headache, nausea, fatigue, and diarrhea [78]. Injection-site reactions are reported in <10 percent of patients.

Cost of first-line therapies — All first-line acute therapies for HAE attacks are costly. In the United States, the cost of one treatment with pdC1-INH, ecallantide, or icatibant ranged from USD $5000 to 10,000 [83]. In European countries, the cost of one treatment with pdC1-INH, rhC1-INH, or icatibant is approximately 1500 to 2000 euros.

PLASMA — Plasma is a second-line therapy in the acute treatment of laryngeal attacks and severe gastrointestinal attacks and should be used only if the therapies discussed above are not available. There have been no studies directly comparing plasma with C1 inhibitor (C1-INH), ecallantide, or icatibant.

Plasma is available as solvent/detergent (S/D) treated plasma or fresh frozen plasma (FFP), and both are reported to be helpful. Guidelines recommend S/D plasma over FFP, when both are available, because S/D-treated plasma theoretically carries a lower risk of viral transmission compared with FFP. However, most of the case reports of HAE treatment used FFP. This is potentially relevant because S/D treatment removes some plasma components, and the effect on C1-INH specifically has not been investigated. (See 'Effectiveness' below.)

Dosing — Two units of plasma are given initially. This dose can be repeated every two to four hours until there is clinical improvement. Once the attack begins to subside, further plasma is not usually required. If a patient has comorbid conditions that increase the risk for volume overload, then dosing of 10 to 15 mL per kg body weight is recommended instead, with monitoring of volume status and cardiopulmonary function [84].

Effectiveness — The efficacy of plasma in treating HAE attacks has been suggested by case reports; no controlled trials have been performed [85-91]. A review of the literature included 23 case reports in which FFP was used for acute treatment of HAE attacks and revealed improvement in 22 cases [92]. The time to first signs of improvement ranged from 30 minutes to 12 hours. No clinical improvement was noted in one case, and transient worsening of symptoms, followed by improvement, was reported in two cases. Subsequently, a study from India included 15 episodes of laryngeal edema treated with FFP (10 mL/kg, maximum 2 units) [93]. The interval between onset of laryngeal edema and administration of FFP varied between 4 and 10 hours. In all instances, symptoms resolved within one hour.

Plasma could theoretically exacerbate angioedema because it contains not only C1-INH but also substrate proteins (prekallikrein and high-molecular-weight kininogen) that could consume the available inhibitor and paradoxically worsen the angioedema, although this has been reported only rarely [92]. Still, the clinician must monitor patients with airway angioedema carefully and be prepared to intubate if necessary.

The data on S/D-treated plasma are scant [94], and we know of no reports comparing S/D plasma and FFP for the acute treatment of angioedema episodes. (See "Clinical use of plasma components".)

Risks — The primary concern with plasma products is disease transmission, and the risks of this must be presented to the patient prior to each administration.

●S/D treatment inactivates enveloped viruses (such as human immunodeficiency virus [HIV], human T lymphotropic virus, and hepatitis B and C) but not prions or nonenveloped viruses (eg, hepatitis A, parvovirus).

●FFP does not undergo processing to remove infectious agents. However, it is obtained from single-donor units rather than pooled plasma, and each unit undergoes serologic testing for viral markers. The risk of infection for a unit of FFP is identical to that of whole blood, which is also obtained from single donors. This risk is summarized in the table and presented in more detail separately (table 3). (See "Epidemiology and transmission of hepatitis C virus infection".)

SPECIAL POPULATIONS

Pregnancy and lactation — The preferred acute treatment of HAE attacks during pregnancy and lactation is plasma-derived C1 inhibitor (pdC1-INH), given at 20 units per kilogram, because there is extensive experience with the pdC1-INH products that have been available in the European Union [95]. Fewer data are available regarding the use of icatibant [96-98], recombinant C1 inhibitor (rhC1-INH) [98,99], or ecallantide in pregnant patients. These should be used only if pdC1-INH is not available.

Children and adolescents — pdC1-INH is safe and effective in patients of all ages [100]. The other first-line therapies have been studied less extensively in children but appear to be safe and effective (table 1):

●rhC1-INH is effective and well-tolerated for HAE attacks in adolescents [101]. In an open-label, phase-II study that included children aged 2 to 13 years with HAE, rhC1-INH was efficacious, safe, and well tolerated [102]. In the European Union, Ruconest was approved for use in children as young as two years of age [103].

●Icatibant has been studied in children and adolescents and was also well tolerated [60]. Icatibant is approved for use in the European Union for children as young as two years of age.

●Ecallantide is approved in the United States for children 12 years of age and older.

INVESTIGATIONAL AGENTS — An effective oral medication for acute treatment of HAE attacks has been lacking in the armamentarium of therapies for HAE, but two oral drugs are in clinical trials: a plasma kallikrein (PKa) inhibitor sebetralstat (KVD-900) [104] and an oral bradykinin B2 receptor antagonist (PHA-022121) [105].

INEFFECTIVE THERAPIES — Therapies that are minimally effective or have no benefit at all in the acute treatment of angioedema in HAE include androgens, tranexamic acid, and treatments for allergic (histaminergic) angioedema.

●Androgens and tranexamic acid are therapies that prevent attacks of angioedema in HAE, but androgens have never been conclusively shown to be useful in acute treatment, and tranexamic acid appears to be minimally effective [106]. If first-line agents are not available, attacks are best managed with plasma products or supportive care. Preventative therapies for HAE are reviewed in detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)

●Epinephrine is effective in histaminergic (allergic) angioedema but is not known to have any impact on the bradykinin-mediated angioedema of HAE. There are isolated case reports suggesting benefit from epinephrine in HAE attacks [107,108]. However, controlled studies would be needed to validate a true effect since the angioedema of HAE resolves spontaneously with time.

●Glucocorticoids and antihistamines are not effective for angioedema associated with disorders of C1 inhibitor (C1-INH) and should not be given once the diagnosis of a C1-INH disorder has been made.

●A few studies have examined the effects of inhaled or injected heparin or heparin-like compounds in treating (and preventing) the symptoms of HAE attacks [109-111]. However, more data are needed before this therapy can be considered.

CARE FOLLOWING ATTACKS — Following any HAE attack, events leading up to the attack should be examined to determine if an identifiable trigger was present. Common triggers include the following [112]:

●Regularly missing doses of prophylactic medication

●Running out of prophylactic medication

●Initiating interfering medications (such as estrogens or angiotensin-converting enzyme inhibitors)

●Infections

●Trauma, including iatrogenic interventions (dental work and other procedures)

●Physical exertion or fatigue

●Mental stress (although often not avoidable, some patients increase their prophylactic medications during stressful periods)

●Menstruation

●Pregnancy

Discussing common triggers with the patient directly after an event should help that individual avoid the same set of circumstances in the future. In addition, the clinician should review how and when the patient sought medical attention and whether the written plan of action was available and utilized. It has been the experience of the authors that such review sessions are consistently illuminating and critical to improving care.

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".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency or dysfunction is a disorder characterized by recurrent episodes of angioedema affecting the upper airway, bowel wall, or skin, which typically last two to four days. The angioedema of HAE is mediated by bradykinin and does not respond to epinephrine, antihistamines, or glucocorticoids. Instead, first-line therapies for HAE act by replacing the C1-INH that is deficient or dysfunctional in this disease or by inhibiting the production or function of bradykinin (figure 1). (See 'Overview' above.)

●Planning for attacks – Clinicians in emergency settings may not be familiar with this rare disease or its treatment. Once the diagnosis has been established, patients should be equipped with acute therapies for at least two attacks, educated about self-administration, and given a personalized form or wallet card containing information about the acute treatment of HAE attacks, which can help them and also assist emergency providers (form 1 and form 2). In addition, call centers have been established in some countries to provide 24-hour access to HAE experts who can assist with emergency management. (See 'Equipping patients for emergency care' above.)

●Available therapies for acute angioedema – First-line acute therapies for HAE and dosing of each agent are summarized in the table (table 1) (see 'First-line agents: Dosing, efficacy, and adverse reactions' above):

•Human plasma-derived C1-INH concentrate (pdC1-INH) (see 'C1 inhibitor (plasma derived)' above)

•Recombinant human C1-INH (rhC1-INH) (see 'Recombinant C1 inhibitor' above)

•Icatibant, a bradykinin B2-receptor antagonist (see 'Bradykinin B2-receptor antagonist' above)

•Ecallantide, a kallikrein inhibitor (available only in the United States) (see 'Kallikrein inhibitor (United States only)' above)

●Act fast in laryngeal attacks – More than 50 percent of all HAE patients experience a laryngeal attack at some point, and laryngeal attacks should always be treated as emergencies. Patients who have first-line therapies at home and self-administer an initial dose of a medication should still seek care promptly in case further intervention is required. The airway should be assessed immediately because laryngeal swelling may progress rapidly and can result in fatal asphyxiation. Those with respiratory distress or stridor may require intubation because even the first-line therapies take approximately 30 minutes or more to begin working. An expert should manage the airway if possible. (See 'Laryngeal attacks' above and 'Airway management' above.)

●Dosing and administration of first-line therapies – In areas of the world where first-line agents are available:

•For patients with a laryngeal attack of any severity, we recommend treatment with a first-line therapy, as described in the table (table 1) (Grade 1A). Choice of agent depends mainly upon availability, although pregnant patients are preferentially treated with pdC1-INH. (See 'Laryngeal attacks' above and 'Pregnancy and lactation' above.)

•For patients with gastrointestinal attacks or cutaneous attacks, we suggest treatment with a first-line therapy (table 2) (Grade 2B). The choice of agent should be based upon availability and patient preference. (See 'Gastrointestinal attacks' above and 'Cutaneous attacks' above.)

●Dosing and administration of second-line therapies – If none of the first-line agents are available, then the approach to treatment depends upon the type and severity of attack:

•For patients with any laryngeal edema or moderate-to-severe gastrointestinal attacks, we suggest solvent-detergent (S/D) treated plasma or, if not available, fresh frozen plasma (FFP) as described in the table (table 1) (Grade 2C). (See 'Plasma' above.)

•For patients with mild gastrointestinal attacks, we suggest supportive therapy (rehydration and symptomatic therapy) (Grade 2C). (See 'Rehydration and symptomatic therapy' above.)

•For patients with cutaneous attacks not involving skin adjacent to the airway, we suggest no treatment (Grade 2C).

●Care following attacks – After an HAE attack, the events leading up to the attack should be reviewed to determine the factors that may have precipitated it. This evaluation is invaluable in helping patients and clinicians identify triggers that are important for that individual and devise strategies to avoid these triggers in the future. In addition, the clinician should review whether the patient was able to access care quickly and improve upon the care plan if necessary. (See 'Care following attacks' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marco Cicardi, MD, who contributed to earlier versions of this topic review.