Official reprint from UpToDate® www.uptodate.com
©2012 UpToDate®
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use (click here) ©2012 UpToDate, Inc.
Treatment of acute attacks in hereditary angioedema
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: Feb 16, 2012.

INTRODUCTION — Hereditary angioedema (HAE) is a rare disorder characterized by recurrent episodes of angioedema without urticaria, which most often affect 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. HAE is associated with deficiency or dysfunction of the C1 inhibitor protein. Patients can be equipped with instructions for emergency care providers (form 1 and form 2).

The treatment of laryngeal attacks, which are the leading cause of mortality in patients with hereditary angioedema, must always begin with immediate and meticulous attention to airway patency, regardless of the therapies available. (See 'Airway management' below.)

First-line therapies for acute attacks of HAE include the following:

  • Purified (C1INHRP) or recombinant (rhC1INH) human C1 inhibitor (various products available worldwide)
  • Ecallantide, a kallikrein inhibitor (available only in the United States)
  • Icatibant, a bradykinin B2 receptor antagonist (available in the United States and the European Union)

The treatment of acute attacks of HAE will be reviewed here. Other aspects of these conditions are discussed elsewhere. (See "Clinical manifestations and pathogenesis of hereditary angioedema" and "Diagnosis of hereditary angioedema" and "Prevention of attacks in hereditary angioedema".)

MEDICATION OPTIONS — The medications used for acute treatment of episodes of angioedema in hereditary angioedema are discussed in this section, with proposed mechanism of action, dosing, efficacy data, and side effects.

C1-inhibitor (plasma-derived) — C1 esterase inhibitor replacement protein (C1INHRP), obtained from pooled human plasma, can be administered intravenously (IV) for treatment of acute attacks. C1INHRP is the best studied first-line therapy for acute episodes of angioedema in patients with HAE, as plasma derived products for this treatment has been available for decades in Europe. C1-inhibitor normally acts at several points in the pathways important in the generation of angioedema (figure 1). (See "Clinical manifestations and pathogenesis of hereditary angioedema", section on 'Pathogenesis'.)

Two C1INHRP products are derived from pooled human plasma: Cinryze® (ViroPharma Inc), and Berinert® or Berinert P® (both from CSL Behring). C1INHRP has been used for years in the EU, Canada, Japan, and Argentina, and became available in the US in 2008/9 [1,2].

Dosing — The dosing of C1INHRP is based upon weight, and the recommended dose is 20 units/kg [3,4]. Each vial of drug contains 500 units of C1INHRP. 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 ≤100 kg (220 pounds)
  • Administer 2000 units if weight is >100 kg (220 pounds)

C1INHRP should be reconstituted, warmed to body temperature before administration, and given through a peripheral vein over 10 minutes. In an emergency, it can be given without prewarming. The solution must not be shaken, as this can cause denaturation of the protein.

Stabilization or improvement in symptoms is usually seen within 30 minutes in laryngeal or gastrointestinal attacks [5]. In one author's experience (MC), fewer than 5 percent of attacks require a second dose. However, if symptoms persist, a second dose can be given approximately two hours after the first, and if symptoms are worsening after the initial dose of C1INHRP, a second dose can be administered after 30 minutes.

The US Food and Drug Administration has not yet approved Cinryze® for treatment of acute attacks (only for prophylaxis). However, there is no empiric reason to suspect that Cinryze® would be less effective than the C1 inhibitor products used for years in Europe.

Efficacy — The efficacy of C1INHRP for treatment of acute attacks of HAE was first reported in 1980 and has been well-demonstrated [3,6-11].

  • The largest randomized trial of C1INHRP (Cinryze®) in the treatment of acute attacks involved 68 patients, assigned to either 1000 units (with the possibility of another 1000 units after one hour based on clinician and patient assessment of need) of C1INHRP or placebo for nonlaryngeal attacks [11]. The median time to onset of unequivocal relief (the primary endpoint) was two hours in the C1INHRP group, compared with over four hours in the placebo group.
  • A subsequent randomized trial of 125 patients with acute gastrointestinal or facial cutaneous attacks compared C1INHRP at doses of 10 units/kg or 20 units/kg to placebo [3]. Patients were treated within five hours of the symptoms reaching moderate intensity. Time to onset of relief was significantly shorter with the higher dose of C1INHRP (0.5 hours) compared to placebo (1.5 hours) or to the lower dose of C1INHRP (1.2 hours). An even greater difference between higher dose C1INHRP and placebo was seen with more severe attacks (0.5 and 13.5 hours, respectively).
  • The effect of C1INHRP on laryngeal attacks was evaluated in a retrospective study comparing C1INHRP to conservative management in 193 episodes of laryngeal swelling [10]. The mean duration of laryngeal edema was 15.3 hours in patients who received C1INHRP concentrate and 101 hours in those who did not. A subsequent nonrandomized trial also confirmed the efficacy of C1INHRP (20 units/kg) in patients with laryngeal edema [12].

An observational trial suggested that the response could be improved when patients were able to self-administer C1INHRP at home at the first sign of swelling (C1INHRP "on demand") [13]. The patients in this study had disease that was refractory to prophylactic therapy with androgens, antifibrinolytics, or both. They reported initiation of relief in a mean of approximately 40 minutes after the onset of symptoms, as compared to about 2.5 hours when the patients were dependent on a health care facility for administration.

C1INHRP has been used successfully in pregnancy and is the preferred treatment for acute attacks [14-17].

Risks and adverse effects — Side effects are unusual and include headache and fever. Rare allergic reactions to C1INHRP have been described [18,19].

Disease transmission is a theoretical risk of C1INHRP treatment, since it is obtained from pooled human plasma that has been pasteurized and ultrafiltrated. However, there have been no reported cases of viral transmission with the most extensively used preparation (Berinert® P), despite the administration of over 100 million units [16,20,21]. The issue of disease transmission with C1 inhibitor products is discussed in more detail elsewhere. (See "Prevention of attacks in hereditary angioedema", section on 'Overview of available agents'.)

Rare patients have been reported who experience an increase in the frequency of attacks during periods in which C1INHRP was administered for treatment of acute attacks [22]. These patients were not receiving C1INHRP for prophylaxis. Although the C1INHRP infusions remained successful in treating acute symptoms, the frequency of attacks gradually increased over a period of years. The mechanism responsible for this paradoxical response is not known. It may be related to the production of antibodies to the C1 inhibitor, although this has not been proved.

Recombinant C1-inhibitor (EU only) — Recombinant human C1-inhibitor (rhC1INH, conestat alfa) (Ruconest™, Pharming Technologies BV in Europe, Rhucin® in other countries) became available in Europe in 2011. It is collected from the milk of transgenic rabbits [23-25]. Compared to the plasma product, rhC1-INH has identical protease inhibitory activity, but a shorter half-life. Thus, higher doses are required to achieve adequate plasma levels, compared to the plasma-derived product. Patients should be screened prior to use for allergic sensitization to rabbit dander and should not receive the medication if skin testing or in vitro IgE immunoassay is positive. The relative advantages and disadvantages of rhC1INH compared with plasma derived C1INHRP have not yet been described. (See 'Safety and adverse effects' below.)

Dose — The recommended dose of Ruconest is 50 units/Kg. Patients generally do not require repeat dosing and relapse is not reported. The medication is a lyophilized powder that is reconstituted in sterile water and administered intravenously. The patient should be observed during administration for signs or symptoms of an allergic reaction.

Effectiveness — In two similar randomized trials, patients received rhC1INH at doses of 100 units/kg body weight (n = 29), 50 (n = 12) units/kg, or placebo (n = 29) [26]. The primary endpoint was time to the beginning of relief of symptoms, which was a median of 66 minutes (95% CI, 61-122), 122 (72 to 136) minutes, and 495 (245 to 520) minutes, respectively. In these same groups, 10, 0, and 60 percent of patients did not begin to respond within four hours, but none of the responders relapsed and none required second doses.

Safety and adverse effects — RhC1INH was well-tolerated at both doses in the previously mentioned studies. A severe allergic reaction was reported in a patient with pre-existing rabbit allergy, hence the recommendation to screen patients for this. No postexposure antibody responses against the product have been detected [27].

Bradykinin B2 receptor antagonist — Icatibant (Firazyr®) is a synthetic bradykinin B2 receptor antagonist, which has been available in the EU since 2008 and became available in the US in 2011 (for patients 18 years of age and older) [28-30]. It 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 treatment of acute attacks of angioedema in adults with C1-inhibitor deficiency.

Icatibant dose and administration — The dose of icatibant is 30 mg, given by slow subcutaneous injection/infusion because of the relatively large volume (3 mL) involved, preferably in the abdominal region [31]. It can be self-administered.

Most patients require only one dose to treat symptoms adequately. However, if clinical response is inadequate, a second injection can be given after six hours and a third injection, if needed, after an additional six hours. A maximum of three doses within 24 hours is recommended.

Studies of efficacy — The 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 acute laryngeal, gastrointestinal, and cutaneous attacks of moderate to severe intensity [32]. FAST-1 compared icatibant to placebo, and FAST-2 compared icatibant to oral tranexamic acid (TA). The primary endpoint was median time to onset of symptom relief, which was not met in FAST-1 (2.0 with icatibant versus 4.2 hours with placebo), but was met in FAST-2 (2 versus 11 hours with TA). In a pooled analysis of the two trials, significantly more patients receiving icatibant had symptom relief within four hours, compared with placebo or TA (73 versus 45 and 29 percent, respectively) [33]. In addition, median time to near-complete symptom relief was significantly shorter with icatibant, compared to placebo or TA (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 [34]. Icatibant significantly reduced median times to ≥50 percent reduction in symptom severity (2.0 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.

Adverse effects and precautions — Mild and transient injection site reactions are the most common adverse reactions to icatibant. Other uncommon adverse effects include nausea, gastrointestinal colic, fever, asthenia, dizziness, increase in transaminases, and headache [35]. Icatibant should be used with caution in patients with acute ischemic heart disease or unstable angina, since antagonism of the bradykinin 2 receptor may decrease coronary blood flow under these circumstances [36].

Kallikrein inhibitor (US only) — Ecallantide (Kalbitor®, Dyax Corp) is a genetically engineered recombinant plasma kallikrein inhibitor [37]. This drug blocks the production of bradykinin by inhibiting plasma kallikrein (figure 1) [28,38-42]. Ecallantide was approved by the US FDA in 2009 for the treatment of acute attacks of HAE in patients 16 years of age or older [43]. It is only available in the US at present [44].

Like C1INHRP, ecallantide is a first-line therapy for acute laryngeal angioedema (following airway protection) and for gastrointestinal attacks. It is occasionally used for severe cutaneous attacks. However, clinical experience with ecallantide is obviously more limited.

Ecallantide should be administered by a physician or a nurse in a medical setting equipped to manage anaphylaxis, as well as severe angioedema related to HAE. Anaphylaxis and allergic reactions were reported in a small percentage of patients in clinical trials. (See 'Side effects' 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.

Efficacy studies — The efficacy of ecallantide was assessed in two Dyax-sponsored randomized trials, EDEMA3 [32] and EDEMA4 [44]. In an analysis of the pooled data from these studies, 143 subjects were treated with either ecallantide or placebo [45]. All types of attacks occurred (gastrointestinal, laryngeal, and cutaneous), with gastrointestinal attacks being most common. Change from baseline mean symptom complex score (MSCS) 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.

Side effects — Ecallantide caused allergic reactions and anaphylaxis in approximately 2.7 percent of patients receiving it subcutaneously in the clinical trials [32,44]. Anaphylaxis presented within one hour of administration as rhinitis, chest discomfort, flushing, pharyngeal edema, pruritus, urticaria, wheezing, and/or hypotension. One-half of patients received epinephrine. Because some symptoms of anaphylaxis overlap with those of HAE (ie, angioedema, throat discomfort), clinicians must observe patients carefully following administration. Anaphylaxis may occur with the first or any subsequent dose. 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. In addition, ecallantide must be administered in a supervised setting by a medically trained provider.

Other adverse effects of ecallantide were generally mild and included headache, nausea, fatigue, and diarrhea (in 16, 13, 12, and 11 percent, respectively) [44]. Injection site reactions were reported in 7 percent of patients.

Plasma — Plasma, in the form of fresh frozen plasma (FFP), has been used in the treatment of acute laryngeal attacks and severe gastrointestinal attacks. This was the leading therapy for acute attacks in the United States until C1INHRP became available in 2008. There have been no studies directly comparing FFP to C1INHRP or ecallantide.

In some countries (not in the US), plasma is also available as solvent/detergent-treated plasma (S/D plasma), which carries a lower risk of viral transmission. However, S/D treatment removes some plasma components, and the effect on C1 inhibitor specifically has not been investigated.

Dosing of plasma preparations — 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 [46].

Effectiveness — The efficacy of FFP in treating acute attacks has been suggested by case reports [47-53]. No controlled trials have been performed. A review of the literature included 23 case reports in which FFP was used for treatment of acute attacks, and revealed improvement in 22 cases [54]. 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.

The data on S/D plasma are scant [55]. Trials are needed to demonstrate that S/D plasma is an equivalent substitute for FFP. (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.

  • Solvent/detergent treatment inactivates enveloped viruses (such as HIV, HTLV, and hepatitis B and C), but not prions or non-enveloped viruses (eg, hepatitis A, parvovirus) (table 1).
  • 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 serological testing for viral markers. The risk of infection for a unit of FFP is identical to that of red blood cells, which are also obtained from single donors (table 1). The issue of disease transmission from red blood cells (and therefore FFP) is presented in more detail elsewhere. (See "Transfusion transmitted HIV infection and AIDS" and "Epidemiology and transmission of hepatitis C virus infection".)

Plasma contains an array of complement components, including C1 inhibitor. It also contains substrate proteins (prekallikrein and high molecular weight kininogen) that could, in theory, consume the available inhibitor and paradoxically worsen the angioedema, although this has been reported only rarely [54].

Cost of therapy — All first-line therapies for acute attacks of HAE are costly. In the US, the cost of one treatment with C1INHRP, ecallantide, or icatibant ranged from $5000 to $10,000 [56]. The cost of one treatment with C1INHRP, rhC1INH, or icatibant in the European Union is about 1500 to 2000 euros.

Ineffective therapies — The 2010 international guidelines for treatment of HAE excluded antifibrinolytics as an option for acute therapy because data of efficacy were lacking [2].

The angioedema of HAE responds poorly or not at all to treatments for allergic angioedema, including epinephrine, antihistamines, and glucocorticoids.

  • There are isolated case reports suggesting benefit from epinephrine in HAE attacks [57,58]. However, most experts believe it is not helpful in the majority of cases, and do not recommend its use. The pharmacologic effects of epinephrine do not address the known pathophysiologic perturbations underlying C1 inhibitor deficiency.
  • Glucocorticoids and antihistamines are NOT effective for angioedema associated with disorders of C1 inhibitor and should not be given once the diagnosis of a C1 inhibitor disorder has been made.

APPROACH TO TREATING ACUTE ATTACKS — Attacks of HAE or acquired angioedema that involve the airway are potentially life-threatening. In contrast, gastrointestinal attacks can range from mild to severe, but usually resolve without serious complications [59]. Cutaneous attacks are largely a cosmetic issue, although patients' lives can be significantly disrupted by repeated episodes.

Consensus guidelines for treatment — In 2012, a multinational committee formulated evidence based recommendations for the management of adolescents and adults with hereditary angioedema [60]. These guidelines expanded upon previous recommendations and incorporated randomized trials of the newer therapies [2,61]. The approach presented in this topic review is consistent with these guidelines.

The mechanisms, dosing, side effects, and efficacy of the different agents were reviewed previously. (See 'Medication options' above.)

LARYNGEAL ATTACKS — Laryngeal attacks are the most dangerous type of attack because edema can lead to fatal airway obstruction. Airway 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. 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.

Airway management — Assessment and protection of the upper airway is the first and most important management issue in the patient with an acute attack involving any part of the airway, because none of the available therapies, including C1-inhibitor replacement (C1INHRP), icatibant, and ecallantide, 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 performed immediately if stridor or signs of respiratory arrest are present. A clinician trained in difficult airway management should be summoned if possible, because failed attempts can lead to fatal obstruction. Emergent cricothyroidotomy may be required in rare cases. (See "Emergent surgical cricothyrotomy (cricothyroidotomy)".)

Once the patient is assessed and either intubated or deemed stable, additional therapies can be considered. Transfer to the intensive care unit should be arranged. 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.

First-line therapies — First-line pharmacotherapy should consist of either a C1-inhibitor product (C1INHRP or rhC1INH), icatibant, or ecallantide (only in the US) (table 2) [2,10,60,62]. The efficacy of these three agents has not been compared in a head-to-head manner, so the choice of agent usually depends upon availability. Dosing is described above (see 'C1-inhibitor (plasma-derived)' above and 'Recombinant C1-inhibitor (EU only)' above and 'Icatibant dose and administration' above and 'Ecallantide dosing and administration' above).

Other options — If none of the first-line therapies is available, other options for acute laryngeal attacks are fresh frozen plasma (in the US) or solvent/detergent treated plasma (in other countries) (table 2). The risks of disease transmission must be discussed with the patient prior to administration (See 'Risks' above.)

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 should be questioned carefully to ascertain if their current symptoms are similar to past episodes.

Gastrointestinal attacks present with varying degrees of gastrointestinal colic, nausea, vomiting and/or diarrhea, which result from bowel wall edema. The clinical presentation of gastrointestinal attacks is reviewed in more detail separately. (See "Clinical manifestations and pathogenesis of hereditary angioedema", section on 'Gastrointestinal attacks'.)

Treatment of angioedema — First-line therapies are (table 2) [2,10,60,62]:

Dosing is described above (see 'C1-inhibitor (plasma-derived)' above and 'Recombinant C1-inhibitor (EU only)' above and 'Icatibant dose and administration' above and 'Ecallantide dosing and administration' above and 'Dosing of plasma preparations' above).

The clinical response to one of these first-line therapies is a valuable tool in distinguishing gastrointestinal attacks of C1 inhibitor disorders from other abdominal pathologies. With all of the first-line therapies, clinical response should be evident within two hours. If there is no response after the initial dose, then evaluation for other problems should proceed.

If none of the first-line therapies (C1INHRP, ecallantide, or icatibant) is available, then management of gastrointestinal attacks is largely supportive. Two units of fresh frozen plasma can be administered if the patient is informed about risk of disease transmission. Dosing is reviewed above. (See 'Dosing of plasma preparations' above.)

Rehydration and symptomatic therapy — In addition to therapy to abort the attack, some (not all) patients with gastrointestinal attacks require treatment for dehydration and pain. The following are suggested:

  • IV rehydration with normal saline.
  • For pain: diclofenac, 100 mg orally (or 75 mg intravenously if vomiting) daily or tramadol, 50 mg orally or intravenously every four to six hours as needed (maximum 300 mg per day for five days) for adults.
  • Parenteral narcotics, such as meperidine, 75 mg administered intramuscularly, may be administered for severe pain. However, as with any chronic disease, a small subset of patients may make inappropriate use of narcotics, although the vast majority does not. Any patient who is experiencing regular attacks requiring emergency care should be reevaluated to assess compliance with prophylactic therapy. Adjustments in prophylactic medications may be necessary. (See 'Care following attacks' below.)
  • For gastrointestinal cramping: butylscopolamine (not available in the US), 20 mg intravenously every four to six hours as needed for adults.
  • For nausea and vomiting: metoclopramide (10 mg intravenously or intramuscularly, every two to three hours for adults) or prochlorperazine (25 mg rectally every 12 hours for adults).

CUTANEOUS ATTACKS — Acute cutaneous attacks usually do not require treatment in the emergency setting (table 2). However, if the attack is severe or disfiguring, the following options are suggested:

OTHER ISSUES

Pregnant women — The preferred treatment of acute attacks in pregnant women is plasma-derived C1INHRP because there is extensive experience with the products that have been available in the EU [17]. Insufficient data are available regarding the use of icatibant, ecallantide, or recombinant C1INH.

Care following attacks — Following any acute attack, events leading up to the attack should be examined to determine if an identifiable trigger was present. Based on our experience, common nontraumatic triggers include the following:

  • Regularly missing doses of medication
  • Running out of medication
  • Initiating interfering medications (such as estrogens or ACE inhibitors)
  • Narcotic addiction

Discussing these common errors with the patient directly after an event should help prevent repetition of the same mistake. 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.

If no precipitating trigger can be identified, then therapy should be increased. As an example, we suggest increasing the dose of long-term androgen prophylaxis by 50 to 100 percent after an attack for which no obvious trigger can be identified. Prophylactic therapy for HAE is discussed separately. (See "Prevention of attacks in hereditary angioedema".)

Home therapy for acute attacks — Another option for the treatment of acute attacks of all types is home-based administration of one of the acute therapies "on demand" (ie, at the first sign of symptoms) [60,63]. Although this approach is technically a form of acute treatment, it is reviewed separately with other forms of outpatient management. (See "Prevention of attacks in hereditary angioedema", section on 'Long-term prophylactic therapies'.)

SUMMARY AND RECOMMENDATIONS — Hereditary angioedema is a rare condition characterized by recurrent episodes of angioedema affecting the upper airway, bowel wall, or skin. Laryngeal swelling can result in fatal asphyxiation. (See 'Introduction' above.)

  • Patients with laryngeal attacks require immediate assessment of the airway. Those with respiratory distress or stridor may require intubation, because even the most effective 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.)
  • We recommend that patients with any severity of laryngeal attack, moderate to severe gastrointestinal attacks, or severe cutaneous attacks be treated with a first-line therapy (Grade 1A). First-line therapies for HAE are:

These agents have not been compared in a head-to-head manner, so the choice of agent should be based upon availability.

  • If none of the first-line agents are available, then the approach to treatment depends upon the type of attack:

  • For patients with laryngeal edema or severe, debilitating gastrointestinal attacks, we suggest either fresh frozen plasma (FFP) or solvent-detergent treated plasma (Grade 2C). (See 'Laryngeal attacks' above.)
  • For patients with mild to moderate gastrointestinal attacks, we suggest supportive therapy (rehydration and symptomatic therapy) (Grade 2C).
  • For patients with cutaneous attacks not involving skin adjacent to the airway, we suggest no treatment (Grade 2C).

  • After an acute attack, the patient's situation should be evaluated to determine what factors contributed to triggering the attack. If no factors are identified, then prophylactic medications should be increased. As an example, a patient receiving long-term androgen prophylaxis would increase the dose by 50 to 100 percent after an attack for which no obvious trigger can be identified. (See 'Other issues' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

  1. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005; 139:379.
  2. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010; 6:24.
  3. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009; 124:801.
  4. Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I.M.P.A.C.T.2 study. Allergy 2011; 66:1604.
  5. Martinez-Saguer I, Rusicke E, Aygören-Pürsün E, et al. Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study. Transfusion 2010; 50:354.
  6. Agostoni A, Bergamaschini L, Martignoni G, et al. Treatment of acute attacks of hereditary angioedema with C1-inhibitor concentrate. Ann Allergy 1980; 44:299.
  7. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996; 334:1630.
  8. Kunschak M, Engl W, Maritsch F, et al. A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. Transfusion 1998; 38:540.
  9. De Serres J, Gröner A, Lindner J. Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinert P) in hereditary angioedema: a review. jean.de.serres@aventis.com. Transfus Apher Sci 2003; 29:247.
  10. Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med 2001; 161:714.
  11. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 2010; 363:513.
  12. Craig TJ, Wasserman RL, Levy RJ, et al. Prospective study of rapid relief provided by C1 esterase inhibitor in emergency treatment of acute laryngeal attacks in hereditary angioedema. J Clin Immunol 2010; 30:823.
  13. Levi M, Choi G, Picavet C, Hack CE. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006; 117:904.
  14. Hermans C. Successful management with C1-inhibitor concentrate of hereditary angioedema attacks during two successive pregnancies: a case report. Arch Gynecol Obstet 2007; 276:271.
  15. Caliskaner Z, Ozturk S, Gulec M, et al. A successful pregnancy and uncomplicated labor with C1INH concentrate prophylaxis in a patient with hereditary angioedema. Allergol Immunopathol (Madr) 2007; 35:117.
  16. Farkas H, Jakab L, Temesszentandrási G, et al. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. J Allergy Clin Immunol 2007; 120:941.
  17. Caballero T, Farkas H, Bouillet L, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012; 129:308.
  18. Zingale LC, Pappalardo E, Zanichelli A, Cicardi M. C1 inhibitor concentrate: efficacy and adverse reaction. Int Immunopharmacol 2002; 318:1385.
  19. Cicardi M, Zingale L. How do we treat patients with hereditary angioedema. Transfus Apher Sci 2003; 29:221.
  20. Agostoni A, Aygören-Pürsün E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004; 114:S51.
  21. Cicardi M, Zingale LC, Zanichelli A, et al. The use of plasma-derived C1 inhibitor in the treatment of hereditary angioedema. Expert Opin Pharmacother 2007; 8:3173.
  22. Bork K, Hardt J. Hereditary angioedema: increased number of attacks after frequent treatments with C1 inhibitor concentrate. Am J Med 2009; 122:780.
  23. Choi G, Soeters MR, Farkas H, et al. Recombinant human C1-inhibitor in the treatment of acute angioedema attacks. Transfusion 2007; 47:1028.
  24. Koles K, van Berkel PH, Pieper FR, et al. N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits. Glycobiology 2004; 14:51.
  25. van Doorn MB, Burggraaf J, van Dam T, et al. A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol 2005; 116:876.
  26. Zuraw B, Cicardi M, Levy RJ, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol 2010; 126:821.
  27. Varga L, Farkas H. rhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused by C1-inhibitor deficiency. Expert Rev Clin Immunol 2011; 7:143.
  28. Han Lee ED, Pappalardo E, Scafidi J, Davis AE 3rd. Approaches toward reversal of increased vascular permeability in C1 inhibitor deficient mice. Immunol Lett 2003; 89:155.
  29. Bork K, Frank J, Grundt B, et al. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol 2007; 119:1497.
  30. Icatibant: HOE 140, JE 049, JE049. Drugs R D 2004; 5:343.
  31. Information about Firazry. http://emc.medicines.org.uk/medicine/21761/SPC/Firazyr%2030%20mg%20solution%20for%20injection%20in%20pre-filled%20syringe/#POSOLOGY (Accessed on February 03, 2010).
  32. Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010; 363:523.
  33. Riedl M. Icatibant, a selective bradykinin B2 receptor antagonist, proves effective and safe in treating the symptoms of hereditary angioedema (HAE) attacks. J Allergy Clin Immunol 2008; 121:S103.
  34. Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the bradykinin B₂ receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol 2011; 107:529.
  35. Deeks ED. Icatibant. Drugs 2010; 70:73.
  36. http://emc.medicines.org.uk/medicine/21761/SPC/Firazyr (Accessed on September 13, 2010).
  37. Lehmann A. Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin Biol Ther 2008; 8:1187.
  38. Schneider L, Lumry W, Vegh A, et al. Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol 2007; 120:416.
  39. Turner MD, Oughourli A, Heaney K, Selvaggi T. Use of recombinant plasma kallikrein inhibitor in hereditary angioedema: a case report and review of the management of the disorder. J Oral Maxillofac Surg 2004; 62:1553.
  40. Lehmann A. Ecallantide (Dyax/Genzyme). Curr Opin Investig Drugs 2006; 7:282.
  41. Levy JH, O'Donnell PS. The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Expert Opin Investig Drugs 2006; 15:1077.
  42. Frank MM, Jiang H. New therapies for hereditary angioedema: disease outlook changes dramatically. J Allergy Clin Immunol 2008; 121:272.
  43. Approval history is available on the FDA website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist/ (Accessed on September 13, 2010).
  44. Levy RJ, Lumry WR, McNeil DL, et al. EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol 2010; 104:523.
  45. Sheffer AL, Campion M, Levy RJ, et al. Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies. J Allergy Clin Immunol 2011; 128:153.
  46. Kreuz W, Fischer D, Martinez-Saguer I, et al. C1-esterase inhibitor substitution in hereditary angioedema. Biomed Prog 1999; 12:1.
  47. Zuraw BL. Diagnosis and management of hereditary angioedema: an American approach. Transfus Apher Sci 2003; 29:239.
  48. Pickering RJ, Good RA, Kelly JR, Gewurz H. Replacement therapy in hereditary angioedema. Successful treatment of two patients with fresh frozen plasma. Lancet 1969; 1:326.
  49. Cohen G, Peterson A. Treatment of hereditary angioedema with frozen plasma. Ann Allergy 1972; 30:690.
  50. Atkinson JP. Diagnosis and management of hereditary angioedema (HAE). Ann Allergy 1979; 42:348.
  51. Beck P, Willis D, Davies GT, et al. A family study of hereditary angioneurotic oedema. Q J Med 1973; 42:317.
  52. Hill BJ, Thomas SH, McCabe C. Fresh frozen plasma for acute exacerbations of hereditary angioedema. Am J Emerg Med 2004; 22:633.
  53. Pekdemir M, Ersel M, Aksay E, et al. Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med 2007; 33:137.
  54. Prematta M, Gibbs JG, Pratt EL, et al. Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2007; 98:383.
  55. Longhurst HJ. Emergency treatment of acute attacks in hereditary angioedema due to C1 inhibitor deficiency: what is the evidence? Int J Clin Pract 2005; 59:594.
  56. Three new drugs for hereditary angioedema. Med Lett Drugs Ther 2010; 52:66.
  57. Roth M, Schreier L, Cutler R. Adrenalin treatment for hereditary angioneurotic edema. Ann Allergy 1975; 35:175.
  58. Trachsel D, Hammer J. A vote for inhaled adrenaline in the treatment of severe upper airway obstruction caused by piercing of the tongue in hereditary angioedema. Intensive Care Med 1999; 25:1335.
  59. Bork K, Staubach P, Eckardt AJ, Hardt J. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol 2006; 101:619.
  60. Cicardi M, Bork K, Caballero T, et al. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012; 67:147.
  61. Bowen T, Brosz J, Brosz K, et al. Management of hereditary angioedema: 2010 Canadian approach. Allergy Asthma Clin Immunol 2010; 6:20.
  62. Bork K, Hardt J, Schicketanz KH, Ressel N. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med 2003; 163:1229.
  63. Longhurst HJ, Carr S, Khair K. C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option. Clin Exp Immunol 2007; 147:11.
Topic 8104 Version 9.0

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.