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Individualized Acute and Long-term Management of Hereditary Angioedema


Hereditary angioedema, a type of C1 esterase inhibitor (C1-INH) deficiency (Type I or Type II), is a rare autosomal dominant genetic disorder that affects 1 in 10,000 to 1 in 50,000 individuals.1,2 A prevalence of about 5000 affected individuals in the United States has been estimated.3 Characteristic signs and symptoms of HAE include acute recurrent episodes of angioedema without pruritus or urticaria. These episodes are referred to as “attacks,” and may involve several areas of the body.4 Acute attacks associated with HAE generally begin during childhood and worsen in frequency and severity during periods of hormonal fluctuations (specifically estrogen) such as puberty, postpartum, and menopause. More than half of patients experience their first HAE attack before the age of 10 years and studies suggest that the mean age of onset is 8 to 12 years.5-7 Attacks are unpredictable in frequency, severity, and swelling location. Before effective treatments were available, patients had an average of 26.9 attacks per year with each attack lasting an average of 61.3 hours.3 The HAE Global Registry reported in 2021 that 38% of patients (representing 5 European countries) had at least 1 HAE attack during the 32-month observational period, and 70.6% of attacks occurred in patients who were not receiving long-term prophylaxis.8

Mutations in the genes responsible for C1-INH secretion or function (SERPING1) give rise to HAE.2,4 In the usual course of the kallikrein-kinin pathway, C1-INH limits the production of bradykinin. However, in the setting of nonfunctional or deficient C1-INH, bradykinin is overproduced, causing enhanced vascular permeability that clinically presents as acute transient swelling. C1-INH deficiency is acquired (i.e., occurs in the absence of a family history of angioedema) in up to 25% of cases.This type of HAE usually presents in middle-aged or older patients and may be associated with autoimmune or lymphoproliferative disease.5,9

A C1-INH deficiency should be suspected in anyone who presents with recurrent angioedema or abdominal pain without urticaria and/or wheals, particularly if a family member has reported similar symptoms.2,4,5 To confirm a diagnosis of HAE, evaluation of serum C1-INH antigenic and functional levels is required.3,10 Table 1 summarizes the laboratory findings for each type of HAE. Type I HAE (85% of cases) presents with low C1-INH antigenic and functional levels, while Type II HAE (15% of cases) presents with normal C1-INH antigenic levels, but low C1-INH functional levels. Low complement factor 4 (C4) levels are present in both Type I and Type II HAE. Since activation of C4 is one of the downstream effects of C1-INH, C4 serves as a marker for C1-INH activity. A very rare third type of HAE, previously referred to as Type III HAE and now called HAE-normal complement, occurs in patients with normal C1-INH antigenic and function levels and normal C4 levels.2,5,10 Hereditary angioedema with normal C1-INH levels is further categorized as of unknown origin or by the underlying gene mutation (F12, ANGPT1, PLG, or KNG1).2,4

Table 1. Laboratory findings for each type of HAE.5,7
Type C4 C1-INH antigen levels C1-INH function
HAE Type 1 Low Low Low
HAE Type 2 Low Normal or elevated Low
HAE-normal complement Normal Normal Normal
Abbreviations: C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema.

The 3 types of HAE are clinically indistinguishable from one another (i.e., clinical presentation is the same) and laboratory testing is needed for accurate diagnosis.5,10 Since low C4 levels are characteristic of HAE, this is often the first laboratory test, followed by C1-INH if the C4 is low.2 Genetic sequencing is seldom performed.7,11 Similar to other rare diseases, misdiagnosis and lack of awareness of the condition at presentation are common challenges. In surveys, a large proportion of patients (almost half) reported a delay of diagnosis of 10 or more years after their initial symptoms.4 Other authors have reported that patients visited an average of 4.4 physicians before receiving the correct diagnosis, and 24% of patients had unnecessary invasive procedures.3 Inappropriate categorization of HAE symptoms as drug allergy has also been reported.12

Diagnosis of HAE may be particularly challenging in children, especially if they are unable to describe their symptoms, even when a family history is present.6 Abdominal pain and discomfort or crying and mood changes may be the predominant signs noticed by caregivers, but these signs may be too general to associate with angioedema. Younger children may also have less severe symptoms. Gradual worsening of swelling over several hours, lack of urticaria, and a 2-to-5-day duration of swelling may be key indicators pointing clinicians to HAE, along with a characteristic dermal rash (erythema marginatum, a serpentine discoloration of the trunk and/or extremities) that is often seen in children during an HAE attack. Increasing frequency and severity of symptoms around the time of puberty may facilitate diagnosis.

Most patients with HAE report a prodrome leading up to acute attacks; commonly reported prodromal symptoms include nausea, rash (which can be erythema marginatum), fatigue, muscle aches, skin tightness, and tingling or other neurologic symptoms.4,9 Acute HAE attacks present as transient swelling of the deep layers of the skin, mucosa, or abdominal viscera. Swelling can either be localized or affect multiple locations simultaneously. Typical locations include the face, hands, feet, genitals, abdomen, and oropharynx (including the larynx, lips, tongue, soft palate, and uvula).9 Cutaneous swelling is the most common symptom. Abdominal attacks are characterized by severe abdominal pain, nausea, and vomiting, which may be too nonspecific to raise suspicion for HAE. Discomfort and pain are common due to vascular congestion, and fluid shifts can lead to hemodynamic changes such as hypotension and tachycardia. During acute attacks, swelling of the affected area(s) generally worsens over the course of 24 hours, plateaus, and slowly resolves over the following 2 to 3 days.4,9 Longer attacks are possible, especially if swelling moves to different sites. Attacks in the oropharynx and larynx are a medical emergency, as they might threaten laryngeal patency; more than half of patients have at least 1 oropharyngeal attack in their lifetime. However, because the location of attacks is not predictable and can change sites, every acute HAE attack is considered potentially life-threatening. Recent data suggests that patients with HAE-normal complement may experience more frequent oropharyngeal swelling than patients with C1-INH deficiency.9

A precipitating cause for most HAE attacks is unknown; however, mental stress, anxiety, depression, and trauma have been recognized as triggers.3,13 Fluctuations in hormones, particularly estrogen levels during puberty and postpartum periods, are another common precipitant of acute attacks.4,9 Additional triggers include angiotensin converting enzyme inhibitors, invasive dental work, surgery, upper airway manipulation, and medical procedures. Data on the relationship between COVID-19 and HAE are still preliminary but do not suggest that COVID-19 infection is a trigger for HAE attacks.14,15


LM is a 10-year-old female (premenarchal) who presents to the emergency department with complaints of worsening abdominal pain over the past 2 days. The pain has prevented her from attending school. She denies nausea or vomiting but states that she has no appetite, and the pain is “unbearable.” Bladder and bowel function are normal. Physical exam is unremarkable except for abdominal tenderness and an arching erythematous rash across her lower back. Abdominal ultrasound reveals diffuse edema. The patient has had prior episodes of abdominal pain (most recently 2 months ago), but this episode is more severe and long-lasting. Family history includes a parent with HAE (most commonly orofacial edema) and a younger brother with frequent abdominal pain. Based on this family history, testing for HAE is performed. LM is found to have low C4 levels, low C1-INH antigen levels, and low C1-INH function, consistent with Type I HAE.


Pharmacotherapy for HAE can be initiated at the onset of an acute attack (i.e., “on-demand”) or can be given prophylactically to prevent the occurrence of attacks.4 Agents specifically approved for use in patients with HAE are sometimes referred to as “HAE-specific therapies,” to differentiate them from conventional (i.e., nonspecific) treatments used for the management of this disease. Since HAE-related angioedema is mediated by bradykinin rather than histamine or leukotriene, conventional first-line agents used for the treatment of angioedema, such as epinephrine, antihistamines, and corticosteroids, are not effective for treatment of HAE angioedema. Currently, there are 4 U.S. Food and Drug Administration (FDA)-approved agents for on-demand treatment. This includes 2 intravenously (IV)-administered C1-INH concentrate replacement products, plasma-derived C1-INH (Berinert) and recombinant C1-INH (Ruconest), a subcutaneously (SC)-administered kallikrein inhibitor (ecallantide [Kalbitor]), and a SC-administered bradykinin receptor antagonist (icatibant [Firazyr and generics]).16 For long-term prophylaxis, IV- (Cinryze) and SC-administered plasma-derived C1-INH concentrates (Haegarda) are FDA-approved for home infusion or self-administration, along with a SC-administered kallikrein inhibitor (lanadelumab [Takhzyro]) and an oral kallikrein inhibitor (berotralstat [Orladeyo]). Danazol is also approved for prophylaxis of HAE attacks. Efficacy data with HAE-specific therapies is limited in patients with HAE-normal complement, but observational data support their use.17,18 The following text summarizes guideline recommendations for use of these agents, followed by more detail of the individual medications.

Guideline Recommendations

Recommendations for on-demand and prophylactic treatment of HAE are outlined in national and international guidelines, of which the most recently updated is a 2021 joint guideline from the World Allergy Organization (WAO) and European Academy of Allergy and Clinical Immunology (EAACI).19 The 2 goals of HAE treatment include achieving total HAE disease control and improving (with the potential of normalizing) the patient’s quality of life.19,20 Per this guideline, on-demand treatment is strongly recommended for all attacks, due to their debilitating and potentially life-threatening nature.19 Strong recommendations are provided for early treatment of attacks with either IV C1-INH concentrates (Berinert, Ruconest), ecallantide (Kalbitor), or icatibant (Firazyr and generics). Furthermore, these guidelines advise that patients have enough medication for on-demand treatment of 2 attacks. Short-term prophylaxis should be offered before medical, surgical, or dental procedures, and before anticipated exposure to known triggers. When deciding whether to initiate long-term prophylaxis, attack frequency, disease burden and patient preference should be considered.21 Plasma-derived C1-INH concentrate (Cinryze, Haegarda), lanadelumab (Takhzyro), or berotralstat (Orladeyo) are recommended first-line, and androgens are recommended as a second-line option.19

The 2020 practice parameter developed by the US Hereditary Angioedema Association (HAEA) Medical Advisory Board provides recommendations for the management of HAE.4 Similar to guidance provided by WAO/EAACI, the US HAEA recommends access to on-demand therapy with an FDA-approved HAE-specific agent for each individual with HAE. Patients should have ready access to at least 2 doses of on-demand treatment. Plasma-derived (Berinert) and recombinant (Ruconest) C1-INH, ecallantide (Kalbitor), and icatibant (Firazyr and generics) are mentioned as treatment options in the context of managing an acute attack; a preference for a particular on-demand agent is not stated. Fresh frozen plasma may also be used for the treatment of attacks if FDA-approved on-demand treatments are not available; however, caution and airway protection are required since fresh frozen plasma may increase bradykinin production and lead to worsening symptoms. Short-term prophylaxis can be achieved with plasma-derived C1-INH concentrate (Berinert, Cinryze, Haegarda), a 7- to 12-day course of anabolic androgens (danazol), or fresh frozen plasma if no other therapy is available. Short-term prophylaxis is generally recommended prior to exposure to known triggers (e.g., invasive dental or surgical procedures). The decision to initiate long-term prophylaxis is patient-specific, and should include consideration of several factors, including the frequency, severity, and location of acute attacks, existing comorbid conditions, and access to acute care facilities. Agents that can be used for long-term prophylaxis of Types I or II HAE include IV (Cinryze) or SC (Haegarda) C1-INH concentrates, lanadelumab (Takhzyro), or berotralstat (Orladeyo). Options for long-term prophylaxis in patients with HAE-normal complement include progestin-only medications and antifibrinolytics; however, the quality of evidence for these therapies is low and they are only weakly recommended. The guidelines strongly recommend that quality of life and burden of illness are actively considered in developing individualized treatment plans.

A 2016 consensus document from the US HAEA Medical Advisory Board and the 2 aforementioned guidelines outline recommendations for the management of HAE in children.4,19,22 Many of the agents used in adults have been used off-label in children, although supportive data in the pediatric population is relatively limited. Recommendations for management in children less than 12 years of age include on-demand treatment of attacks with C1-INH (Berinert, Ruconest) or icatibant (Firazyr and generics) and trigger avoidance.19 The 2020 HAEA guideline supports the use of on-demand and prophylactic treatment with plasma-derived C1-INH but also states that medication choice in children may be limited by regulatory age limits for individual agents.4 Table 2 provides a summary of the major HAE guideline recommendations for both adults and children with Type I or II HAE.

Table 2. Practice guideline recommendations for HAE attack treatment and prophylaxis.4,19,22
Guideline Recommended on-demand treatment Recommended short-term prophylaxis Recommended long-term prophylaxis
World Allergy Organization/ European Academy of Allergy and Clinical Immunology (2021) C1-INH (IV [Berinert, Ruconest]), ecallantide (Kalbitor), or icatibant (Firazyr and generics) are recommended as treatments of choice C1-INH (plasma-derived, IV [Berinert, Cinryze]) recommended first-line C1-INH (plasma-derived [Cinryze, Haegarda]), lanadelumab (Takhzyro), and berotralstat (Orladeyo) are recommended first-line
US Hereditary Angioedema Association (2020) C1-INH (plasma-derived [Berinert] or recombinant [Ruconest]), ecallantide (Kalbitor), or icatibant (Firazyr and generics) should be used first-line when possible Not specified C1-INH (IV [Cinryze] or SC [Haegarda]), or lanadelumab (Takhzyro) should be used first-linea
World Allergy Organization/ European Academy of Allergy and Clinical Immunology (2021) C1-INH (plasma-derived [Berinert]) or icatibant (Firazyr and generics) in children <12 years of age, ecallantide (Kalbitor) is mentioned as a licensed option in adolescents in the U.S. C1-INH (plasma derived [Berinert, Cinryze, Haegarda]) is first-line C1-INH (plasma derived [Cinryze, Haegarda]) is first-line
US Hereditary Angioedema Association (2020) C1-INH (plasma derived [Berinert]) is mentioned as the treatment of choice Not specified C1-INH (plasma derived [Cinryze, Haegarda]) is mentioned as the preferred agent
US HAEA Medical Advisory Board (2016) C1-INH (plasma-derived [Berinert] and recombinant [Ruconest]) and ecallantide (Kalbitor) are listed as available options C1-INH (plasma derived [Berinert, Cinryze, Haegarda]) is mentioned as the preferred agent Only C1-INH (plasma derived [Cinryze, Haegarda]) is mentioned as an available agent
Abbreviations: C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema; IV, intravenous; SC, subcutaneous.
a First-line long-term prophylaxis in patients with HAE-normal complement is a progestin or antifibrinolytic medication.

Upon discharge from the emergency department, LM receives a prescription for 2 doses of an on-demand treatment and a referral to an HAE specialist. At her follow-up appointment with the specialist, LM’s parents state that they have not been able to fill the prescription due to the high cost at their usual pharmacy. Together, LM and the specialist develop a management plan that involves using the specialty pharmacy required by their insurance provider, 2 doses of on-demand C1-INH administered by LM’s parents at home, access to supplies and home nurse education about self-administration, and instructions to call for short-term prophylaxis in case of planned dental work. After discussion of the effect of past HAE attacks on LM’s quality of life, the decision is made to defer long-term prophylaxis until the onset of puberty, with an expectation that attacks will worsen in frequency and severity at that time. The HAE specialist also recommends that LM’s brother be tested for HAE.

HAE-Specific Medications

The 8 FDA-approved HAE-specific agents for the treatment and prophylaxis of HAE attacks have different mechanisms of action, modes of administration, and side effect profiles.4,16 Therefore, close collaboration between patients, providers, and specialty pharmacists is critical in developing treatment plans that are specifically adapted to individual patient circumstances. Table 3 summarizes the available medications for HAE. In some cases, an investigational agent may be the best option and patients should be encouraged to consider participating in interventional (or observational) clinical trials.

Table 3. HAE-specific medications for on-demand treatment and long-term prophylaxis of HAE attacks.16,23-30
Medication Population Formulation Patient or caregiver administration possible Dosing Major safety concerns Patient assistance program?
On-demand treatment
C1-INH, plasma-derived (Berinert) Adults and children (studied in children ≥5 years) Vial, requires reconstitution Yes 20 units/kg IV Hypersensitivity, thromboembolism Yes
C1-INH, recombinant (Ruconest) Adults and adolescents (studied in patients ≥13 years) Vial, requires reconstitution Yes 50 units/kg IV (body weight <84 kg, maximum 4200 units/dose) or 4200 units IV (body weight ≥84 kg) A second dose can be administered if needed (no more than 2 doses in 24 hours) Hypersensitivity, thromboembolism, contraindicated with rabbit allergy Yes
Icatibant (Firazyr and generics) Adults (≥18 years) Prefilled syringe Yes 30 mg SC Subsequent doses can be administered after at least 6 hours if needed (no more than 3 doses in 24 hours) None Yes
Ecallantide (Kalbitor) Age ≥12 years Vial No 30 mg SC in 3 separate injections A second dose can be administered if needed (no more than 2 doses in 24 hours) Anaphylaxis (boxed warning) Yes
Long-term prophylaxis
C1-INH, plasma-derived (Cinryze) Age ≥6 years Vial, requires reconstitution Yes Adults and adolescents: 1000 units IV every 3 or 4 days Children: 500 units IV every 3 or 4 days Hypersensitivity, thromboembolism Yes
C1-INH, plasma-derived (Haegarda) Age ≥6 years Vial, requires reconstitution Yes 60 units/kg SC twice weekly (every 3 or 4 days) Hypersensitivity, thromboembolism Yes
Lanadelumab (Takhzyro) Age ≥2 years Prefilled syring, single dose vial Yes Adults and adolescents ≥12 years:
300 mg SC every 2 weeks
Age 6 years to <12 years:
150 mg SC every 2 weeks
Age 2 years to <6 years:
150 mg SC every 4 weeks; dosing every 4 weeks can be considered in patients who have been attack-free for ≥6 months
Hypersensitivity Yes
Berotralstat (Orladeyo) Age ≥12 years Capsule Yes 150 mg orally once daily with food Drug interactions, GI adverse effects, dose reduction needed for moderate/severe hepatic impairment Yes
Abbreviations: C1-INH, C1 esterase inhibitor; GI, gastrointestinal; HAE, hereditary angioedema; IV, intravenous; SC, subcutaneous.

Medications for On-Demand Treatment

For on-demand treatment of acute HAE attacks, both plasma-derived (Berinert) and recombinant (Ruconest) C1-INH concentrates are available.23,24 These agents inhibit Factor XII and kallikrein, which prevents further bradykinin formation. All C1-INH concentrates used for on-demand therapy are available for IV self-administration, and none is approved for SC use. Apart from C1-INH concentrates, 2 novel agents are available for the acute treatment of HAE attacks. Ecallantide (Kalbitor), a plasma kallikrein inhibitor that prevents formation of bradykinin, is approved for patients 12 years of age or older and can only be administered by a health care professional due to risk of anaphylaxis, and icatibant (Firazyr and generics), a bradykinin receptor antagonist, is approved for adults only but can be self-administered.25,26 On-demand treatment must be given as soon as the attack is recognized to halt swelling progression and minimize morbidity and mortality, so the need for ecallantide (Kalbitor) to be administered by a health care provider is a barrier to its clinical utility.31 The expected time to onset for all on-demand medications is 30 to 120 minutes and repeat dosing is not needed unless the attack begins to worsen after initial improvement. Randomized trials in patients with Type I and II HAE have shown that these agents stop the progression of HAE attacks.

There are some unique safety concerns with all agents used in on-demand therapy. For example, the currently available recombinant C1-INH concentrate product (Ruconest) may cause anaphylaxis in those with known allergies to rabbit proteins, ecallantide (Kalbitor) has a boxed warning for hypersensitivity reactions including anaphylaxis, and icatibant (Firazyr and generics) is associated with a high incidence of local reactions.4,24-26 Thromboembolism is a theoretical concern with C1-INH concentrates but few cases have been published.23,24,27,28,32

Medications for Long-Term Prophylaxis

For long-term prevention of HAE attacks, both conventional and HAE-specific therapies are available. Conventional therapies used for prophylaxis include orally administered danazol for short- and long-term use, and tranexamic acid and aminocaproic acid for long-term use.4 These treatments have limited use due to poor tolerability and toxicity. Danazol should not be used in pregnant or lactating patients, children younger than 16 years of age, or patients with liver disease, and patients must undergo regular monitoring of weight, blood pressure, lipids, liver function, and signs of virilization. Among the HAE-specific long-term prophylaxis options, 2 are plasma-derived C1-INH concentrates (IV-administered Cinryze and SC-administered Haegarda), 1 is a SC-administered kallikrein inhibitor (lanadelumab [Takhzyro]), and 1 is an oral kallikrein inhibitor (berotralstat [Orladeyo]).27-30 The plasma-derived C1-INH concentrates used for short and long-term prophylaxis are available for IV (Cinryze) or SC (Haegarda) home administration.27,28 Lanadelumab (Takhzyro) requires less frequent SC dosing (once every 2 or 4 weeks).29

In clinical trials, long-term prophylaxis with the C1-INH concentrates (Cinryze and Haegarda) lowered HAE attack rates by 50% or more compared to placebo.33,34 A long-term study in which patients received SC-administered C1-INH (Haegarda) for up to 140 weeks found that patients who were treated for at least 12 months had a median of 1 attack per year and half of patients were attack-free throughout the study.35 Lanadelumab (Takhzyro) reduced HAE attack frequency by 87% compared to placebo and 44.4% of patients who received lanadelumab were attack-free (versus 2.6% of the placebo group, P < 0.01) during the 26-week trial.36 Berotralstat (Orladeyo) is the most recently FDA-approved therapy for prevention of HAE attacks.30 In a Phase 3 clinical trial (APeX-2) berotralstat (Orladeyo) reduced the rate of HAE attacks during the 24-week study period by 44% compared to placebo (P < 0.001) and 58% of patients had a 50% or more reduction in attack frequency.37 The ongoing APeX-S study will provide long-term (96 weeks) data on the safety of berotralstat (Orladeyo) and efficacy in preventing HAE attacks and maintaining quality of life in patients aged 12 years and older.38 Recombinant C1-INH (Ruconest) has been compared to placebo for long-term prophylaxis in a small randomized trial, but it is only approved for treatment of acute attacks.39

Limitations with medications used for long-term prophylaxis include a lack of direct head-to-head comparisons and varying endpoint definitions among clinical trials. In part due to varying clinical trial endpoints, standard definitions of disease activity and symptom severity that can be used to objectively compare disease control are lacking. Quality of life scales specific to HAE have been proposed and may be the most clinically appropriate way to assess disease activity, since they reflect the individualized patient experience.40

On-Demand Treatment and Long-Term Prophylaxis in Children

Knowledge of treatment and prophylaxis of HAE-related attacks in children is largely based on data from adult patients.4 For on-demand treatment of attacks, plasma-derived (Berinert) and recombinant (Ruconest) C1-INH are approved for use in children and have been studied in patients 5 years of age and older and 13 years of age and older, respectively.23,24 Recombinant C1-INH (Ruconest 50 units/kg) for treatment of HAE attacks was evaluated in an open-label cohort study in children 2 to 13 years of age, but it is not approved in this age group.41 Ecallantide (Kalbitor) is approved for on-demand therapy in adolescents who are 12 years of age and older.26 A cohort study in children and adolescents (2 to 17 years of age) found that a single SC dose of icatibant (Firazyr and generics) effectively controlled HAE attack symptoms, but use in that age group remains off-label.42

Long-term prophylactic options in children and adolescents include IV-administered C1-INH (Cinryze) and SC-administered C1-INH (Haegarda) (both approved in patients 6 years of age and older) and berotralstat (Orladeyo) (approved in patients 12 years of age and older).27-30 Lanadelumab (Takhzyro) was approved in February 2023 to prevent HAE attacks in children aged 2 to 12 years, and is the first medication approved for prophylaxis in children younger than 6 years of age.43


Three years later, LM is now experiencing more frequent HAE attacks, sometimes as frequently as once every 2 weeks. LM started menstruating 8 months ago. She is worried that the attacks may get worse in a few months when she begins high school. LM has learned to self-administer her on-demand treatment since she is often away from home with her travel soccer club, but she feels self-conscious about administering the medication IV and wonders if her teammates think she is “wimpy” because she sometimes has to sit on the sidelines due to abdominal pain. She has also had some oral swelling during her attacks. After discussion with the HAE specialist, LM and her parents decide to start long-term prophylaxis. LM is willing to continue using IV C1-INH (Berinert) for on-demand treatment in hopes that she will have fewer attacks after starting long-term prophylaxis. The HAE specialist recommends lanadelumab (Takhzyro) due to its frequency of administration (every 2 weeks), which will be convenient for LM’s athletic travel schedule.

Short-Term Prophylaxis

Short-term prophylaxis can be considered before planned HAE-triggering events.44 Invasive dental procedures, screening tests such as mammograms or colonoscopy, and surgery may warrant short-term prophylaxis, even if the patient tolerated the procedure in the past. Prophylaxis is preferred over deferring or avoiding routine procedures since effective health maintenance can prevent health complications, more traumatic procedures, or surgery, all of which could also provoke an HAE attack. Even if short-term prophylaxis is used, 2 doses of on-demand therapy should be available during and for 3 days after the procedure since angioedema can be delayed. Local anesthesia is preferred to general anesthesia, and intubation should be avoided. If intubation is necessary or if it is a major procedure, C1-INH can be infused 1 hour before the procedure. In general, IV C1-INH (Berinert, Cinryze) is preferred for short-term prophylaxis over nonspecific agents (tranexamic acid or danazol) due to its favorable pharmacokinetics (rapid onset, duration for 3 days) and superior efficacy, although prospective head-to-head data is limited. Other HAE-specific therapies such as SC-administered C1-INH (Haegarda), icatibant (Firazyr and generics), ecallantide (Kalbitor), lanadelumab (Takhzyro), and berotralstat (Orladeyo) have pharmacokinetic profiles that are unfavorable for short-term prophylaxis (i.e., delayed absorption, delayed onset, or short half-life). Non-medical HAE-triggering events that may warrant short-term prophylaxis include school examinations, competitions, travel, and family crises.6

Investigational Therapies

Several medications for HAE are currently in late-stage development.45 Sebetralstat is an oral kallikrein inhibitor for on-demand treatment of HAE attacks.46 A Phase 3 trial with 2 years of open-label follow-up in adults and adolescents is ongoing (KONFIDENT and KONFIDENT-S). The manufacturer plans to submit for FDA approval in 2024. Garadacimab is a monoclonal antibody against Factor XIIa that has completed a multicenter, double-blind, randomized Phase 3 clinical trial (VANGUARD) in patients 12 years of age and older.47 Compared to placebo, SC garadacimab given monthly for 6 months effectively prevented HAE attacks. The manufacturer plans to pursue FDA approval in 2023. Donidalorsen is a SC-administered antisense medication that decreases production of prekallikrein. This agent is being investigated in a double-blind, placebo-controlled, randomized Phase 3 study with follow-up for 52 weeks (OASIS-HAE).48


Although HAE is rare, it is associated with a substantial burden of illness.4 In a recent survey, 78.7% of patients reported having an attack in the past month despite a high prevalence of long-term prophylaxis (68.5%).48 Anxiety was reported by about half of the survey respondents and depression was reported by about one-quarter of respondents – both of which can trigger HAE attacks.49,50 Some of the burden of illness of HAE includes physical discomfort, disruptions in social and professional obligations, fear of travel, disability, financial strain, fear of death from an airway attack, and decreased quality of life. Caregivers and family members, many of whom have HAE as well, often share these daily life disruptions.50,51 Concomitant conditions such as cardiovascular disease, venous thromboembolism, hypertension, hyperlipidemia, and autoimmune disease may add to the HAE disease management burden.52 Frustrations with the availability, convenience, and affordability of treatments is a more silent burden of HAE.50,53

Children with HAE may experience more stress and anxiety than others in their age group.6 Fear of experiencing an attack, in part due to their unpredictable nature and unpredictable implications for academic and social activities, is a daily concern. Current on-demand treatment for individuals 18 years of age or younger is limited to self-administered IV therapies or SC treatment in a physician’s office. Treatment of anxiety symptoms should be considered, especially for older children who may have worsening symptoms due to puberty or other stressful life events.

The impact of estrogen on HAE symptoms leads to a greater disease burden in females.54 Beyond the burden of varying symptoms as hormones change throughout time, including a monthly worsening of attacks due to the menstrual cycle, multiple women’s health needs are affected. Estrogen-containing contraceptives and hormone replacement therapy can precipitate HAE attacks and should be avoided when possible; progestin-only medications can be used. An intrauterine device is another contraceptive option, but on-demand treatment should be available in case the insertion procedure triggers an attack. Women with hormone-sensitive cancers should not receive androgens, and use of estrogen modulators (tamoxifen) require caution. Pregnancy, cesarean delivery, and lactation may increase the frequency and severity of HAE attacks. Treatment and prophylaxis with C1-INH in pregnant women has been followed by healthy deliveries in several observational studies, and plasma-derived C1-INH (Berinert, Cinryze, Haegarda) is recommended for this purpose.4,19,54,55 There is much less data with recombinant C1-INH (Ruconest) in pregnant patients.55

Many of the burdens of HAE are directly related to the frequency of HAE attacks, which is why guidelines and other experts strongly recommend focusing both on disease control and maximizing quality of life.4,40 Patients must be closely monitored since symptoms can vary between individuals and in the same individual over time, especially in females due to hormonal fluctuations and changes.4 Shared decision-making, written treatment plans for when an attack occurs, use of short- and long-term prophylaxis as needed, and facilitating access to medications are all critical components of a robust approach to helping the patient achieve their desired quality of life.4,56,57 Qualitative patient interviews have found that patients using long-term prophylaxis experience improved quality of life due to a greater sense of freedom from HAE, less worry and anxiety, increased confidence and optimism, increased productivity, and improved relationships.58

Healthcare providers should work with all patients with HAE to develop a comprehensive and individualized management plan.59 In some cases, the patient’s entire healthcare team may need to provide input to ensure that the plan is truly comprehensive. Consultation with an expert physician is ideal for all patients, which may necessitate travel to a specialized center such as the US HAEA Angioedema Center at the University of California San Diego.60 Specific elements of the management plan that should be considered include trigger recognition, emergency management of attacks, how to handle transitions of care if admitted to the emergency department or hospital, travel, school or work needs, sports involvement, short-term prophylaxis for dental or other procedures, management of concurrent disease states, and anticipated future hormonal changes (in women).59 One randomized trial suggests that HAE call centers staffed by expert clinicians may help patient decision-making about self-treatment of attacks and prevent emergency department visits or hospital admissions.61,62

Coordination of access to HAE medications is one of the primary roles of the pharmacist. In 2020, average wholesale cost of medications for on-demand treatment ranged from $5000 to more than $10,000 per attack, and the average cost of medications for long-term prophylaxis was more than $500,000 yearly.3 Both on-demand treatments and long-term prophylactic medications may require prior authorization and use of a specialty pharmacy. Some insurance plans may designate a particular specialty pharmacy that the patient must use. Even with prior authorization, medication cost may be prohibitive without a manufacturer assistance program or funding from a foundation. These forms and authorizations may need to be updated periodically or repeated regularly. Any change to the patient’s insurance coverage will require the medication access process to begin again. Pharmacists can provide logistical help in obtaining home infusion services and supplies. Specialty pharmacists may also be called upon to conduct pharmacovigilance programs and report metrics to manufacturers on real-world experience.

Patient and caregiver education about HAE medications is another major role of the pharmacist. Appropriate medication storage, preparation, dosing and administration, expected therapeutic effects, and potential adverse effects or safety concerns can all be discussed. Other education topics can include trigger avoidance, medications that can worsen HAE, mental health screening, contraception, immunizations, and smoking cessation.

The need for individualized treatment plans necessitates careful clinical evaluation by pharmacists who care for patients with HAE. Recent literature suggests that access, cost, and adverse effects continue to limit the availability of treatments for patients with HAE. Therefore, providers who may encounter patients with HAE will need to be aware of how to choose from among these available life-saving medications. Managed care and specialty pharmacists can play an integral role in the management of patients with HAE, acting as drug therapy experts and promoting cost-effective therapy utilization.63 A recent survey conducted by the US HAEA found that among the 737 patients with HAE that responded to the survey, the number of acute attacks per year was 77% lower and impairment-related quality of life scores were almost 60% higher among those who used SC prophylactic medication compared to on-demand only treatment.64

Genetic counseling is an important aspect of caring for families with HAE, especially women.11 Individuals with HAE have a 50% chance of passing the gene mutation to each of their children.5 Children of a parent with known HAE can work with a genetic specialist to receive C1-INH and C4 testing after the first year of life, which is important so that parents and other caregivers are prepared with on-demand medication.


LM has had fairly infrequent HAE attacks for the past few years and is satisfied with her on-demand and long-term prophylaxis medication. She is progressing well academically through high school and is enjoying photography in addition to soccer club. After hearing about LM’s new boyfriend, the HAE specialist provides some counseling about progestin-only contraceptive options (including intrauterine devices), the possible risk of worsening HAE with both pregnancy and abortion procedures, and the 50% chance that LM could pass the HAE gene to her offspring. The HAE specialist also suggests that LM have a greater involvement in the medication access process (i.e., contacting her insurance and the specialty pharmacy directly) since she will soon be away at college without as much parental support in managing her disease.

As insurers develop programs to address both quality and cost of care, managed care pharmacists possess the drug therapy knowledge and experience to help determine safe and effective ways to meet these goals. This includes effectively incorporating emerging evidence into practice. Managed care pharmacists are also well-positioned to guide the prior authorization process for HAE medications. Prior authorization is an effective method to ensure that drug benefits are administered as they have been designed, and that plan members with HAE receive the medication therapy they need. Managed care pharmacists must be educated and prepared to critically evaluate available data and current guideline recommendations as the basis for prior authorization approval.


Treatment of HAE aims to prevent attacks and improve (or possibly normalize) the patient’s quality of life. These therapeutic goals require aggressive medical management, including self-administered on-demand treatment, short-term prophylaxis before known triggering events, and long-term prophylaxis to prevent attacks. Over the past decade, numerous HAE-specific medications have become available which has expanded opportunities to individualize treatment plans based on specific patient preferences and needs. Managed care and specialty pharmacists ensure effective coordination of therapeutic needs, access to care, and benefits design to optimize outcomes. Pharmacists are also strategic members of the health care team who can provide education to patients on medication administration technique, the importance of adherence, and potential adverse effects. As knowledge and the available landscape of HAE medications continue to evolve, pharmacists will play a major role in ensuring access to and appropriate use of the medications that maximize outcomes in patients with HAE.


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