Recognizing and managing hereditary angioedema
ABSTRACTHereditary angioedema is a rare but life-threatening disease characterized by recurring attacks of swelling of any part of the body, without hives. Prompt recognition is critical so that treatment can be started to minimize morbidity and the risk of death. Drugs have recently become available to prevent and treat acute attacks.
KEY POINTS
- Swelling in the airways is life-threatening and requires rapid treatment.
- Almost half of attacks involve the abdomen, and abdominal attacks account for many emergency department visits, hospitalizations, and unnecessary surgical procedures for acute abdomen.
- Acute attacks can be managed with plasma-derived or recombinant human preparations of C1 inhibitor (which is the deficient factor in this condition), ecallantide (a specific plasma kallikrein inhibitor), or icatibant (a B2 bradykinin receptor antagonist).
- Short-term prophylaxis may be used before events that could provoke attacks (eg, dental work or surgery). Long-term prophylaxis may be used in patients who have frequent or severe attacks or require more stringent control of their disease. Plasma-derived C1 inhibitor is both safe and effective when used as prophylaxis. Attenuated androgens are effective but associated with many adverse effects.
Plasma-derived C1 inhibitors
Several plasma-derived C1 inhibitors are available (Cinryze, Berinert, Cetor). They are prepared from fractionated plasma obtained from donors, then pasteurized and nanofiltered.
Berinert and Cinryze were each found to be superior to placebo in double-blind, placebo-controlled trials: attacks usually resolved 30 to 60 minutes after intravenous injection.16,17 Berinert 20 U/kg is associated with the onset of symptom relief as early as half an hour after administration, compared with 1.5 hours with placebo. Early use (at the onset of symptoms) of a plasma-derived C1 inhibitor in a low dose (500 U) can also be effective.18,19 Efficacy appears to be consistent at all sites of attack involvement, including laryngeal edema. Safety and efficacy have been demonstrated during pregnancy and lactation and in young children and babies.20
Plasma-derived C1 inhibitors can be self-administered. The safety and efficacy of self-administration (under physician supervision) were demonstrated in a study of Cinryze and Cetor, in which attack duration, pain medication use, and graded attack severity were significantly less with self-administered therapy than with therapy in the clinic.21
A concern about plasma-derived products is the possibility of blood-borne infection, but this has not been confirmed by experience.22
Recombinant human C1 inhibitor
A recombinant human C1 inhibitor (Rhucin) has been studied in two randomized placebo-controlled trials. Although this product has a shorter half-life than the plasma-derived C1 inhibitors (3 vs more than 24 hours), the two are equipotent: 1 U of recombinant human C1 inhibitor is equivalent to 1 U of plasma-derived C1 inhibitor. Because the supply of recombinant human C1 inhibitor is elastic, dosing has been higher, which may provide more efficacy.23 Similar to plasma-derived C1 inhibitor products, the recombinant human C1 inhibitor resulted in more rapid symptom relief than with saline (66 vs 122 minutes) and in a shorter time to minimal symptoms (247−266 vs 1,210 minutes).24
Allergy is of concern: in one study, a healthy volunteer with undisclosed rabbit allergy experienced an allergic reaction. Patients should be screened by a skin-prick test or serum testing for specific IgE to rabbit epithelium before being prescribed recombinant human C1 inhibitor. No data are available for use during pregnancy or breastfeeding.
Ecallantide
Ecallantide (Kalbitor) is a selective inhibitor of plasma kallikrein that is given in three subcutaneous injections. Ecallantide 30 mg was found superior to placebo during acute attacks.25,26
Ecallantide is well tolerated, with the most common adverse effects being headache, nausea, fatigue, diarrhea, and local injection-site reactions. Antibodies to ecallantide can be found in patients with increasing drug exposure but do not appear to correlate with adverse events. Hypersensitivity reactions have been observed in 2% to 3% of patients receiving repeated doses. Because of anaphylaxis risk, ecallantide must be administered by a health care professional.
Icatibant
Icatibant (Firazyr) is a bradykinin receptor-2 antagonist that is given in a single subcutaneous injection. Icatibant 30 mg significantly shortened time to symptom relief and time to almost complete resolution compared with placebo.27,28 Icatibant’s main adverse effect is transient local pain, swelling, and erythema at the injection site. Icatibant can be self-administered by patients.
Fresh-frozen plasma
Fresh-frozen plasma contains C1 inhibitor and was used before the newer products became available. Several noncontrolled studies reported benefit of its use in acute attacks.29 However, its use is controversial because it also contains contact-system proteins that could provide additional substrate for the generation of bradykinin, which could exacerbate attacks in some patients.1 This may be particularly dangerous in patients presenting with laryngeal edema: in such a situation, the physician should be ready to treat a sudden exacerbation with intubation. The risk of acquiring a blood-borne pathogen is also higher than with plasma-derived C1 inhibitor.
PROPHYLACTIC MANAGEMENT
Short-term and long-term prophylaxis have important roles in preventing attacks (Table 3).
Short-term prophylaxis before an anticipated attack
Short-term prophylaxis is used for patients whose disease is generally well controlled but who anticipate exposure to a potentially exacerbating situation, such as an invasive medical, surgical, or dental procedure. (Routine dental cleanings are generally considered safe and do not require prophylaxis.)
Prophylactic treatments include:
- Plasma-derived C1 inhibitor, 500 to 1,500 U 1 hour before the provoking event
- High-dose 17-alpha alkylated (attenuated) androgens (eg, danazol [Danocrine] 200 mg orally 3 times daily) for 5 to 10 days before the provoking event
- Fresh-frozen plasma, 2 U 1 to 12 hours before the event.1
Yet even with short-term prophylaxis, on-demand treatment should be available.
Long-term prophylaxis
While many patients can be managed with on-demand treatment only, other patients (reflecting the severity of their attacks, as well as their individual needs) may benefit from a combination of on-demand treatment plus long-term prophylaxis. Several options are available (Table 3).
17-alpha alkylated androgens. Patients treated with danazol 600 mg/day were attack-free 90% of the time during a 28-day period compared with only 2.2% of the time in placebo-treated patients.30 Use of anabolic androgens, however, is limited by their adverse effects, including weight gain, virilization, menstrual irregularities, headaches, depression, dyslipidemia, liver enzyme elevation, liver adenomas, and hepatocellular carcinoma. Arterial hypertension occurs in about 25% of treated patients.
Because adverse effects are dose-dependent, treatment should be empirically titrated to find the minimal effective dose, generally recommended to be no more than 200 mg per day of danazol or the equivalent.15
Contraindications include use by women during pregnancy or lactation and by children until growth is complete.
Regular follow-up is recommended every 6 months, with monitoring of liver enzymes, lipids, complete blood counts, alpha fetoprotein, and urinalysis. Abdominal ultrasonography (every 6 months if receiving 100 mg/day or more of danazol, every 12 months if less than 100 mg/day) is advisable for early diagnosis of liver tumors.
Antifibrinolytic drugs. Tranexamic acid (Lysteda) and aminocaproic acid (Amicar) have been found to be effective in reducing the number of attacks of hereditary angioedema compared with placebo but are considered to be less reliable than androgens. These drugs have been used in patients who do not tolerate anabolic androgens, and in children and pregnant women. Tranexamic acid is given at a dose of 20 to 50 mg/kg/day divided into two or three doses per day. The therapeutic dose of aminocaproic acid is 1 g orally three to four times per day.31 Patients with a personal or family history of thromboembolic disease may be at greater risk of venous or arterial thrombosis, but this has not occurred in clinical studies.
Plasma-derived C1 inhibitors. In a 24-week crossover study in 22 patients with hereditary angioedema, Cinryze 1,000 U every 3 to 4 days reduced the rate of attacks by 50% while also reducing their severity and duration.17 An open-label extension study in 146 patients for almost 3 years documented a 90% reduction in attack frequency with no evidence of tachyphylaxis.32
New treatments are costlier
The newer on-demand and prophylactic drugs are substantially costlier than the older alternatives (androgens, antifibrinolytics, and fresh-frozen plasma); however, they have a substantially better benefit-to-risk ratio. Furthermore, the costs of care for an attack requiring emergency treatment are also high. Hereditary angioedema patients are often young, otherwise healthy, and capable of leading normal productive lives. While formal pharmacoeconomic studies of the optimal use of these newer drugs have not yet been done, it is important that the use of these drugs be well justified. Ideally, physicians who prescribe these drugs should be knowledgeable in the management of hereditary angioedema.
