REVIEW Treatment of hereditary angioedema: a review Neeti Bhardwaj1 and Timothy J. Craig2 Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self-limiting tissue swelling. The management of HAE has transformed dramatically with recently approved therapies in the United States. However, there is lack of awareness among physicians about these new modalities. The aim of this review is to update the practicing physician about various therapeutic options available for HAE patients. An exhaustive literature search of PubMed and OVID was performed to develop this article. Management of HAE is traditionally classified into treatment of acute attacks or on-demand therapy, short-term (preprocedural) prophylaxis, and long-term prophylaxis. Newer therapies include C1 esterase inhibitor (C1-INH) and contact system modulators, namely, ecallantide and icatibant. Recombinant C1-INH, which is available in Europe, is awaiting approval in the United States. C1-INH concentrate is approved for prophylaxis as well as on-demand therapy while ecallantide and icatibant are approved for acute treatment only. Effective HAE management further includes patient education, reliable access to specific medications, and regular follow-up to monitor therapeutic response and safety.
ABBREVIATIONS: C1-INH = C1 esterase inhibitor; FAST = For Angioedema Subcutaneous Treatment; HAE = hereditary angioedema; LTP = long-term prophylaxis; MSCS = mean symptom complex severity; pdC1-INH = plasma-derived C1-INH. From the 1Division of Pediatric Allergy and Immunology, Department of Pediatrics, and the 2Division of Allergy and Immunology, Department of Medicine, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, Pennsylvania. Address reprint requests to: Neeti Bhardwaj, MD, MS, Pediatric Allergy and Immunology, Department of Pediatrics, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; e-mail: [email protected]
Received for publication January 7, 2014; revision received February 28, 2014, and accepted March 3, 2014. doi: 10.1111/trf.12674 © 2014 AABB TRANSFUSION **;**:**-**.
ereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self-limiting tissue swelling.1 It is caused by deficiency and/or dysfunction of C1 esterase inhibitor (C1-INH) enzyme. C1-INH has a regulatory role in the classic complement, contact (Factor [F]XII and kallikrein), coagulation (FXI and thrombin), and fibrinolytic (tissue-type plasminogen activator) cascades.2-4 Reduced activity of C1-INH may lead to elevated plasma levels of bradykinin, the key mediator in development of angioedema.5-7 Prevalence of HAE is estimated at one in 10,000 to one in 50,000 and the majority of cases can be categorized into two types.8,9 Type I HAE characterized by low production of functionally active C1-INH accounts for 85% of cases. Type II HAE characterized by normal or elevated levels of dysfunctional C1-INH protein accounts for the remainder of the cases. A third type of HAE, previously known as Type III, but now referred to as HAE with normal C1-INH, is characterized by normal C1-INH level and function and believed to be caused by a mutation in FXII protease (Hageman factor).2,10,11 Patients with HAE present with acute episodes of well-circumscribed, nonitching edema of subcutaneous and submucosal tissues, affecting the upper airways, face, extremities, genitals, and gastrointestinal system.12,13 Angioedema of the larynx can be life-threatening. Attacks may last 1 to 4 days and can involve one or more sites, severely affecting the quality of life. Symptoms of HAE are secondary to elevated levels of bradykinin in the body. Deficiency of C1-INH leads to activation of FXII and kallikrein at an accelerated rate, leading to overproduction of bradykinin from high-molecular-weight kininogen (Fig. 1). Excess bradykinin generation causes increased vascular permeability leading to angioedema.1 Management of HAE is traditionally classified into treatment of acute attacks or on-demand therapy, shortterm (preprocedural) prophylaxis, and long-term prophylaxis (LTP).14 Until recently, limited treatment options for HAE were available in the United States, consisting of androgens, fresh-frozen plasma (FFP), tranexamic acid, narcotics, and hydration. Androgens, which are effective for both short-term and LTP of HAE, are associated with serious adverse effects. Tranexamic acid, an oral antifibrinolytic agent, has been shown to improve symptoms during acute attacks, but its efficacy has not been established in controlled studies. FFP is effective for Volume **, ** **
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FXII High-molecular-weight kininogen
High-molecular-weight kininogen FXI
and school absenteeism. In addition to disease-specific treatment such as C1-INH replacement and contact system modulators, supportive therapy with hydration and pain relief is also recommended. Acute laryngeal attacks may be life-threatening and should be treated as early as possible with specific therapies; intubation, cricothyrotomy, or tracheostomy may be necessary to maintain the airway.15,16,18,19
Plasma-derived C1-INH (Berinert)
Berinert (CSL Behring, King of Prussia, PA) is a plasma-derived, nanofiltered, Ecallantide lyophilized, pasteurized C1-INH conFibrin centrate that was approved in the degradation United States in 2009 for treatment of products High-molecular-weight acute abdominal and facial HAE attacks kininogen and recently for laryngeal attacks as Bradykinin well. It has been used in the European Kallikrein Union for more than three decades and was approved for self-administration by Bradykinin B2 Icatibant appropriately trained patients in the Receptor United States in early 2012.20 A large randomized, double-blind placebocontrolled trial, called International Multicenter Prospective Angioedema C1-inhibitor Trial 1 (IMPACT1), estabEndothelial Cell lished the efficacy and safety of Berinert at a dose of 20 U/kg in treatment of Vasodilation, edema acute HAE episodes. The study showed that onset of relief for facial or abdomiFig. 1. Contact pathway and sites of action of HAE therapies. Dotted arrows indicate nal attacks occurred in a median of 0.5 negative effects. hours, compared with 1.5 hours for placebo (p = 0.003). The median time to complete resolution of all HAE symptoms was 4.9 hours attacks, but this intervention lacks controlled studies versus 7.8 hours (p = 0.02).20 IMPACT2 was an open-label demonstrating its efficacy.15,16 The management of HAE has transformed dramatically with recently approved extension of IMPACT1 to evaluate the efficacy and safety therapies in the United States, which were previously of long-term treatment with 20 U/kg C1-INH for succesavailable only in Western Europe.17 The aim of this review sive HAE attacks.21 During median study duration of 24 is to update the practicing physician about various treatmonths, 1085 attacks were treated in 57 patients. In the ment modalities available in the United States for HAE per-patient analysis, the median time to onset of patients. symptom relief was 0.46 hours and was similar for all types of attacks (0.39-0.48 hr); the median time to complete resolution of symptoms was 15.5 hours. No inhibitory ON-DEMAND THERAPIES anti-C1-INH was detected in any patient. The study concluded that a single dose of 20 U/kg C1-INH concentrate Consensus guidelines recommend that all patients with is safe and provides reliable efficacy in the long-term treatHAE should have on-demand therapy available for acute ment of successive HAE attacks at any location in the attacks.15,16,18 Over the past 5 years, the US Food and Drug body.21 Berinert is generally well tolerated with the most Administration (FDA) has approved three novel therapies for treatment of acute HAE episodes, and one is awaiting common adverse events being headache, abdominal pain, approval. Acute attacks must be treated as early as posnausea, vomiting and diarrhea, and muscle spasms. Most sible to decrease morbidity, possible mortality, and work of these adverse events are related to the type of attack 2
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and not the medication itself.20 There is no evidence of thromboembolic disease associated with Berinert administration.22 No transmission of infectious agents has been reported.
Ecallantide (Kalbitor) Ecallantide (Kalbitor, Dyax Corp., Cambridge, MA) is a potent kallikrein inhibitor that blocks the production of kallikrein and its by-product, bradykinin, and was approved in the United States in 2009 for treatment of acute peripheral, abdominal, and laryngeal HAE attacks.23 The recommended dose is 30 mg given subcutaneously as three 1-mL injections. It is not approved for self-administration at home because of risk of anaphylaxis.23 Two large Phase 3 placebo-controlled trials, EDEMA3 and EDEMA4, have evaluated ecallantide for the acute treatment of moderate to severe HAE attacks.24,25 In EDEMA3 trial, the primary endpoint was treatment outcome score 4 hours after ecallantide administration: these scores range from +100 (designated in the protocol as significant improvement in symptoms) to –100 (significant worsening of symptoms). The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (p = 0.004). The estimated time to significant improvement of symptoms was 165 minutes with ecallantide versus more than 240 minutes with placebo (p = 0.14).24 The primary efficacy endpoint in EDEMA4 trial was change from baseline in mean symptom complex severity (MSCS) score 4 hours after dosing. Among the 96 patients enrolled, mean change from baseline in MSCS score 4 hours after dosing was significantly greater with ecallantide use (–0.8) compared with placebo use (–0.4; p = 0.01).25 The median change in MSCS score at 4 hours was –1.00 with ecallantide, versus −0.50 with placebo (p = 0.01), in EDEMA3 trial. A post hoc integrated analysis of the EDEMA3 and EDEMA4 clinical trials established significantly better response to ecallantide versus placebo. Treatment with ecallantide within 6 hours of symptom onset was shown to lead to more rapid and sustained improvement of symptoms.26 Ecallantide is generally well tolerated with the most commonly reported adverse events being headache, nausea, diarrhea, fever, injection-site reaction, and upper respiratory infections.23-25 Anaphylaxis has been reported in approximately 3.0% of patients receiving ecallantide. This prompted a black-box warning mandating that it can only be administered by a health care provider trained in managing anaphylaxis. Postmarketing studies have not shown an increased incidence of anaphylaxis. Some patients produce specific immunoglobulins against the medication, but these have not been shown to interfere with the functionality of the drug.23
Icatibant (Firazyr) Icatibant (Firazyr, Ireland, Italy) is a specific and selective bradykinin B2 receptor antagonist. It was approved by the FDA in August 2011 for treatment of acute attacks of HAE in adults 18 years of age and older.27 Initially, two doubleblind, randomized, multicenter trials evaluated the effect of icatibant in patients with cutaneous or abdominal HAE attacks. In the For Angioedema Subcutaneous Treatment (FAST)-1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid.27 Primary endpoint was the median time to clinically significant relief of symptoms, which was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in FAST-1 trial (p = 0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in FAST-2 trial (p < 0.001). Benefit of icatibant compared with placebo in FAST-1 trial was insignificant with regard to the primary end point. Early use of rescue medication (C1-INH concentrate, antiemetic agents, or opiates) was thought to have obscured the benefit of icatibant in the placebo trial.27 The FAST-3 study was designed to evaluate again the efficacy and safety of icatibant compared with placebo. The primary endpoint (median time to 50% or more reduction in symptom severity) was significantly reduced in the icatibant group (2.0 hours) compared to placebo group (19.8 hr; p < 0.001).28 No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events was similar in icatibant- and placebo-treated subjects (41 and 52%, respectively). The most common adverse events were injection-site reactions, which were mild to moderate and transient.28 Icatibant can be stored at room temperature. It is approved for self-administration at a dose of 30 mg subcutaneously. If response is inadequate or symptoms recur, additional injections of 30 mg may be administered at 6-hour intervals, not to exceed three injections in 24 hours.
Recombinant C1-INH (conestat alfa) Production of plasma-derived C1-INH is dependent on plasma donations and also carries the theoretical risk of transmission of blood-borne infections. The Dutch company Pharming (Leiden, the Netherlands) developed conestat alfa, a recombinant human C1-INH (rhC1-INH) isolated from the milk of transgenic rabbits and purified for human administration.29 Conestat alfa is currently approved for use in the European Union under the name Ruconest and is under review by the FDA under the brand name Rhucin. Highly purified, functionally active recombinant protein can be produced in large quantities with extremely low risk of pathogen transmission, with functionality comparable to human C1-INH in terms of its ability to inhibit C1, plasma kallikrein, FXIa, and FXIIa. Because of differences in glycosylation, the half-life of rhC1-INH is less than that of human-derived C1-INH.29 Volume **, ** **
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Two similar independent, randomized, salinecontrolled, double-blind studies conducted in Europe and North America, evaluated the efficacy and safety of rhC1INH in treatment of acute HAE attacks.30 Efficacy was assessed by using patient-reported visual analog scale outcomes. Patients were randomized to receive intravenously (IV) 100 or 50 U/kg rhC1-INH or saline in the North American study, or 100 U/kg rhC1-INH or saline in the European study, 1 unit of C1-INH being defined as the amount in 1 mL of pooled normal human plasma. Data from both studies were pooled for analysis. Median times to the beginning of relief of symptoms with rhC1-INH at 100 (n = 29) and 50 (n = 12) U/kg body weight were 66 and 122 minutes, compared with 495 minutes with saline (p < 0.001 and p = 0.013, respectively).30 Treatmentrelated adverse events were minimal and no postexposure antibody responses against rhC1-INH were observed. Since 50 and 100 U/kg doses were equally efficacious, the 50 U/kg dose is approved for treatment of acute attacks of HAE. An open-label extension study of the North American randomized controlled trial examined the efficacy, safety, and tolerability of repeated treatments with rhC1INH in HAE patients who were treated with IV 50 U/kg dose with option for an additional dose of 50 U/kg based on clinical response.31 Time to beginning of relief was assessed by patients using a 100-mm visual analog scale. Median times to beginning of symptom relief for the first five attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1-INH. There was no requirement for increased dosing with successive treatments. A European open-label extension study had also reported similar safety and efficacy data.31 The most commonly reported adverse effects were headache and nasopharyngitis, of mild to moderate severity. Clinical trials have not reported antibodies against rabbit protein or C1-INH.30,31 In a study involving 137 healthy volunteers and HAE patients, testing for presence of IgE antibodies against four rabbit allergens found five subjects with positive result.29 Three of the five subjects positive for IgE against rabbit allergens reported allergic symptoms after conestat alfa exposure. One healthy volunteer had an anaphylactic reaction after the first exposure to conestat alfa. He had not disclosed history of rabbit allergy and his serum IgE level for rabbit dander was 39 kU/L. Excluding the presence of anti-rabbit IgE antibodies is advised before initiating therapy with conestat alfa.29 Conestat alfa is available as a sterile, preservativefree, freeze-dried powder. Each vial should be aseptically reconstituted with 14 mL of sterile water for injection. The reconstituted solution contains 150 U/mL conestat alfa. It is for IV use only and must be administered by a health care professional. One unit of conestat alfa activity is equivalent to the C1-INH activity provided by 1 mL of pooled normal plasma and one vial contains 2100 U 4
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conestat alfa. The recommended dose is one IV injection of 50 U/kg for adults with a body weight of less than 84 kg and one IV injection of 4200 U (two vials) for adults with a body weight of at least 84 kg.32
FFP FFP, which contains C1-INH, may abort most attacks of HAE. However, a paradoxical worsening of symptoms occasionally occurs as plasma contains substrate proteins that could consume the available C1-INH and exacerbate the angioedema.33,34 No controlled or comparative studies demonstrating plasma efficacy in HAE are available. Moreover, FFP carries the risk of transmission of bloodborne pathogens, transfusion reactions, and transfusionrelated acute lung injury. In most parts of the world, however, FFP is still the only therapy available for HAE attacks. Therapy consists of transfusing 2 units of FFP initially, repeating every 2 to 4 hours until there is clinical improvement.
PROPHYLAXIS While multiple treatment modalities have been proven to terminate acute attacks of HAE, the need for long-term and short-term prophylaxis exists. LTP refers to long-term therapy aimed at preventing acute episodes. HAE is known to cause significant morbidity and can have farreaching economic consequences in terms of physician and hospital costs and costs of missed work, thereby justifying preventive therapy.35 Short-term prophylaxis is indicated in patients at risk of having an HAE attack, such as undergoing surgery, having extensive dental work, going through stressful life events, and in traumatic accidents.16
LTP LTP is recommended in HAE patients who continue to experience life-limiting angioedema episodes despite adequate on-demand therapy; however, at this time there are no clinical studies to support any specific prophylactic regimen.36-38 A prophylactic strategy may be considered at any point, if on-demand therapy alone is thought to be inadequate. The decision to institute LTP should be taken after detailed discussion with the patient of the expected benefits and side effects, with consideration for disease course and its effect on quality of life.39 Attenuated androgens and plasma-derived C1-INH (pdC1-INH) concentrates are the recommended options.15,16,18,19 Antifibrinolytic agents have also undergone controlled clinical trials against placebo, but the efficacy data for them is inferior.15,16 Danazol is the most commonly used androgen and can be used up to 200 mg three times a day. Most consensus publications recommend daily dosing of
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200 mg danazol or less. Alternatives include stanozolol, oxandrolone, and methyltestosterone. Long-term treatment with androgens is associated with a wide range of potential, dose-dependent adverse effects including weight gain, hypertension, dyslipidemia, acne, menstrual irregularities, virilization, premature closure of growth plates, hepatic necrosis, and hepatic neoplasm.40 Androgen-related side effects are dose dependent. Androgen derivatives are not recommended for pregnant and lactating women or children until after growth is complete. Therapy should be adjusted based on clinical response and not serum C4 levels. Regular follow-up visits every 6 months are recommended. Liver enzymes, lipid profile, complete blood cell count, alpha-fetoprotein, and urinalysis should be performed during follow-up visits. Abdominal ultrasound yearly is advisable for early diagnosis of liver tumors.15,16,18,19 The efficacy of nanofiltered pdC1-INH concentrate for long-term prophylaxis of HAE was first demonstrated in a crossover trial involving 22 HAE patients, comparing prophylactic 2-weekly injections of nanofiltered C1-INH concentrate (1000 units) with placebo during two 12-week periods.41 The number of attacks per 12-week period was 6.26 with C1-INH concentrate given as prophylaxis, compared with 12.73 with placebo (p < 0.001). The subjects who received the C1-INH concentrate had significant reductions in both the severity and the duration of attacks, need for rescue therapy, and total number of days with swelling. The reported side effects were pruritus, rash, light-headedness, and fever.41 Transmission of bloodborne pathogens is a theoretical risk; obtaining baseline hepatitis B, hepatitis C, and human immunodeficiency virus serology is advisable.15 Thrombosis associated with indwelling catheters used for the administration of LTP C1-INH has been reported.42 In the United States, C1-INH (Cinryze) is approved for LTP in adolescents and adults at a dose of 1000 units every 3 or 4 days. The efficacy of higher doses of C1-INH is being assessed in an ongoing study. Other C1-INH products (Berinert and Cetor) have been used outside the United States for this indication but no controlled clinical trials to support their efficacy in LTP have been performed.
Short-term prophylaxis Physical trauma and emotional stress are well recognized as precipitants of HAE attacks. There is paucity of data comparing various therapeutic options for short-term prophylaxis. Evidence for efficacy of preprocedural prophylaxis is lacking. Angioedema episodes related to surgery usually occur within 4 to 30 hours after the procedure. Dental surgery is considered especially high risk because of vicinity of surgical site to upper airway.16,43 C1-INH replacement dosed by weight appears to be the logical choice; however, the dose for this needs investiga-
tion. Recommendations vary from 10 to 20 U/kg body weight or 1000 units, administered 1 to 6 hours before procedure. Bork and colleagues44 retrospectively compared doses of 500 and 1000 units of C1-INH and placebo and found a reduction in postprocedure attacks with both doses, but even at 1000 units attacks were recorded, suggesting higher doses may be necessary. An alternative for short-term prophylaxis is 200 mg of danazol by mouth three times a day for 5 to 7 days before procedure and 2 days after the procedure.16 Efficacy of androgens compared to C1-NH replacement has not been studied for preprocedural prophylaxis. Androgens may be used when the surgery-related risk is relatively low and when C1-INH concentrate is not available. Adverse events with short-term use of androgens are minimal. They are less expensive and easier to use although they are not suitable for pregnant and nursing females. Ecallantide, icatibant, and rhC1-INH have short half-lives and are unlikely to be of benefit in the setting of short-term prophylaxis; however, it may be helpful to have doses of these on-demand therapies available at the time of the procedure.
MANAGEMENT IN PEDIATRIC POPULATION HAE symptoms may occur at any age, but attacks usually begin during school-age years or adolescence. pdC1-INH concentrate (Berinert) is the only approved drug for HAE on-demand treatment in children 12 years and older in the United States.16 pdC1-INH is the first-line short-term prophylactic option, but short courses of androgens can be used as second line in the event C1-INH is not available. Ecallantide is approved for on-demand treatment of HAE attacks in individuals 16 years and older.45 The majority of children do not require LTP. The preferred therapy for LTP is pdC1-INH (Cinryze). Androgens are not recommended for LTP in prepubertal children.16
DISCUSSION The management of HAE has been transformed drastically in recent years due to availability of newly licensed therapies. Salient features of the available HAE therapies are presented in Table 1. Several expert groups have published consensus recommendations to provide guidance for management of HAE patients.15,16,18,19 In the United States, Berinert (C1-INH), ecallantide, and icatibant are available for acute management of HAE episodes. rhC1INH, which is approved in Europe under the brand name Ruconest is awaiting FDA approval in the United States for on-demand treatment. Cinryze (C1-INH) is also licensed for this indication in Europe, but not in the United States. When selecting an agent for acute therapy, a detailed discussion with the patient is essential. Preference for IV versus subcutaneous route, home administration versus Volume **, ** **
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TABLE 1. Comparison of HAE medications Drug class pdC1-INH
Advantages Extensive clinical experience Corrects the fundamental defect Long half-life
Disadvantages Infectious risk Needs IV access Limited supply
Corrects the fundamental defect No infectious risk Scalable supply
Needs IV access Short half-life Potential for allergic reactions
No infectious risk Subcutaneous administration
No infectious risk Stable at room temperature Subcutaneous administration
Antibodies may cause allergic reaction or neutralization Short half-life Black box warning for anaphylaxis Repeat dosing Short half-life Local pain/irritation Repeat dosing
Inexpensive Oral administration
Little to no clinical effect
Inexpensive Oral Effective
Frequent adverse effects Risks may outweigh benefits if dose is more than equivalent of 200 mg of danazol daily
administration in a health care facility versus home health, patient’s location, and lifestyle (such as need for frequent travel) all play an important role in this selection process.39 Prophylactic treatment is indicated for patients in whom on-demand therapy alone is not sufficient. Cinryze (C1-INH) and attenuated androgens are available for LTP in the United States. While management plans and periodic evaluation may be done at tertiary care or referral centers, coordination with primary care and emergency room physicians is necessary for implementation of therapy. In general, three treatment models have been used: self-administration at home, home treatment versus visiting nurse, and health care facility treatment (such as hospital, clinic, or infusion center).39 If self-administration is selected, the patient and/or their caregivers should be thoroughly trained on technique.46 Berinert, Cinryze, and icatibant are approved for self-administration. Ecallantide is not approved for self-administration but can be effectively administered by visiting nurses. HAE, being a rare disease, is frequently underdiagnosed and misdiagnosed. The diagnosis is often delayed by 8 years on average.47,48 Antihistamines and corticosteroids, which are effective for histamine-induced angioedema, are completely ineffective for HAE.49 Patients often undergo unnecessary surgery for abdominal pain or receive ineffective medications for airway angioedema. Therefore, it is very important for HAE specialists to effectively communicate the diagnosis and specific treatment for HAE patients to health care providers in the community.39 A brief letter or treatment action plan from the HAE 6
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Best use Acute attacks Short-term prophylaxis LTP Acute attacks Short- and LTP Prodrome
Acute attacks in office or by home health care provider
Self-treatment of acute attacks Easy to use during travel Not recommended for acute attacks May have some role in LTP Short- and LTP
Status Berinert: on-demand therapy Cinryze: prophylaxis Rhucin: used for on-demand therapy in Europe Ruconest awaiting FDA approval Kalbitor: on-demand therapy
Firazyr: on-demand therapy
Tranexamic acid, aminocaproic acid both available, but effect minimal Danazol: used for short- and LTP
specialist can be an effective communication tool for management of acute episodes and preventing unnecessary investigations and procedures. Clinical follow-up at regular intervals must be maintained. At each visit, detailed review of the treatment plan should be done, in terms of frequency, severity, and duration of HAE episodes, use of medications, and their success or failure thereof. The recently approved medications for HAE have revolutionized the management of this condition. Continued international effort is needed to improve diagnosis and management of patients with HAE throughout the world and to help initiate uniform care and availability of therapies to all with the diagnosis regardless of their place of residence.
CONFLICTS OF INTEREST NB has disclosed no conflicts of interest. TJC performs research, consults, and speaks for Shire, the maker of icatibant.
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