Version May 2024
INTRODUCTION — Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent angioedema without wheals [1]. All forms of HAE are characterized by recurrent episodes of angioedema without pruritus or urticaria, which most often affect the skin and/or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although swelling resolves spontaneously in two to five days in the absence of treatment, angioedema can often be temporarily debilitating, and laryngeal angioedema may cause fatal asphyxiation. There are several different forms of HAE. The recommendations in this topic apply to those due to C1 inhibitor (C1-INH) deficiency.
Dental and medical procedures, emotional stress, hormonal changes (related to menstruation or pregnancy), infections, and medications (including oral contraceptives and ACE-inhibitors) are among the most common stimuli that can trigger episodes of angioedema. The various prophylactic therapies that are used prior to prevent HAE attacks ("preprocedural" prophylaxis) will be reviewed here. Long-term prophylaxis to reduce the frequency and severity of angioedema episodes and other issues in the diagnosis and management of HAE are discussed separately:
●(See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)
●(See "Hereditary angioedema: Acute treatment of angioedema attacks".)
●(See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)
●(See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis".)
●(See "Hereditary angioedema with normal C1 inhibitor".)
INDICATIONS FOR SHORT-TERM PROPHYLAXIS — The most common indications for short-term prophylaxis are invasive procedures (especially dental/intraoral surgery, endotracheal intubation, or endoscopies) or anticipated stressful events [2-4]. Prophylaxis may also be given for a brief period of time (ie, "extended" short-term/intermittent prophylaxis) for travel to remote areas or countries in which there may not be ready access to health care or for a period of weeks or months during which increased stress is anticipated (eg, students during exam periods) [5].
The need for short-term prophylaxis is influenced by the availability of one of the "on-demand" treatments: C1 inhibitor (C1-INH) concentrates, icatibant, or ecallantide. If none of the on-demand therapies are available, then pre-procedural short-term prophylaxis is especially important. Mechanisms of action, efficacy, dosing, and administration of on-demand therapies are discussed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'First-line agents: Dosing, efficacy, and adverse reactions'.)
Patients already on long-term prophylaxis — For patients already receiving long-term prophylaxis with intravenous C1-INH or androgens, dosing can be modified prior to a procedure. For example, patients receiving regular intravenous injections of plasma-derived C1-INH (pdC1-INH) can arrange to have an injection immediately before the procedure, or patients taking androgens can increase the dose for five days prior to the procedure and continued for additional two to three days after procedure [3,4]. The risk of procedural angioedema in patients receiving subcutaneous pdC1-INH or lanadelumab is unknown, and because of this uncertainty, the authors will often recommend an injection of intravenous pdC1-INH prior to the procedure to be safe.
Risk associated with specific procedures — The highest-risk procedures are intubation, oral surgery, and major dental work (ie, cutting of tissue or injections of anesthetics), which can trigger symptoms in most patients [6,7]. These procedures can induce both cutaneous and upper airway edema. Short-term prophylaxis should always be administered prior to these procedures, even if the patient has access to acute therapies.
Dental work — Because of the precautions required, many patients with HAE report hurdles to obtaining appropriate dental care. However, the treatment of severe oral pathology can have a positive impact on the course of the disease [8].
In a series of 577 tooth extractions when prophylaxis was not given, 21.5 percent of the extractions were followed by angioedema symptoms with 116 of the 124 episodes resulting in swelling of the face, upper airway, or a combination [9]. Symptoms occurred up to 72 hours after the procedure, with a mean time to onset of 14 hours. Among procedures in which patients received prophylaxis with pdC1-INH concentrate, 12.5 percent resulted in swelling, at a mean of eight hours after the procedure. The fewest attacks were seen in patients receiving 1000 units of pdC1-INH concentrate, administered one hour before the procedure.
Minor dental procedures (eg, routine cleanings, filling of cavities, crown placement, restorative work) are lower risk, and the patient's past response to similar interventions can guide the decision to give prophylaxis. However, patients vary in their sensitivity to procedure-induced swelling. Those who have developed swelling in similar situations in the past should receive preprocedural prophylaxis in the future, even for minor interventions. Those who have tolerated these procedures in the past are likely to continue to do so. If a patient's tolerance for a given procedure is unknown, short-term prophylaxis is indicated.
Typical timing of onset of symptoms — HAE attacks can occur anywhere from hours to several days after a procedure, and typically begin within 48 hours of the intervention [7,9,10]. Patients should be advised that swelling often occurs one day or so after the procedure, and a specific plan of treatment should be in place for symptoms that arise during this period, including access to on-demand therapies. In the study of tooth extractions discussed above, patients who received prophylaxis with pdC1-INH concentrate were at highest risk during the 12 hours after the procedure [9]. Some attacks began during the night while the patients were asleep and were therefore recognized later than if they had occurred during waking hours. For this reason, some experts advise patients to schedule procedures as early as possible in the day.
AVAILABLE AGENTS — The agents that can be used for short-term prophylaxis are C1 inhibitor (C1-INH) concentrate, attenuated androgens, and plasma products. These are reviewed here, with availability, efficacy, and adverse effects [11].
Note that ecallantide (a kallikrein inhibitor) and icatibant (a bradykinin B2-receptor antagonist), which are other on-demand therapies, are not used before procedures, because these two agents have short half-lives (six hours or less). Thus, they are only used to stop an HAE attack once it has commenced. Their utility as prophylactic agents has not been defined. Only a single report has been published on the use of a bradykinin B2-receptor antagonist for short-term prophylaxis [12].
Tranexamic acid (TA), an antifibrinolytic agent, has been recommended by some guidelines but without theoretical rationale or practical evidence of efficacy. Therefore, the authors do not recommend use of TA for short-term prophylaxis.
Comparative efficacy — Overall, C1-INH concentrate is likely the most effective therapy for short-term prophylaxis, followed by attenuated androgens. Although there are no controlled trials directly comparing the efficacy of different therapies for short-term prophylaxis, a retrospective analysis found that post-procedural HAE attacks occurred in fewer patients treated with prophylactic pdC1-INH concentrate, compared with those who received danazol (6 versus 13 percent, respectively) [7].
Evaluation of the efficacy of various agents in short-term prophylaxis is complicated by the unpredictability of HAE attacks. Procedures that have triggered attacks in a given patient do not necessarily do so reproducibly, and major interventions that would be expected to precipitate attacks in most patients may not, even in the absence of prophylaxis. A registry-based survey has provided some additional real world data [6]. Because of this inherent unpredictability, it is prudent to give prophylaxis if there is any uncertainty about the risk of an HAE attack.
C1 inhibitor concentrate — Plasma-derived C1 inhibitor (pdC1-INH) concentrate may be administered intravenously for short-term prophylaxis. This is also the treatment of choice for short-term prophylaxis during pregnancy [13]. Note that subcutaneous administration has not been studied for short-term prophylaxis and is not recommended.
In the United States, two human plasma-derived products (pdC1-INH) are available for intravenous administration, Cinryze and Berinert. Cinryze is US Food and Drug Administration (FDA)-approved for long-term prophylaxis, and Berinert for acute treatment of HAE attacks; both are effective for short-term prophylaxis. Both Cinryze and Berinert are approved for short-term prophylaxis in Europe.
Dose and timing — Based on a small number of publications, a dose of 500 to 1000 units is effective in most children and adults [14,15]. The risk of angioedema has been shown to be closely linked to the plasma functional C1-INH level, with a level of 50 percent of normal offering near complete protection [16]. Therefore, the authors recommend that the dose of pdC1-INH be sufficient to achieve a functional C1-INH level of ≥50 percent at the time of the procedure, an outcome typically achieved immediately after a dose of 20 international units (IU) per kg body weight.
C1-INH concentrate is ideally given one hour prior to or immediately before the major procedure. However, if necessary, dosing can be given further in advance of the procedure. The half-life of a single weight-based dose of pdC1-INH is 30 to 39 hours [17,18], and in the study discussed above, administration up to 24 hours before was sufficient to prevent attacks [14]. However, a dose of pdC1-INH could conceivably be consumed within 24 hours in some patients, and the median time to maximal serum concentrations is 0.5 to 1 hour [18]. For these reasons, it is preferable to administer pdC1-INH as close in time (less than six hours) to the procedure as possible.
Efficacy — pdC1-INH concentrate as a single prophylactic agent is generally accepted as effective based upon retrospective series and observational studies [8,9,14,19,20]:
●In one series, 33 adults and 8 children received 1000 units of pdC1-INH within the 24 hours preceding 91 dental and medical procedures [14]. Angioedema occurred in only 2 percent of procedures.
●Preprocedure treatment with Cinryze was evaluated in an open-label study. A single, 1000-U dose was administered before 96 percent of the procedures (56 percent were dental, and 44 percent involved surgery or a diagnostic intervention); HAE attacks did not occur after 72 hours of C1-INH administration in 98 percent of the procedures [14].
A recombinant human C1 inhibitor (rhC1-INH) preparation, conestat alfa (Ruconest in Europe and the United States, Rhucin in other countries) is also available. It has not been approved for prophylaxis, although rhC1-INH given intravenously one hour prior to the procedure has also been used successfully for short-term prophylaxis in case reports and a retrospective multicenter study [21,22]. The half-life (three hours) of the recombinant product is significantly shorter than that of the plasma-derived product (30 to 39 hours), and its efficacy for short-term prophylaxis may not be identical.
Adverse effects — Side effects of C1-INH concentrate are rare and include headache, nausea, fever, and anaphylaxis [23].
Attenuated androgens — Synthetic 17-alpha-alkylated androgens ("attenuated" or anabolic androgens) include danazol, stanozolol, tibolone, and methyltestosterone. The choice of androgen is based largely upon availability, since differences among drugs have not been well-characterized. Danazol is widely available throughout the world. Stanozolol is not produced commercially in the United States, although it is available by prescription and can be compounded by individual pharmacies. Tibolone may be less virilizing than other agents [24-26]. Methyltestosterone is another alternative [27].
Efficacy — Small, uncontrolled studies and individual case reports suggest that attenuated androgens are effective for short-term prophylaxis [28,29]. As an example, attacks were completely prevented in 12 patients with a history of angioedema after dental procedures who were administered danazol (600 mg/day) four days before and four days after various procedures [28].
Dosing — There are several approaches to dosing attenuated androgens for short-term prophylaxis, and no comparative data exist to recommend one approach over another. Danazol is used in the following examples, although equivalent doses of other attenuated androgens as well as similar timeframes are mentioned. In the United States, danazol and stanozolol are FDA-approved for prophylaxis in patients with HAE, while the other androgens are not. For patients already on long-term attenuated androgens, the doses may be increased temporarily to those described below.
●For patients not already taking androgens, danazol at a dose of 400 to 600 mg/day or an equivalent androgen at a comparable dose may be given for five days before and two to three days after a procedure (table 1) [3,4,30]. Lower, weight-based dosing is advised (2.5 to 10 mg/kg) when children have to be treated, although the use of androgens in children should be avoided whenever possible.
●Stanozolol is another agent with which the authors of this topic have experience. Adult dosing is 4 to 6 mg daily for five days before and two to three days after (2 mg stanozolol is approximately equivalent to 200 mg of danazol).
●For patients already taking androgens regularly, the dose may be increased to 400 to 600 mg daily for five days before and two to three days after a procedure.
These recommendations are based upon the assumption that for the individual patient in question, a dose of this magnitude or less has been effective in the past. If not, a higher effective dose must be determined for that patient.
Adverse effects and contraindications — Short-term attenuated androgen therapy (ie, one or two weeks) is well-tolerated by most postpubertal males and by many female patients as well because the side effects are of minor significance when attenuated androgens are used only briefly. However, elevations in transaminases have been observed when excessively large doses were given (eg, 4 to 16 mg of stanozolol daily in adults) [31]. These doses are not routinely used. A pediatric endocrinology specialist should be consulted if androgens are used in children.
There are no absolute contraindications to short-term prophylaxis with attenuated androgens, except possibly pregnancy, since androgens can cause virilization of female fetuses. Androgens were even used successfully in pregnant women with HAE in the past when other options were lacking, with close collaboration with an obstetrician. However, with the alternative therapies available, attenuated androgen use in pregnancy is best avoided altogether [13].
Plasma products — Human plasma contains C1-INH and can be used for short-term prophylaxis. However, the efficacy is not as well-established as that of C1-INH preparations. Replacement plasma is available in two forms: fresh frozen plasma (FFP) and solvent/detergent-treated plasma (S/D plasma). (See "Clinical use of plasma components", section on 'Plasma products'.)
Dosing and timing — The usual dose is 2 units for adults, 10 mL/kg in children, given one to two hours before the procedure. Optimal dosing has not been studied.
Efficacy — The efficacy of FFP for short-term prophylaxis is supported by several case reports and observational series [32-35]. In a review of the literature, 148 cases were identified in which FFP was administered as short-term prophylaxis, with six instances of angioedema [32]. No controlled trials have been performed.
The efficacy data on S/D plasma are only anecdotal. Studies would be needed to demonstrate that it is an equivalent substitute for FFP, since S/D treatment may theoretically inactivate some proteins, and the effect on C1-INH concentration has not been reported. (See "Pathogen inactivation of blood products", section on 'Potential limitations'.)
Adverse effects — FFP has been associated acutely with urticaria, anaphylactic shock, and hemolysis, although we are not aware of reports of these events in patients with HAE. (See "Clinical use of plasma components".)
The primary concern with plasma products is disease transmission and the risks of this must be presented to the patient.
●S/D treatment inactivates enveloped viruses (such as human immunodeficiency virus [HIV], human T lymphotropic virus, and hepatitis B and C) but not prions or nonenveloped viruses (eg, hepatitis A, parvovirus). (See "Pathogen inactivation of blood products", section on 'Potential benefits'.)
●FFP does not undergo processing to remove infectious agents. The risk of disease transmission from FFP and other plasma products is presented in more detail separately. (See "Blood donor screening: Laboratory testing", section on 'Infectious disease screening and surveillance' and "Blood donor screening: Medical history", section on 'Screening for infectious risks'.)
OUR APPROACH — Several guidelines and practice parameters on the treatment of HAE have been published [3,4,30,36-41]. However, few studies have evaluated short-term prophylaxis specifically, and recommendations in the guidelines are largely extrapolated from data of efficacy of different agents in long-term prophylaxis. The approach presented in this topic review is consistent with available guidelines, although it is largely based on the experience of the authors and editors.
As mentioned previously, angioedema triggered by a procedure usually occurs within 48 hours of the procedure, so it is important that plans be made for both the procedure and the postprocedure period. Because angioedema does not typically develop during or immediately after the procedure, we do not insist that patients only receive dental care to hospital-based clinics or put other additional restrictions on them, provided on-demand therapy is accessible.
General precautions
●Communication between the patient, specialist performing the procedure, and allergist/immunologist (or other HAE expert) is critical. Both the clinician performing the procedure and the patient should know how to reach the HAE expert clinician in case advice is needed. A printable form summarizing the acute treatment of HAE is available to assist in this communication (form 1).
●Ideally, two doses of an on-demand therapy should be available to patients undergoing procedures, and these doses should be available to the patient both in the clinic and for two to three days after the procedure.
●We suggest that the patient be observed for at least two hours after the procedure, before being discharged home. However, as mentioned above, swelling related to the procedure may begin within the ensuring 48 hours, so patients must also have a plan in place to access on-demand therapy if needed.
High-risk procedures — There are two principal approaches for preprocedural prophylaxis for high-risk procedures, such as oral surgery and intubation (table 1) [30].
●Plasma-derived C1 inhibitor (pdC1-INH) concentrate (20 units per kg) may be given one hour before the procedure, with two additional doses available for on-demand use if symptoms develop. Alternatively, ecallantide (a kallikrein inhibitor), icatibant (a bradykinin B2-receptor antagonist), and recombinant human C1 inhibitor (C1-INH) could be used if symptoms develop (although ecallantide and icatibant are not used before the procedure, as their efficacy as prophylaxis is not known). Dosing of pdC1-INH concentrate is discussed above. (See 'C1 inhibitor concentrate' above.)
OR
●If pdC1-INH is not available, attenuated androgens may be given for five days before and two to three days after the procedure, administered as described below This option is usually reserved for patients who are known to tolerate attenuated androgens or have experience taking these drugs for long-term prophylaxis and for countries in which access to C1-INH, icatibant, and ecallantide is limited. (See 'Attenuated androgens' above.)
●A third option, if none of the above therapies is available, is solvent/detergent-treated plasma (S/D plasma) or fresh frozen plasma (FFP). (See 'Plasma products' above.)
Lower-risk procedures — If on-demand therapies are available, then short-term prophylaxis may not be necessary. On-demand therapies include C1-INH concentrate, icatibant, or ecallantide (United States only). If on-demand therapies are not immediately available, we would administer attenuated androgen premedication, unless the individual tolerated that specific procedure in the past.
Emergency procedures — In an emergency situation in which prophylaxis is indicated, C1-INH concentrate should be given, if available. If no acute therapies are available and there is not enough time for attenuated androgen pretreatment, plasma products (FFP or S/D plasma) may be given. (See 'Plasma products' above.)
Travel to remote areas — Patients traveling to remote areas who are not already receiving long-term prophylaxis may want to take extended short-term prophylaxis (such as attenuated androgens) temporarily and should also have on-demand medications that can be self-administered.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary angioedema and other forms of nonhistaminergic angioedema".)
INFORMATION FOR PATIENTS — Patients can access detailed, patient-oriented information through the United States Hereditary Angioedema Association and the International Patient Organization for C1 Inhibitor Deficiencies.
SUMMARY AND RECOMMENDATIONS
●In patients with hereditary angioedema (HAE), "short-term" or "preprocedural" prophylaxis refers to the administration of medications briefly before a procedure or stressful event that is likely to precipitate an episode of angioedema. It may also be given to patients traveling to remote areas in which they may not be able to access health care. (See 'Indications for short-term prophylaxis' above.)
●Angioedema typically begins within 48 hours of a triggering event or procedure. Patients should be advised that swelling often occurs one day or so after the procedure, and a specific plan of treatment should be in place for symptoms that arise during this period. (See 'Typical timing of onset of symptoms' above.)
●Some procedures, such as oral surgery, intubation, endoscopy, and dental work that involves injections or cutting of tissues, reliably trigger symptoms in most patients. However, individuals vary in their susceptibility to HAE attacks. If a patient has had symptoms with a given procedure, then it should be considered high risk for that patient, and prophylaxis should be administered for future similar procedures. (See 'Risk associated with specific procedures' above.)
●None of the available therapies confer complete protection from an HAE attack, and the supervising clinician must be prepared to recognize and manage angioedema with on-demand therapies immediately available. (See 'General precautions' above.)
●For patients undergoing high-risk procedures (eg, major dental procedures, surgery, intubation, endoscopy), we recommend administering prophylactic therapy (table 1) (Grade 1B) (see 'High-risk procedures' above):
•We suggest giving plasma-derived C1 inhibitor (pdC1-INH) concentrate (Grade 2C). We prefer weight-based dosing (ie, 20 units per kg). This should be injected as close in time to the procedure as is feasible (optimally within the hour before the procedure). At least two additional doses of an on-demand therapy (C1 inhibitor [C1-INH], icatibant, or ecallantide) should be available to the patient in case symptoms develop either during the procedure or during the two to three days following the procedure. (See 'C1 inhibitor concentrate' above.)
•If pdC1-INH concentrate is not available, we suggest premedication with attenuated androgens (Grade 2C). A representative regimen is danazol (10 mg/kg per day to a maximum of 600 mg/day), beginning five days before and extending for two to three days after the procedure. (See 'Attenuated androgens' above.)
●For patients undergoing low-risk procedures, we suggest not administering attenuated androgens in advance, provided C1-INH concentrate, ecallantide (United States), or icatibant is immediately available to treat any symptoms that arise (table 1) (Grade 2C). If one of these acute therapies is not immediately available, we would administer attenuated androgen premedication, unless the patient tolerated that specific procedure in the past. (See 'Lower-risk procedures' above.)
●In an emergency situation in which prophylaxis is indicated but no acute therapies are available and there is not enough time for attenuated androgen pretreatment, plasma products (fresh frozen plasma [FFP] or solvent/detergent-treated plasma [S/D plasma]) may be given. (See 'Emergency procedures' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marco Cicardi, MD, who contributed to earlier versions of this topic review.
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