The prophylactic use of C1 inhibitor in hereditary angioedema patients undergoing invasive surgical procedures: a retrospective study

Background Hereditary Angioedema (HAE) is a rare autosomal dominant condition characterized by episodic angioedema, which may be triggered by invasive procedures and surgery. C1 inhibitor (C1 INH) was approved in the United States and Canada in 2009 and 2010, respectively, for the treatment of acute attacks. Most recently in April 2013, it was approved in Europe for short-term prophylaxis (STP), prior to medical, dental, or surgical procedures, to prevent HAE attacks in both children and adults. Currently, C1 INH is not approved in Canada or the United States for STP of HAE attacks. Our objective was to demonstrate the effectiveness of C1 INH as a short-term prophylactic treatment for patients with Type I HAE undergoing invasive surgical procedures. Methods A retrospective chart review between 1997-2013 was performed at one Canadian Tertiary Care Allergy and Asthma Clinic affiliated with The Ottawa Hospital, in Ottawa, Canada. The standard dose of C1 INH for STP was 10 or 20 U/kg. Results In all 24 procedures, there were no post-procedure HAE attacks after short-term prophylactic administration of C1 INH. Conclusions In this retrospective chart review at one tertiary care Allergy and Clinical Immunology Clinic, short-term prophylactic use of C1 INH was found to be effective at preventing post-procedure HAE attacks, in patients diagnosed with Type I HAE.


Background
Hereditary Angioedema (HAE) is a rare autosomal dominant disease with a prevalence of approximately 1 in 50,000 [1]. There are 3 variants of HAE, which present with episodic attacks of non-pitting and nonpruritic edema; however, they may be differentiated by CI INH level and function. Type I affects 85% of patients and is distinguished by low plasma levels of C1 INH; while in Type II, which affects 15% of patients, inactive C1 INH is produced, but plasma levels are normal. Type III is rare, primarily affects females, and is characterized by normal C1 INH level and function; it may be estrogen dependent [1].
Significant mortality is associated with HAE; undiagnosed HAE carries a 30-40% mortality rate, mainly from upper airway obstruction [2]. Furthermore, patients suffer from important morbidity and disabling symptoms, and may be debilitated for 20-100 days per year [3]. New medications have been developed for both treatment of acute attacks and for prophylaxis (short-term and longterm). Short-term prophylaxis (STP) is used to prevent attacks surrounding known triggers (surgeries, invasive dental procedures, stressful life events), while long-term prophylaxis is reserved for patients who suffer from frequent HAE attacks.
The World Allergy Organization (WAO) recognizes that physical and emotional stress associated with surgery may elicit HAE attacks. These attacks usually occur 4-30 hours post-surgery, and commonly near the site of physical trauma, suggesting that dental surgery may be associated with significant risk because of potential airway edema [4]. C1 INH has been marketed for the treatment of HAE attacks in Europe for over 30 years; it was officially approved in Europe for acute HAE attacks in 2008. It was approved in the United States (US) and Canada, in 2009 and 2010, respectively, for the treatment of moderate to severe acute abdominal and facial attacks. In April 2013, C1 INH was approved in Europe for STP in children and adults, prior to medical, dental, or surgical procedures. It is not currently approved for STP in Canada or the US. Our objective is to demonstrate the effectiveness of C1 INH as a short-term prophylactic treatment for patients with Type I HAE undergoing surgical procedures.

Methods
A retrospective chart review was performed at one Canadian Tertiary Care Allergy and Clinical Immunology Clinic (Yang Medicine), affiliated with The Ottawa Hospital in Ottawa, Canada. The study included all patients with type I HAE who had received short-term prophylactic treatment with C1 INH (Berinert®) prior to an invasive procedure, surgery, dental work, or child birth, between 1997-2013. The diagnosis of Type I HAE was established in these patients based on clinical history, family history, and laboratory values (C4 level, C1 INH level). The primary outcome was the number of postprocedural HAE attacks after short-term prophylactic administration of C1 INH.
Prior to 2010 (when Berinert® was approved in Canada for acute attacks), the medication was only accessible through Health Canada's Special Access Programme on a case-by-case basis. It was requested for each HAE patient on the basis of the possible serious and potential life-threatening nature of an HAE episode caused by an invasive procedure or surgery.

Results
At total of 24 surgical procedures (Table 1) were performed on 12 patients (4 male, 8 female) with Type I HAE. The average number of procedures per patient was 2 (range 1-6), and the average age at the time of the procedure was 42 (range 19-62).
The majority of surgical procedures (22/24) were treated with a short-term prophylactic C1 INH dose of 1000 U, 1500 U, or 2000 U, which corresponded to a dose of 10 or 20 U/kg, administered IV over a 20-30 minute period just before the procedure. Procedure 4 was treated with an infusion of C1 INH, resulting in a higher cumulative dose. This decision was based on mutiple factors, including the invasiveness of the surgery, the need for intubation, the patient's history of a possible previous laryngeal attack, and the patient being off his Danazol at the time of the surgery. Procedure 20 also received a higher prophylactic dose of C1 INH (3000 U), because of the seriousness and length of the surgery.
In eight of the procedures, the patient received STP with C1 INH in addition to long-term treatment with Danazol. STP with C1 INH was provided to these patients as they continued to experience HAE attacks while taking Danazol.
In all 24 surgical procedures, there were no postprocedure HAE attacks after short-term prophylactic administration of C1 INH. Furthermore, no patient required additional dosing because of concern regarding prodromal symptoms of an impending HAE attack.

Discussion
In our experience, C1 INH was an effective short-term prophylactic treatment for Type I HAE patients undergoing invasive procedures. There were no post-procedural HAE attacks following any of the 24 procedures. Our results are consistent with a previous report by Grant et al, where pre-procedural nanofiltered C1 INH (Cinryze®) was used to prevent HAE attacks. In that study, 41 patients (33 adults, 8 children) received C1 INH prior to 91 procedures (87/91 procedures were treated with a dose of 1000 U for STP). No HAE attack followed 89 of 91 procedures; the 2 attacks were successfully treated with 1000 U of C1 INH [6]. It is noteworthy, however, that the majority of the procedures in the study by Grant et al did not require pretreatment.
While the studies by Grant [6,7] and for all 24/24 procedures, patients in our study received doses greater than the dose of 500 U employed by Farkas et al. [8].
Historically, treatment options for HAE have included stimulating endogenous C1 INH synthesis using attenuated androgens, reducing C1 INH consumption with protease inhibitors (e.g. transexamic acid), and replacing C1 INH with fresh frozen plasma or C1 INH (plasma derived or recombinant); plasma derived C1 INH being the prefered option for acute attacks for the last 30 years [9]. Recombinant C1 INH has also been investigated for its use as a prophylactic treatment and prelimary results may be promising; [10] however, the half-life for recombinant C1 INH is shorter than that of plasma derived, which may limit its effectiveness for prophylaxis and more data are needed before commencing this therapy. Newer medications are approved for the treatment of acute attacks, STP, or long-term prophylaxis. Tables 2, 3, and 4, present the approved treatments in Canada, the United States, and Europe for the treatement of acute HAE attacks, short-term prophylaxis of HAE attacks, and long-term prophylaxis of HAE attacks, respectively.
The 2010 International consensus algorithm for the diagnosis, therapy and management of HAE provided guidelines for STP, suggesting that it is not routinely required before minor manipulations (e.g. minor dental work), so long as C1 INH is immediately available and the manipulation has not previously triggered an attack. For major procedures or intubation, they recommended shortterm prophylactic C1 INH 1-6 hours before the procedure [11]. Similarly, the WAO urges considering prophylactic C1 INH 1-6 hours before surgeries, especially dental and intraoral, those requiring endotracheal intubation, those manipulating the upper airway or pharynx, and for endoscopy and bronchoscopy procedures [4]. Both groups acknowledged that the optimal dose of C1 INH is unknown, but suggest a dose of 10-20 U/kg [4,11], or 1000 U [4]. Finally, the US Hereditary Angioedema Association Medical Advisory Board 2013 recommended that C1 INH for STP be administered 1-12 hours before the stressor; alternatively, anabolic steroids given 7-10 days before the stressor may be provided for STP. The importance of having ondemand treatment available, regardless of whether the patient was given STP for the stressor or not, was strongly emphasized [12].

Conclusions
We have demonstrated successful use of C1 INH as STP for Type I HAE patients undergoing invasive procedures. Our study was limited by our small sample size, the retrospective design, and only assessing a single agent, C1 INH. Other agents, such as attenuated androgens, fresh frozen plasma, and transexamic acid were not specifically included in our study. Although future prospective trials are needed, data suggest that pre-procedural treatment with C1 INH, Berinert®, may be an effective to substantially decrease post-procedural HAE attacks. Authors' contributions WHY created the study, and participated in its design and coordination and helped to draft the manuscript. All the patients in this study are patients of WHY. SS is the head nurse and coordinator in for HAE patients in WHY's allergy clinic. SS communicated with all the patients, collected data, and helped draft the manuscript. GG organized, analyzed, and interpreted all of the data, and was the principal author in drafting the manuscript. RH assisted in drafting the manuscript, and collected data for the manuscript. JK Table 3 Medications approved for short-term prophylaxis of HAE attacks

Attenuated androgens
Danazol 200 mg PO TID × 5-7 d before procedure, and 4 d post-procedure ✓ Of note: androgens are contraindicated in: pregnancy, lactation, and growing children. They are also associated with severe side-effects. *Recommendation varies as dose yet to be fully investigated.

Attenuated androgens
Danazol ≦ 200 mg PO TID ✓ Of note: androgens are contraindicated in: pregnancy, lactation, and growing children. They are also associated with severe side-effects.
assisted in the manuscript overall design and journal selection. All authors read and approved the final manuscript.