Treatment of Hereditary Angioedema: items that need to be addressed in practice parameter

Who is a suitable candidate for long-term prophylaxis with C-1 esterase inhibitor?

The individuals deemed candidates for long-term prophylaxis were identified in a previous literature review and those situations are listed in appendix 1[5]. Additionally, patients who fail, have adverse reactions to or are unable to tolerate androgen therapy should be considered for prophylaxis with C1-inh.

Currently, the medications used for prophylaxis can include androgens, antifibrinolytics, and C-1esterase inhibitor. It is likely that the short half life associated with the bradykinin receptor antagonist (icatabant) and kallikrein inhibitor (ecallantide) will limit they use as prophylactic therapy. The androgen, danazol, is the current medication of choice for prophylaxis due to its cost effectiveness and ease of administration. However, danazol has numerous side effects that may lead to the discontinuation of the drug and/or noncompliance in some patients.

Danazol, a synthetic derivative of ethisterone, is effective in decreasing the severity and frequency of attacks in patients with HAE [4]. However, due to the numerous side effects, which include weight gain, virilization, menstrual irregularities, depression, headache and abnormal liver function tests, it is often poorly tolerated. In a long-term study of 118 patients with HAE, 30 (25.4%) patients had to discontinue the drug due to these adverse effects [4]. Not only does danazol often lead to the intolerable side effects noted above it has also been shown to have a negative effect on lipid profiles. This unfavorable lipid profile may also exist in the setting of increased blood pressure in some patients on long-term danazol therapy and a subsequent increased risk of cardiac and vascular disease [8]. Another frequent adverse event is the increase risk of liver disease, including hepatic cell necrosis, cholestasis and even to the development of hepatocellular adenoma and hepatocellular carcinomas. The adverse effects are dose related with increased dosages being associated with increased adverse effects [4, 6, 8]. Appendix 2 demonstrates the adverse effects of androgen therapy [6].

In addition to androgen therapy, other medications have been investigated as prophylactic agents for HAE. Icatibant, a specific antagonist of bradykinin B2 receptors, is currently approved in Europe for the treatment of acute HAE attacks. However, it is not suitable as a candidate for prophylaxis due to its relatively short half-life of 1.2-1.5 hours with SQ administration [9].

Ecallantide is an inhibitor of the protein kallikrein and as of Nov 2009 has been approved for the use of acute attacks of HAE in the United States. However, similarly to icatibant, its use as a prophylactic agent is limited, secondary to its short half-life, which approximates 2 hours [4].

Antifibrinolytics, such as epsilon-aminocaproic acid, has also been used as a prophylactic agent for HAE. It is used to inhibit the formation of plasmin and fragments of the Hageman factor, leading to the inhibition of kallikrein and bradykinin production [10]. Anti-fibrinolytics have been used not only in patients with HAE but also to control bleeding after cardiac surgeries and in other hematologic diseases. Its major side effects include hypotension, cardiac arrhythmias, rhabdomyolysis, and generation of thrombi and associated risk of emboli. Because of the side effect profile, limited effectiveness and need to dose frequently physicians have not utilized this therapy to the same extend as androgens [11].

In comparison to these agents, plasma derived nano-filtered-C-1 esterase inhibitor, known as Cinryze, has a half-life of 36-48 hours when administered intravenously and could lead to significant protection for 72 hours or greater [12]. However, due to its expense, the need for IV administration and need to re-dose every 3-4 days suggest it should be used in those with severe disease or in those that their HAE has a significant impact on their quality of life.

The use of nano-filtered-C-1 esterase inhibitor (nf-C1-INH) for prophylaxis has been well received in the USA. Dosing twice per week seems to be important to limit break through attacks, but even with twice weekly dosing acute attacks often occur requiring additional doses of nf-C1-INH. From personal communications with physicians prescribing nf-C1-INH most are encouraging patients to self-treat or be infused by family members. Some have advocated the use of indwelling central catheters or ports; however, the benefits of a port need to be weighted against the adverse events associated with them. In our cohort the use of nf-C1-INH infused through a port has been complicated with thrombi.

Treating at the time of Prodromal Symptoms

Treatment at the time of prodromal symptoms, which may result in occasional over treatment, but which will still conserve concentrate and reduce cost when compared to prophylactic therapy, would decrease morbidity and mortality associated with HAE. Treatment before any swelling, onset of abdominal pain or throat swelling would improve quality of life of patients and reduce loss of productivity. Prior manuscripts by M Prematta and J Kemp, both published in 2009 in the Proceedings of Allergy and Asthma, demonstrated that prodromal symptoms are a sensitive predictor that an attack may occur in hours or days, but the exact specificity of prodromal symptoms for an attack is not known. The most common identifiable prodromal symptoms include unusual fatigue, rash on arms or legs and muscle aches. The retrospective study, noted above, conducted in 2009 by Prematta et al has already established that prodromal symptoms can be used as a sensitive measure to predict an acute attack [7].

This study, utilizing a 4-page survey, was conducted in order to investigate the reliability with which prodromal syndromes can be used to identify an imminent attack. The results, demonstrated in figure 1 indicate that 3 (6.5%) patients could predict the onset of symptoms 100% of the time; 23 (50.0%) answered the ability to predict acute attacks 75% of the time; 4 (8.7%) patients answered 50% of time; and 12 (26.1%) answered 25% of the time. Only 4 (8.7%) reported not being able to predict the onset of HAE attacks [7]. Among the patients that remembered the timing of past prodromes, 20 of 44 (45.5%) patients reported that the average time of the onset of a prodrome was less than 24 hours before an HAE attack. Meanwhile, 24 of 44 (54.5%) patients reported that, on average, the onset of prodromal symptoms developed greater than 24 hours before HAE symptoms initiate. Figure 2 demonstrates these data [7].

These data support that prodromal symptoms occur commonly before acute HAE attacks with 87.0% of patients having had a prodrome before their last HAE attack, and 95.7% of patients reported having had a prodromal symptom before at least one acute attack in the past [7]. These data have demonstrated that prodromal symptoms could indeed be a sensitive measure of predicting acute HAE attacks and could possibly be used to initiate therapy before the onset of an acute attack, thus reducing morbidity and possibly mortality. In addition, this could lead to a better quality of life and decreased anxiety for patients with HAE [7].

Who is fit to self-administer C1-inh at home?

The ability of patients to self-administer intravenous C1-inh at home would allow for greater flexibility, increased convenience and an increased quality of life, provided they were able to demonstrate the techniques noted in appendix 3 [13]. It also would decrease time to treatment if able to be administered by the patient for an acute attack, which should lead to a reduction of severity and duration of acute attacks. The benefit of self administration of prophylactic C1-inh would decrease cost and allow the patient significant flexibility to travel and administer therapy at the most suitable time. The current dosage recommended by the FDA for routine prophylaxis is 1000 units intravenously every 3-4 days and would require significant time and inconvenience to the patient if this had to be administered solely by a health professional.

Two studies have shown that select patients may benefit tremendously from self-administration of C1 esterase inhibitor and with self-treatment are able to improve quality of life [14]. These 9 patients were experiencing severe and frequent attacks of HAE. Their quality of life was assessed before and after 3 to 48 months of self-administered therapy. The QOL was assessed using the Dermatology Life Quality Index (DLQI) and the 36 Item Short form Survey questionnaires. The mean DLQI fell significantly from 12.6 +/- 4.65 to 2.7 +/- 1.38. The mean for the Short Form survey also improved significantly. No adverse events occurred during the 3-year period of intravenous self-administration [14].

In addition to affecting positively the patient's quality of life, one study also investigated whether self-administration was feasible and safe for the patients. Levi et al examined 31 patients using C1-inh as an "on demand" treatment and 12 patients using C1-inh prophylactically. Both groups were able to successfully administer the concentrate with a failure rate of less than 2%. During self administration attacks decreased from 4.0 to 0.3 per month in the group using prophylactic C1INH, but also self administration significantly decreased time to relief onset in those patients using it on demand for acute attacks [15]. This study not only confirmed the efficacy of self administered intravenous C1INH both as on demand treatment and as prophylactic therapy, but also demonstrated that patient administration is a viable and safe option. A manuscript published our manuscript further investigates self-infusion therapy and outlines the technique, quality assurance, training and reassessment of patients' prescribed self-infusion at home.

Unless peripheral access is limited, indwelling central catheters should be avoided due to the adverse events associated with port-o-catheters and similar devices. The most common complications of central lines include mechanical complications, infections and thrombotic events. Adverse events associated with indwelling central catheters are listed in appendix 4 [16].

Unfortunately, ecallantide has not been approved in the USA for home nor self-administration. The surveillance program required by the FDA for ecallantide limits its use to the clinic, and should be given by a health care provider who is capable of treating anaphylaxis, since anaphylaxis is a rare side effect of ecallantide. Dyax is hoping that the post-marketing surveillance program will demonstrate the safety of ecallantide allowing it to be self administered by the patient at home via the subcutaneous route.

Icatibant is presently repeating phase 3 studies in the USA and is anticipating approval for self-administration by the subcutaneous route. The drug is stable at room temperature and this combined with approval of icatibant for self subcutaneous injection will provide significant flexibility for patients with HAE to travel, camp, hike and do other recreational activities. It is projected that icatibant will be approved in the USA in 2012.

Appendix 1

Modified from Craig et al, Annals of Allergy asthma and Immunology, 2009 [5]

Candidates for long-term prophylaxis. Individuals who suffer from the listed consequences of their HAE and hence have a diminished quality of life are candidates for prophylaxis with C1-inh.

Appendix 2

Modified from Craig et al, Proceeding of Allergy and Asthma, 2007

Adverse Effects of Danazol [6]

Appendix 3

Adapted from Nentwich, Intravenous Therapy, 1990 [13]

Procedure for Self-Infusing of C-1 Esterase inhibitor

Procedure for self-administration of IV medications. The necessary procedure that must be demonstrated in order to be able to successfully self-administer IV medications is listed. Careful selection of the proper patient is essential in order to ensure compliance.

Appendix 4

Modified from McGee et al NEJM, 2003 [16]

Adverse events associated with indwelling central catheters. Indwelling catheters are associated with many significant adverse events, some which can be life threatening.

**Depends on site of insertion