Successful treatment of acute hereditary angioedema attacks with self-administered icatibant in patients with venous access problems

Abstract

Hereditary angioedema is a rare and potentially fatal autosomal dominant disorder characterised by unpredictable skin, gastrointestinal tract or respiratory tract oedema. Plasma-derived C1-esterase inhibitors are effective in the prophylaxis or treatment of hereditary angioedema type I and II attacks, but must be administered intravenously. This may be problematic in patients with venous access difficulties. Icatibant, a bradykinin B₂-receptor antagonist, is administered subcutaneously. In July 2008 icatibant received approval for healthcare professional-administered treatment of hereditary angioedema attacks in adults. In 2011 it received European Medicines Agency and US Food and Drug Administration licences for patient-administered treatment of hereditary angioedema attacks. Given these approvals, and with the appropriate training, icatibant could provide the opportunity for patients to self-administer treatment. This is one of the first long-term follow-up reports of patients with hereditary angioedema using self-administered icatibant. During follow-up, icatibant remained effective and patient satisfaction was high.

Background

Hereditary angioedema is a potentially fatal autosomal dominant disorder characterised by recurrent episodes of non-pruritic and non-pitting oedema, most commonly affecting the skin, gastrointestinal tract and respiratory tract.¹ Attack onset is unpredictable and episodes vary in frequency, severity and location.²

Hereditary angioedema affects between 1 in 10 000 and 1 in 50 000 people, with no clear ethnic variation.² For most patients, hereditary angioedema hinders their education and career choices and also impairs their daily activities to an extent comparable with severe asthma or Crohn's disease.³

The pathophysiology of hereditary angioedema has been linked to the deficiency (type I) or dysfunction (type II) of C1-INH, an important regulator of the contact-kinin system that controls bradykinin production.⁴ Plasma levels of bradykinin are higher in patients with hereditary angioedema than in normal controls and increase further during attacks.⁵

Icatibant is a selective bradykinin B₂-receptor antagonist that inhibits bradykinin-induced oedema formation.⁶ The results from three phase III studies demonstrated that subcutaneously administered icatibant was an effective and safe treatment option for acute attacks of hereditary angioedema types I and II.^{7 8} Icatibant is licensed in 39 countries for healthcare professional- or patient-administered symptomatic treatment of acute attacks of hereditary angioedema in adults aged 18 years or older with C1-INH deficiency and was approved for self-administration by the European Medicines Agency and the Food and Drug Administration in 2011.

C1-INH replacement therapy can prevent or treat a hereditary angioedema attack. This requires the administration of human plasma-derived C1-INH concentrate injected intravenously. Patients with frequent hereditary angioedema attacks need repeated intravenous injections and, if patients have poor venous access, central venous access devices may be required. We report on the successful treatment with subcutaneous icatibant of two patients with hereditary angioedema type I with frequent attacks and long-term venous access difficulties. Qualitative feedback assessing patient satisfaction is also provided. This is one of the first examples of long-term follow-up using self-administered subcutaneous icatibant.

Case presentation

Patient 1

A 70 kg Caucasian woman aged 35 years was diagnosed with hereditary angioedema type I at the age of 2 years. Typically, she suffered moderate-to-severe cutaneous attacks (of the face and hands), although severe abdominal attacks were occasionally reported. Her attack frequency fluctuated markedly. Before receiving subcutaneous icatibant in September 2009 she received on-demand treatment (but not prophylaxis) with intravenous C1-INH concentrate (1000 U). This was often distressing for her as her concomitant conditions (systemic lupus erythematosus, activated protein C resistance and hypothyreosis) had necessitated frequent intravenous injections and infusions since childhood, and it had sometimes taken three or more attempts to locate a suitable vein. This had culminated in a strong aversion to intravenous procedures.

Patient 2

A 67 kg Caucasian woman aged 53 years was diagnosed with hereditary angioedema type I during childhood. She suffered frequent abdominal, cutaneous (hands, feet and face) and mucosal swellings of moderate-to-severe intensity. Before receiving subcutaneous icatibant she received on-demand treatment (but not prophylaxis) with intravenous C1-INH concentrate (1000 U). Her veins were abnormally thin and had a tendency to burst during access procedures. This sometimes resulted in haematoma and made it extremely difficult to locate a suitable vein.

Both patients were identified as candidates for acute treatment with subcutaneous icatibant.

Self-administration training

Both patients received icatibant self-administration training during an in-clinic visit in September 2009. They received a patient diary and diary supplement which comprised the following:

• Information on how to recognise an acute attack, including prodromal symptoms

• An easy-to-use step-by-step self-administration guide with pictograms depicting how and when self-administered medication should be used

• A summary of how, when and what information to record during an acute hereditary angioedema attack.

Following training, both patients treated each attack with a single injection of subcutaneous icatibant (30 mg).

Outcome and follow-up

Treatment efficacy

Between September 2009 and October 2010, patient 1 suffered 10 attacks. Her attack frequency increased markedly between October 2010 and November 2011, with 78 attacks being reported. Over the same overall period (September 2009 to November 2011) patient 2 suffered 70 attacks, including a period in September 2010 when her attack frequency increased significantly to an average of one moderate-to-severe attack every 48 h.

Attack severity was measured using a 100 mm 3-symptom (skin swelling, skin pain and abdominal pain) composite visual analogue scale score.⁸ Icatibant treatment outcomes relating to patient-assessed initial symptom improvement and complete resolution of symptoms are shown in table 1. Both patients experienced injection site reactions comprising reddening, burning and itching. All the injection site reactions were mild and transient and resolved within 4 h without further medical intervention. No other adverse events were reported.

Table 1.

Treatment outcomes with icatibant

	Patient 1 (88 attacks)	Patient 2 (70 attacks)
Median time from treatment administration to first improvement of symptoms	30 min	2.5 h
Median time from treatment administration to complete resolution of symptoms	2.0 h	5.5 h
Adverse events	Mild reddening, burning and itching at the injection site Resolved without intervention within 4.0 h	Mild reddening, burning and itching at the injection site Resolved without intervention within 4.0 h

Median time to first improvement of symptoms and median time to complete resolution of symptoms were patient-assessed and measured using a 100 mm 3-symptom (skin swelling, skin pain, abdominal pain) visual analogue scale score.

Patient satisfaction

Patient satisfaction with icatibant treatment was assessed approximately 1 week after treatment by an 8-question 5-point questionnaire. Both patients reported a high level of satisfaction with subcutaneous icatibant. The responses are summarised in table 2.

Table 2 .

Patient satisfaction summary

Question	Patient 1 response	Patient 2 response
How sufficient was the self-administration training? (not at all sufficient, not sufficient, neither sufficient nor insufficient, sufficient, or very sufficient)	Very sufficient	Very sufficient
How convenient was it to carry icatibant around? (not at all convenient, not convenient, neither convenient nor inconvenient, convenient, or very convenient)	Very convenient	Very convenient
How difficult was it to prepare the injection site prior to self-injection? (very difficult, difficult, neither difficult nor easy, easy, or very easy)	Very easy	Very easy
How difficult was it to assemble and handle the syringe? (very difficult, difficult, neither difficult nor easy, easy, or very easy)	Very easy	Very easy
How stressful did you find the idea of self-injecting icatibant during an HAE attack? (very stressful, stressful, indifferent, not stressful, or not al all stressful)	Not at all stressful	Not at all stressful
How difficult was it to actually self-inject icatibant? (very difficult, difficult, neither difficult nor easy, easy, or very easy)	Very easy	Very easy
How satisfied were you with the way icatibant relieved your symptoms, compared to your usual treatment for an HAE attack? (not at all satisfied, not satisfied, neither satisfied nor unsatisfied, satisfied, or very satisfied)	Very satisfied	Very satisfied
To what degree did you prefer self-administration over administration in the clinic? (not at all preferable, not preferable, indifferent, preferable, or very preferable)	Indifferent (because of fear of needles)	Very preferable

Questions were graded on a 5-point scale (response options provided in parentheses). Responses were collated approximately 1 week after icatibant administration.

HAE, hereditary angioedema.

Discussion

The time to complete resolution of an acute attack is strongly influenced by the interval between symptom onset and institution of effective treatment.⁹ Self-treatment may help to minimise morbidity from such attacks.¹⁰

During the 2-year follow-up period the median time to first improvement of symptoms in our patients was 30 min and 2.5 h, respectively, and the median time to complete resolution of symptoms was 2.0 h and 5.5 h, respectively. In the non-laryngeal population (n=98) of the most recent phase III trial of icatibant, the For Angioedema Subcutaneous Treatment (FAST)-3 trial,⁸ the patient-assessed median time to initial symptom improvement was 0.8 h for icatibant compared with 3.5 h for placebo (p<0.001), and the median time to almost complete symptom relief was 8.0 h compared with 36.0 h for placebo (p=0.012).

In conclusion, we have demonstrated that, following appropriate in-clinic training, two patients with hereditary angioedema type I and poor venous access were successfully treated with self-administered subcutaneous icatibant over the follow-up period.

Learning points.

• Hereditary angioedema attacks are unpredictable; laryngeal attacks can be life-threatening and must be treated quickly.

• Plasma-derived C1-INH is effective in the treatment of hereditary angioedema but must be administered intravenously. This can cause problems for patients with venous access difficulties.

• Icatibant, a bradykinin B₂-receptor antagonist, can be subcutaneously self-administered by patients with hereditary angioedema type I and II following in-clinic training by a healthcare professional.

• Two patients with hereditary angioedema type I with poor venous access were successfully treated with icatibant. In these two patients, self-administered icatibant remained effective during the period of observation (>2 years). Both patients considered icatibant to be very convenient and very easy to use.

• It is important to recognise why alternative treatment should be considered in adult patients with hereditary angioedema type I and II with venous access difficulties who are receiving C1-INH.