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Three Part Question

In [an adult presenting with known or suspected hereditary angioedema] will [treatment with icatibant versus no intervention] [reduce time to resolution of angioedema]?

Clinical Scenario

An 18-year-old woman self-presents to the emergency department with a 12 h history of light headedness, nausea and vomiting, severe abdominal pain, tachycardia and hypotension. She has had previous similar episodes of abdominal pain associated with swellings of her hands and feet which have become more frequent of late. There is no urticaria or pruritus. She is on oral contraception medication started 4 months ago. She mentions her father has had similar episodes. As you secure intravenous access, you wonder if there is any value in administering a bradykinin receptor antagonist you've heard a lot about.

Search Strategy

The databases Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations (24 February 2011), Ovid MEDLINE(R) (1948 to February week 3 2011) and Ovid OLDMEDLINE(R) (1946 to 1965) were searched.

A search of the Cochrane database yielded no relevant articles.
The search strategy was as follows: exp Angioedemas, Hereditary/ OR Hereditary angiooedema.mp. AND exp Receptor, Bradykinin B2/ or exp Adrenergic beta-Antagonists/ or exp Bradykinin/ or exp Angioedemas, Hereditary/ or exp Receptors, Bradykinin/ LIMIT to English language.

Search Outcome

A total of 168 articles were identified of which 1 was relevant for inclusion.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Cicardi et al, 2010, USA	56 known adult HAE patients (type I and II) in the For Angioedema Subcutaneous Treatment (FAST-1) trial (USA). Eenrolled for treatment within 6 hours of onset with moderate to severe HAE attack and received either icatibant (27 patients) or placebo (29 patients) 74 known adult HAE patients (type I and II) for FAST-2 trial (Europe) for treatment within 6 hours of onset with moderate to severe HAE attack and received either icatibant (36 patients) 30gm once subcutaneously or oral tranexamic acid (38 patients) 3g daily for 2 days Exclusion criteria: <18 years of age, diagnosis of angioedema other than HAE, serious concomitant illness, pregnancy or lactation, received analgesia for current attack. Outcomes assessed by both patients and study investigators	Level 2b – data from two multi-centre prospective randomised double-blind phase 3 trials.	Primary – median time required for relief of the most severe symptom	FAST-1 trial Primary end point reached in 2.5hrs with icatibant vs 4.6hrs with placebo (P=0.14) FAST-2 trial Primary end point reached in 2.0hrs with icatibant vs 12.0hrs with tranexamic acid (P=<0.001)	Small samples with risk of underpower in FAST-1 trial Comparison with oral tranexamic acid may be flawed as it is not the ‘gold standard’ treatment for acute exacerbation of hereditary angioedema. This may be hampered by the centres being in different parts of the world where ‘gold standard’ treatment differs (eg. Europe vs USA) Of those initially screened, some of those were enrolled for each of the two trials but slightly less was assigned treatment. There was no mention of what happened or why those enrolled did not get randomised and no mention of drop-out rates of those who were assigned treatment. Measurements are subjective according to each patient and investigator. Both trials designed and funded by Jerini (German manufacturer of Icatibant seeking FDA approval). Assistance with medical writing by Carl V. Felton at Prime Healthcare supported by Jerini.
			Secondary – median time required for relief of all symptoms	FAST-1 Trial Secondary end point reached in 8.5hrs with icatibant vs 19.4hrs with placebo (P=0.08) FAST-2 Secondary end point reached in 10.0hrs with icatibant vs 51.0hrs with tranexamic acid (P=<0.001
			Rescue medication	In FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication (C1 esterase inhibitor concentrate, antiemetic agents or opiates) within the first 12hrs In FAST-2 study, 0 recipients of icatibant and 5 recipients of tranexamic acid needed treatment with rescue medication within the first 12hrs No icatibant-related serious adverse events were reported

Comment(s)

The well conducted prospective multicentre double blinded randomised phase 3 trial for an orphan drug showed promising results for the bradykinin receptor antagonist icatibant. The early use of rescue medication may have obscured the benefit of icatibant in the placebo FAST-1 trial leading to a type II error. Other case reports or case series were not included in the BestBET analysis as they were deemed to have a weaker level of evidence with risk of publication bias.

Editor Comment

HAE, Hereditary Angioedema

Clinical Bottom Line

There is promising evidence for the use of the bradykinin receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema (types I and II) over placebo or tranexamic acid for quicker onset of relief and resolution of clinically relevant and significant symptoms. Larger clinical trials currently underway will further clarify the efficacy of icatibant.

References

1. Cicardi M, Banerji A, Bracho F et al. Icatibant, a New Bradykinin-Receptor antagonist, in Hereditary Angioedema. New England Journal of Medicine 2010; 363: 532-541.