Effectiveness of ecallantide in treating angiotensin-converting enzyme inhibitor–induced angioedema in the emergency department

Abstract

Background

Angiotensin-converting enzyme inhibitor–induced angioedema (ACEI-AE) is mediated by bradykinin. There remains an unmet treatment need because these patients, when presenting to the emergency department (ED), do not respond to conventional therapies, such as antihistamines and corticosteroids.

Objective

To estimate the treatment effect of ecallantide, a recombinant plasma kallikrein inhibitor, in ED patients with ACEI-AE in whom conventional therapy fails.

Methods

This was a triple-blind (patient, physician, and statistician), randomized, controlled, phase 2 study to estimate the magnitude of safety and efficacy signals for designing a definitive phase 3 trial comparing conventional therapy with ecallantide to conventional therapy with placebo. Patients were enrolled from April 1, 2010, through January 31, 2013. The primary efficacy study end point was achieving discharge criteria from the ED within 4 hours after initiating study-related treatment.

Results

Discharge criteria from the ED was met in 4 hours or less for 8 (31%) of 26 patients receiving ecallantide vs 5 of (21%) 24 patients receiving placebo (difference in proportions, 10%; 95% confidence interval, −14% to 34%). Ecallantide was well tolerated in both groups.

Conclusion

The results from this preliminary study reveal that ecallantide is safe to use and may increase the proportion of patients who meet early discharge criteria by approximately10%. A larger phase 3 study is necessary to confirm the efficacy and evaluate the cost-effectiveness of ecallantide use for ACEI-AE in the ED setting.

Trial Registration

clinicaltrials.gov Identifier: NCT01036659

Introduction

Angioedema secondary to angioedema-converting enzyme inhibitors (ACEIs) has become the most common cause of angioedema in patients presenting to the emergency department (ED).[1], [2], [3] The incidence of ACEI–induced angioedema (ACEI-AE) continues to increase in the United States because of the increased use of ACEIs for a number of chronic medical conditions. In 2008, ACEIs were the fourth most commonly prescribed medication, accounting for approximately 160 million prescriptions written annually.⁴ The prevalence of ACEI-AE is estimated at 0.1% to 4%, with most patients being older than 65 years and African American.[5], [6], [7] Retrospective medical record review studies have reported that approximately 30% to 40% of angioedema cases seen in the ED can be attributed to ACEIs.[8], [9] The annual rate of visits to the ED for ACEI-AE is estimated at 0.7 per 100,000 ED visits.⁸ Only slightly more than half of these patients are discharged home from the ED.⁸

The pathogenesis of ACEI-AE involves accumulation of excess bradykinin similar to hereditary angioedema (HAE). In contrast to patients with HAE who have SERPING1 gene mutations on chromosome 11 that lead to functionally abnormal C1 esterase inhibitor (C1INH) levels,[10], [11], [12], [13] patients with ACEI-AE produce more bradykinin because of the inhibition of C1INH. C1INH is a potent regulator of plasma kallikrein, which is important for regulating the conversion of high-molecular-weight kininogen to bradykinin.¹⁴ The 3- to 4.5-fold higher incidence of ACEI-AE in African American compared with white individuals is believed to be due to genomic and plasma variability of proteins interfering with bradykinin catabolism.[15], [16], [17], [18], [19], [20] Not surprisingly, patients with ACEI-AE characteristically do not respond to conventional therapy, including antihistamines or corticosteroids.[7], [21] Bradykinin-targeted drugs, available for treatment of HAE due to C1INH deficiency, could be effective in ACEI-AE. Ecallantide is a novel kallikrein inhibitor approved in the United States for the treatment of HAE in persons older than 16 years. Ecallantide works by preventing the breakdown of high-molecular-weight kininogen to bradykinin.²²

To determine whether ecallantide would also be a safe and effective treatment for acute ACEI-AE, we conducted a randomized, controlled, phase 2 study in ED patients with ACEI-AE in whom conventional therapy with histamine₁ (H₁)–antihistamines and corticosteroids failed. The purpose of the study was to estimate the magnitude of the efficacy and safety signals so that a phase 3 study could be appropriately designed.