Abdominal attacks and treatment in hereditary angioedema with C1-inhibitor deficiency

Abstract

Background: Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients.

Methods: Information collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response.

Results: Forty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 × 10(9)/L) in 23% of attacks (mean ± SD: 15.1 ± 11.27 × 10(9)/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77 ± 33 versus 29 ± 65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients.

Conclusions: HAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea.

Trials registration: The data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.The following trials have been registered at http://www.clinicaltrials.gov: EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).

Figures

Figure 1

Additional symptom complexes associated with all attacks with any abdominal symptoms treated with subcutaneous ecallantide. All patients treated with 30 mg SC ecallantide in EDEMA2, EDEMA3, EDEMA4, and DX-88/19. Ext. = external, H/N = head/neck, Int. = internal, SC = subcutaneous. Percentages based on number of attacks.

Figure 2

Changes in pain during an HAE attack at 4 hours post-dosing with 30 mg SC ecallantide. A) McGill Pain Score in both the affective and sensory dimensions at baseline and 4 hours post-dosing with ecallantide. B) Visual Analog Scale pain intensity score at baseline and 4 hours post-dosing with ecallantide. Data from both analyses includes all patients treated with 30 mg SC ecallantide in EDEMA2 and DX-88/19 with any abdominal symptoms; analysis excludes attacks with missing data.

Figure 3

Treatment Outcome Score (TOS) in all HAE attacks with any abdominal symptoms treated with SC ecallantide. Includes all patients treated with 30 mg SC ecallantide in EDEMA2, EDEMA3, EDEMA4, and DX-88/19 (N = 521 attacks in 149 patients); analysis excludes attacks with missing data.