A 2018 systematic review evaluated the efficacy of icatibant, ecallantide, and tranexamic acid (TA) for angiotensin-converting enzyme inhibitor (ACEi) induced and idiopathic angioedema (non-hereditary AE). This systematic review included 61 studies with 38 describing treatment in the acute setting, although the majority of evidence was case reports. There were no direct comparisons between icatibant, ecallantide, or TA. For ACEi-induced AE, two randomized controlled studies of ecallantide do not suggest a significant benefit based on response rate versus placebo (10%-16% response rate). Icatibant may have similar efficacy to C1NH and fresh frozen plasma (FFP) with an average response time of less than 2 hours, but the majority of included studies were not controlled and of lower quality. Data for TA in ACEi-induced AE was not available. [1]
For idiopathic AE, a single study on TA use observed a 54% response rate (13 to 24 patients). Data for icatibant and ecallantide are limited to response times. Icatibant reported an initial response time of 20 to 45 minutes. For complete response, icatibant reported a range between 45 minutes to 26.6 hours while ecallantide complete response was <1 hour. However, only one case report was available for ecallantide while icatibant presented various case reports and two cohorts. Prophylactic treatment of idiopathic AE using TA found improvement of symptoms in 73% of patients, based on six studies, and 16% achieved complete absence of symptoms. Prophylaxis with icatibant and ecallantide was unexplored. Based on these results, the authors prefer icatibant over ecallantide for ACEi-induced or idiopathic AE while TA may be used as a prophylaxis agent against idiopathic AE. However, with the lack of direct comparative data, the optimal agent of the three remains uncertain. [1]
Although direct comparative data is not provided, a 2016 review discusses management strategies for angioedema due to ACEi therapy, including use of ecallantide and icatibant. While ecallantide has been studied in ACEi-induced angioedema patients, there is a lack of data demonstrating significant benefits. Both a pilot study and a larger multicenter trial showed no statistically significant differences in resolution times between the ecallantide and placebo groups, leading to the conclusion that ecallantide is not currently recommended for ACEi-induced angioedema. Conversely, the authors emphasize that icatibant has shown promise in the management of ACEi-induced angioedema. In a phase 2 trial (Table 1), icatibant was associated with faster symptom resolution (median 8 hours vs. 27.1 hours with placebo) and quicker onset of relief (2 hours vs. 11.7 hours), with a higher percentage of complete resolution in the icatibant group. However, concerns remain about its cost-effectiveness and its efficacy in more severe cases or in non-white populations. Despite these concerns, it is suggested that icatibant may potentially be considered for off-label use in life-threatening orolaryngeal ACEi-induced angioedema. [2]
Another 2016 review article examined various pharmacologic interventions for ACEi-induced angioedema, including icatibant and ecallantide. Although the underlying mechanism of ACEI-induced angioedema is not fully understood, it is believed to be related to excessive bradykinin production, which these interventions aim to reduce or antagonize its activity. Currently, both ecallantide and icatibant are Food and Drug Administration (FDA) approved for the treatment of hereditary angioedema, but lack formal approval for ACEI-induced angioedema. However, icatibant has demonstrated positive effects in several case reports where symptom resolution had occurred rapidly (median, 30 minutes; interquartile range [IQR] 27.5 to 70 minutes) with complete resolution occurring at 5 hours (IQR, 4 to 7 hours). Conversely, a small placebo-controlled Phase II study assessing the safety and efficacy of ecallantide in patients with moderate to severe ACEI-induced angioedema found no significant difference in the primary outcome, defined as number of patients meeting discharge criteria (ecallantide vs. placebo: 31% vs. 21%; 95% confidence interval [CI] -14% to 34%). Nevertheless, the study revealed that ecallantide was well tolerated and may increase the proportion of patients responding to nonconventional therapies. Overall, the authors concluded that icatibant has shown benefits in managing symptoms of ACEI-induced angioedema while trials of ecallantide have shown no advantages over conventional therapies and therefore should be avoided. Of note, there were no direct comparative studies evaluating the safety and efficacy of ecallantide versus icatibant for ACEi-induced angioedema. [3]