A 2019 meta-analysis of three identified randomized controlled trials (RCTs; N= 179) was conducted to evaluate the effectiveness and tolerability of icatibant in the treatment of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema (AE). Included RCTs were determined to have low risk of bias, with similar patient baseline characteristics among all trials. While one trial administered icatibant 30 mg subcutaneously twice, with six hours between the two doses, as compared to only once for the other two RCTs, data from the three RCTs were combined to determine the elapsed time to complete resolution of edema. For the primary efficacy outcome of the time taken to achieve complete resolution of symptoms, defined as absence of symptoms of edema, patients treated with icatibant reached complete symptom resolution earlier than those in control group (mean difference -7.77 hours, 95% confidence interval [CI] -25.18 to 9.63 hours), although this difference was not found to be statistically significant (p= 0.38). For the secondary outcomes, the number of patients exhibiting complete resolution of symptoms after <4 hours was marginally increased in the icatibant group than the control group (relative risk [RR] 1.20; 95% CI 0.48 to 3.04; p= 0.70). Again, no significant difference was noted in the time to onset of symptom relief between the two groups. For the safety outcomes, there was no significant difference in adverse event incidence (RR 0.95, 95% CI 0.43 to 2.10) or drug‐related adverse event incidence (RR 1.29, 95% CI 0.58 to 2.87) between the two groups, respectively. In summary, the results of this meta-analysis indicate that the reduction in time to complete symptom resolution seen from icatibant administration in patients with ACEI-induced AE was not clinically significant. Additionally, further research is required to accurately evaluate the efficacy of icatibant therapy for ACEI‐induced AE before it can be recommended for use in clinical practice. Results of this meta-analysis are not necessarily specific to patients with acute severe ACEI-induced AE. [1]
A systematic review published in 2017 describes available evidence behind various therapies for ACEI-induced angioedema. It is noted that the inclusion of mild angioedema in the large randomized controlled trial evaluating icatibant makes results difficult to generalize to patients in the emergency department with more acute severe cases. Use of icatibant in these patients may be more cost-effective as icatibant may help prevent progression to intubation or tracheostomy and help shorten the course. Overall, data supporting use of icatibant, specifically in acute severe cases, are limited. [2]
A 2021 retrospective study investigated the indications and efficacy of off-label use of icatibant for the management of acute non-hereditary AE. A review of pharmacy records revealed 8 males and 10 females receiving icatibant (median age of 62 years), with 14 cases prescribed for drug-induced AE. Angiotensin-converting enzyme inhibitors were most commonly implicated (n= 7), while other culprit drugs included angiotensin receptor blockers (ARB; n= 3), tissue plasminogen activator (tPA; n= 3) and dipeptidyl peptidase-4 (DPP4) inhibitors (n= 1, in combination with ARB). Most patients (78% of cases) received initial icatibant administration in the emergency department. Severity of AE score was categorized as Type 1, lip and anterior tongue involvement; Type 2, floor of mouth, palatal or oropharyngeal edema; Type 3, laryngeal or hypopharyngeal edema. Based on these measurements, one patient with ACEI-induced AE had Type 1, one had Type 1/2, three had Type 2, and two had Type 3. The reported median resolution time was 9 h in patients presenting with ACEI-associated AE, which was shorter than the 18 h for all causes. Overall, individual cases of both ACEI- and non-ACEI-associated AE appeared to have favorable responses to icatibant. [3]
A 2018 systematic review evaluated the efficacy of icatibant, ecallantide, and tranexamic acid (TA) for ACEI-induced and idiopathic AE (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 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. [4]
As opposed to tranexamic acid, there are more studies for icatibant with polarizing results. One randomized comparison study between TA and conventional therapy consisting of steroids and antihistamines for ACEI-induced AE found significant benefits for icatibant therapy in reducing time to edema resolution and complete resolution. However, two placebo-controlled studies reported time to resolution of symptoms no better than placebo. Generalizability of these results, specifically to patients with severe ACEI-induced AE, may be limited. [5], [6]