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We thank Javaud et al1Javaud N. Fain O. Adnet F. Icatibant for ACE-inhibitor angioedema, an opportunity to treat the patients?.J Allergy Clin Immunol Pract. 2017; 5: 1803Abstract Full Text Full Text PDF Scopus (3) Google Scholar for their insightful comments on our phase III study2Sinert R. Levy P. Bernstein J.A. Body R. Sivilotti M.L.A. Moellman J. et al.Randomized trial of icatibant for angiotensin-converting enzyme inhibitor-induced upper airway angioedema.J Allergy Clin Immunol Pract. 2017; 5: 1402-1409Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar and appreciate the opportunity to respond. Javaud et al describe positive findings from their group's observational study published in 2015,3Javaud N. Achamlal J. Reuter P.G. Lapostolle F. Lekouara A. Youssef M. et al.Angioedema related to angiotensin-converting enzyme inhibitors: attack severity, treatment, and hospital admission in a prospective multicenter study.Medicine (Baltimore). 2015; 94: e1939Crossref PubMed Scopus (25) Google Scholar in which 62 patients with angiotensin-converting enzyme (ACE) inhibitor–induced angioedema attacks visiting 1 of 4 emergency departments in Paris were diagnosed with the aid of a centralized call center linking emergency physicians with experts in diagnosing bradykinin-mediated angioedema. They reported a significantly shorter median time from drug administration to onset of symptom relief in patients receiving icatibant or plasma-derived C1 inhibitor versus no specific treatment (0.5 vs 3.9 hours, respectively; P < .0001).3Javaud N. Achamlal J. Reuter P.G. Lapostolle F. Lekouara A. Youssef M. et al.Angioedema related to angiotensin-converting enzyme inhibitors: attack severity, treatment, and hospital admission in a prospective multicenter study.Medicine (Baltimore). 2015; 94: e1939Crossref PubMed Scopus (25) Google Scholar These findings are encouraging but should be interpreted within the context of clear study design limitations, including the absence of a control group and the likelihood of multiple confounders between patients receiving treatment and those not receiving treatment. Moreover, and in direct contrast to our study, Javaud et al did not include a standardized measure for patient reassessment and there is likely to have been inherent variability in subjective determination of symptom relief. The fact that more than half of the 27 patients admitted to the hospital were discharged within 24 hours, only 2 were admitted to the intensive care unit, and just 1 was intubated also raises questions about the purported severity of cases included in their cohort. With regard to Dr. Javaud's suggestion of a lack of diagnostic expertise in our phase III study, we appreciate the potential benefits of a centralized call center providing expert assistance with diagnosing ACE inhibitor–induced angioedema, particularly in a country like France where emergency medicine is not a recognized specialty and dedicated residency training does not exist. However, nearly all patients in our study were enrolled at academic medical centers in the United States, United Kingdom, and Canada, where a rigorous board certification process for emergency physicians exists, ensuring that clinicians involved in our study were adequately qualified to recognize the presence of this condition without such support. It is, of course, possible that our study population inadvertently included some patients with histamine-induced angioedema (as may have occurred in Dr. Javaud's observational study). However, this is an underlying limitation of a pragmatic study design, evaluating the efficacy of icatibant in a real-world practice setting in which the use of traditional antiallergy medications is commonplace. Given that our trial had strict inclusion and exclusion criteria, required senior medical review before patient enrollment, and used a validated clinical rating scale for assessing symptom severity, we feel that possible misclassification had limited impact on our outcomes. We do acknowledge that our stringent inclusion and exclusion criteria may have impacted enrollment but, as Javaud et al surely know, it is unrealistic to compare recruitment rates in a phase III prospective, randomized, controlled trial that required written informed consent within 12 hours of symptom onset before administration of study drug with an observational study, where all comers were eligible. In summary, our phase III study did not demonstrate the efficacy of icatibant in the treatment of ACE inhibitor–induced angioedema. Future research efforts (such as the type of clinical study suggested by Dr. Javaud) may shed further light on the possible utility of icatibant for this condition. Icatibant for ACE-inhibitor angioedema, an opportunity to treat the patients?The Journal of Allergy and Clinical Immunology: In PracticeVol. 5Issue 6PreviewIcatibant was no more effective than placebo in treating at least moderately severe ACE-inhibitor (ACE-I)-induced angioedema in a phase III trial as reported by Sinert et al.1 However, in this study, more than 90% of the subjects received corticosteroids, antihistamines, or epinephrine before the study drug, and the time to onset of symptom relief was 2 hours in the placebo group. This rapidly favorable outcome of patients in the placebo group (who received antihistamines and/or corticosteroids in a large majority of cases), contrary to all descriptions of bradykinin angioedema, may lead to the mistaken inclusion of histamine-mediated angioedema and explain the absence of a difference. Full-Text PDF

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