Washington University Emergency Medicine Journal Club- February 2025
Vignette
You’re working one afternoon in TCC when you get a page that a triage patient is coming to room 2L. You enter the room just as a male patient substantial swelling to his upper and lower lip is being wheeled in. The patient informs you that the swelling began about two hours prior to arrival, was initially getting progressively worse, but now seems to have stabilized. He is handling his secretions well and is speaking full sentences. There is no evidence of swelling past the lips and no stridor. He denies any prior history of facial swelling, denies any new medications or allergen exposures, and has been taking lisinopril for hypertension for the past six months.
You and your attending discuss treatment options for bradykinin-mediated (ACE inhibitor) angioedema, including steroids and antihistamines. You consider alternative treatments such as TXA and FFP but given the stability of your patient elect to hold off on these. When you check on the patient 30 minutes later, he has since developed swelling to his tongue. He is having more difficulty, is not handling his secretions, and has difficulty speaking. You elect to nasotracheally intubate the patient and begin preparing your equipment. You again wonder about other pharmacologic treatments you should be administering, but securing his airway takes precedent.
Having secured the patient’s airway and admitted him to the MICU, you again wonder whether there was anything else you could have done to prevent the need for intubation in this case. You remember seeing previous Washington University EM Journal Club reviews on TXA in other conditions (GI hemorrhage and trauma), but don’t remember seeing its use evaluated in angioedema, nor any evaluation of FFP, ecallantide, or icatibant. You decide to search the literature to see what you can find…
PICO Question
Population: Adults patients presenting to the ED with ACE inhibitor induced
angioedema
Intervention: Tranexamic acid (TXA), fresh frozen plasma (FFP), icatibant,
ecallantide, C1 esterase inhibitor
Comparison: Standard of care
Outcome: Need for airway intervention, ICU admission, ED length of stay, hospital
length of stay, mortality
Search Strategy
Article 1: Hassen GW, Kalantari H, Parraga M, Chirurgi R, Meletiche C, Chan C, Ciarlo J, Gazi F, Lobaito C, Tadayon S, Yemane S, Velez C. Fresh frozen plasma for progressive and refractory angiotensin-converting enzyme inhibitor-induced angioedema. J Emerg Med. 2013 Apr;44(4):764-72. doi: 10.1016/j.jemermed.2012.07.055. Epub 2012 Oct 28. PMID: 23114109. Answer Key.
Article 2: Lawlor CM, Ananth A, Barton BM, Flowers TC, McCoul ED.
Pharmacotherapy for Angiotensin-Converting Enzyme Inhibitor-Induced
Angioedema: A Systematic Review. Otolaryngol Head Neck Surg. 2018
Feb;158(2):232-239. Answer Key.
Article 3: Hasara S, Wilson K, Amatea J, Anderson J. Tranexamic Acid for the
Emergency Treatment of Angiotensin-Converting Enzyme Inhibitor-Induced
Angioedema. Cureus. 2021 Sep 20;13(9):e18116. Answer Key.
Article 4: Lindauer KE, Lo BM, Weingart GS, Karpov MV, Gartman GH, Neubauer LE,
Kaplan MC. Tranexamic acid for angiotensin converting enzyme inhibitor induced
angioedema: A retrospective multicenter study. Am J Emerg Med. 2024
May;79:33-37. Answer Key.
Bottom Line
While steroids, antihistamines, and epinephrine are often administered to patients presenting to the emergency department (ED) with signs and symptoms of ACE inhibitor-induced angioedema (ACE-IIA), there is no evidence that these interventions have any effect on disease progression. Rather than causing histamine-mediated allergic reactions, ACE inhibitors impede the degradation of bradykinin (see figure) whose accumulation leads to increased vascular permeability. As a result, several treatments for ACE-IIA aimed at reducing bradykinin production (ecallantide, tranexamic acid), breaking down bradykinin (fresh frozen plasma), or preventing bradykinin from binding with its receptors (icatibant) have been proposed in the management of ACE-IIA.
Tranexamic acid (TXA) is an antifibrinolytic agent which prevents the breakdown of plasminogen to plasmin, a key step in the pathway to bradykinin formation (Wang 2021). While this proposed mechanism for TXA in the management of ACE-IIA is reasonable, little evidence exists either supporting or refuting any benefit. A single-center case series of 16 patients treated in the ED with TXA for ACE-IAA was published in 2021 (Hasara 2021). In this series, no adverse events were documented following the administration of TXA. Fourteen patients (87%; 95% CI 62% to 98%) experienced partial or complete resolution of symptoms with only three patients admitted to the ICU for a higher level of care. The remaining patients were admitted to the medical floor for observation or discharged home and the overall average ED LOS was 3.5 hours. Two patients required intubation prior to TXA administration while intubation was avoided in the remaining fourteen. While limited given the lack of a control group, this series does suggest that TXA is safe in the management of ACE-IIA, and may be effective.
A slightly more robust multicenter, retrospective cohort study was conducted using the electronic medical records of a 17-ED health system in Virginia between January 1, 2018 and August 31, 2021 (Lindauer 2024). This study sought to compare outcomes between 73 patients with ACE-IIA who received TXA (treatment group) and 189 patients who did not (control group). While these authors found that patients in the treatment group were more likely to be admitted to the ICU compared to the control group (OR = 2.59, 95% CI: 1.23–5.43 ) and that median length of stay was significantly longer in the treatment group (median 40.28 vs 21.08 hours, p < 0.0001), it should be noted that there were significant differences in baseline prognosis between these groups. Patients in the treatment group were much less likely to have Ishoo stage I edema (facial rash, facial edema, lip edema; 34.3% vs. 64.6%) and far more likely to have stage III edema, in which the larynx is involved (42.5% vs. 26.5%). It is therefore not surprising that patients in the treatment group fared worse overall; the authors did not attempt to use statistical tools (e.g. propensity matching or logistic regression) to control for these differences.
Fresh frozen plasm (FFP) contains kininase II, which breaks down bradykinin, thus providing a theoretical benefit in ACE-IIA (Stewart 2012). In a case series of 7 patients with “progressive and refractory” ACE-IA, all of whom received IV antihistamines and IV steroids and all but one of whom received IM epinephrine, patients were given IV FFP (1 or 2 units) (Hassen 2013). All 7 patients had improved symptoms and noted that progression of swelling stopped within 2 to 4 hours of administration of FFP. It is notable that all patients were treated with medications typically used in anaphylaxis, none of which has ever shown benefit in ACE-IIA. Additionally, most patients with ACE-IIA improve spontaneously, with only around 1% requiring intubation for edema (Weisman 2020) and there was no control group to provide comparison in outcomes. It is unclear based on this small case series whether these FFP provided any benefit, as these patients would likely have improved without it. Despite this limitation, FFP is safe and may provide some benefit in ACE-IIA.
A 2018 systematic review of clinical evidence related to pharmacologic treatment of acute onset ACE-IIA identified five studies comprising 218 cases (Lawlor 2018). Two studies, one a prospective case-control series and one a randomized controlled trial (RCT), found a shorter time to symptom relief and decreased edema with icatibant when compared with control. A prospective case-control series comparing outcomes in 10 patients receiving C1 esterase-inhibitor with 47 historical controls found a shorter mean time to complete symptom relief with C1 esterase-inhibitor administration, Two RCTs evaluating ecallantide found no significant improvement in outcomes. While the review found the most promise with subcutaneous icatibant in management of ACE-IIA, a larger RCT (Sinert 2017) and a subsequent meta-analysis of three RCTs (Jeon 2019) both demonstrated no improvement in time to resolution of symptoms.
Given the limited data on this topic, it is difficult to make firm recommendations regarding pharmacologic management of ACE-IIA. TXA and FFP are both relatively inexpensive and quite safe, and are reasonable options in cases at high risk of progression to airway compromise. Given the rather high cost of icatibant and subsequent evidence of inefficacy, its use seems far less reasonable. Early intubation in cases of airway compromise seems the safest route in these patients given the lack of clear evidence for pharmacologic interventions.