Introduction

  • The overall prevalence of ACE inhibitor angioedema is low (~0.2-0.7%), however it makes up the majority of visits to the ED for angioedema
  • ACE inhibitor angioedema is caused by the buildup of bradykinin which leads to increased vascular permeability and the release of substance P resulting in vasodilation and fluid extravasation into tissues
  • ACE inhibitor angioedema can occur at any time, with the majority of cases occurring within the first month of therapy.
  • Risk factors for ACE inhibitor angioedema includes female sex, African American race, chronic heart failure, coronary artery disease, history of smoking, and concomitant use of dipeptidyl peptidase 4 (DPP4) inhibitors

Clinical Detail

 Fresh Frozen Plasma (FFP)IcatibantTranexamic Acid (TXA)
Dose2-4 units30 mg1000 mg
AdministrationIntravenousSubcutaneousIntravenous
PK/PDOnset: ~ 2 hoursOnset: 2 hours
Duration: 6 hours		Onset: ~ 2 hours
Adverse EffectsHypervolemia, TRALI, thrombosis, hyperfibrinolysis, infectionInjection site reactions, LFT elevations, dizzinessAbdominal pain, headache, musculoskeletal pain/spasms
Drug Interactions and warningsCalcium administration within the same line (may produce precipitants)NoneContraindicated in patients with SAH or active intravascular clotting
CompatibilityN/AN/ACompatible with NS, D5W, or LR
CommentsTakes ~ 30-45 minutes to thaw & process once orderedCosts ~ $4,500 per 30 mg syringe (AWP)Available in most emergency departments. Inject 1000 mg TXA in 100 mL of diluent

Evidence

Author, yearDesign/ sample sizeIntervention & ComparisonOutcome
Baş, 2015RCT (n = 27)SubQ Icatibant 30 mg vs. prednisolone + clemastineTime to complete symptom resolution: 8 hours vs. 27.1 hours (P=0.002).

Time to onset of symptom relief: 2 hours vs. 11.7 hours (P=0.03).

All patients experienced complete resolution of edema.
Straka, 2017RCT (n = 33)SubQ Icatibant 30 mg vs placeboTime-to-resolution (27.2 hrs vs 35.3 hrs) and amount of swelling over time were similar in placebo and icatibant treatment groups.
Sinert, 2017RCT (n = 121)SubQ Icatibant 30 mg vs placeboThere were no difference time to meeting discharge criteria between groups (4 hrs vs 4 hrs).
Karim, 2002Case Report (n = 1)4 units FFP following chlorpheniramine, hydrocortisone, and epinephrineDramatic improvement within 2 hours following FFP administration allowing for extubation.
Warrier, 2004Case Report (n = 1)2 units FFP following antihistamine, corticosteroid, epinephrine, antileukotrienes, cyclosporine, and IVIG (all without improvement)Complete resolution of symptoms within 2-4 hours following FFP administration.
Bolton, 2012Case Report (n = 1)2 units FFP following antihistamine and corticosteroid administrationNear complete resolution of symptoms within 2 hours following FFP administration.
Hassen, 2013Case series (n = 7)2 units FFP following antihistamine and corticosteroid administrationTemporal association between the administration of FFP and improvement in angioedema in 7 cases of presumed ACEI-induced angioedema that were refractory to histamine-related anaphylaxis.
Stewart, 2013Case Report (n = 2)2 units FFP administeredAdministration of FFP resulted in rapid resolution of symptoms in both patients.
Beauchêne, 2018Case Series (n = 33)Tranexamic Acid
IV: 24 patients (73%)
PO: 8 patients (24%)
Unknown: 1 patient (3%)

Dosage: 500 mg – 4 grams (55% received 1 g)		81.8% patients achieved significant improvement following TXA administration alone.

39.3% patients experienced symptom improvement within 1 hr of TXA administration.
Wang, 2020Case Report (n = 1)TXA 1000 mg IVPB over 10 minutes administered following diphenhydramine, famotidine, methylprednisolone, and epinephrineImprovement in speech observed within 30 minutes of TXA administration with complete resolution of symptoms at 2 hrs.

Patient discharged 2.5 hours following presentation to ED.
Manzano, 2021Case series (n = 11)TXA 1000 mg IVThe median length of stay in the hospital was 1.2 days (0.4-18.2 days).

No noted adverse effects related to medication administration of TXA.

Conclusions

  • Many cases of ACE inhibitor angioedema will resolve on their own with the cessation of the offending agent.
  • More studies are needed to evaluate the use of investigational therapies including tranexamic acid and FFP.
  • In severe cases of ACE inhibitor angioedema, it is reasonable to consider using tranexamic acid or FFP if icatibant is unavailable after weighing the risks versus benefits.

References

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