ACE Inhibitor-Induced Angioedema

• 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

Fresh Frozen Plasma

(FFP)

Icatibant

Tranexamic Acid (TXA)

Dose

2-4 units

30 mg

1000 mg

Administration

Intravenous

Subcutaneous

Intravenous

PK/PD

Onset: ~ 2 hours

Onset: 2 hours

Duration: 6 hours

Onset: ~ 2 hours

Adverse

Effects

Hypervolemia, TRALI,

thrombosis,

hyperfibrinolysis, infection

Injection site reactions, LFT

elevations, dizziness

Abdominal pain, headache,

musculoskeletal

pain/spasms

Drug

Interactions

and warnings

Calcium administration

within the same line (may

produce precipitants)

None

Contraindicated in patients

with SAH or active

intravascular clotting

Compatibility

N/A

N/A

Compatible with NS, D5W, or

LR

Author, year

Design/ sample

size

Intervention & Comparison

Outcome

Baş,

2015

RCT

(n = 27)

SubQ Icatibant 30 mg vs. prednisolone +

clemastine

Time 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,

2017

RCT

(n = 33)

SubQ Icatibant 30 mg vs placebo

Time-to-resolution (27.2 hrs vs 35.3 hrs) and

amount of swelling over time were similar

in placebo and icatibant treatment

groups.

Sinert,

2017

RCT

(n = 121)

SubQ Icatibant 30 mg vs placebo

There were no difference time to meeting

discharge criteria between groups (4 hrs

vs 4 hrs).

Karim,

2002

Case Report

(n = 1)

4 units FFP following chlorpheniramine,

hydrocortisone, and epinephrine

Dramatic improvement within 2 hours

following FFP administration allowing for

(Christian Leppert & [email protected]

• 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.

• Lexicomp Online, Hudson, Ohio: UpToDate, Inc.; 2021; April 22, 2021. Available from:

http://online.lexi.com/lco/action/home

• Brown T, Gonzalez J, Monteleone C. Angiotensin-converting enzyme inhibitor-induced angioedema: a review

of the literature. J Clin Hypertens. 2017;19:1377-1382.

• Campo P, Fernandez TD, Canto G, et al. Angioedema induced by angiotensin-converting enzyme inhibitors.

Curr Opin Allergy Clin Immunol. 2013;13:337-344.

• Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor-associated

angioedema. Hypertension. 2008;51:141-147.

• Straka BT, Ramirez CE, Byrd JB, Stone E, Woodard-Grice A, Nian H, Yu C, Banerji A, Brown NJ. Effect of

bradykinin receptor antagonism on ACE inhibitor-associated angioedema. J Allergy Clin Immunol. 2017

Jul;140(1):242-248.e2. doi: 10.1016/j.jaci.2016.09.051. Epub 2016 Nov 29. PMID: 27913306; PMCID: PMC5705179.

• Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J, Schranz J, Baptista J, Kimura A, Nothaft W;

CAMEO study group. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced

Upper Airway Angioedema. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1402-1409.e3. doi:

• 1016/j.jaip.2017.03.003. Epub 2017 May 25. PMID: 28552382.
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Med. 2015;372:418-425.

• Karim MY, Masood A. Fresh-frozen plasma as a treatment for life-threatening ACE-inhibitor angioedema. J

Allergy Clin Immunol. 2002;109(2):370-1.

• Warrier MR, Copilevitz CA, Dykewicz MS, et al. Fresh frozen plasma in the treatment of resistant angiotensin-

converting enzyme inhibitor angioedema. Ann Allergy Asthma Immunol. 2004;92:573-575

• 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

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Epub 2012 Oct 28. PMID: 23114109.

• Bolton MR, Dooley-Hash SL. Angiotensin-converting enzyme inhibitor angioedema. J Emerg Med.

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• Wang K, Geiger H, McMahon A. Tranexamic acid for ACE inhibitor induced angioedema – A case report. Am

J Emerg Med. 2020;S0735-6757(20)30923-2.

• Beauchêne C, Martins-Héricher J, Denis D, et al. Tranexamic acid as first-line emergency treatment for

episodes of bradykinin-mediated angioedema induced by ACE inhibitors. Rev Med Interne. 2018;39(10):772-

• Martinez Manzano JM, Lo KB, Patarroyo-Aponte G, Azmaiparashvili Z. The use of intravenous tranexamic acid

for patients with angiotensin-converting enzyme inhibitor-induced angioedema: A case series. Ann Allergy

Asthma Immunol. 2021 Feb 14:S1081-1206(21)00129-0. doi: 10.1016/j.anai.2021.02.011. Epub ahead of print.

PMID: 33592284.