ACE Inhibitor-Induced Angioedema: a Review
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Purpose of Review
This study aims to examine current knowledge on the occurrence, pathophysiology, and treatment of angioedema among patients who receive angiotensin-converting enzyme inhibitors.
Angiotensin-converting enzyme inhibitors (ACE-I), a medication class used by an estimated 40 million people worldwide, are associated with angioedema that occurs with incidence ranging from 0.1 to 0.7%. The widespread use of ACE-I resulted in one third of all emergency department visits for angioedema. Angioedema occurs more frequently in African Americans, smokers, women, older individuals, and those with a history of drug rash, seasonal allergies, and use of immunosuppressive therapy. The pathophysiology of ACE-I-induced angioedema involves inhibition of bradykinin and substance P degradation by ACE (kininase II) leading to vasodilator and plasma extravasation. Treatment modalities include antihistamines, steroids, and epinephrine, as well as endotracheal intubation in cases of airway compromise. Patients with a history of ACE-I-induced angioedema should not be re-challenged with this class of agents, as there is a relatively high risk of recurrence.
ACE-I are frequently used therapeutic agents that are associated with angioedema. Their use should be avoided in high-risk individuals and early diagnosis, tracheal intubation in cases of airway compromise, and absolute avoidance of re-challenge are important.
KeywordsAngiotensin II Angioedema Angiotensin-converting enzyme inhibitors Hypertension Bradykinin
Compliance with Ethical Standards
Conflict of Interest
The authors declare no conflict of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent
No human or animal data were collected in writing this review.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 5.IQVIA Institute for Human Data Science. Medicines use and spending in the U.S. [Internet]. 2017 May. Available from: https://www.iqvia.com/institute/reports/medicines-use-and-spending-in-the-us-a-review-of-2016.
- 13.• Byrd JB, Touzin K, Sile S, Gainer JV, Yu C, Nadeau J, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension. 2008;51:141–7. This study demonstrated a decrease of dipeptidyl peptidase IV activity and antigen in sera of patients with ACE-I induced angioedema as compared to ACE-I exposed control subjects who did not develop angioedema. CrossRefPubMedCentralPubMedGoogle Scholar
- 14.Ni H, Li L, Liu G, Hu S-Q. Inhibition mechanism and model of an angiotensin I-converting enzyme (ACE)-inhibitory hexapeptide from yeast (Saccharomyces cerevisiae). Cox D, editor. PLoS One. 2012;7:e37077–7.Google Scholar
- 24.• Woodard-Grice AV, Lucisano AC, Byrd JB, Stone ER, Simmons WH, Brown NJ. Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics. 2010;20:532–6. This case control study showed that polymorphism of XPNPEP2 C-2399A (a genotype associated with serum aminopeptidase P activity) was associated with ACE-I induced angioedema in men but not in women. CrossRefPubMedCentralPubMedGoogle Scholar
- 25.• Rasmussen E, Mey K, Bygum A. Angiotensin-converting enzyme inhibitor-induced angioedema—a dangerous new epidemic. Acta Derm Venerol. 2014;94:260–4. This review article from a dermatology perspective discusses ACE-I induced angioedema, its prognosis and treatment options. CrossRefPubMedCentralPubMedGoogle Scholar
- 26.Hoover T, Lippmann M, Grouzmann E, Marceau F, Herscu P. Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors. Clin Exp Allergy. 2009;40:733–12.Google Scholar
- 28.• Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J, et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med. 2005;165:1637–42. This is the only randomized controlled clinical trial with blind adjudication of angioedema by a committee of angioedema experts. CrossRefPubMedCentralPubMedGoogle Scholar
- 36.Kostis WJ, Cabrera J, Daeumer J, Chowdhury YS, Shetty M, Kostis JB. Prediction of angioedema among 12,557 patients receiving enalapril. Circulation. 2017;136:A13789.Google Scholar
- 41.Caballero T, Baeza ML, Cabañas R, Campos A, Cimbollek S, Gómez-Traseira C, et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations. J Investig Allergol Clin Immunol. 2011;21:422–41.PubMedPubMedCentralGoogle Scholar
- 43.• Duerr M, Glander P, Diekmann F, Dragun D, Neumayer HH, Budde K. Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients. Clin J Am Soc Nephrol. 2010;5:703–8. This study demonstrates a significantly higher incidence (6.6%) of angioedema in kidney transplant patients receiving both mTOR inhibitors and ACE-I as compared to either drug alone. CrossRefPubMedCentralPubMedGoogle Scholar
- 48.• Baş M, Greve J, Stelter K, Havel M, Strassen U, Rotter N, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015;372:418–25. A multicenter, double blind, randomized phase 2 trial demonstrated that time to complete resolution of edema in patients with ACE-I induced angioedema was shorter with icatibant as compared to combination therapy with glucocorticoids and antihistamines. CrossRefPubMedCentralPubMedGoogle Scholar
- 52.• Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, et al. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013;131:1491–1493.e25. A comprehensive update published in 2013 outlining guidelines and recommendations for the management of angioedema resulting from hereditary causes, C1 inhibitor deficiency or secondary to ACE-I use. CrossRefPubMedCentralPubMedGoogle Scholar
- 54.• Adebayo O, Wilkerson RG. Angiotensin-converting enzyme inhibitor–induced angioedema worsened with fresh frozen plasma. Am J Emerg Med. 2017;35:192.e1–2. An interesting case bringing to light the controversy of risk vs. benefit involving the use of FFP in the treatment of ACE-I induced angioedema. CrossRefGoogle Scholar
- 56.• Toh S, Reichman ME, Houstoun M, Ross Southworth M, Ding X, Hernandez AF, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med. 2012;172:1582–8. A retrospective, observational, inception cohort study that investigated the risks for angioedema with use of ACE-I, ARBs and aliskiren. It found the risk of angioedema to be three times with use of ACE-I and aliskiren. CrossRefPubMedCentralPubMedGoogle Scholar
- 58.• McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. A double-blind trial demonstrating the superiority of combined angiotensin-neprilysin inhibition as compared to enalapril in terms of reducing the risk of death and hospitalization in patients with heart failure with reduced ejection fraction. The cardiovascular benefit came at the cost of higher fraction of patients suffering from hypotension and angioedema. CrossRefPubMedCentralPubMedGoogle Scholar