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ACE Inhibitor-Induced Angioedema: a Review

  • William J. Kostis
  • Mrinali Shetty
  • Yuvraj Singh Chowdhury
  • John B. Kostis
Guidelines/Clinical Trials/Meta-Analysis (JB Kostis, Section Editor)
  • 346 Downloads
Part of the following topical collections:
  1. Topical Collection on Guidelines/Clinical Trials/Meta-Analysis

Abstract

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.

Recent Findings

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.

Conclusion

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.

Keywords

Angiotensin II Angioedema Angiotensin-converting enzyme inhibitors Hypertension Bradykinin 

Notes

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.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Osler W. Hereditary angio-neurotic oedema. Am J Med Sci. 1888;95:362–7.CrossRefGoogle Scholar
  2. 2.
    Hedner T, Samuelsson O, Lunde H, Lindholm L, Andrén L, Wiholm BE. Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors. BMJ. 1992;304:941–6.CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Nussberger J, Cugno M, Cicardi M. Bradykinin-mediated angioedema. N Engl J Med. 2002;347:621–2.CrossRefGoogle Scholar
  4. 4.
    Lin RY, Cannon AG, Teitel AD. Pattern of hospitalizations for angioedema in New York between 1990 and 2003. Ann Allergy Asthma Immunol. 2005;95:159–66.CrossRefGoogle Scholar
  5. 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.
  6. 6.
    Lin RY, Shah SN. Increasing hospitalizations due to angioedema in the United States. Am Coll Allergy Asthma Immunol. 2008;101:185–92.CrossRefGoogle Scholar
  7. 7.
    Ferreira SH. A bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca. Br J Pharmacol Chemother. 1965;24:163–9.CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Bakhle YS. Conversion of angiotensin I to angiotensin II by cell-free extracts of dog lung. Nature. 1968;220:919–21.CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Ondetti MA, Rubin B, Cushman DW. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science. 1977;196:441–4.CrossRefGoogle Scholar
  10. 10.
    Cushman DW, Ondetti MA. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension. 1991;17:589–92.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Yang HY, Erdös EG, Levin Y. A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim Biophys Acta. 1970;214:374–6.CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema. Lancet. 1998;351:1693–7.CrossRefPubMedCentralGoogle Scholar
  13. 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. CrossRefPubMedCentralGoogle Scholar
  14. 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
  15. 15.
    Kostis JB. Angiotensin converting enzyme inhibitors. I. Pharmacology. Am Heart J. 1988;116:1580–91.CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Marceau F, Hess JF, Bachvarov DR. The B1 receptors for kinins. Pharmacol Rev. 1998;50:357–86.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Cugno M, Nussberger J, Cicardi M, Agostoni A. Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol. 2003;3:311–7.CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med. 1992;117:234–42.CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Byrd JB, Shreevatsa A, Putlur P, Foretia D, McAlexander L, Sinha T, et al. Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor-induced peritracheal edema. J Allergy Clin Immunol. 2007;120:403–8.CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Adam A, Cugno M, Molinaro G, Perez M, Lepage Y, Agostoni A. Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors. Lancet. 2002;359:2088–9.CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Abbud ZA, Wilson AC, Cosgrove NM, Kostis JB. Angiotensin-converting enzyme gene polymorphism in systemic hypertension. Am J Cardiol. 1998;81:244–6.CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Gulec M, Caliskaner Z, Tunca Y, Ozturk S, Bozoglu E, Gul D, et al. The role of ace gene polymorphism in the development of angioedema secondary to angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Allergol Immunopathol (Madr). 2008;36:134–40.CrossRefGoogle Scholar
  23. 23.
    Pare G, Kubo M, Byrd JB, McCarty CA, Woodard-Grice A, Teo KK, et al. Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics. 2013;23:470–8.CrossRefPubMedCentralGoogle Scholar
  24. 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. CrossRefPubMedCentralGoogle Scholar
  25. 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. CrossRefPubMedCentralGoogle Scholar
  26. 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
  27. 27.
    Kostis J. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17:103–11.CrossRefGoogle Scholar
  28. 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. CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Slater EE, Merrill DD, Guess HA, Roylance PJ, Cooper WD, Inman WH, et al. Clinical profile of angioedema associated with angiotensin converting-enzyme inhibition. JAMA. 1988;260:967–70.CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Messerli FH, Nussberger J. Vasopeptidase inhibition and angio-oedema. Lancet. 2000;356:608–9.CrossRefPubMedCentralGoogle Scholar
  31. 31.
    Miller DR, Oliveria SA, Berlowitz DR, Fincke BG, Stang P, Lillienfeld DE. Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension. 2008;51:1624–30.CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Makani H, Messerli FH, Romero J, Wever-Pinzon O, Korniyenko A, Berrios RS, et al. Meta-analysis of randomized trials of angioedema as an adverse event of renin–angiotensin system inhibitors. Am J Cardiol. 2012;110:383–91.CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Banerji A, Clark S, Blanda M, LoVecchio F, Snyder B, Camargo CA. Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. Ann Allergy Asthma Immunol. 2008;100:327–32.CrossRefGoogle Scholar
  34. 34.
    • Vasekar M, Craig TJ. ACE inhibitor-induced angioedema. Curr Allergy Asthma Rep. 2011;12:72–8. A comprehensive review of ACE-I induced angioedema with emphasis on application of drugs used in hereditary angioedema in the management of ACE-I induced angioedema. CrossRefGoogle Scholar
  35. 35.
    Lefebvre J, Murphey LJ, Hartert TV, Jiao Shan R, Simmons WH, Brown NJ. Dipeptidyl peptidase IV activity in patients with ACE-inhibitor-associated angioedema. Hypertension. 2002;39:460–4.CrossRefPubMedCentralGoogle Scholar
  36. 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
  37. 37.
    Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther. 1996;60:8–13.CrossRefGoogle Scholar
  38. 38.
    Gainer JV, Nadeau JH, Ryder D, Brown NJ. Increased sensitivity to bradykinin among African Americans. J Allergy Clin Immunol. 1996;98:283–7.CrossRefPubMedCentralGoogle Scholar
  39. 39.
    Gibbs CR, Lip GY, Beevers DG. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol. 1999;48:861–5.CrossRefPubMedCentralGoogle Scholar
  40. 40.
    Dean DE, Schultz DL, Powers RH. Asphyxia due to angiotensin converting enzyme (ACE) inhibitor mediated angioedema of the tongue during the treatment of hypertensive heart disease. J Forensic Sci. 2001;46:1239–43.CrossRefPubMedCentralGoogle Scholar
  41. 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
  42. 42.
    Walford HH, Zuraw BL. Current update on cellular and molecular mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112:413–8.CrossRefPubMedCentralGoogle Scholar
  43. 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. CrossRefPubMedCentralGoogle Scholar
  44. 44.
    Brown NJ, Snowden M, Griffin MR. Recurrent angiotensin-converting enzyme inhibitor-associated angioedema. JAMA. 1997;278(3):232–3.CrossRefPubMedCentralGoogle Scholar
  45. 45.
    Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419–0.CrossRefPubMedCentralGoogle Scholar
  46. 46.
    Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009;373:1341–51.CrossRefGoogle Scholar
  47. 47.
    Craig TJ, Bernstein JA, Farkas H, Bouillet L, Boccon-Gibod I. Diagnosis and treatment of bradykinin-mediated angioedema: outcomes from an angioedema expert consensus meeting. Int Arch Allergy Immunol. 2014;165:119–27.CrossRefPubMedCentralGoogle Scholar
  48. 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. CrossRefPubMedCentralGoogle Scholar
  49. 49.
    Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J, et al. Randomized trial of Icatibant for angiotensin-converting enzyme inhibitor-induced upper airway angioedema. J Allergy Clin Immunol Pract. 2017;5:1402–3.CrossRefPubMedCentralGoogle Scholar
  50. 50.
    Lewis LM, Graffeo C, Crosley P, Klausner HA, Clark CL, Frank A, et al. Ecallantide for the acute treatment of angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter, randomized, controlled trial. Ann Emerg Med. 2015;65:204–13.CrossRefPubMedCentralGoogle Scholar
  51. 51.
    Moellman JJ, Bernstein JA, Lindsell C, Banerji A, Busse PJ, Camargo CA Jr, et al. A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med. 2014;21:469–84.CrossRefPubMedCentralGoogle Scholar
  52. 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. CrossRefPubMedCentralGoogle Scholar
  53. 53.
    Erickson DL, Coop CA. Angiotensin-converting enzyme inhibitor-associated angioedema treated with c1-esterase inhibitor: a case report and review of the literature. Allergy Rhinol (Providence). 2016;7:168–71.CrossRefGoogle Scholar
  54. 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
  55. 55.
    Lewis LM. Angioedema: etiology, pathophysiology, current and emerging therapies. J Emerg Med. 2013;45:789–96.CrossRefPubMedCentralGoogle Scholar
  56. 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. CrossRefPubMedCentralGoogle Scholar
  57. 57.
    Parving H-H, Brenner BM, McMurray JJV, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204–13.CrossRefPubMedCentralGoogle Scholar
  58. 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. CrossRefPubMedCentralGoogle Scholar
  59. 59.
    Kostis JB, Moreyra AE, Kostis WJ. Angioedema with renin angiotensin system drugs and neutral endopeptidase inhibitors. J Am Soc Hypertens. 2016;10:387–9.CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • William J. Kostis
    • 1
  • Mrinali Shetty
    • 2
  • Yuvraj Singh Chowdhury
    • 2
  • John B. Kostis
    • 1
  1. 1.Rutgers Robert Wood Johnson Medical SchoolCardiovascular InstituteNew BrunswickUSA
  2. 2.Saint Peter’s University HospitalNew BrunswickUSA

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