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Home , ACE inhibitor, Adverse effect

clinical ACEI associated

Nick Andrew Genevieve Gabb Matthew Del Fante A case study and review

department of the local with Background ‘macroglossus of uncertain aetiology’. Angioedema is an infrequent but potentially serious adverse effect of The ’s past medical history converting inhibitors (ACEIs). included bipolar affective disorder, Objective , hyperlipidaemia, ischaemic This article describes a case of ACEI associated angioedema and reviews important , peptic ulcer disease, clinical features of the condition. primary hyperparathyroidism (treated Discussion surgically), and chronic renal impairment. The mechanism of ACEI associated angioedema is not allergic (histamine mediated), She had experienced one less severe but rather due to an alteration of the balance of and other vasodilator episode of tongue swelling 6 months prior, mediators. Onset may be delayed for weeks, months or years and episodes may be which resolved spontaneously. She did recurrent. Occasionally, airway obstruction may occur. Diagnosis is from history and not seek a medical opinion regarding this physical examination; there is no specific diagnostic test. In contrast to allergic previous episode. angioedema, ACEI associated angioedema is generally unresponsive to and , although these agents are often used by convention. In the longer term, cessation of the ACEI is necessary to reduce the of recurrent episodes. The patient was taking the following regular : Keywords: angiotensin-converting enzyme inhibitors; angioedema; • 125 mg/day • trifluoperazine 5 mg/day • felodipine 10 mg/day • 4 mg/day Case study • atorvastatin 80 mg/day A woman, 78 years of age, from a psychiatric • clopidogrel 75 mg/day hostel, presented to a general practitioner at 8 o’clock in the morning complaining of a • pantoprazole 40 mg/day ‘swollen tongue’ associated with a tingling • budesonide/eformoterol (200/6) twice daily sensation of her lips and oral mucosa. She • alendronate 70 mg weekly had not eaten that morning. Examination • annual . was unremarkable. She was reassured and The only recent change had been a sent back to the hostel. switch from to clopidogrel 2 months prior; The woman presented again 6 hours later all other medications had been prescribed long complaining of difficulty swallowing. Her term with no recent adjustments. She had tongue was now markedly swollen and been taking trandolapril for 4 years and had no protruding from her mouth. There was no known drug . stridor, however, auscultation of her chest Upon arrival at the hospital her vital signs revealed transmitted turbulent sounds were: Glasgow Coma Scale (GCS) 15, temperature from the pharynx. The patient was still able to speak, and denied difficulty breathing 36.7ºC, pressure 194/100, heart rate 100 or voice change. She was given 100 mg bpm, respiratory rate 18 breaths/min, and hydrocortisone and 25 mg saturation 100% on 6L oxygen via a CIG mask. intramuscularly. An ambulance was called She had a large protruding tongue that completely and she was transferred to the emergency obscured the view of the posterior pharynx, but

Reprinted from Australian Family Vol. 40, No. 12, December 2011 985 clinical ACEI associated angioedema – a case study and review no lip or facial oedema. There was bilateral described by the German physician Quincke in submandibular swelling, but full and pain free 18821 and may be due to inherited or acquired C1 neck range of motion and the larynx and cricoids inhibitor deficiency, environmental exposures (eg. were readily palpable. She was nose breathing, bee stings) or medicines.2 A range of medicines but without stridor or signs of respiratory distress. have been associated with angioedema, but Examination of her chest, abdomen, cardiovascular ACEIs appear to be by far the most frequent system and neurological system was unremarkable. single cause.2 The first case of ACEI associated The patient was given four doses of intravenous angioedema was described in 1980 due to adrenaline 0.3 mg, as well as intravenous .3 Initially this was thought to be a rare hydrocortisone and ranitidine. An urgent awake adverse effect;4 however recent studies have fibre optic nasotracheal intubation was performed found that approximately 30% of angioedema in theatre and the patient was then managed in the cases may be associated with an ACEI.5 intensive care unit under sedation. Moderate glottic Unlike allergic angioedema, which is mediated oedema was noted during intubation. by mast cell degranulation and histamine release, Serum biochemistry revealed acute-on- ACEI associated angioedema is thought to be chronic renal dysfunction with a trough lithium mediated by increased bradykinin and substance concentration of 1.0 mmol/L (<0.8 mmol/L). P, 6,7 as these molecules are normally metabolised Figure 1. Lateral cervical spine X-ray Complete blood picture, studies, by ACEIs (Table 1). Binding of bradykinin and showing the edentulous woman with gross tongue swelling completely filling the a vasculitic screen, thyroid function tests, substance P to their vascular receptors (BK2 oropharynx. The superior-posterior margin complement levels, and C1 inhibitor level were and NK1, respectively) causes vasodilatation of the tongue is indicated by arrows all normal. A lateral cervical spine X-ray showed and increased vascular permeability leading to complete obliteration of the oropharynx by the interstitial fluid accumulation.2 Incidence patient’s tongue, but was otherwise unremarkable As occurred in this case, ACEI associated (Figure 1). Plain chest X-ray was normal. angioedema usually presents with localised, The best estimate of incidence of angioedema The tongue swelling peaked on day two nonpitting oedema around the head and neck.2 with ACEIs comes from the OCTAVE trial, a large 6 of admission and had largely resolved by day It is morphologically identical to angioedema month study in the hypertensive population using six. Unfortunately by this time the patient had from other causes and most commonly involves .19 Angioedema was specifically looked developed a ventilator associated and the lips, tongue, cheek and pharynx5,8,9 (Table for prospectively and occurred at a rate 0.68% was requiring haemodialysis for her acute renal 2). As ACEI associated angioedema is due to over 6 months in subjects on enalapril. As there dysfunction. On day eight, the patient suffered an elevated levels of vasodilators caused by ACEI is an ongoing risk of angioedema,15 this suggests ST elevation , which was inhibition,2,6,10 rather than immune mechanisms, that annual incidence may be greater than 1%. then complicated by pulmonary haemorrhage while it occurs typically without urticaria.2,11,12 Considering that ACEIs are usually continued on a therapeutic heparin infusion. In consultation Swelling develops over about 4–6 hours and for many years, the cumulative risk to a patient with the woman’s family, the decision was made usually takes 24–48 hours to resolve,5,13 during their lifetime may be significant. Many to palliate the patient. She died on day nine of although it may persist for longer. As occurred other studies have not looked specifically for admission following extubation. in this case, there may be a history of preceding angioedema, therefore its incidence is possibly episodes, with long symptom free intervals.14,15 underestimated.4,15,20 Discussion Severity varies between cases and ranges from The time lag between initiation of an ACEI This case outlines multiple characteristics that are very mild to life threatening. In approximately and onset of ACEI associated angioedema is typical for angiotensin converting 10% of cases airway obstruction occurs.5,9 variable. In the late 1980s to early 1990s there (ACEI) associated angioedema. These include the Fatalities from ACEI associated angioedema are were a number of publications from national distribution and evolution of swelling, the presence extremely rare, with only isolated case reports drug regulatory authorities suggesting that most of a preceding episode, and the poor response in the literature.5 To the authors’ knowledge, cases occurred early (within the first week) of to conventional . For this reason, the the case presented here is the first documented commencement of an ACEI.21,22 However, this case serves as a useful learning tool for clinicians fatality with ACEI associated angioedema conclusion was based on the trend shown by wishing to better understand the phenomenon. It caused by trandolapril. spontaneous case reports, which are inherently should be noted however, that the severity of this Occasionally, angioedema of the intestine biased for reporting early onset adverse effects, case was unusual. may occur.16 This should be considered in the as delayed effects are less likely to be recognised. Angioedema or transient and localised differential diagnosis for with otherwise More recently, audits of angioedema15,23 suggest swelling of the deeper layers of the dermis, unexplained episodic abdominal pain who are that late onset of ACEI associated angioedema subcutaneous or submucosal tissues was first taking an ACEI.17,18 is more common and may occur months or

986 Reprinted from Australian Family Physician Vol. 40, No. 12, December 2011 ACEI associated angioedema – a case study and review clinical

Table 1. The pathophysiological basis of angioedema The rise in drug interactions Drug interactions may become more important in C1 inhibitor deficiency Allergic ACEI associated the future. The ‘gliptins’ are a new class of orally (inherited* or acquired) angioedema angioedema active hypoglycaemics. They exert their effect Mechanism Increased due to Mast cell Increased kinins due to increased production degranulation decreased degradation via inhibition of dipeptidyl peptidase 4 (DPP-4) activity, potentiating the action of ‘incretins’.29 Urticaria Typically absent Present Typically absent Dipeptidyl peptidase-4 is also involved in the * Also known as breakdown of other such as bradykinin. As it is now appreciated that bradykinin plays Table 2. Frequency with which ACEI associated angioedema affects different a central role in the pathophysiology of ACEI anatomical sites associated angioedema, the relationship between the use of a gliptin, ACEI exposure, and Banerji et al, 20085* (n=220) Grant et al, 20079* (n=228) occurrence of angioedema has been investigated Lip 70% 54% as part of the premarketing surveillance of Tongue 52% • Anterior tongue 40% vildagliptin.30 Among patients taking an ACEI, • Base of tongue 11% vildagliptin use was associated with an increased Laryngeal 59% • Larynx 4% risk of angioedema (OR: 4.57, CI: 1.57–13.28), • Supraglottis 12% although there was no increased risk with • Pharynx 9% vildagliptin alone.30 Vildagliptin (and potentially Cheek 20% Data not recorded sitagliptin) use may be associated with increased Periorbital 10% Data not recorded risk of angioedema among patients taking Hand 0% <1% ACEIs.30,31 Given the widespread and long term Genitals 0% <1% use of ACEIs, and the potential for long term use * Both these studies were retrospective chart reviews of patients presenting to of the gliptins, awareness of the potential for this emergency departments with ACEI associated angioedema. The study by Grant interaction is important. Importantly, the patient et al was undertaken by a department of otolaryngology head and neck , presented here was not documented to be taking which may explain the more precise characterisation of airway swelling a gliptin. For an individual patient the question that years after commencement of treatment.15,23 will develop angioedema with an ACEI, arises is, was the angioedema due to the ACEI or An average duration of prior exposure of 12–14 although there are a number of recognised was it just a chance occurrence? Epidemiological months has been suggested.9,11 The delayed onset risk factors. The most significant of these studies suggest that there is an attributable risk of the reaction makes the association difficult to are a previous episode of angioedema and of 50–80%.7,15 Attributable risk is defined here as recognise. African ancestry.2,14 Smoking, older age and the proportion of the incidence of angioedema in being female also increase risk, although those exposed to ACEIs that can be attributed to Risk factors less dramatically.2,19 There is a reduced risk the exposure.7,15 That is, about 50–80% of new Recognition of ACEI angioedema has improved in people with .7,19 Pharmacogenetic cases of angioedema in patients taking an ACEI over time from approximately 10–25% of cases in studies are currently investigating genetic would be eliminated if the ACEI was avoided. the early 1990s23 to about 80% in a recent audit.24 factors associated with increased risk.28 There However, perhaps because of delayed onset, is no clearly identifiable relationship with Treatment infrequent occurrence and inadequate physician dose, or whether risk varies between different There have been no trials of antihistamines or awareness,25 some cases remain unrecognised. ACEIs.2 Concomitant medications as a potential corticosteroids for ACEI associated angioedema Misdiagnosing the event as a or drug precipitant for ACEI associated angioedema and these treatments are of unproven and has been cited as the most common physician have not been studied extensively as many may be ineffective. error resulting in failure to diagnose, and thus studies have been retrospective case note bradykinin receptor antagonists are currently correctly treat, ACEI associated angioedema.26 In audits of emergency department attendance in development, although these do not yet have an the case study patient, symptoms were unlikely where medication use is not well documented. established role or regulatory approval for use in to be attributable to food allergy, as it would However, a possible increased risk with ACEI associated angioedema.32 In the longer term, be unusual for this to present late in life, with aspirin, nonsteroidal anti-inflammatories and cessation of the ACEI is important to reduce the isolated tongue swelling and without urticaria.27 immunosuppressive agents has recently been probability of further episodes, as with ongoing Furthermore, the patient had not eaten that day. suggested.2 The patient presented here was not ACEI , recurrent events are likely and may It is not possible to predict which patients documented to be taking any of these. be more severe.26,33,34

Reprinted from Australian Family Physician Vol. 40, No. 12, December 2011 987 clinical ACEI associated angioedema – a case study and review

Summary veterans initiating angiotensin-converting enzyme 26. roberts DS, Mahoney EJ, Hutchinson CT, Aliphas inhibitors. Hypertension 2008;51:1624–30. A, Grundfast KM. Analysis of recurrent angiotensin • Awareness of the possibility of ACEI 8. Sica DA, Black HR. Current concepts of pharma- converting enzyme inhibitor-induced angioedema. angioedema is essential for timely recognition cotherapy in hypertension: ACE inhibitor-related Laryngoscope 2008;118:2115–20. 27. ortolani C, Bruijnzeel-Koomen C, Bengtsson U, of the problem. angioedema: can angiotensin-receptor blockers be safely used? J Clin Hypertens 2002;4:375–80. et al. Controversial aspects of adverse reactions • The mechanism of ACEI associated 9. Grant NN, Deeb ZE, Chia SH. Clinical experience to food. European Academy of Allergology and angioedema is not immune. with angiotensin-converting enzyme inhibitor- Clinical Immunology (EAACI) Reactions to Food induced angioedema. Otolaryngol Head Neck Surg Subcommittee. Allergy 1999;54:27–45. • Swelling develops gradually over several 2007;137:931–5. 28. Duan QL, Nikpoor B, Dube MP, et al. A variant in hours, a period of observation may be 10. byrd JB, Adam A, Brown NJ. Angiotensin-converting XPNPEP2 is associated with angioedema induced appropriate to ensure the airway is not enzyme inhibitor-associated angioedema. Immunol by angiotensin I-converting enzyme inhibitors. Am J Allergy Clin North Am 2006;26:725–37. Hum Genet 2005;77:617–26. threatened. 11. Zingale LC, Beltrami L, Zanichelli A, et al. 29. martin JH, Deacon CF, Gorrell MD, Prins JB. • marked base of tongue and floor of mouth Angioedema without urticaria: a large clinical survey. Incretin-based therapies: review of the physiology, and emerging clinical experience. oedema are the most reliable indicators of the CMAJ 2006;175:1065–70. 12. Agostoni A, Cicardi M. Drug-induced angioedema Intern Med J 2011;41:299–307. need for airway intervention. without urticaria. Drug Saf 2001;24:599–606. 30. brown NJ, Byiers S, Carr D, Maldonado M, Warner • Antihistamines and corticosteroids are often 13. Chiu AG, Newkirk KA, Davidson BJ, Burningham AR, BA. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angi- used as standard therapy, however these Krowiak EJ, Deeb ZE. Angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter review oedema. Hypertension 2009;54:516–23. medications are of unproven efficacy. and an algorithm for airway management. Ann Otol 31. rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. • In the long term, cessation of the ACEI is Rhinol Laryngol 2001;110:834–40. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglita- necessary to reduce the risk of recurrent 14. Gibbs CR, Lip GY, Beevers DG. Angioedema due to ACE inhibitors: increased risk in patients of African zone therapy in patients with : a episodes. origin. Br J Clin Pharmacol 1999;48:861–5. 24-week, multicenter, randomized, double-blind, 15. Gabb GM, Ryan P, Wing LM, Hutchinson KA. -controlled, parallel-group study. Clin Ther Authors Epidemiological study of angioedema and ACE inhibi- 2006;28:1556–68. Nick Andrew MBBS, is an intern, Department tors. Aust N Z J Med 1996;26:777–82. 32. bas M, Greve J, Stelter K, et al. Therapeutic efficacy 16. Gregory KW, Davis RC. Images in clinical medi- of in angioedema induced by angiotensin- of Medicine, Royal Adelaide Hospital, South converting enzyme inhibitors: a case series. Ann . [email protected] cine. Angioedema of the intestine. N Engl J Med 1996;334:1641. Emerg Med 2010;56:278–82. 33. Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Genevieve Gabb MBBS(Hons), FRACP, 17. oudit GY, Dill-Macky MJ, Allard JP. Image of the Angioedema associated with angiotensin-converting GradDipClinEpi, is Senior Staff Specialist, month. Angiotensin-converting enzyme (ACE) enzyme inhibitor use: outcome after switching to a Department of Medicine, Royal Adelaide Hospital, inhibitor angioedema of the intestine. Gastroenterol different treatment. Arch Intern Med 2004;164:910–3. 2000;119:1190, 424. South Australia 34. brown NJ, Snowden M, Griffin MR. Recurrent 18. oudit G, Girgrah N, Allard J. ACE inhibitor-induced angiotensin-converting enzyme inhibitor associated Matthew Del Fante MBBS, is resident medical angioedema of the intestine: , incidence, angioedema. JAMA 1997;278:232–3. officer, Department of Medicine, Royal Adelaide pathophysiology, diagnosis and management. Can J Hospital, South Australia. Gastroenterol 2001;15:827–32. 19. Kostis JB, Packer M, Black HR, Schmieder R, Henry Conflict of interest: none declared. D, Levy E. and enalapril in patients with hypertension: the Omapatrilat Cardiovascular References Treatment vs. Enalapril (OCTAVE) trial. Am J 1. Quincke HI. Uber akutes umschriebenes Hautodem. 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988 Reprinted from Australian Family Physician Vol. 40, No. 12, December 2011