Accepted Manuscript Angiotensin Converting Enzyme Inhibitor Induced Angioedema Shira Bezalel, M.D Keren Mahlab-Guri, M.D Ilan Asher, M.D Ben Werner, M.D Zev Moshe Sthoeger, M.D PII:
S0002-9343(14)00591-9
DOI:
10.1016/j.amjmed.2014.07.011
Reference:
AJM 12611
To appear in:
The American Journal of Medicine
Received Date: 2 October 2013 Revised Date:
13 July 2014
Accepted Date: 14 July 2014
Please cite this article as: Bezalel S, Mahlab-Guri K, Asher I, Werner B, Sthoeger ZM, Angiotensin Converting Enzyme Inhibitor Induced Angioedema, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.07.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Review
Angiotensin Converting Enzyme Inhibitor Induced Angioedema Shira Bezalel, M.D.
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Keren Mahlab-Guri, M.D. Ilan Asher, M.D. Ben Werner, M.D.
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Zev Moshe Sthoeger, M.D.
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Departments of Medicine B, Clinical Immunology Allergy and AIDS, Kaplan Medical Center, Rehovot, Israel.
Corresponding author: Prof. Z.M. Sthoeger
Kaplan Medical Center Rehovot, 76100 Israel.
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Tel +972 8 9441917
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Head, Dept. Medicine B, Allergy and Clinical Immunology and AIDS center
Fax +972 8 9410461
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E-mail address: [email protected], [email protected] Cell phone number: +972 54 4617570
Conflict of interest for all authors – none Funding- none All authors had accesse to the data and had a role in writing the manuscript
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Abstract Angiotensin converting enzyme inhibitors (ACE-I) are widely used, effective and well tolerated anti-hypertensive agents. The mechanisms by which those agents act can
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cause side effects such as decreased blood pressure, hyperkalemia and impaired
renal function. ACE-I can induce cough in 5-35% and angioedema in up to 0.7% of the treated patients. Since cough and angioedema are considered class adverse effects,
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switching treatment to other ACE-I agents is not recommended. Angioedema due to
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ACE-I has a low fatality rate, although deaths have been reported when the angioedema involves the airways. Here, we review the role of bradykinin in the development of angioedema in patients treated with ACE-I as well as the incidence, risk factors, clinical presentation and available treatments for ACE-I induced
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angioedema. We also discuss the risk for recurrence of angioedema after switching
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from ACE-I to angiotensin receptor blockers (ARBs) treatment.
Key words: ACE-I (Angiotensin converting enzyme inhibitor), angioedema, cough,
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bradykinin, ARBs (angiotensin receptor blockers), Icatibant, Ecallantide.
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ACCEPTED MANUSCRIPT The first angiotensin converting enzyme Inhibitor (ACE-I), Captopril, was approved by the Food and Drug Administration (FDA) in the early 1980s 1. The treatment was proven to be effective in lowering blood pressure with an excellent tolerability profile. Since then, ACE-I agents have been widely used for the treatment of
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hypertension, congestive heart failure, diabetic nephropathy, post myocardial infarction and chronic kidney disease with proteinuria 2.
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ACE-I medications are divided into three groups based on their molecular structure at the active site of the drug: Sulfhydryl containing agents (e.g. Captopril) have the
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strongest chelating function and may cause skin rash and loss of taste. Dicarboxylate containing agents are weaker chelators (e.g. Enalapril, Ramipril) and are designed as prodrugs. The phosphonate containing agents (e.g. Fosinopril) are also a prodrug eliminated from the body via both, renal and hepatic pathways 3.
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Mechanism of action
The mechanism of ACE-I was considered a breakthrough in the treatment of hypertension. It is based on blocking the renin-angiotensin-aldosterone cascade.
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Normally, renin is produced and secreted by the juxtaglomerular apparatus in the
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kidneys in response to a drop in blood pressure or to a decrease in filtered sodium chloride concentration. The secreted renin cleaves the hepatic angiotensinogen to the inactive peptide angiotensin I. Angiotensin I is then converted into the active angiotensin II by ACE (angiotensin converting enzyme), which is produced mainly in the lung capillaries. Angiotensin II has a number of physiological effects. It increases blood vessel resistance, acts on the adrenal cortex to release aldosterone, stimulates the release of the antidiuretic hormone Vasopressin from the posterior pituitary, stimulates thirst centers, facilitates norepinephrine release from sympathetic nerve 3
ACCEPTED MANUSCRIPT endings and inhibits norepinephrine re-uptake (Figure 1) 1,2. ACE-I is a competitive inhibitor of the ACE enzyme, preventing the conversion of angiotensin I to the active angiotensin II. ACE is also responsible for the degradation of bradykinin. Active bradykinin is produced once its precursor, kininogen, is cleaved by kallikrein.
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Bradykinin has a short half-life due to rapid degradation primarily by ACE. Thus, the inhibition of ACE by ACE-I medications can prolong the half-life of bradykinin,
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increasing its concentration and activity 4 (Figure 1).
Angiotensin receptor blockers (ARBs), also known as AT1 receptor antagonists, block
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the binding of angiotensin II to its receptors, causing vasodilation, reduced secretion of vasopressin and reduced production and secretion of aldosterone (Figure 1) 5. As ACE-I, the ARBs are indicated for the treatment of hypertension, heart failure and diabetic nephropathy. ARBs do not have any effect on the activity of ACE. Therefore,
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ARBs medications do not inhibit the breakdown of bradykinin (Figure 1) 6. Consequently, ACE-I and ARBs differ in some of their adverse effects. ACE-I adverse effects
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Some of the adverse events of ACE-I result from the drug’s action. Hypotension, causing weakness, dizziness or syncope, caused about 1.7% of the patients to
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discontinue the drug 6. Hypotension is marked in hypovolemic patients. Severe reduction in the glomerular filtration rate (GFR) may be seen in patients with bilateral renal artery stenosis, hypertensive nephrosclerosis, heart failure, polycystic kidney disease or chronic kidney disease 7. In the above disorders the intrarenal perfusion pressure is reduced and the GFR is maintained mainly by angiotensin II, which increases the resistance at the postglomerular arterioles. Hence, treating these patients with ACE-I may cause renal dysfunction 6. Hyperkalemia is another 4
ACCEPTED MANUSCRIPT common side effect. ACE-I inhibits aldosterone release, which is the major stimulus for urinary potassium excretion. The overall incidence of hyperkalemia in patients treated with ACE-I is about 3.3%. Usually the potassium increment does not exceed 0.5mg/L 6. More prominent ACE-I induced hyperkalemia may be seen in patients
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with concomitant renal insufficiency, diabetes or concurrent use of potassium sparing agents or non-steroidal anti-inflammatory agents (NSAIDs) 8.
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ARBs treatment may also cause the above adverse events since they block
angiotensin II activity (Figure 1). Indeed, Fried et al recently recommended the
to hyperkalemia and renal failure 9.
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avoidance of ACE-I and ARBs combination in patients with diabetic nephropathy due
Captopril may cause sulfhydryl related adverse events, such as rash, neutropenia, taste abnormalities and nephritic syndrome. Some of those side effects are
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idiosyncratic while others are dose related 10. In the current dosage used (up to 150mg/day), those side effects are quite rare and do not reoccur with the other groups of ACE-I 10.
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ACE-I induced cough
Cough is a well described class adverse effect of ACE-I. The incidence of ACE-I
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induced cough is reported to be 5-35% 11 (9.9% in controlled randomized trials and 1.7% in cohort studies 12). In the ON Going Telmisartan Alone and in combination with the Ramipril Global Endpoint Trial (ONTARGET), cough caused the discontinuation of Ramipril in 4.2% of the treated patients 6. The precise mechanism by which ACE-I causes cough is not yet defined, but increased concentrations of bradykinin, substance P, prostaglandins and thromboxane (as discussed below) are most likely involved 13. Cough may occur within hours following the first dose of the 5
ACCEPTED MANUSCRIPT medication but it may delayed for weeks to months after the initiation of ACE-I agents. Switching treatment from one ACE-I to another is not effective since cough is a class adverse effect 11. When ACE-I is discontinued, improvement of the cough occurs within 1 to 4 weeks. In some patients resolution of the cough may take few
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months11. The incidence of ARBs induced cough is much lower (3.2% in controlled
trials and 0.6% in cohort studies 12). Although cough may occur with ARBs, they are
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considered an alternative treatment for patients who discontinued ACE-I due to cough and who need the blockade of the renin-angiotensin cascade.
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ACE-I induced angioedema
Angioedema is a self-limiting swelling (edema) of the skin (dermis and subdermis), mucosal tissues and organs such as the tongue, lips, eyelids, intestine wall or genitalia, all of which are rich in capillary blood supply 14. The edema is caused by
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hyperpermeability of post capillary venules due to vasoactive agents. There are two main types of angioedema. The allergic- histamine mediated angioedema develops rapidly and is associated with pruritus and rash (urticaria). In some patients systemic
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anaphylaxis may also occur 14, caused either by allergen specific IgE (e.g. food, drug,
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insect bite, aeroallergens) or by direct mast cell degranulation 15. On the other hand, the non-allergic angioedema (non-IgE mediated) is mediated mainly by bradykinin. The latter is a non-pruritic angioedema with a gradual onset, without rash, involving the extremities, face, larynx (airway obstruction) or intestinal lining (abdominal pain). This non-allergic angioedema is seen in patients with hereditary angioedema (HAE) and in patients with ACE-I induced angioedema 4. The exact mechanism by which ACE-I causes angioedema is not fully understood although bradykinin was shown to play a role in the pathogenesis of this adverse 6
ACCEPTED MANUSCRIPT event 16. The binding of bradykinin to its vascular receptor (BK2) results in vasodilation and increased vascular permeability, which in turn leads to interstitial fluid accumulation and angioedema 17. Normally, bradykinin has a short half-life due to rapid degradation. Three metaloproteinases are primarily involved in the
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degradation of bradykinin: ACE/kininase II, aminopeptidase P (APP) and neutral
endopeptidase (NEP). ACE is more effective in the degradation of bradykinin than
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APP, which is more effective than NEP 18. ACE-I medications block ACE/kininase II activity, thereby reducing the rate of bradykinin degradation, which leads to
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increased bradykinin levels (Figure 1). Nonetheless, only a small portion (0.3-0.68%) of patients treated with ACE-I develop angioedema 6,19. This may point towards other mechanism(s) in the pathogenesis of ACE-I induced angioedema. Bradykinin is metabolized by ACE/kininase II to the active bradykinin metabolite N-Arg-bradykinin.
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Approximately half the patients experiencing ACE-I induced angioedema were shown to have an enzymatic defect in the degradation of this active metabolite,
activity 20.
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which in the presence of ACE-I may result in further augmentation of bradykinin
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The fact that ARBs have no effect on bradykinin metabolism (Figure 1) may explain the low incidence of ARBs induced angioedema (0.11%), which is less than half of the rate (0.3%) observed in control trials of ACE-I treated patients 19. Incidence and risk factors Omapatrilat, an antihypertensive agent that inhibits both neutral endopeptidase and ACE, was not approved by the FDA due to a high rate (2.17%) of angioedema 21. The incidence of angioedema in the Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) trial, which randomized 12,634 patients to Enalapril 7
ACCEPTED MANUSCRIPT treatment, was 0.68% 21. Recently, Makani et al. reported an incidence of 0.3% of ACE-I induced angioedema in a meta-analysis of 26 randomized trials (74,875 patients) 19. Although angioedema is an uncommon adverse event of ACE-I treatment, due to the huge number of patients treated with those medications, it
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accounts for one third of angioedema cases treated in emergency rooms 22, 23.
Patients experiencing angioedema to one ACE-I agent will typically have angioedema
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to all other ACE-I because angioedema is a class adverse event and not a
hypersensitivity reaction. Thus, usage of any other ACE-I in patients with a history of
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ACE-I induced angioedema is contraindicated 23.
ACE-I induced angioedema was found to be more prevalent in patients of African ancestry 24, in patients older than 65 years, in females, in smokers, in patients with heart failure, in patients treated with statins, aspirin or sirolimus and in those with a
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history of any drug rash, seasonal allergies or previous angioedema 23, 25. A history of ACE-I induced cough was also reported to be a risk factor for angioedema 25 . On the other hand, diabetic patients were shown to have a lower risk for ACE-I induced
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angioedema as compared to non-diabetic patients 25. It should be noted that
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treatment with ACE-I is contraindicated in patients with HAE unless they are treated with purified C1-inhibitor concentrates, such as Berinet, Cinryze and Reconest, on a regular basis 26. Time of onset
The time interval between the initiation of ACE-I treatment and the development of angioedema is variable. Some patients may develop symptoms within one day, while in others symptoms may take as long as 8-10 years to develop 27. About 50% of patients with ACE-I induced angioedema develop it within the first week of 8
ACCEPTED MANUSCRIPT treatment 28. In the OCTAVE trial the incidence of angioedema was significantly higher shortly after the initiation of ACE-I therapy (3.6/1,000 patients in the first month of treatment vs. 0.4/1,000 patients after 24 weeks of treatment). The average time was 10.2 months following treatment initiation 21.
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Clinical presentation
ACE-I induced angioedema typically presents as a subcutaneous, non-pitting edema,
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evolving gradually over several hours without itching, rash or pain 14. The
angioedema usually involves the face, lips, tongue and the arms. Other cutaneous
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sites are less commonly involved 29. ACE-I induced angioedema may involve the gastrointestinal mucosa, causing abdominal pain accompanied by diarrhea, nausea, vomiting and ascites 30. Some of those patients are subjected to unnecessary invasive diagnostic or surgical procedures due to incorrect diagnosis 31. When the
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oral cavity and larynx are affected, the angioedema can rapidly progress to lifethreatening oropharyngeal obstruction and asphyxia 32. Currently, there are no laboratory tests for the diagnosis of ACE-I induced angioedema (in contrast to the
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low C2, C4 and C1 esterase inhibitor levels seen in HAE 14). Rather, a clinical
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diagnosis is made based on the prior usage of ACE-I medications and the disappearance of the angioedema following the discontinuation of medication. As mentioned above, in the OCTAVE trial, which involved 12,557 patients treated with Enalapril, the prevalence of angioedema was 0.68%. None of the patients with angioedema was affected severely enough to require intubation, and no deaths were reported 21. Other studies, however, reported that 10% of the patients with ACE-I induced oral cavity angioedema required endotracheal intubation 33.
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ACCEPTED MANUSCRIPT Furthermore, another study reported death in 7 African American patients due to ACE-I induced angioedema 34.
Management of ACE-I induced angioedema
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Most cases of ACE-I induced angioedema are mild, without any airway obstruction 21. Once ACE-I induced angioedema is suspected, the culpable drug must be stopped
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immediately. Drug discontinuation solved the problem in the vast majority of
patients within several hours (up to 48 hours), but the angioedema may last longer . If the ACE-I agents are not withdrawn, the angioedema episodes increase in
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frequency and in severity 35. Some patients experience one or more episodes of angioedema after discontinuation of the causative ACE-I. In a long term retrospective study, 88% of the relapses occurred within the first month following
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ACE-I discontinuation 36. In some cases, relapses continued for up to six months. In the case of persistent angioedema, patients should be further evaluated for other causes of angioedema 36. Since ACE-I induced angioedema is a class adverse effect, a
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switch to another ACE-I agent is contraindicated 35.
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Assessing airway patency is the most important element in managing patients with ACE-I induced angioedema, especially in those with facial and/or laryngeal angioedema. When indicated, endotracheal intubation or emergency tracheostomy should be done immediately. Antihistamines, anticholinergic agents, corticosteroids or epinephrine are not effective since ACE-I angioedema is not mediated by histamine 26. Fresh frozen plasma, which contains ACE as well as C1 esterase inhibitor, both able to decrease bradykinin levels (Figure 1), was shown to be effective in a few case 10
ACCEPTED MANUSCRIPT reports of patients with ACE-I induced laryngeal edema 37 . However, since C1 esterase inhibitor levels are normal in those patients, fresh frozen plasma is not a recommended treatment. Purified C1-inhibitor concentrates, such as Berinet, Cinryze and Reconest, which inhibit Kallikerin and thus decrease the amount of
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bradykinin (Figure 1), were also shown to be effective for ACE-I induced angioedema in a few case reports 38, 39, 40.
The bradykinin receptor type 2 (BR2) antagonist, Icatibant, was approved for the
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treatment of HAE 26. Since ACE-I induced angioedema is likely, at least in part, to be
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caused by high bradykinin levels (decreased degradation), treatment with the bradykinin receptor antagonist is reasonable (Figure 1). A small number of case reports and case series demonstrated beneficial effects of Icatibant in patients with ACE-I induced angioedma. Icatibant treatment in those patients resulted in a rapid
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reduction of the edema, preventing the need for tracheal intubation 41, 42, 43. In a clinical series of 8 patients with ACE-I induced angioedema, Icatibant shortened the time to full recovery as compared to an historical series of 47 patients with ACE-I
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induced angioedema of similar severity
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. In a retrospective case series of 7 patients
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with ACE-I associated angioedema, all patients responded well to Icatibant 45. Further large randomized studies, like the phase 3 NCT01919801 ongoing trial, are needed in order to define the role of Icatibant in the treatment of ACE-I induced angioedema.
Ecallantide is a recombinant protein that inhibits kallikerin activity, thus decreasing the conversion of high molecular weight (HMW) kininogen to bradykinin (Figure 1). Indeed, Ecallantide was shown to be more effective than placebo in 76 patients with ACE-I Induced angioedema 46 . Studies aimed to evaluate the efficacy of Ecallantide 11
ACCEPTED MANUSCRIPT in ACE-I induced angioedema, such as the phase 2 NCT01036659 trial, are currently in progress. It should be noted that both Icatibant and Ecallantide are very expensive drugs. Thus, in mild cases of ACE-I induced angioedema without any airway compromise,
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we recommend drug discontinuation (with close monitoring of the patients) as the primary therapeutic approach. In patients with laryngeal angioedema, which may
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compromise airway patency, however, endotracheal intubation or urgent
tracheostomy should be considered. In those patients, we recommend immediate
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administration of Icatibant (30 mg subcutaneously).
The data regarding the safety of ARBs in patients with previous ACE-I induced angioedema is limited. Theoretically, ARBs should be safe since they do not affect bradikinin metabolism (Figure 1). ARBs were, however, reported to cause
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angioedema (though at a much lower rate than ACE-I 19). Moreover, there are several reports of recurrent angioedema in patients who switched from ACE-I to ARBs due to the latter adverse event 47. It should be noted that in most of the above
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patients, the angioedema took place shortly after switching, indicating that the
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angioedema was probably still related to the previous ACE-I treatment 47, 48.Taking together, switching ACE-I to ARBs in patients with previous ACE-I angioedema is quite safe, but close monitoring of those patients (for the development of angioedema) is mandatory. In patients with a previous severe life-threatening ACE-I induced angioedema, we recommend avoiding both, ACE-I and ARBs medications. In summary, ACE-I are widely prescribed drugs with excellent tolerability and safety profiles. These drugs might cause side effects which result from the drug mechanism(s) of action, such as reduction of GFR, hypotension and hyperkalemia. In 12
ACCEPTED MANUSCRIPT our review we emphasize the class adverse effects, such as cough and angioedema. These class effects are due (at least in part) to bradykinin accumulation. Once diagnosed, treatment with ACE-I should be ceased immediately. Patients experiencing angioedema to one ACE-I will typically have angioedema to all other
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ACE-I agents; hence, switching to another ACE-I medication is contraindicated. Patients with ACE-I induced angioedema who need the blockade of the renin-
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angiotensin cascade (e.g. cardiac protection) can switch to ARBs with close monitoring. Treating severe ACE-I angioedema with antihistamines or
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corticosteroids is not effective, whereas treatment with a bardykinin receptor
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antagonist, such as Icatibant, seems promising.
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33. Grant NN, Deeb ZE, Chia SH. Clinical experience with angiotensin-converting enzyme inhibitor-induced angioedema. Otolaryngol Head Neck Surg. 2007;137(6):931-5. 34. 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(5):1239-43. 35. Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment. Arch Intern Med. 2004;164(8):910-3. 36. Beltrami L, Zanichelli A, Zingale L, Vacchini R, Carugo S, Cicardi M. Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema. J Hypertens. 2011;29(11):2273-7. 37. Hassen GW, Kalantari H, Parraga M, Chirurgi R, Meletiche C, Chan C, et al. Fresh frozen plasma for progressive and refractory angiotensin-converting enzyme inhibitor-induced angioedema. J Emerg Med. 2013;44(4):764-72. 38. Nielsen EW, Gramstad S. Angioedema from angiotensin-converting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate. Acta Anaesthesiol Scand. 2006;50(1):120-2. 39. Steinbach O, Schweder R, Freitag B. C1-esterase inhibitor in ACE inhibitorinduced severe angioedema of the tongue. Anaesthesiol Reanim. 2001;26(5):133-7. 40. Gelée B, Michel P, Haas R, Boishardy F. Angiotensin-converting enzyme inhibitor-related angioedema: emergency treatment with complement C1 inhibitor concentrate. Rev Med Interne. 2008;29(6):516-9 . 41. Illing EJ, Kelly S, Hobson JC, Charters S. Icatibant and ACE inhibitor angioedema. BMJ Case Rep. 2012;30:2012. 42. Manders K, van Deuren M, Hoedemaekers C, Simon A. Bradykinin-receptor antagonist icatibant: possible treatment for ACE inhibitor-related angiooedema. Neth J Med. 2012;70(8):386-7. 43. Gallitelli M, Alzetta M. Icatibant: a novel approach to the treatment of angioedema related to the use of angiotensin-converting enzyme inhibitors. Am J Emerg Med. 2012;30(8):1664.e1-2. 44. Bas M, Greve J, Stelter K, Bier H, Stark T, Hoffmann TK, et al. Therapeutic efficacy of icatibant in angioedema induced by angiotensin-converting enzyme inhibitors: a case series. Ann Emerg Med. 2010;56(3):278-82. 45. Fok JS, Katelaris CH, Smith WB. The use of icatibant in angiotensin converting enzyme inhibitor associated angioedema: our experience in Austrelia. Abstract No.1919, presented at EAACI WAO congress, Milano, Italy 2013. 46. Dyax Corporation. Evaluation of Ecallantide for treatment of Angiotensin Converting Enzyme (ACE) Inhibitor induced angioedema. Available at http:// clinicaltrials.gov/ct2/show/NCT01343823. 47. Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol. 2008;101(5):495-9.
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48. Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema. Ann Pharmacother. 2011;45(4):520-4.
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ACCEPTED MANUSCRIPT Legends to Figures
Figure1. Mechanisms of ACE-I adverse events. ACE induces the conversion of
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angiotensin I to the active angiotensin II. In addition, ACE enhances the degradation of bradykinin. ACE-I block both, the production of the active angiotensin II (may
cause hypotension, hyperkalemia, renal failure) and the degradation of bradikinin
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resulting in bradikinin accumulation (may cause cough or angiedema).
(+) indicates stimulation, (-) indicates inhibition. ACE-Angiotensin converting enzyme, ACE-I-Angiotensin converting enzyme inhibitor, ARBs-Angiotensin receptor
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blockers , HMW-high molecular weight, Inh-inhibitor, APP-Aminopeptidase P, NEP-
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Neutral endopeptidase.
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Clinical significance and bullet points •
Angioedema, like cough, is a class effect of angiotensin converting enzyme inhibitors.
•
The estimated incidence of ACE-I induced angioedema is 0.68%. Due to worldwide
•
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usage of these medications ACE-I induced angioedema is not uncommon.
ACE-I induced angioedema typically involves lips and tongue, but involvement of the gastrointestinal mucosa is an important presentation which might cause unnecessary invasive procedures.
Acute life threatening events should be addressed by measures that inhibit
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•
bradykinin.
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Patients who experienced angioedema to one ACE-I will typically have angioedema to all other ACE-I agents; hence, switching to another ACE-I medication is
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contraindicated.
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•
S0002-9343(14)00591-9
DOI:
10.1016/j.amjmed.2014.07.011
Reference:
AJM 12611
To appear in:
The American Journal of Medicine
Received Date: 2 October 2013 Revised Date:
13 July 2014
Accepted Date: 14 July 2014
Please cite this article as: Bezalel S, Mahlab-Guri K, Asher I, Werner B, Sthoeger ZM, Angiotensin Converting Enzyme Inhibitor Induced Angioedema, The American Journal of Medicine (2014), doi: 10.1016/j.amjmed.2014.07.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Review
Angiotensin Converting Enzyme Inhibitor Induced Angioedema Shira Bezalel, M.D.
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Keren Mahlab-Guri, M.D. Ilan Asher, M.D. Ben Werner, M.D.
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Zev Moshe Sthoeger, M.D.
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Departments of Medicine B, Clinical Immunology Allergy and AIDS, Kaplan Medical Center, Rehovot, Israel.
Corresponding author: Prof. Z.M. Sthoeger
Kaplan Medical Center Rehovot, 76100 Israel.
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Tel +972 8 9441917
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Head, Dept. Medicine B, Allergy and Clinical Immunology and AIDS center
Fax +972 8 9410461
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E-mail address: [email protected], [email protected] Cell phone number: +972 54 4617570
Conflict of interest for all authors – none Funding- none All authors had accesse to the data and had a role in writing the manuscript
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Abstract Angiotensin converting enzyme inhibitors (ACE-I) are widely used, effective and well tolerated anti-hypertensive agents. The mechanisms by which those agents act can
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cause side effects such as decreased blood pressure, hyperkalemia and impaired
renal function. ACE-I can induce cough in 5-35% and angioedema in up to 0.7% of the treated patients. Since cough and angioedema are considered class adverse effects,
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switching treatment to other ACE-I agents is not recommended. Angioedema due to
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ACE-I has a low fatality rate, although deaths have been reported when the angioedema involves the airways. Here, we review the role of bradykinin in the development of angioedema in patients treated with ACE-I as well as the incidence, risk factors, clinical presentation and available treatments for ACE-I induced
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angioedema. We also discuss the risk for recurrence of angioedema after switching
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from ACE-I to angiotensin receptor blockers (ARBs) treatment.
Key words: ACE-I (Angiotensin converting enzyme inhibitor), angioedema, cough,
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bradykinin, ARBs (angiotensin receptor blockers), Icatibant, Ecallantide.
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ACCEPTED MANUSCRIPT The first angiotensin converting enzyme Inhibitor (ACE-I), Captopril, was approved by the Food and Drug Administration (FDA) in the early 1980s 1. The treatment was proven to be effective in lowering blood pressure with an excellent tolerability profile. Since then, ACE-I agents have been widely used for the treatment of
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hypertension, congestive heart failure, diabetic nephropathy, post myocardial infarction and chronic kidney disease with proteinuria 2.
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ACE-I medications are divided into three groups based on their molecular structure at the active site of the drug: Sulfhydryl containing agents (e.g. Captopril) have the
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strongest chelating function and may cause skin rash and loss of taste. Dicarboxylate containing agents are weaker chelators (e.g. Enalapril, Ramipril) and are designed as prodrugs. The phosphonate containing agents (e.g. Fosinopril) are also a prodrug eliminated from the body via both, renal and hepatic pathways 3.
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Mechanism of action
The mechanism of ACE-I was considered a breakthrough in the treatment of hypertension. It is based on blocking the renin-angiotensin-aldosterone cascade.
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Normally, renin is produced and secreted by the juxtaglomerular apparatus in the
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kidneys in response to a drop in blood pressure or to a decrease in filtered sodium chloride concentration. The secreted renin cleaves the hepatic angiotensinogen to the inactive peptide angiotensin I. Angiotensin I is then converted into the active angiotensin II by ACE (angiotensin converting enzyme), which is produced mainly in the lung capillaries. Angiotensin II has a number of physiological effects. It increases blood vessel resistance, acts on the adrenal cortex to release aldosterone, stimulates the release of the antidiuretic hormone Vasopressin from the posterior pituitary, stimulates thirst centers, facilitates norepinephrine release from sympathetic nerve 3
ACCEPTED MANUSCRIPT endings and inhibits norepinephrine re-uptake (Figure 1) 1,2. ACE-I is a competitive inhibitor of the ACE enzyme, preventing the conversion of angiotensin I to the active angiotensin II. ACE is also responsible for the degradation of bradykinin. Active bradykinin is produced once its precursor, kininogen, is cleaved by kallikrein.
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Bradykinin has a short half-life due to rapid degradation primarily by ACE. Thus, the inhibition of ACE by ACE-I medications can prolong the half-life of bradykinin,
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increasing its concentration and activity 4 (Figure 1).
Angiotensin receptor blockers (ARBs), also known as AT1 receptor antagonists, block
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the binding of angiotensin II to its receptors, causing vasodilation, reduced secretion of vasopressin and reduced production and secretion of aldosterone (Figure 1) 5. As ACE-I, the ARBs are indicated for the treatment of hypertension, heart failure and diabetic nephropathy. ARBs do not have any effect on the activity of ACE. Therefore,
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ARBs medications do not inhibit the breakdown of bradykinin (Figure 1) 6. Consequently, ACE-I and ARBs differ in some of their adverse effects. ACE-I adverse effects
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Some of the adverse events of ACE-I result from the drug’s action. Hypotension, causing weakness, dizziness or syncope, caused about 1.7% of the patients to
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discontinue the drug 6. Hypotension is marked in hypovolemic patients. Severe reduction in the glomerular filtration rate (GFR) may be seen in patients with bilateral renal artery stenosis, hypertensive nephrosclerosis, heart failure, polycystic kidney disease or chronic kidney disease 7. In the above disorders the intrarenal perfusion pressure is reduced and the GFR is maintained mainly by angiotensin II, which increases the resistance at the postglomerular arterioles. Hence, treating these patients with ACE-I may cause renal dysfunction 6. Hyperkalemia is another 4
ACCEPTED MANUSCRIPT common side effect. ACE-I inhibits aldosterone release, which is the major stimulus for urinary potassium excretion. The overall incidence of hyperkalemia in patients treated with ACE-I is about 3.3%. Usually the potassium increment does not exceed 0.5mg/L 6. More prominent ACE-I induced hyperkalemia may be seen in patients
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with concomitant renal insufficiency, diabetes or concurrent use of potassium sparing agents or non-steroidal anti-inflammatory agents (NSAIDs) 8.
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ARBs treatment may also cause the above adverse events since they block
angiotensin II activity (Figure 1). Indeed, Fried et al recently recommended the
to hyperkalemia and renal failure 9.
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avoidance of ACE-I and ARBs combination in patients with diabetic nephropathy due
Captopril may cause sulfhydryl related adverse events, such as rash, neutropenia, taste abnormalities and nephritic syndrome. Some of those side effects are
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idiosyncratic while others are dose related 10. In the current dosage used (up to 150mg/day), those side effects are quite rare and do not reoccur with the other groups of ACE-I 10.
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ACE-I induced cough
Cough is a well described class adverse effect of ACE-I. The incidence of ACE-I
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induced cough is reported to be 5-35% 11 (9.9% in controlled randomized trials and 1.7% in cohort studies 12). In the ON Going Telmisartan Alone and in combination with the Ramipril Global Endpoint Trial (ONTARGET), cough caused the discontinuation of Ramipril in 4.2% of the treated patients 6. The precise mechanism by which ACE-I causes cough is not yet defined, but increased concentrations of bradykinin, substance P, prostaglandins and thromboxane (as discussed below) are most likely involved 13. Cough may occur within hours following the first dose of the 5
ACCEPTED MANUSCRIPT medication but it may delayed for weeks to months after the initiation of ACE-I agents. Switching treatment from one ACE-I to another is not effective since cough is a class adverse effect 11. When ACE-I is discontinued, improvement of the cough occurs within 1 to 4 weeks. In some patients resolution of the cough may take few
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months11. The incidence of ARBs induced cough is much lower (3.2% in controlled
trials and 0.6% in cohort studies 12). Although cough may occur with ARBs, they are
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considered an alternative treatment for patients who discontinued ACE-I due to cough and who need the blockade of the renin-angiotensin cascade.
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ACE-I induced angioedema
Angioedema is a self-limiting swelling (edema) of the skin (dermis and subdermis), mucosal tissues and organs such as the tongue, lips, eyelids, intestine wall or genitalia, all of which are rich in capillary blood supply 14. The edema is caused by
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hyperpermeability of post capillary venules due to vasoactive agents. There are two main types of angioedema. The allergic- histamine mediated angioedema develops rapidly and is associated with pruritus and rash (urticaria). In some patients systemic
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anaphylaxis may also occur 14, caused either by allergen specific IgE (e.g. food, drug,
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insect bite, aeroallergens) or by direct mast cell degranulation 15. On the other hand, the non-allergic angioedema (non-IgE mediated) is mediated mainly by bradykinin. The latter is a non-pruritic angioedema with a gradual onset, without rash, involving the extremities, face, larynx (airway obstruction) or intestinal lining (abdominal pain). This non-allergic angioedema is seen in patients with hereditary angioedema (HAE) and in patients with ACE-I induced angioedema 4. The exact mechanism by which ACE-I causes angioedema is not fully understood although bradykinin was shown to play a role in the pathogenesis of this adverse 6
ACCEPTED MANUSCRIPT event 16. The binding of bradykinin to its vascular receptor (BK2) results in vasodilation and increased vascular permeability, which in turn leads to interstitial fluid accumulation and angioedema 17. Normally, bradykinin has a short half-life due to rapid degradation. Three metaloproteinases are primarily involved in the
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degradation of bradykinin: ACE/kininase II, aminopeptidase P (APP) and neutral
endopeptidase (NEP). ACE is more effective in the degradation of bradykinin than
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APP, which is more effective than NEP 18. ACE-I medications block ACE/kininase II activity, thereby reducing the rate of bradykinin degradation, which leads to
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increased bradykinin levels (Figure 1). Nonetheless, only a small portion (0.3-0.68%) of patients treated with ACE-I develop angioedema 6,19. This may point towards other mechanism(s) in the pathogenesis of ACE-I induced angioedema. Bradykinin is metabolized by ACE/kininase II to the active bradykinin metabolite N-Arg-bradykinin.
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Approximately half the patients experiencing ACE-I induced angioedema were shown to have an enzymatic defect in the degradation of this active metabolite,
activity 20.
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which in the presence of ACE-I may result in further augmentation of bradykinin
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The fact that ARBs have no effect on bradykinin metabolism (Figure 1) may explain the low incidence of ARBs induced angioedema (0.11%), which is less than half of the rate (0.3%) observed in control trials of ACE-I treated patients 19. Incidence and risk factors Omapatrilat, an antihypertensive agent that inhibits both neutral endopeptidase and ACE, was not approved by the FDA due to a high rate (2.17%) of angioedema 21. The incidence of angioedema in the Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) trial, which randomized 12,634 patients to Enalapril 7
ACCEPTED MANUSCRIPT treatment, was 0.68% 21. Recently, Makani et al. reported an incidence of 0.3% of ACE-I induced angioedema in a meta-analysis of 26 randomized trials (74,875 patients) 19. Although angioedema is an uncommon adverse event of ACE-I treatment, due to the huge number of patients treated with those medications, it
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accounts for one third of angioedema cases treated in emergency rooms 22, 23.
Patients experiencing angioedema to one ACE-I agent will typically have angioedema
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to all other ACE-I because angioedema is a class adverse event and not a
hypersensitivity reaction. Thus, usage of any other ACE-I in patients with a history of
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ACE-I induced angioedema is contraindicated 23.
ACE-I induced angioedema was found to be more prevalent in patients of African ancestry 24, in patients older than 65 years, in females, in smokers, in patients with heart failure, in patients treated with statins, aspirin or sirolimus and in those with a
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history of any drug rash, seasonal allergies or previous angioedema 23, 25. A history of ACE-I induced cough was also reported to be a risk factor for angioedema 25 . On the other hand, diabetic patients were shown to have a lower risk for ACE-I induced
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angioedema as compared to non-diabetic patients 25. It should be noted that
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treatment with ACE-I is contraindicated in patients with HAE unless they are treated with purified C1-inhibitor concentrates, such as Berinet, Cinryze and Reconest, on a regular basis 26. Time of onset
The time interval between the initiation of ACE-I treatment and the development of angioedema is variable. Some patients may develop symptoms within one day, while in others symptoms may take as long as 8-10 years to develop 27. About 50% of patients with ACE-I induced angioedema develop it within the first week of 8
ACCEPTED MANUSCRIPT treatment 28. In the OCTAVE trial the incidence of angioedema was significantly higher shortly after the initiation of ACE-I therapy (3.6/1,000 patients in the first month of treatment vs. 0.4/1,000 patients after 24 weeks of treatment). The average time was 10.2 months following treatment initiation 21.
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Clinical presentation
ACE-I induced angioedema typically presents as a subcutaneous, non-pitting edema,
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evolving gradually over several hours without itching, rash or pain 14. The
angioedema usually involves the face, lips, tongue and the arms. Other cutaneous
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sites are less commonly involved 29. ACE-I induced angioedema may involve the gastrointestinal mucosa, causing abdominal pain accompanied by diarrhea, nausea, vomiting and ascites 30. Some of those patients are subjected to unnecessary invasive diagnostic or surgical procedures due to incorrect diagnosis 31. When the
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oral cavity and larynx are affected, the angioedema can rapidly progress to lifethreatening oropharyngeal obstruction and asphyxia 32. Currently, there are no laboratory tests for the diagnosis of ACE-I induced angioedema (in contrast to the
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low C2, C4 and C1 esterase inhibitor levels seen in HAE 14). Rather, a clinical
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diagnosis is made based on the prior usage of ACE-I medications and the disappearance of the angioedema following the discontinuation of medication. As mentioned above, in the OCTAVE trial, which involved 12,557 patients treated with Enalapril, the prevalence of angioedema was 0.68%. None of the patients with angioedema was affected severely enough to require intubation, and no deaths were reported 21. Other studies, however, reported that 10% of the patients with ACE-I induced oral cavity angioedema required endotracheal intubation 33.
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ACCEPTED MANUSCRIPT Furthermore, another study reported death in 7 African American patients due to ACE-I induced angioedema 34.
Management of ACE-I induced angioedema
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Most cases of ACE-I induced angioedema are mild, without any airway obstruction 21. Once ACE-I induced angioedema is suspected, the culpable drug must be stopped
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immediately. Drug discontinuation solved the problem in the vast majority of
patients within several hours (up to 48 hours), but the angioedema may last longer . If the ACE-I agents are not withdrawn, the angioedema episodes increase in
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35
frequency and in severity 35. Some patients experience one or more episodes of angioedema after discontinuation of the causative ACE-I. In a long term retrospective study, 88% of the relapses occurred within the first month following
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ACE-I discontinuation 36. In some cases, relapses continued for up to six months. In the case of persistent angioedema, patients should be further evaluated for other causes of angioedema 36. Since ACE-I induced angioedema is a class adverse effect, a
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switch to another ACE-I agent is contraindicated 35.
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Assessing airway patency is the most important element in managing patients with ACE-I induced angioedema, especially in those with facial and/or laryngeal angioedema. When indicated, endotracheal intubation or emergency tracheostomy should be done immediately. Antihistamines, anticholinergic agents, corticosteroids or epinephrine are not effective since ACE-I angioedema is not mediated by histamine 26. Fresh frozen plasma, which contains ACE as well as C1 esterase inhibitor, both able to decrease bradykinin levels (Figure 1), was shown to be effective in a few case 10
ACCEPTED MANUSCRIPT reports of patients with ACE-I induced laryngeal edema 37 . However, since C1 esterase inhibitor levels are normal in those patients, fresh frozen plasma is not a recommended treatment. Purified C1-inhibitor concentrates, such as Berinet, Cinryze and Reconest, which inhibit Kallikerin and thus decrease the amount of
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bradykinin (Figure 1), were also shown to be effective for ACE-I induced angioedema in a few case reports 38, 39, 40.
The bradykinin receptor type 2 (BR2) antagonist, Icatibant, was approved for the
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treatment of HAE 26. Since ACE-I induced angioedema is likely, at least in part, to be
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caused by high bradykinin levels (decreased degradation), treatment with the bradykinin receptor antagonist is reasonable (Figure 1). A small number of case reports and case series demonstrated beneficial effects of Icatibant in patients with ACE-I induced angioedma. Icatibant treatment in those patients resulted in a rapid
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reduction of the edema, preventing the need for tracheal intubation 41, 42, 43. In a clinical series of 8 patients with ACE-I induced angioedema, Icatibant shortened the time to full recovery as compared to an historical series of 47 patients with ACE-I
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induced angioedema of similar severity
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. In a retrospective case series of 7 patients
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with ACE-I associated angioedema, all patients responded well to Icatibant 45. Further large randomized studies, like the phase 3 NCT01919801 ongoing trial, are needed in order to define the role of Icatibant in the treatment of ACE-I induced angioedema.
Ecallantide is a recombinant protein that inhibits kallikerin activity, thus decreasing the conversion of high molecular weight (HMW) kininogen to bradykinin (Figure 1). Indeed, Ecallantide was shown to be more effective than placebo in 76 patients with ACE-I Induced angioedema 46 . Studies aimed to evaluate the efficacy of Ecallantide 11
ACCEPTED MANUSCRIPT in ACE-I induced angioedema, such as the phase 2 NCT01036659 trial, are currently in progress. It should be noted that both Icatibant and Ecallantide are very expensive drugs. Thus, in mild cases of ACE-I induced angioedema without any airway compromise,
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we recommend drug discontinuation (with close monitoring of the patients) as the primary therapeutic approach. In patients with laryngeal angioedema, which may
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compromise airway patency, however, endotracheal intubation or urgent
tracheostomy should be considered. In those patients, we recommend immediate
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administration of Icatibant (30 mg subcutaneously).
The data regarding the safety of ARBs in patients with previous ACE-I induced angioedema is limited. Theoretically, ARBs should be safe since they do not affect bradikinin metabolism (Figure 1). ARBs were, however, reported to cause
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angioedema (though at a much lower rate than ACE-I 19). Moreover, there are several reports of recurrent angioedema in patients who switched from ACE-I to ARBs due to the latter adverse event 47. It should be noted that in most of the above
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patients, the angioedema took place shortly after switching, indicating that the
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angioedema was probably still related to the previous ACE-I treatment 47, 48.Taking together, switching ACE-I to ARBs in patients with previous ACE-I angioedema is quite safe, but close monitoring of those patients (for the development of angioedema) is mandatory. In patients with a previous severe life-threatening ACE-I induced angioedema, we recommend avoiding both, ACE-I and ARBs medications. In summary, ACE-I are widely prescribed drugs with excellent tolerability and safety profiles. These drugs might cause side effects which result from the drug mechanism(s) of action, such as reduction of GFR, hypotension and hyperkalemia. In 12
ACCEPTED MANUSCRIPT our review we emphasize the class adverse effects, such as cough and angioedema. These class effects are due (at least in part) to bradykinin accumulation. Once diagnosed, treatment with ACE-I should be ceased immediately. Patients experiencing angioedema to one ACE-I will typically have angioedema to all other
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ACE-I agents; hence, switching to another ACE-I medication is contraindicated. Patients with ACE-I induced angioedema who need the blockade of the renin-
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angiotensin cascade (e.g. cardiac protection) can switch to ARBs with close monitoring. Treating severe ACE-I angioedema with antihistamines or
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corticosteroids is not effective, whereas treatment with a bardykinin receptor
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antagonist, such as Icatibant, seems promising.
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ACCEPTED MANUSCRIPT References
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48. Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema. Ann Pharmacother. 2011;45(4):520-4.
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ACCEPTED MANUSCRIPT Legends to Figures
Figure1. Mechanisms of ACE-I adverse events. ACE induces the conversion of
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angiotensin I to the active angiotensin II. In addition, ACE enhances the degradation of bradykinin. ACE-I block both, the production of the active angiotensin II (may
cause hypotension, hyperkalemia, renal failure) and the degradation of bradikinin
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resulting in bradikinin accumulation (may cause cough or angiedema).
(+) indicates stimulation, (-) indicates inhibition. ACE-Angiotensin converting enzyme, ACE-I-Angiotensin converting enzyme inhibitor, ARBs-Angiotensin receptor
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blockers , HMW-high molecular weight, Inh-inhibitor, APP-Aminopeptidase P, NEP-
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Neutral endopeptidase.
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Clinical significance and bullet points •
Angioedema, like cough, is a class effect of angiotensin converting enzyme inhibitors.
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The estimated incidence of ACE-I induced angioedema is 0.68%. Due to worldwide
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usage of these medications ACE-I induced angioedema is not uncommon.
ACE-I induced angioedema typically involves lips and tongue, but involvement of the gastrointestinal mucosa is an important presentation which might cause unnecessary invasive procedures.
Acute life threatening events should be addressed by measures that inhibit
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•
bradykinin.
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Patients who experienced angioedema to one ACE-I will typically have angioedema to all other ACE-I agents; hence, switching to another ACE-I medication is
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contraindicated.
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•
