The Laryngoscope C 2015 The American Laryngological, V
Rhinological and Otological Society, Inc.
Treatment of Angiotensin Receptor Blocker-Induced Angioedema: A Case Series Ulrich Strassen, MD; Murat Bas, MD; Thomas K. Hoffmann, MD; Andreas Knopf, MD; Jens Greve, MD Background: Angiotensin II receptor antagonists have been proposed as a replacement therapy after the occurrence of either an angiotensin converting enzyme (ACE) inhibitor-induced angioedema or cough. However, recent studies indicate that angioedema is associated with elevated bradykinin levels in a small fraction of patients treated with angiotensin-II-receptor blockers, suggesting a common pathophysiological mechanism. To date, a standard treatment for angiotensin II receptor blocker-induced angioedema does not exist. Methods: We present a case series of patients admitted to our hospital due to angioedema induced by an angiotensin II receptor blocker. The patients were either treated with either icatibant (n 5 3) or prednisolone-21-hydrogen succinate/clemastine (n 5 5). Both patient groups were compared with an untreated patient cohort (n 5 3). All patients were previously diagnosed with essential hypertonia. Results: Icatibant was an effective therapy for angiotensin II receptor blocker-induced angioedema. Full symptom recovery was achieved after 5 to 7 hours, whereas symptom remission occurred within 27 to 52 and 24 to 54 hours in patients treated with Solu-Decortin prednisolone/clemastine and untreated patients, respectively. The recovery time for icatibant was similar to that described in previous studies regarding the therapeutic efficacy of icatibant for the treatment of hereditary angioedema and patients suffering from angiotensin converting enzyme inhibitor-induced angioedema. Conclusions: Icatibant is a safe and effective substance for the treatment of angiotensin II receptor blocker–induced angioedema. Although the pathophysiology of angiotensin II receptor blocker-induced angioedema remains unclear, it appears to be associated with the bradykinin pathway. Key Words: Angioedema, icatibant, B2 receptor antagonist, angiotensin receptor blocker , Quincke edema. Level of Evidence: 4. Laryngoscope, 125:1619–1623, 2015
INTRODUCTION Up to 18% of patients treated with angiotensin converting enzyme inhibitors (ACEi) suffer from ACEiinduced cough,1,2 and approximately 0.1% to 0.7%3–5 of patients present with angioedema of the head and neck region. These so-called ACEi-induced angioedema (AE) episodes account for approximately 25% to 38%6–8 of all AE patients admitted to emergency departments.
From the Department of Otorhinolaryngology, Head and Neck Surgery, Technical University of Munich (U.S., M.B., A.K), Munich; and the Department of Oto–Rhino–Laryngology, Head and Neck Surgery, Ulm University Medical Center (T.K.H., J.G.), Ulm, Germany. Editor’s Note: This Manuscript was accepted for publication December 19, 2014. Ulrich Strassen, M.D., was an investigator in company-sponsored scientific studies for CSL Behring, Shire, and ViroPharma GmbH; and he received a travel grant from Shire and ViroPharma to present at a scientific congress. Jens Greve, M.D., and Murat Bas, M.D., were investigators in company-sponsored scientific studies for Jerini AG, ViroPharma GmbH, and BioAlliance Pharma SA; and they received a travel grant from Shire and CSL Behring to present at a scientific congress. Both investigators have presented at company-sponsored meetings for Shire and received honoraria from CLS Behring, Shire, and ViroPharma GmbH. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Dr. Med, Ulrich Strassen, Department of Otorhinolaryngology, Head and Neck Surgery, Technical University of Munich, Ismaningerstr 22, 81675 Munich, Germany. E-mail: [email protected] DOI: 10.1002/lary.25163
Laryngoscope 125: July 2015
Reduced metabolism of bradykinin via ACE has been suggested as the underlying cause of these side effects.9,10 First-line therapy consists of replacing the antihypertensive medication. The B2 receptor antagonist icatibant (Firazyr, Shire, Lexington, MA) could be effective for the treatment of those attacks.11,12 Angiotensin receptor blockers (ARB) are recommended as a secondline treatment in these cases13 because of their similar ability to improve the long-term prognosis of patients suffering from arterial hypertension and congestive heart failure. Although ACEi treatment is the most common cause of angioedema, there are other important factors. Recent case reports and reviews indicate that patients receiving ARB therapy can also develop similar angioedema. Such AE cases have been reported after therapy with candesartan,14 losartan,15,16 olmesartan17 and valsartan,18 and the patients were treated with different dosages of corticosteroids, H1 and H2 antihistamines, and epinephrine. These patients remitted between 24 hours19 and a few days16 after treatment. The localization of these AE cases is similar to that of ACEi-induced AE. The cumulative incidence of ARB-induced AE per 1,000 persons is approximately 0.44 to 0.81 and appears to be most prevalent in patients treated with valsartan.20 The incidence of ARB-induced AE in patients who suffered from ACEi-induced AE is estimated to be approximately 10%.13 Strassen et al.: Treatment of ARB-Induced Angioedema
1619
Although ACEi-induced AE is caused by the decreased degradation of bradykinin via ACE and the subsequent elevation of bradykinin levels, leading to AE via the B2 receptor,21,22 other mechanisms have been postulated to cause ARB-induced AE.10,23 Angiotensin II (AT-II) receptor blockage causes a compensatory increase in angiotensin II levels24 and binding to the AT-II receptor. Stimulation of endothelial AT-II receptors elevates the concentration of bradykinin.25,26 Furthermore, the fraction of angiotensin II binding to AT-II-receptors increases when the AT-I receptor is blocked.27 Recent publications demonstrate that bradykinin concentrations are increased in patients treated with losartan.28 Therefore, the formation of bradykinin-induced AE is likely in this patient group. Direct binding of ARB to AT-II receptors might also explain the existence of ARB-induced AE. Interestingly, losartan can bind the B2-receptor and act as a partial agonist.29 ACE- and ARB-induced AE are usually localized in the upper aerodigestive tract, and they can lead to severe upper airway obstruction, with the need for either intubation or a tracheotomy; therefore, these conditions should be handled with extreme care despite their rarity. The current treatment strategy of ARBinduced AE consists of glucocorticoids and antihistamines, although these drugs are largely ineffective.30 To date, causal therapeutic schemes have not been developed. The present study aimed to determine the therapeutic efficacy of different treatment strategies for ARBinduced angioedema.
AE symptomatology, after which they were admitted to our hospital until complete symptom remission. The following data were recorded from patient files: time between the onset of swelling; time to initial symptom relief; and time between clinical onset and complete symptom relief, as assessed by direct fiberoptic nasopharyngolaryngoscopy that was performed until the complete remission of symptoms. Complete symptom relief was defined as complete recovery from all visual symptoms, as documented in the patient file, and was associated with discharge of the patient from the hospital with no further drug treatment related to angioedema. Patients were also questioned regarding side effects, including the relapse and recurrence of swelling in either the same or a different location at the time of discharge and 3 months thereafter.
RESULTS The clinical data for all patients are listed in Table I. Photo documentation of one patient upon presentation in the emergency department (a) and after complete symptom remission (b) is provided in Figure 1.
Untreated Patients All three patients experienced angioedema of the tongue. Of these, one patient presented an additional AE of the ary region, one presented an additional AE of the mouth floor, and one experienced an AE of the supraglottic endolarynx. Patients were taking irbesartan, candesartan, and losartan at 30, 8, and 50 mg, respectively. The mean time interval to complete symptom relief was 38 hours (range 24–54 hours) (Fig. 2). During the follow-up period, neither side effects nor AE reoccurrences were reported.
MATERIALS AND METHODS Study Design This retrospective analysis was based on cases treated in the two German clinics (Technical University of Munich and Ulm University Medical Center). Patients aged 18 years were treated and monitored at the Department of Otorhinolaryngology, Head and Neck Surgery at the Technical University of Munich, Germany, and the Department of Oto–Rhino–Laryngology, Head and Neck Surgery at the Ulm University Medical Center, Ulm, Germany. The diagnosis of an ARB-induced AE was based on the patients’ medical history and accurate examination. AEs of unknown origin, those occurring in the absence of ARB treatment, and those with a known etiology other than ARB treatment (e.g., C1-esterase inhibitor deficiency, ACEi treatment, or allergic urticaria) were excluded. ARB medication was discontinued in all patients, and replacement antihypertensive drugs were prescribed after a cardiology consultation.
Data Collection At first patient contact in our outpatient clinic, the cutaneous and subcutaneous swellings were recorded with respect to clinical symptoms, severity, and course of the attacks. A mirror exam and direct fiberoptic nasopharyngolaryngoscopy were carried out in all subjects. Patients were then personally interviewed and examined by physicians experienced in
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Patients Treated With Icatibant Three patients were treated with 30 mg of icatibant. Of these, one patient presented with AE of the endolarynx, aryepiglottic folds, and inter-ary region; one presented with AE of the lower lip, cheek and tongue; and one had an angioedema of the tongue and the aryepiglottic fold. All patients received an ARB regimen, which consisted of daily doses of candesartan, valsartan, and olmesartan (32, 160, and 10 mg, respectively), to treat arterial hypertension. The mean time to complete symptom relief was 6 hours (range 5–7 hours) (Fig. 2). All of the patients treated with icatibant experienced local skin irritation with erythema and cutaneous burning. In all cases, these local reactions resolved spontaneously within approximately 2 hours. Neither side effects nor AE reoccurrences were reported during the follow-up period.
Patients Treated With Prednisolone-21-Hydrogen Succinate/Clemastine Five patients were treated with 250 mg of prednisolone-21-hydrogen succinate and 2.68 mg of clemastine intravenously. Three patients suffered from AE of the tongue, two showed edema of the epiglottis, two Strassen et al.: Treatment of ARB-Induced Angioedema
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Strassen et al.: Treatment of ARB-Induced Angioedema
1621
arterial hypertension
arterial hypertension, diabetes mellitus, hypothyreosis
arterial hypertension, diabetes mellitus 2 arterial hypertension, coronary heart disease arterial hypertension, bronchial asthma
Uvula, upper lip
Tongue, uvula
Epiglottis, aryepiglottic fold Epiglottis, tongue
arterial hypertension, coronary heart disease
arterial hypertension
Tongue, aryepiglottic fold Lip, tongue, endolarynx
Tongue, mouth floor
Tongue
none
none
Icatibant none
Icatibant
Corticosteroid/H1 antihistamine Corticosteroid/H1 antihistamine Icatibant
Corticosteroid/H1 antihistamine
Corticosteroid/H1 antihistamine
Corticosteroid/H1 antihistamine
Therapy
108
not done
112
117 not done
9.1
8
5.4
5.53
4.56
6
107 not done
8.8
8.1
12.08
8.8
Leukocytes
115
103
not done
110
fC1-INH
15.1
0.9
3.4 0.8
not done
0.8
0.3
0.7
0.15
1.2
2.3
CRP
ACE 5 angiotensin converting enzyme; ARB 5 angiotensin receptor blockers; C1-INH 5 C1 esterase inhibitor; CRP 5 C-reactive protein.
arterial hypertension
arterial hypertension arterial hypertension
Lip, tongue, cheek
Epiglottis, aryepliglott fold
arterial hypertension, hypothyreosis
Medical Conditions
Tongue, aryepiglottic fold
Localization
not done
not done
5 not done
23
46
22
not done
not done
44
not done
ACE
not done
0.7
0.9 not done
1.1
1.1
1.2
0.9
1.2
0.8
0.5
Creatinine
730
183
365 200
unknown
1825
365
730
274
unknown
> 730
Time of ARB intake
TABLE I. Characteristics of All Patients Included in the Study (ACE Levels in U/L; Creatinine and CRP in Mg/Dl; Leukocytes in G/L; C1-INH Activity In %).
24
54
6 36
7
5
36
48
52
36
27
Time to Remission
male
male
female female
male
female
female
male
male
male
female
Sex
Fig. 2. Time (hours) to complete remission of symptoms for all patients and mean time (hours) to complete symptom remission (hours) for the three patient groups.
Fig. 1. Patient suffering from angiotensin receptor blockersinduced angioedema upon presentation in the emergency department (a) and after complete symptom remission (b). [Color figure can be viewed in the online issue, which is available at www. laryngoscope.com.]
presented with edema of the aryepiglottic folds, one had an edema of the upper lip and one presented AE of the uvula. All of the patients received an ARB regimen, which consisted of daily doses of losartan, candesartan and valsartan (50, 8 and 160 mg, respectively), to treat arterial hypertension. The mean time to complete relief of symptoms was 39.8 hours (range 27–52 hours) (Fig. 2). Neither side effects nor AE reoccurrences were reported during the follow-up period.
option for hereditary and ACEi-induced AE11,12 and could have a beneficial effect on ARB-induced AE if the edema was induced by bradykinin. In the icatibant group, the time to symptom improvement and remission were satisfactory compared with the untreated patients and patients treated with prednisolone-21-hydrogen succinate and clemastine in our clinic, as well as cases reported in the literature. Symptom remission was observed after 5 to 7 hours for patients in the icatibant group, whereas remission times of 24 to 54 hours and 27 to 52 hours were observed for untreated and combined corticosteroid and antihistamine-treated patients, respectively. These data correspond to the mean time to symptom relief for icatibant in the treatment of hereditary and ACEi AE. The mean time to complete symptom remission in these studies was between 4 an 10 hours for the icatibant group and between 19 and 51 hours for the placebo group.11,34 No adverse effects except for a local skin irritation at the injection site were observed after the administration of icatibant.
DISCUSSION Bradykinin effects vascular leakage primarily via the bradykinin B2 receptor.31,32 As a result, kinininduced acute AE is not responsive to classic antiallergic drugs.11 However, the current strategy to treat acute ARB-induced AE consists of the application of corticosteroids and antihistamines.33 Remission times after this therapy are similar to the values observed by placebo treatment. Therefore, novel and efficient therapeutic concepts are urgently needed. Binding of the competitive antagonist icatibant to the B2 bradykinin receptor reduces its activation. As a result, this drug represents an effective therapeutic Laryngoscope 125: July 2015
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CONCLUSION One major weakness of this study is that the AE severity was not graded in any of the patients. Nevertheless, the severity grade at admission is not correlated with the clinical course of AE in the subsequent hours; the time from the beginning of an attack of the upper airway to life-threatening asphyxiation can vary from 10 minutes to 14.3 hours, and initial symptoms can be minor.35 Despite the observed rapid symptom relief in ARBinduced AE after treatment with icatibant, our case series can only provide proof of concept and does not Strassen et al.: Treatment of ARB-Induced Angioedema
meet the level of high significance achieved in randomized, blinded, and prospective studies. The small sample size of this study did not allow us to assess statistical significance. Additional randomized, blinded prospective studies with larger sample sizes are needed to determine whether icatibant is an effective therapy for ARBinduced AE. Although the sample size is small due to the low incidence of ARB-induced AE, this is the first case series comparing different treatment schemes. In summary, the administration of 30 mg of icatibant might serve as an effective therapeutic option for the treatment of ARB-induced AE.
BIBLIOGRAPHY 1. Powers B, Greene L, Balfe LM. Updates on the treatment of essential hypertension: a summary of AHRQ’s comparative effectiveness review of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and direct renin inhibitors. J Manag Care Pharm 2011;17(suppl 8): S1–S14. 2. White CM, Greene L. Summary of AHRQ’s comparative effectiveness review of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers added to standard medical therapy for treating stable ischemic heart disease. J Manag Care Pharm 2011;17(suppl 5):S1–S15. 3. Powers BJ, Coeytaux RR, Dolor RJ, et al. Updated report on comparative effectiveness of ACE inhibitors, ARBs, and direct renin inhibitors for patients with essential hypertension: much more data, little new information. J Gen Intern Med 2012;27:716–729. doi: 10.1007/s11606-0111938-8. 4. Slater EE, Merrill DD, Guess HA, et al. Clinical profile of angioedema associated with angiotensin converting-enzyme inhibition. JAMA 1988; 260:967–970. 5. Bas M, Kojda G, Bier H, Hoffmann TK. [ACE inhibitor-induced angioedema in the head and neck region. A matter of time?]. Article in German. HNO 2004;52:886–890. 6. Rai MR, Amen F, Idrees F. Angiotensin-converting enzyme inhibitor related angioedema and the anaesthetist. Anaesthesia 2004;59:283–289. 7. Megerian CA, Arnold JE, Berger M. Angioedema: 5 years’ experience, with a review of the disorder’s presentation and treatment. Laryngoscope 1992;102:256–260. 8. Agah R, Bandi V, Guntupalli KK. Angioedema: the role of ACE inhibitors and factors associated with poor clinical outcome. Intensive Care Med 1997;23:793–796. 9. Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G. Nonallergic angioedema: role of bradykinin. Allergy 2007;62:842–856. 10. 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 2010;40:50–61. 11. Bas M, Greve J, Stelter K, et al. Therapeutic efficacy of icatibant in angioedema induced by angiotesin-converting enzyme inhibitors: a case series. Ann Emerg Med 2010;56:278–282. 12. Bas M, Bier H, Greve J, Kojda G, Hoffmann TK. Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant. Allergy 2006;61:1490–1492. 13. Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitorinduced angioedema. Ann Pharmacother 2011;45:520–524.
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14. Hamasaki H, Hiraishi C, Yanai H. Severe angioedema induced by angiotensin II receptor blocker. Int J Cardiol 2013;168:e15–e16. 15. Kazim SF, Shahid M. Losartan associated anaphylaxis and angioneurotic oedema. J Pak Med Assoc 2010;60:685–686. 16. van Rijnsoever EW, Kwee-Zuiderwijk WJ, Feenstra J. Angioneurotic edema attributed to the use of losartan. Arch Intern Med 1998;158: 2063–2065. 17. Nykamp D, Winter EE. Olmesartan medoxomil-induced angioedema. Ann Pharmacother 2007;41:518–520. 18. Kalra A, Cooley C, Palaniswamy C, Kalra A, Zanotti-Cavazzoni SL. Valsartan-induced angioedema in a patient on angiotensin-converting enzyme inhibitor for years: case report and literature review. Am J Ther 2012;19:e189–e192. 19. Lo KS. Angioedema associated with candesartan. Pharmacotherapy 2002; 22:1176–1179. 20. Toh S, Reichman ME, Houstoun M, 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– 1589. 21. Caballero T, Baeza ML, Cabanas R, et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis. J Investig Allergol Clin Immunol 2011;21:333–347; quiz follow 347. 22. Bas M, Hoffmann TK, Kojda G, Bier H. [ACE-inhibitor induced angioedema]. Article in German. Laryngorhinootologie 2007;86:804–808, quiz 809–813. 23. Cohen DL, Townsend RR. Can an angiotensin receptor blocker be used in a patient in whom angioedema developed with an angiotensinconverting enzyme inhibitor? J Clin Hypertens (Greenwich) 2008;10: 949–950. 24. Weir MR. Effects of renin-angiotensin system inhibition on end-organ protection: can we do better? Clin Ther 2007;29:1803–1824. 25. Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000;35:155–163. 26. Sosa-Canache B, Cierco M, Gutierrez CI, Israel A. Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension. J Hum Hypertens 2000;14(suppl 1):S40–S46. 27. Taylor AA, Siragy H, Nesbitt S. Angiotensin receptor blockers: pharmacology, efficacy, and safety. J Clin Hypertens (Greenwich) 2011;13:677–686. 28. Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation 2005;111:315–320. 29. Bonde MM, Olsen KB, Erikstrup N, et al. The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling. Regul Pept 2011;167:21–25. 30. Bas M, Hoffmann TK, Kojda G. Evaluation and management of angioedema of the head and neck. Curr Opin Otolaryngol Head Neck Surg 2006;14:170–175. 31. Han ED, MacFarlane RC, Mulligan AN, Scafidi J, Davis AE 3rd. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002;109:1057–1063. 32. Davis AE 3rd. The pathogenesis of hereditary angioedema. Transfus Apher Sci 2003;29:195–203. 33. Chiu AG, Krowiak EJ, Deeb ZE. Angioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology. Laryngoscope 2001;111:1729–1731. 34. Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010;363:532–541. 35. Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol 2012; 130:692–697.
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Rhinological and Otological Society, Inc.
Treatment of Angiotensin Receptor Blocker-Induced Angioedema: A Case Series Ulrich Strassen, MD; Murat Bas, MD; Thomas K. Hoffmann, MD; Andreas Knopf, MD; Jens Greve, MD Background: Angiotensin II receptor antagonists have been proposed as a replacement therapy after the occurrence of either an angiotensin converting enzyme (ACE) inhibitor-induced angioedema or cough. However, recent studies indicate that angioedema is associated with elevated bradykinin levels in a small fraction of patients treated with angiotensin-II-receptor blockers, suggesting a common pathophysiological mechanism. To date, a standard treatment for angiotensin II receptor blocker-induced angioedema does not exist. Methods: We present a case series of patients admitted to our hospital due to angioedema induced by an angiotensin II receptor blocker. The patients were either treated with either icatibant (n 5 3) or prednisolone-21-hydrogen succinate/clemastine (n 5 5). Both patient groups were compared with an untreated patient cohort (n 5 3). All patients were previously diagnosed with essential hypertonia. Results: Icatibant was an effective therapy for angiotensin II receptor blocker-induced angioedema. Full symptom recovery was achieved after 5 to 7 hours, whereas symptom remission occurred within 27 to 52 and 24 to 54 hours in patients treated with Solu-Decortin prednisolone/clemastine and untreated patients, respectively. The recovery time for icatibant was similar to that described in previous studies regarding the therapeutic efficacy of icatibant for the treatment of hereditary angioedema and patients suffering from angiotensin converting enzyme inhibitor-induced angioedema. Conclusions: Icatibant is a safe and effective substance for the treatment of angiotensin II receptor blocker–induced angioedema. Although the pathophysiology of angiotensin II receptor blocker-induced angioedema remains unclear, it appears to be associated with the bradykinin pathway. Key Words: Angioedema, icatibant, B2 receptor antagonist, angiotensin receptor blocker , Quincke edema. Level of Evidence: 4. Laryngoscope, 125:1619–1623, 2015
INTRODUCTION Up to 18% of patients treated with angiotensin converting enzyme inhibitors (ACEi) suffer from ACEiinduced cough,1,2 and approximately 0.1% to 0.7%3–5 of patients present with angioedema of the head and neck region. These so-called ACEi-induced angioedema (AE) episodes account for approximately 25% to 38%6–8 of all AE patients admitted to emergency departments.
From the Department of Otorhinolaryngology, Head and Neck Surgery, Technical University of Munich (U.S., M.B., A.K), Munich; and the Department of Oto–Rhino–Laryngology, Head and Neck Surgery, Ulm University Medical Center (T.K.H., J.G.), Ulm, Germany. Editor’s Note: This Manuscript was accepted for publication December 19, 2014. Ulrich Strassen, M.D., was an investigator in company-sponsored scientific studies for CSL Behring, Shire, and ViroPharma GmbH; and he received a travel grant from Shire and ViroPharma to present at a scientific congress. Jens Greve, M.D., and Murat Bas, M.D., were investigators in company-sponsored scientific studies for Jerini AG, ViroPharma GmbH, and BioAlliance Pharma SA; and they received a travel grant from Shire and CSL Behring to present at a scientific congress. Both investigators have presented at company-sponsored meetings for Shire and received honoraria from CLS Behring, Shire, and ViroPharma GmbH. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Dr. Med, Ulrich Strassen, Department of Otorhinolaryngology, Head and Neck Surgery, Technical University of Munich, Ismaningerstr 22, 81675 Munich, Germany. E-mail: [email protected] DOI: 10.1002/lary.25163
Laryngoscope 125: July 2015
Reduced metabolism of bradykinin via ACE has been suggested as the underlying cause of these side effects.9,10 First-line therapy consists of replacing the antihypertensive medication. The B2 receptor antagonist icatibant (Firazyr, Shire, Lexington, MA) could be effective for the treatment of those attacks.11,12 Angiotensin receptor blockers (ARB) are recommended as a secondline treatment in these cases13 because of their similar ability to improve the long-term prognosis of patients suffering from arterial hypertension and congestive heart failure. Although ACEi treatment is the most common cause of angioedema, there are other important factors. Recent case reports and reviews indicate that patients receiving ARB therapy can also develop similar angioedema. Such AE cases have been reported after therapy with candesartan,14 losartan,15,16 olmesartan17 and valsartan,18 and the patients were treated with different dosages of corticosteroids, H1 and H2 antihistamines, and epinephrine. These patients remitted between 24 hours19 and a few days16 after treatment. The localization of these AE cases is similar to that of ACEi-induced AE. The cumulative incidence of ARB-induced AE per 1,000 persons is approximately 0.44 to 0.81 and appears to be most prevalent in patients treated with valsartan.20 The incidence of ARB-induced AE in patients who suffered from ACEi-induced AE is estimated to be approximately 10%.13 Strassen et al.: Treatment of ARB-Induced Angioedema
1619
Although ACEi-induced AE is caused by the decreased degradation of bradykinin via ACE and the subsequent elevation of bradykinin levels, leading to AE via the B2 receptor,21,22 other mechanisms have been postulated to cause ARB-induced AE.10,23 Angiotensin II (AT-II) receptor blockage causes a compensatory increase in angiotensin II levels24 and binding to the AT-II receptor. Stimulation of endothelial AT-II receptors elevates the concentration of bradykinin.25,26 Furthermore, the fraction of angiotensin II binding to AT-II-receptors increases when the AT-I receptor is blocked.27 Recent publications demonstrate that bradykinin concentrations are increased in patients treated with losartan.28 Therefore, the formation of bradykinin-induced AE is likely in this patient group. Direct binding of ARB to AT-II receptors might also explain the existence of ARB-induced AE. Interestingly, losartan can bind the B2-receptor and act as a partial agonist.29 ACE- and ARB-induced AE are usually localized in the upper aerodigestive tract, and they can lead to severe upper airway obstruction, with the need for either intubation or a tracheotomy; therefore, these conditions should be handled with extreme care despite their rarity. The current treatment strategy of ARBinduced AE consists of glucocorticoids and antihistamines, although these drugs are largely ineffective.30 To date, causal therapeutic schemes have not been developed. The present study aimed to determine the therapeutic efficacy of different treatment strategies for ARBinduced angioedema.
AE symptomatology, after which they were admitted to our hospital until complete symptom remission. The following data were recorded from patient files: time between the onset of swelling; time to initial symptom relief; and time between clinical onset and complete symptom relief, as assessed by direct fiberoptic nasopharyngolaryngoscopy that was performed until the complete remission of symptoms. Complete symptom relief was defined as complete recovery from all visual symptoms, as documented in the patient file, and was associated with discharge of the patient from the hospital with no further drug treatment related to angioedema. Patients were also questioned regarding side effects, including the relapse and recurrence of swelling in either the same or a different location at the time of discharge and 3 months thereafter.
RESULTS The clinical data for all patients are listed in Table I. Photo documentation of one patient upon presentation in the emergency department (a) and after complete symptom remission (b) is provided in Figure 1.
Untreated Patients All three patients experienced angioedema of the tongue. Of these, one patient presented an additional AE of the ary region, one presented an additional AE of the mouth floor, and one experienced an AE of the supraglottic endolarynx. Patients were taking irbesartan, candesartan, and losartan at 30, 8, and 50 mg, respectively. The mean time interval to complete symptom relief was 38 hours (range 24–54 hours) (Fig. 2). During the follow-up period, neither side effects nor AE reoccurrences were reported.
MATERIALS AND METHODS Study Design This retrospective analysis was based on cases treated in the two German clinics (Technical University of Munich and Ulm University Medical Center). Patients aged 18 years were treated and monitored at the Department of Otorhinolaryngology, Head and Neck Surgery at the Technical University of Munich, Germany, and the Department of Oto–Rhino–Laryngology, Head and Neck Surgery at the Ulm University Medical Center, Ulm, Germany. The diagnosis of an ARB-induced AE was based on the patients’ medical history and accurate examination. AEs of unknown origin, those occurring in the absence of ARB treatment, and those with a known etiology other than ARB treatment (e.g., C1-esterase inhibitor deficiency, ACEi treatment, or allergic urticaria) were excluded. ARB medication was discontinued in all patients, and replacement antihypertensive drugs were prescribed after a cardiology consultation.
Data Collection At first patient contact in our outpatient clinic, the cutaneous and subcutaneous swellings were recorded with respect to clinical symptoms, severity, and course of the attacks. A mirror exam and direct fiberoptic nasopharyngolaryngoscopy were carried out in all subjects. Patients were then personally interviewed and examined by physicians experienced in
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Patients Treated With Icatibant Three patients were treated with 30 mg of icatibant. Of these, one patient presented with AE of the endolarynx, aryepiglottic folds, and inter-ary region; one presented with AE of the lower lip, cheek and tongue; and one had an angioedema of the tongue and the aryepiglottic fold. All patients received an ARB regimen, which consisted of daily doses of candesartan, valsartan, and olmesartan (32, 160, and 10 mg, respectively), to treat arterial hypertension. The mean time to complete symptom relief was 6 hours (range 5–7 hours) (Fig. 2). All of the patients treated with icatibant experienced local skin irritation with erythema and cutaneous burning. In all cases, these local reactions resolved spontaneously within approximately 2 hours. Neither side effects nor AE reoccurrences were reported during the follow-up period.
Patients Treated With Prednisolone-21-Hydrogen Succinate/Clemastine Five patients were treated with 250 mg of prednisolone-21-hydrogen succinate and 2.68 mg of clemastine intravenously. Three patients suffered from AE of the tongue, two showed edema of the epiglottis, two Strassen et al.: Treatment of ARB-Induced Angioedema
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arterial hypertension
arterial hypertension, diabetes mellitus, hypothyreosis
arterial hypertension, diabetes mellitus 2 arterial hypertension, coronary heart disease arterial hypertension, bronchial asthma
Uvula, upper lip
Tongue, uvula
Epiglottis, aryepiglottic fold Epiglottis, tongue
arterial hypertension, coronary heart disease
arterial hypertension
Tongue, aryepiglottic fold Lip, tongue, endolarynx
Tongue, mouth floor
Tongue
none
none
Icatibant none
Icatibant
Corticosteroid/H1 antihistamine Corticosteroid/H1 antihistamine Icatibant
Corticosteroid/H1 antihistamine
Corticosteroid/H1 antihistamine
Corticosteroid/H1 antihistamine
Therapy
108
not done
112
117 not done
9.1
8
5.4
5.53
4.56
6
107 not done
8.8
8.1
12.08
8.8
Leukocytes
115
103
not done
110
fC1-INH
15.1
0.9
3.4 0.8
not done
0.8
0.3
0.7
0.15
1.2
2.3
CRP
ACE 5 angiotensin converting enzyme; ARB 5 angiotensin receptor blockers; C1-INH 5 C1 esterase inhibitor; CRP 5 C-reactive protein.
arterial hypertension
arterial hypertension arterial hypertension
Lip, tongue, cheek
Epiglottis, aryepliglott fold
arterial hypertension, hypothyreosis
Medical Conditions
Tongue, aryepiglottic fold
Localization
not done
not done
5 not done
23
46
22
not done
not done
44
not done
ACE
not done
0.7
0.9 not done
1.1
1.1
1.2
0.9
1.2
0.8
0.5
Creatinine
730
183
365 200
unknown
1825
365
730
274
unknown
> 730
Time of ARB intake
TABLE I. Characteristics of All Patients Included in the Study (ACE Levels in U/L; Creatinine and CRP in Mg/Dl; Leukocytes in G/L; C1-INH Activity In %).
24
54
6 36
7
5
36
48
52
36
27
Time to Remission
male
male
female female
male
female
female
male
male
male
female
Sex
Fig. 2. Time (hours) to complete remission of symptoms for all patients and mean time (hours) to complete symptom remission (hours) for the three patient groups.
Fig. 1. Patient suffering from angiotensin receptor blockersinduced angioedema upon presentation in the emergency department (a) and after complete symptom remission (b). [Color figure can be viewed in the online issue, which is available at www. laryngoscope.com.]
presented with edema of the aryepiglottic folds, one had an edema of the upper lip and one presented AE of the uvula. All of the patients received an ARB regimen, which consisted of daily doses of losartan, candesartan and valsartan (50, 8 and 160 mg, respectively), to treat arterial hypertension. The mean time to complete relief of symptoms was 39.8 hours (range 27–52 hours) (Fig. 2). Neither side effects nor AE reoccurrences were reported during the follow-up period.
option for hereditary and ACEi-induced AE11,12 and could have a beneficial effect on ARB-induced AE if the edema was induced by bradykinin. In the icatibant group, the time to symptom improvement and remission were satisfactory compared with the untreated patients and patients treated with prednisolone-21-hydrogen succinate and clemastine in our clinic, as well as cases reported in the literature. Symptom remission was observed after 5 to 7 hours for patients in the icatibant group, whereas remission times of 24 to 54 hours and 27 to 52 hours were observed for untreated and combined corticosteroid and antihistamine-treated patients, respectively. These data correspond to the mean time to symptom relief for icatibant in the treatment of hereditary and ACEi AE. The mean time to complete symptom remission in these studies was between 4 an 10 hours for the icatibant group and between 19 and 51 hours for the placebo group.11,34 No adverse effects except for a local skin irritation at the injection site were observed after the administration of icatibant.
DISCUSSION Bradykinin effects vascular leakage primarily via the bradykinin B2 receptor.31,32 As a result, kinininduced acute AE is not responsive to classic antiallergic drugs.11 However, the current strategy to treat acute ARB-induced AE consists of the application of corticosteroids and antihistamines.33 Remission times after this therapy are similar to the values observed by placebo treatment. Therefore, novel and efficient therapeutic concepts are urgently needed. Binding of the competitive antagonist icatibant to the B2 bradykinin receptor reduces its activation. As a result, this drug represents an effective therapeutic Laryngoscope 125: July 2015
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CONCLUSION One major weakness of this study is that the AE severity was not graded in any of the patients. Nevertheless, the severity grade at admission is not correlated with the clinical course of AE in the subsequent hours; the time from the beginning of an attack of the upper airway to life-threatening asphyxiation can vary from 10 minutes to 14.3 hours, and initial symptoms can be minor.35 Despite the observed rapid symptom relief in ARBinduced AE after treatment with icatibant, our case series can only provide proof of concept and does not Strassen et al.: Treatment of ARB-Induced Angioedema
meet the level of high significance achieved in randomized, blinded, and prospective studies. The small sample size of this study did not allow us to assess statistical significance. Additional randomized, blinded prospective studies with larger sample sizes are needed to determine whether icatibant is an effective therapy for ARBinduced AE. Although the sample size is small due to the low incidence of ARB-induced AE, this is the first case series comparing different treatment schemes. In summary, the administration of 30 mg of icatibant might serve as an effective therapeutic option for the treatment of ARB-induced AE.
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