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Original Investigation |

Angioedema Associated With Angiotensin-Converting Enzyme Inhibitor Use:  Outcome After Switching to a Different Treatment FREE

Marco Cicardi, MD; Lorenza C. Zingale, MD; Luigi Bergamaschini, MD; Angelo Agostoni, MD
Arch Intern Med. 2004;164(8):910-913. doi:10.1001/archinte.164.8.910.
Text Size: A A A
Published online

Background  Angiotensin-converting enzyme (ACE) inhibitors are associated with angioedema episodes that are potentially life-threatening. Few data are available on the outcome of patients reporting this adverse effect when they are switched to another drug. Scattered reports of angioedema associated with angiotensin II receptor blocker (ARB) use question the safety of using these drugs in patients with ACE inhibitor–related angioedema. We describe 64 consecutive patients with ACE inhibitor–related angioedema, the outcome after discontinuing this treatment, and the safety of using ARBs.

Methods  Retrospective analysis of 64 consecutive patients (January 1993 to June 2002) presenting with angioedema onset while receiving treatment with an ACE inhibitor.

Results  Patients were recommended to stop ACE inhibitor use, substituting it upon advice of the physician. Fifty-four patients were available for follow-up (median follow-up, 11 months; range, 1-80 months): 26 had switched to an ARB, 14 to a calcium antagonist, and 14 to other antihypertensive drugs. Angioedema disappeared or drastically reduced upon withdrawal of the ACE inhibitor in 46 patients (85%). For the remaining 8 patients, angioedema was due to a cause other than ACE inhibitor use in 2; angioedema persisted independent of the treatment and without apparent cause (idiopathic angioedema) in 4; angioedema persisted after switching to an ARB and disappeared upon its withdrawal in 2.

Conclusions  Stopping ACE inhibitor use without further assessments is a successful measure in the large majority of patients developing angioedema while taking this drug. Only a small percentage of patients with ACE inhibitor–related angioedema continue with this symptom when switched to an ARB.

Angioedema is a self-limiting, nonpitting edema that occurs in the skin and mucous membranes. Drugs are among the multiple precipitating factors.1 In drug-induced angioedema, the close temporal relationship between drug intake and appearance of angioedema is usually the key element that makes obvious identification and subsequent withdrawal of the offending medication.

Angiotensin-converting enzyme (ACE) inhibitors have long been recognized to cause angioedema,2 with reported incidence varying from 0.1% to 1%, although most of the large studies indicate incidence of about 0.1% to 0.2% of treated patients.3 Unlike other cases of drug-related angioedema, this adverse reaction of ACE inhibitor use is frequently missed because it can start years after beginning the treatment and recur inconstantly while the drug is continued. However, it has been shown that continuing use of ACE inhibitors after the first episode of angioedema results in a markedly increased rate of angioedema recurrence with serious morbidity.4 Six cases of fatal airway obstruction caused by angioedema related to ACE inhibitor use have been recently reported.5 It is therefore mandatory to recommend that patients presenting with angioedema while taking ACE inhibitors withdraw such treatment.

Inhibition of ACE blocks angiotensin conversion and reduces catabolism of bradykinin, a potent vasoactive peptide, which is degraded by ACE.6 Hence, it has been speculated, and there is now some experimental evidence, that ACE inhibitors induce angioedema by increasing availability of bradykinin.79 For this reason it has been assumed that drugs not affecting bradykinin metabolism should not present a risk of angioedema for patients who had this complication while taking ACE inhibitors.

Angiotensin II receptor blockers (ARBs), introduced in 1995 for treatment of hypertension, have a pharmacological profile similar to ACE inhibitors in blocking the renin-angiotensin system. Because they do not theoretically affect bradykinin, they are good candidates to substitute for ACE inhibitors in patients with bradykinin-related adverse reactions to these drugs.10,11 Nevertheless, occurrence of angioedema with different ARBs has been reported and the safety of these drugs for this indication is now debated.1222

The reports that describe large series of patients with angioedema during treatment with ACE inhibitors or ARBs are reviews of data from institutes for pharmacovigilance or from hospital files, and do not contain information on the recurrence of angioedema after treatment was changed. Thus, they lack a main clue to substantiate the diagnosis of drug-related angioedema. Actually, it is possible that angioedema will continue independent of the treatment, either because of the presence of a preexisting condition causing the angioedema23 or because the association with the drug was fortuitous.

We report on the outcome of 64 consecutive patients with ACE inhibitor–related angioedema after discontinuing ACE inhibitor treatment and on the safety of using ARBs.

STUDY POPULATION

From January 1993 through June 2002 we saw at our outpatient clinic 1168 patients for symptoms of angioedema with or without urticaria. Sixty-four of these patients were receiving treatment with an ACE inhibitor and had no other obvious causes for angioedema; 38 were men and 26 were women. Median age was 63 years (range, 46-84 years). Known causes of angioedema were excluded by clinical history that included detailed information about personal and familial allergies; relationship of angioedema to potential causative agents (eg, food, drugs, and chemicals); and complete physical examination. If known causes were excluded, patients were simply recommended to discontinue the ACE inhibitor and, after obtaining informed consent to participate to this study, to return for follow-up.

PLASMA MEASUREMENT

To rule out the possibility of a deficiency of C1 inhibitor (C1-INH) as the cause of angioedema, all patients were tested for C1-INH function, as measured by chromogenic assay (Baxter), and for C1-INH, C4, C3, and C1q antigens, as measured by radial immunodiffusion (NOR-Partigen, LOW-Partigen for C1q; Behringwerke AG, Marburg, Germany).

The ACE inhibitors used by the 64 patients at the time of onset of angioedema are shown below.

Scattered but unequivocal symptoms of angioedema before starting the ACE inhibitor therapy were recorded in 6 patients, and in 4 patients it could not be clarified whether angioedema or urticaria had previously been present. These patients were included in the study because the frequency of angioedema clearly worsened after starting ACE inhibitor therapy. Fifty-four patients denied any previous symptoms of urticaria or angioedema. The median length of ACE inhibitor treatment before the appearance of angioedema was 12 months (range, 0-156 months) and the median duration of ACE inhibitor use after the appearance of the first angioedema episode was also 12 months (range, 0-120 months). Grouping of the patients according to the duration of ACE inhibitor use after the first episode of angioedema is as follows: less than 1 month, 14 patients; 1 to 6 months, 12 patients; 6 to 12 months, 11 patients; and longer than 12 months, 27 patients. For patients continuing to take ACE inhibitors for 1 year or more after the first episode of angioedema, 7 (22%) had recurrences after 12 years; 9 (28%) had recurrences for 6 to 11 years; and 16 (50%) had recurrences between 1 and 5 years.

The face was the site most commonly involved (55 patients), followed by the tongue (25 patients). Other cutaneous locations were rare (9 patients) as well as abdominal symptoms referable to edema of the bowel mucosa (3 patients). Six patients had episodes of dyspnea due to laryngeal involvement. One of them underwent endotracheal intubation.

Withdrawal of the ACE inhibitor was recommended to all patients. Ten patients did not return for the follow-up visit and therefore are not further considered. Of the remaining 54 patients, 26 switched to an ARB, 14 to a calcium antagonist, and 14 to other treatments (β-blocker [5], α-lytic [1], diuretic [3], no treatment [5]). In these 3 groups, patients were not significantly different in terms of age, sex, duration of ACE inhibitor treatment before and after appearance of angioedema symptoms, presence of angioedema and/or urticaria before starting the ACE inhibitor use, or frequency of angioedema recurrence. The median length of the follow-up was 11 months (range, 1-80 months). Withdrawing the ACE inhibitor resulted in complete disappearance of angioedema in 37 patients (69%) and in drastic reduction in frequency and severity, so that the patients considered them negligible, in additional 9 patients (17%). Eight patients (15%) did not experience any improvement. Evolution of angioedema by means of the new therapeutic regimen is reported in Table 1.

Table Graphic Jump LocationOutcome of Angioedema in 54 Patients With ACE Inhibitor−Related Angioedema After Changing the Therapeutic Regimen*

The 8 patients who did not benefit from stopping ACE inhibitor use (5 who switched to ARBs and 3 to calcium antagonists) underwent further evaluation consisting of a second physical examination and laboratory tests aimed to discover other causes of angioedema such as infections, autoimmune disorders, or mailignancies. In 6 patients it was concluded that angioedema was not due to the antihypertensive treatment. In 1 patient, the angioedema disappeared after removal of a dental granuloma; in another patient, following a histamine-free diet resulted in angioedema disappearance; and in the remaining 4 patients, angioedema continued without recognizable etiology and regardless of changing or discontinuing the antihypertensive regimen. In the last 2 patients there is the possibility that the ARB, substituted for the ACE inhibitor, could have been causing angioedema. In the first patient, angioedema first appeared 3 months after starting treatment with enalapril and recurred over the course of 2 years while taking this drug. Episodes of angioedema continued for 2 months after candesartan was substituted for enalapril and then stopped after switching to a β-blocker. The other patient, receiving hemodyalisis for 3 years and taking enalapril for 5 years, had one angioedema episode that involved the face and upper airway, necessitating endotracheal intubation. After this episode he stopped taking enalapril and started losartan. Six months later he had a second angioedema episode of the face that resolved in 3 days without complications. Losartan use was stopped and nifedipine started. At the latest follow-up, 18 months later, he had not had any further episodes. All patients had normal complement parameters.

Occurrence of angioedema has been reported with the use of all ACE inhibitors and it is considered a class-related side effect.3 Our data confirm this finding, listing 10 different ACE inhibitors used at the time of onset of angioedema. The strikingly higher rate of recurrence with enalapril (55%) is remarkable. However, this is by far the most commonly used ACE inhibitor in Italy. Although we cannot exclude that enalapril carries a higher risk for angioedema compared with other preparations, it is still likely that our finding is just the consequence of its prominent position on the market. Angioedema related to ACE inhibitor use belongs to the group of angioedema that occurs in absence of significant rush of urticaria.24 The best recognized example in this group is hereditary angioedema, which is due to C1-INH deficiency, and likely is mediated by bradykinin.25 Along with these clinical and pathogenetic analogies, ACE inhibitor–related and hereditary angioedema share the emblematic, unexplained feature of recurrence of symptoms at randomly variable frequency, despite the constant persistence of the etiologic factor (C1-INH deficiency on one hand, ACE inhibitor treatment on the other).26,27 Efforts to identify the additional condition(s) that could link up with the initial cause in order to have angioedema to emerge remain unconvincing. A partial C1-INH deficiency has been hypothesized to be the predisposing factor for ACE inhibitor–related angioedema,3 but this supposition has never been confirmed; moreover, our patients' complement parameters were normal.

The severity of a condition characterized by angioedema depends on the rate of recurrences rather than on the risk of fatalities. Analysis of patients who remained on the ACE inhibitor for 1 year or longer after the first angioedema episode shows that in half of them symptoms recurred from a minimum of one every other month up to a weekly frequency. Considering that each attack lasts 48 to 96 hours, it results in disability of 10 to 120 days per year. This fact, along with the mentioned risk of fatality (in our series 1 patient underwent tracheostomy), emphasizes the importance of recognizing ACE inhibitors as a cause of angioedema. Unfortunately, the knowledge of this important adverse effect of ACE inhibitor use among practitioners is still lacking. The median of 10 months between appearance of angioedema and withdrawal of the drug should be regarded as an unacceptable medical error that needs to be corrected because it exposes patients to severe risks.

We examined the outcome of patients upon withdrawal the ACE inhibitor. In most, angioedema recurrence stopped or was drastically reduced, thereby reinforcing the evidence of a cause-effect relationship between the side effect and the treatment. The beneficial effect of stopping the drug was also verified in patients with a previous history of angioedema, which is an acknowledged risk factor for developing ACE inhibitor–related angioedema. A favorable outcome upon stopping the treatment was recorded in all 6 patients with such a history. Thus, since 85% of the patients solved the problem just upon stopping the drug, we recommend that this simple measure, without further assessments, should be immediately taken in patients who experience angioedema while taking ACE inhibitors.28,29

The final relevant point from this study concerns the safety of ARBs. As highlighted, these drugs appear the more obvious substitutes for ACE inhibitors, but reports of angioedema with their use suggest to reserve their use for patients with ACE inhibitor–related angioedema. Based on animal studies showing that the hypotensive effect of ARBs could be realized in part through release of vasodilators such as bradykinin,30 it also has been postulated that with these drugs angioedema could be bradykinin dependent.13 However, we found that these drugs do not worsen the frequency and the severity of symptoms in patients with hereditary angioedema, as one would expect with a drug that increases bradykinin levels or activity, and as it occurs with ACE inhibitors.29,31 Six of our patients with hereditary angioedema are taking an ARB for hypertension or renal disease since 6 months or more without effect on angioedema recurrences.

In the case of patients with ACE inhibitor–related angioedema, our overall experience on using ARBs as substitutive therapy is largely favorable, and this confirms another recent report32 on this issue. Twenty percent of patients in both the group taking calcium antagonists and ARBs did not benefit from just stopping the ACE inhibitor. However, this percentage also comprises patients in whom the association between antihypertensive drug and angioedema was shown to be just fortuitous. That an ARB could have sustained angioedema was a possibility for 2 (8%) of the 26 patients who switched to this class of drugs. This limited percentage does not seem a strong argument to consider ARBs as a contraindication in patients with ACE inhibitor–related angioedema.

Corresponding author and reprints: Marco Cicardi, MD, Dipartimento di Medicina Interna, Via Pace 9, 20122 Milan, Italy (e-mail: marco.cicardi@unimi.it).

Accepted for publication June 20, 2003.

Agostoni  ACicardi  M Drug-induced angioedema without urticaria. Drug Saf. 2001;24599- 606
PubMed Link to Article
Israili  ZHHall  WD Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology. Ann Intern Med. 1992;117234- 242
PubMed Link to Article
Vleeming  Wvan Amsterdam  JGStricker  BHde Wildt  DJ ACE inhibitor-induced angioedema: incidence, prevention and management. Drug Saf. 1998;18171- 188
PubMed Link to Article
Brown  NJSnowden  MGriffin  MR Recurrent angiotensin-converting enzyme inhibitor–associated angioedema. JAMA. 1997;278232- 233
PubMed Link to Article
Dean  DESchultz  DLPowers  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;461239- 1243
PubMed
Kaplan  APJoseph  KSilverberg  M Pathways for bradykinin formation and inflammatory disease. J Allergy Clin Immunol. 2002;109195- 209
PubMed Link to Article
Molinaro  GCugno  MPerez  M  et al.  Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther. 2002;303232- 237
PubMed Link to Article
Adam  ACugno  MMolinaro  GPerez  MLepage  YAgostoni  A Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors. Lancet. 2002;3592088- 2089
PubMed Link to Article
Nussberger  JCugno  MCicardi  M Bradykinin-mediated angioedema. N Engl J Med. 2002;347621- 622
PubMed Link to Article
Hernandez-Hernandez  RSosa-Canache  BVelasco  MArmas-Hernandez  MJArmas-Padilla  MCCammarata  R Angiotensin II receptor antagonists role in arterial hypertension. J Hum Hypertens. 2002;16 ((suppl 1)) S93- S99
PubMed Link to Article
Grossman  EMesserli  FHNeutel  JM Angiotensin II receptor blockers: equal or preferred substitutes for ACE inhibitors? Arch Intern Med. 2000;1601905- 1911
PubMed Link to Article
Lo  KS Angioedema associated with candesartan. Pharmacotherapy. 2002;221176- 1179
PubMed Link to Article
Howes  LGTran  D Can angiotensin receptor antagonists be used safely in patients with previous ace inhibitor-induced angioedema? Drug Saf. 2002;2573- 76
PubMed Link to Article
Abdi  RDong  VMLee  CJNtoso  KA Angiotensin II receptor blocker-associated angioedema: on the heels of ACE inhibitor angioedema. Pharmacotherapy. 2002;221173- 1175
PubMed Link to Article
Chiu  AGKrowiak  EJDeeb  ZE Angioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology. Laryngoscope. 2001;1111729- 1731
PubMed Link to Article
Warner  KKVisconti  JATschampel  MM Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother. 2000;34526- 528
PubMed Link to Article
Messerli  FHNussberger  J Vasopeptidase inhibition and angio-oedema. Lancet. 2000;356608- 609
PubMed Link to Article
Rivera  JO Losartan-induced angioedema. Ann Pharmacother. 1999;33933- 935
PubMed Link to Article
van Rijnsoever  EWKwee-Zuiderwijk  WJFeenstra  J Angioneurotic edema attributed to the use of losartan. Arch Intern Med. 1998;1582063- 2065
PubMed Link to Article
Sharma  PKYium  JJ Angioedema associated with angiotensin II receptor antagonist losartan. South Med J. 1997;90552- 523
PubMed Link to Article
Frye  CBPettigrew  TJ Angioedema and photosensitive rash induced by valsartan. Pharmacotherapy. 1998;18866- 868
PubMed
Acker  CGGreenberg  A Angioedema induced by the angiotensin II blocker losartan [case reports]. N Engl J Med. 1995;3331572
PubMed Link to Article
Kleiner  GIGiclas  PStadtmauer  GCunningham-Rundles  C Unmasking of acquired autoimmune C1-inhibitor deficiency by an angiotensin-converting enzyme inhibitor. Ann Allergy Asthma Immunol. 2001;86461- 464
PubMed Link to Article
Kaplan  AP Clinical practice: chronic urticaria and angioedema. N Engl J Med. 2002;346175- 179
PubMed Link to Article
Nussberger  JCugno  MAmstutz  CCicardi  MPellacani  AAgostoni  A Plasma bradykinin in angio-oedema. Lancet. 1998;3511693- 1697
PubMed Link to Article
Schiller  PIMessmer  SLHaefeli  WESchlienger  RGBircher  AJ Angiotensin-converting enzyme inhibitor-induced angioedema: late onset, irregular course, and potential role of triggers. Allergy. 1997;52432- 435
PubMed Link to Article
Carugati  APappalardo  EZingale  LCCicardi  M C1-inhibitor deficiency and angioedema. Mol Immunol. 2001;38161- 173
PubMed Link to Article
Orfan  NPatterson  RDykewicz  MS Severe angioedema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA. 1990;2641287- 1289
PubMed Link to Article
Agostoni  ACicardi  M Contraindications to the use of ace inhibitors in patients with C1 esterase inhibitor deficiency [case reports]. Am J Med. 1991;90278
PubMed Link to Article
Sosa-Canache  BCierco  MGutierrez  CIIsrael  A Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension. J Hum Hypertens. 2000;14 ((suppl 1)) S40- S46
PubMed Link to Article
Ebo  DGStevens  WJBosmans  JL An adverse reaction to angiotensin-converting enzyme inhibitors in a patient with neglected C1 esterase inhibitor deficiency. J Allergy Clin Immunol. 1997;99425- 426
PubMed Link to Article
Gavras  IGavras  H Are patients who develop angioedema with ACE inhibitor at risk of the same problem with AT1 receptor blockers? Arch Intern Med. 2003;163240- 241
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationOutcome of Angioedema in 54 Patients With ACE Inhibitor−Related Angioedema After Changing the Therapeutic Regimen*

References

Agostoni  ACicardi  M Drug-induced angioedema without urticaria. Drug Saf. 2001;24599- 606
PubMed Link to Article
Israili  ZHHall  WD Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology. Ann Intern Med. 1992;117234- 242
PubMed Link to Article
Vleeming  Wvan Amsterdam  JGStricker  BHde Wildt  DJ ACE inhibitor-induced angioedema: incidence, prevention and management. Drug Saf. 1998;18171- 188
PubMed Link to Article
Brown  NJSnowden  MGriffin  MR Recurrent angiotensin-converting enzyme inhibitor–associated angioedema. JAMA. 1997;278232- 233
PubMed Link to Article
Dean  DESchultz  DLPowers  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;461239- 1243
PubMed
Kaplan  APJoseph  KSilverberg  M Pathways for bradykinin formation and inflammatory disease. J Allergy Clin Immunol. 2002;109195- 209
PubMed Link to Article
Molinaro  GCugno  MPerez  M  et al.  Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther. 2002;303232- 237
PubMed Link to Article
Adam  ACugno  MMolinaro  GPerez  MLepage  YAgostoni  A Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors. Lancet. 2002;3592088- 2089
PubMed Link to Article
Nussberger  JCugno  MCicardi  M Bradykinin-mediated angioedema. N Engl J Med. 2002;347621- 622
PubMed Link to Article
Hernandez-Hernandez  RSosa-Canache  BVelasco  MArmas-Hernandez  MJArmas-Padilla  MCCammarata  R Angiotensin II receptor antagonists role in arterial hypertension. J Hum Hypertens. 2002;16 ((suppl 1)) S93- S99
PubMed Link to Article
Grossman  EMesserli  FHNeutel  JM Angiotensin II receptor blockers: equal or preferred substitutes for ACE inhibitors? Arch Intern Med. 2000;1601905- 1911
PubMed Link to Article
Lo  KS Angioedema associated with candesartan. Pharmacotherapy. 2002;221176- 1179
PubMed Link to Article
Howes  LGTran  D Can angiotensin receptor antagonists be used safely in patients with previous ace inhibitor-induced angioedema? Drug Saf. 2002;2573- 76
PubMed Link to Article
Abdi  RDong  VMLee  CJNtoso  KA Angiotensin II receptor blocker-associated angioedema: on the heels of ACE inhibitor angioedema. Pharmacotherapy. 2002;221173- 1175
PubMed Link to Article
Chiu  AGKrowiak  EJDeeb  ZE Angioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology. Laryngoscope. 2001;1111729- 1731
PubMed Link to Article
Warner  KKVisconti  JATschampel  MM Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother. 2000;34526- 528
PubMed Link to Article
Messerli  FHNussberger  J Vasopeptidase inhibition and angio-oedema. Lancet. 2000;356608- 609
PubMed Link to Article
Rivera  JO Losartan-induced angioedema. Ann Pharmacother. 1999;33933- 935
PubMed Link to Article
van Rijnsoever  EWKwee-Zuiderwijk  WJFeenstra  J Angioneurotic edema attributed to the use of losartan. Arch Intern Med. 1998;1582063- 2065
PubMed Link to Article
Sharma  PKYium  JJ Angioedema associated with angiotensin II receptor antagonist losartan. South Med J. 1997;90552- 523
PubMed Link to Article
Frye  CBPettigrew  TJ Angioedema and photosensitive rash induced by valsartan. Pharmacotherapy. 1998;18866- 868
PubMed
Acker  CGGreenberg  A Angioedema induced by the angiotensin II blocker losartan [case reports]. N Engl J Med. 1995;3331572
PubMed Link to Article
Kleiner  GIGiclas  PStadtmauer  GCunningham-Rundles  C Unmasking of acquired autoimmune C1-inhibitor deficiency by an angiotensin-converting enzyme inhibitor. Ann Allergy Asthma Immunol. 2001;86461- 464
PubMed Link to Article
Kaplan  AP Clinical practice: chronic urticaria and angioedema. N Engl J Med. 2002;346175- 179
PubMed Link to Article
Nussberger  JCugno  MAmstutz  CCicardi  MPellacani  AAgostoni  A Plasma bradykinin in angio-oedema. Lancet. 1998;3511693- 1697
PubMed Link to Article
Schiller  PIMessmer  SLHaefeli  WESchlienger  RGBircher  AJ Angiotensin-converting enzyme inhibitor-induced angioedema: late onset, irregular course, and potential role of triggers. Allergy. 1997;52432- 435
PubMed Link to Article
Carugati  APappalardo  EZingale  LCCicardi  M C1-inhibitor deficiency and angioedema. Mol Immunol. 2001;38161- 173
PubMed Link to Article
Orfan  NPatterson  RDykewicz  MS Severe angioedema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA. 1990;2641287- 1289
PubMed Link to Article
Agostoni  ACicardi  M Contraindications to the use of ace inhibitors in patients with C1 esterase inhibitor deficiency [case reports]. Am J Med. 1991;90278
PubMed Link to Article
Sosa-Canache  BCierco  MGutierrez  CIIsrael  A Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension. J Hum Hypertens. 2000;14 ((suppl 1)) S40- S46
PubMed Link to Article
Ebo  DGStevens  WJBosmans  JL An adverse reaction to angiotensin-converting enzyme inhibitors in a patient with neglected C1 esterase inhibitor deficiency. J Allergy Clin Immunol. 1997;99425- 426
PubMed Link to Article
Gavras  IGavras  H Are patients who develop angioedema with ACE inhibitor at risk of the same problem with AT1 receptor blockers? Arch Intern Med. 2003;163240- 241
PubMed Link to Article

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