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Abstract

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References

Angioedema is a well-recognized side effect of angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema can also be seen with angiotensin receptor blocker therapy but much less frequently than is the case with ACE inhibitors. For unclear reasons, ACE inhibitor-related angioedema occurs more commonly in black patients. Angioedema can be life threatening but more times than not its occurrence can be managed with conservative treatment measures including discontinuation of the medication and/or administration of an antihistamine. Occasionally, epinephrine and/or steroid therapy may be warranted. In a patient having experienced ACE inhibitor-related angioedema, angiotensin receptor blockers should be used cautiously if at all. If angiotensin receptor blocker therapy is being considered in a patient with prior ACE inhibitor-related angioedema there should be some justification for the use. Such justification might include the presence of heart failure or proteinuric nephropathic states among other considerations.

The term angioedema denotes a well demarcated, non-pitting edema that occurs as large erythematous areas in skin and subcutaneous tissues. Any area of the body may be involved with angioedema. Angioedema may or may not be accompanied by urticaria and can occur as either a hereditary or an acquired condition, with the latter often being medication-related. Angiotensin-converting enzyme (ACE) inhibitors have come to represent one of the more common causes of drug-related angioedema. In the instance of ACE inhibitor-related angioedema the most common sites of involvement are the tongue and the mucous membranes of the oropharynx and the periorbital/perioral regions. Angioedema of the cheeks, lids, and/or nose is observed but is somewhat less common with ACE inhibitor-related angioedema.1,2 Tongue swelling can be a particularly prominent finding with ACE inhibitor-induced angioedema and is a significant predictor that a patient may require laryngoscopy and/or hospitalization (Figure 1 and Figure 2).3,4 Isolated angioedema of the uvula has also been observed.5

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Figure 1. An illustrative case showing angioedema secondary to angiotensin-converting enzyme inhibitor use. Note the prominent swelling of the tongue.

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Figure 2. Same patient shown in Figure 1, now with resolution of the marked tongue swelling.

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ACE inhibitor-related angioedema may be accompanied by swelling of the extremities, genitalia, and viscera with the latter presenting with diarrhea, nausea, and/or abdominal pain.6,7 Urticaria and cough may also be present, but are not required for the diagnosis.8 Cough and angioedema often occur independently, suggesting that it is unlikely that they share a single common pathologic mechanism. Angioedema of the upper respiratory tract can progress to serious acute respiratory distress, airway obstruction, and death in the absence of appropriate intervention.9–11 ACE inhibitor-related angioedema is not typically accompanied by bronchospasm and when respiratory distress occurs it is secondary to upper airway obstruction. This form of angioedema is typically painless though it can be preceded by tingling paresthesias of the skin. ACE inhibitor-related angioedema develops in minutes to hours and resolves spontaneously. The time course of resolution can be quite varied ranging from hours to several days. Swelling that does not resolve within 3—4 days is unlikely to be angioedema. Occasionally, deaths have been reported with ACE inhibitor-related angioedema.10,11 Death generally occurs because of upper airway obstruction and an inability to adequately ventilate a patient.

INCIDENCE AND ONSET

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References

Angioedema with ACE inhibitors was first reported in 1984 and since then there has been a steady increase in the number of reported occurrences.12 ACE inhibitor-related angioedema is more common than was first imagined with the risk being as high as 5.54% in blacks.13 ACE inhibitor treated patients who have experienced an episode of angioedema can have a similar occurrence with angiotensin receptor blocker (ARB) therapy, albeit much less frequently.14–24 Angioedema, although life threatening, seldom proves fatal.11,13 ACE inhibitor-induced angioedema does not appear to have any clearly identifiable relationship to gender, age, or dosage. It tends to be more severe with repeat episodes if angioedema goes unrecognized and the medication is continued. The majority of reactions and the most severely symptomatic events occur in the first week after starting an ACE inhibitor and can occur within hours of the initial dose.8,11 Some cases are noted after a more prolonged course of therapy, even after several years of treatment with an ACE inhibitor.25

Cases of late onset angioedema have also been reported at variable times after discontinuation of an ACE inhibitor.26 Such a delayed presentation of angioedema may represent sporadic cases of angioedema, idiopathic or otherwise uncategorized, with no true temporal relationship to ACE inhibitor therapy. In fact, the early cases of ACE inhibitor-associated angioedema emphasized the occurrence of the reaction within days of beginning therapy. More recent reports suggest that the reaction can be a delayed one, literally occurring at any time during treatment.1,9 ACE inhibitor-induced angioedema remains underappreciated, in part, relating to its unpredictability. Rechallenge with an ACE inhibitor in a patient who has had angioedema after stopping an ACE inhibitor would allow for a distinction between sporadic idiopathic angioedema and that induced by ACE inhibitors but cannot be viewed as ethical. Patients having previously experienced any form of angioedema should not be administered an ACE inhibitor.

The estimate of the incidence of angioedema with ACE inhibitors comes from studies that did not assess the risk as a function of duration of therapy.11 Since knowledge of adverse drug reactions frequently comes from spontaneous reports it would be expected that initial reports would emphasize the early onset of the reaction, as reactions occurring in proximity to the initiation of therapy are more apt to be recognized; thus, the typical literature citations of an incidence of 0.1%–0.2% for ACE inhibitor-related angioedema may underestimate the true occurrence rate. For example, a controlled trial with enalapril showed that the occurrence of angioedema was at least ten times more frequent than could be derived from spontaneously reported occurrences. In the recently reported Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) trial the incidence rate for angioedema in a carefully performed prospective look at the angioedema incidence rate over 6 months of therapy with enalapril was 0.68% in 12,557 patients.13

CLINICAL PRESENTATION

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References

ACE Inhibitor Angioedema

It is crucial that physicians not only treat angioedema but also that they recognize its etiology. There are a number of case series in the literature demonstrating that ACE inhibitor-related angioedema is responsible for as many as 40% of angioedema episodes.3 Whether the incidence of angioedema varies with the different ACE inhibitors is not known. The available literature suggests that ACE inhibitor-related angioedema is poorly recognized. The causal association between ACE inhibitor use and an episode of angioedema is important since continued use of an ACE inhibitor results in a markedly increased rate of angioedema recurrence with serious morbidity.27 In one series of six patients with ACE inhibitor-associated angioedema who presented to emergency rooms, the role of ACE inhibitors was only recognized on one occasion.28 Moreover, it was reported that a patient presented with angioedema 18 times during a 3-year period before it was correctly diagnosed as being ACE inhibitor-related.29 Failure to recognize the cause has often led to extreme and often unnecessary diagnostic studies.

ACE Inhibitor-Related Angioedema of the Intestine

ACE inhibitor-induced angioedema of the intestine is rare. Its clinical presentation has a constellation of abdominal symptoms, pronounced bowel edema, and ascites with occasional facial and/or oropharyngeal swelling. It does not routinely occur as a first-dose phenomenon. ACE inhibitor-related intestinal angioedema is diagnosed based on the temporal relationship between the symptom profile and drug ingestion, absence of alternative diagnoses including other causes of angioedema, and the resolution of symptoms shortly after discontinuation of the ACE inhibitor. Prompt radiologic investigation (abdominal computerized tomography and/or ultrasound) is critical in establishing an early diagnosis and in preventing unnecessary surgical intervention. There is a female predominance to this form of intestinal angioedema, which may reflect an interaction of estradiol with the various pathways involved in the pathophysiology of this disease. Management of ACE inhibitor-related angioedema of the intestine consists mainly of conservative measures, the most important of which is the discontinuation of the ACE inhibitor. Angiotensin II receptor antagonists should not be considered as appropriate alternatives to an ACE inhibitor in an individual who has experienced this variant of intestinal angioedema.6,7

RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References

Several risk factors have been proposed for the induction of ACE inhibitor-associated angioedema including a history of idiopathic angioedema,30 head and neck surgery, and allergy to seafood. Acute external trauma may recruit vasoactive substances, which may contribute to the development of angioedema, particularly in ACE inhibitor-treated patients.31 Most of these suggested risk factors are derived from anecdotal reports without adequate controls. The most important predisposing risk factor, evidenced by case-control studies, appears to be ethnic differences.32,33 The risk of angioedema with ACE inhibitors is higher in blacks and appears not to be related to dose, specific ACE inhibitors, or concomitant medications.32 Although the basis for the increased likelihood of angioedema with ACE inhibitors in blacks is unclear, bradykinin has been implicated in its pathogenesis. Because urinary kallikrein is decreased in African Americans with hypertension it has been hypothesized that endogenous bradykinin levels may be lower in this population and that they may be more sensitive to sudden increases in bradykinin levels which occur with ACE inhibitor therapy.34 Previous tolerance to an ACE inhibitor does not exclude the risk for angioedema when therapy is modified to a different ACE inhibitor.11

MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References

The pathobiologic mechanism of angioedema with regard to ACE inhibitor therapy is believed to relate to the kallikrein-kinin plasma effector system. One hypothesis is that bradykinin, which is normally degraded by kininase II/ACE, accumulates in tissues. In this regard, plasma bradykinin has been shown to increase up to 12-fold during acute angioedema attacks in patients with hereditary or acquired forms of angioedema. Plasma bradykinin has also been shown to be elevated during an ACE inhibitor-related episode of angioedema in a 72-year-old patient on long-term treatment with captopril (50 mg/day).35

An additional study has reported decreased levels of carboxypeptidase N and C1 esterase inhibitor in affected patients treated with an ACE inhibitor.36 More recently, low levels of aminopeptidase P and dipeptidyl peptidase IV, enzymes known to catabolize bradykinin, have been suggested as predisposing factors for development of angioedema in patients treated with ACE inhibitors.37,38 The mechanism of angioedema with ACE inhibitors is not believed to be immunologic because angioedema may occur within hours to years after an ACE inhibitor is first taken.39 Thus, ACE inhibitors do not mediate angioedema through an allergic or idiosyncratic reaction: they seem to facilitate angioedema in predisposed individuals. Despite the aforementioned associations no skin or blood test is currently available to predictably identify patients at risk for angioedema from ACE inhibitors.

MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References

Angioedema is the result of leakage of fluid out of blood vessels beneath the skin. Once fluid is in the subcutaneous tissue, time is required to reabsorb the fluid. Intervention can only hope to prevent additional leakage. Once the swelling has resolved, no further treatment of the episode is needed other than avoidance of the drug that originally triggered the angioedema. In the 1980s life-threatening airway obstruction requiring intubation was reported in up to 22% of angioedema cases caused by ACE inhibitors, with an overall mortality of 11%.11 These mortality numbers have declined dramatically during the past decade at least, in part, in relationship to earlier intervention in the course of an angioedema episode. In fact, most episodes of angioedema are fairly mild and readily managed with drug discontinuation and antihistamine administration.

Maintenance of adequate airway function is critical in an ACE inhibitor treated patient experiencing angioedema. In cases where ventilation is threatened, the patient should be observed and hospitalized for 12–24 hours as needed. A standard for the acute treatment of angioedema should include antihistamines, preferably given by a route other than the oral route, subcutaneous epinephrine, and intravenous steroids (Table); however, to date no controlled studies have demonstrated the efficacy of these agents in ACE inhibitor-related angioedema31 and the administration of these therapeutic measures appears not to shorten the recovery period although they may modify the progression of the disease.40 Recently, fresh-frozen plasma has been shown to substantially improve ACE inhibitor-related angioedema.41 High-risk patients, such as those having previously had idiopathic angioedema and who are now receiving an ACE inhibitor, should be prescribed a bee-sting kit.

Table Table.  Therapy of ACE Inhibitor- or ARB-Related Angioedema
Immediately discontinue ACE inhibitor or ARB
Close clinical observation of respiratory status including pulse oximetry
Administer oxygen as indicated by oxygen saturation
Antihistamines
Epinephrine 1:1000 (0.3–0.5 mL)
Corticosteroids
Fresh-frozen plasma
Consider prophylactic intubation if airway compromise seems imminent
Failed intubation is an indication for tracheotomy
ACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker Adapted from Eur Arch Oto-Rhino-Laryngol [serial online]. May 24,2002.42

Use of ARBs

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References

Shortly after the release of ARBs, reports began to appear describing angioedema as a complication. These reports were in patients having previously experienced angioedema with an ACE inhibitor.23,24 A number of the early reports occurred in patients with renal insufficiency.16,23 Over time reports have appeared wherein ARB-related angioedema has occurred either in patients not having previously been exposed to an ACE inhibitor or in those having previously received an ACE inhibitor and not having developed angioedema.15,22 Recurrent episodes of angioedema have been reported in patients in whom the inciting ARB was not discontinued following the initial episode of angioedema.43 As with ACE inhibitors, there can be a lag time of a number of months before the appearance of angioedema with an ARB.15

The exact mechanism of ARB-related angioedema is unknown and, moreover, it is unclear as to what factors predispose a patient with ACE inhibitor-related angioedema to the subsequent development of angioedema with an ARB or what the exact frequency of its occurrence is.14,22 It is also unclear as to what degree sporadic idiopathic angioedema is falsely attributed to ARB therapy simply because an ARB was being given at the time of the episode. ARB-related angioedema seems to occur rarely in clinical trials. For example, in the Losartan Intervention for Endpoints (LIFE) trial44 there were six reported cases of angioedema in a total of 4605 patients treated for 4 years with losartan for an incidence rate of 0.1%. In the atenolol-treatment limb of the same trial in a total of 4588 patients treated for 4 years there were 11 episodes of angioedema for an incidence rate of 0.2%.44 These data would suggest that although angioedema can occur with an ARB that much of its occurrence is sporadic and not medication-specific.

Despite the relatively benign nature of most angioedema episodes and the infrequency of cross-reactivity for angioedema with an ARB these drugs cannot be used without some risk, albeit small, in patients having previously experienced angioedema with an ACE inhibitor. If ARB therapy is contemplated in a patient with prior ACE inhibitor-related angioedema there should be a reasonable justification for its use.45,46 Such justifications include congestive heart failure therapy, proteinuric nephropathy states, high-risk cardiovascular patients, resistant hypertension responsive only to interruption of the renin-angiotensin axis, and/or multiple medication sensitivities requiring therapy with a medication class devoid of side effects. No doubt additional therapeutic areas will emerge where the small risk of angioedema with an ARB can be justified by the benefit of such therapy.

Whenever an ARB is prescribed for a patient having previously experienced ACE inhibitor-related angioedema an open line of communication must exist between patient and physician since angioedema can be subtle in its presentation. All patients starting ARB therapy after having previously experienced ACE inhibitor-related angioedema should be made aware of the possibility of recurrent angioedema and instructed to inform their doctors' of any lip swelling, difficulty in breathing or swallowing, or episodes of muffled voice. If angioedema develops with one or the other of these drug classes the patient should contact a physician immediately. Patients should be instructed to self-administer an antihistamine—a number of which are available over-the-counter—pending a more formal evaluation by a physician. Angioedema can be self-limited, treatable with antihistamines, and not necessarily require immediate emergency room evaluation.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References

Angioedema is a well-described side effect of treatment with both ACE inhibitors and ARBs. The presentation of this form of angioedema is fairly classical with the predominant changes being found in the upper respiratory tract. Tongue swelling can be a particularly prominent finding in this disorder. There is currently no diagnostic test that specifically identifies those at risk for development of angioedema. Once angioedema has occurred with an ACE inhibitor or an ARB the offending agent should not be readministered. Angioedema can be treated with antihistamines, epinephrine, and/or steroids, although the specific efficacy of these agents has not been prospectively studied. Most episodes of angioedema are managed with antihistamine therapy alone.

References

  1. Top of page
  2. Abstract
  3. INCIDENCE AND ONSET
  4. CLINICAL PRESENTATION
  5. RISK FACTORS AND ACE INHIBITOR-INDUCED ANGIOEDEMA
  6. MECHANISMS INVOLVED IN ACE INHIBITOR-INDUCED ANGIOEDEMA
  7. MANAGEMENT OF PATIENTS WITH ACE INHIBITOR-INDUCED ANGIOEDEMA
  8. Use of ARBs
  9. CONCLUSIONS
  10. References
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