Brief Reports
Angioedema Associated With Lisinopril RICHARD S. REES, MD, JEFFREY BERGMAN, RINA RAMIREZ-ALEXANDER, Angioedema has been reported to occur in association with all angiotensin-converting enzyme inhibitors used in the United States. We reviewed nine cases of angioedema associated with llsinopril use seen in the emergency department at our hospital among 1,970 patients that had been prescribed lisinopril from March 1989 to May 1990. Cases were considered as probably (six cases) or possibly (three cases) drug related, depending on the temporal relationship of the initiation of therapy and the onset of angloedema. All of the cases had edema of the lips, buccal mucosa, and or face. None presented with laryngeal edema or stridor. The angioedema resolved within 1 to 2 days with diphenhydramine treatment and discontinuation of lisinopril. Our data suggest that the incidence of angioedema associated with lisinopril is greater than that associated with captopril or enalapril. (Am J Emerg Med 1!!2;10:321-322. Copyright 0 1992 by W.8. Saunders Company)
Angioedema has been reported to occur in association with all angiotensin-converting enzyme (ACE) inhibitors. Although this is an infrequent complication, it can be life threatening. ‘J Until March 1, 1989, all three ACE inhibitors available for use in the United States were on our hospital formulary. Thereafter, enalapril was deleted from the formulary (to reduce pharmacy costs). As a result, large numbers of patients were subsequently started on lisinopril. From that time until May 1990 we saw nine cases of angioedema associated with lisinopril in the emergency department. These
cases
are the subjects
of this report.
PATIENTS AND METHODS From March 1989 to May 1990 a computer search revealed that 1,970 patients were prescribed lisinopril at our hospital. After the first case of angioedema associated with lisinopril was seen in the emergency department, the staff was requested to report all subsequent cases. Cases were considered probably drug related if there was a close temporal relationship between initiation of therapy and onset of angioedema. Cases were considered possibly drug related in patients taking lisinopril who had no prior history of angioedema. RESULTS
Clinical data for the nine cases are shown in Table 1. All of the patients were men and all were being treated for hyper-
From the Departments of Medicine and Ambulatory Care, the Department of Veterans Affairs Medical Center, New York, NY; and the NYU School of Medicine, New York, NY. Manuscriot received November 7. 1991: acceoted November . 25,199l. . Address reprint requests to Dr Rees, Medical Service, Department of Veterans Affairs Medical Center, 423 E 23rd St, New York, NY 10010. Key Words: Angioedema, lisinopril, angiotensin-converting enzyme inhibitors. Copyright 0 1992 by W.B. Saunders Company 0735-6757/92/l 004-0010$5.0010
MD, MD
tension. None of the patients had a prior history of allergy or angioedema. All of the patients had edema of the lips, buccal mucosa, and/or face, except patient no. 9 who had edema of the tongue only. None of the patients had obvious laryngeal edema or stridor, although patient no. 8 reported that he experienced “throat tightening and swelling” after the first dose. All of the patients were examined during the acute reaction except for patients no. 5 and 8 who reported to the emergency department after the angioedema had resolved. Their descriptions, however, were classic for angioedema in that they both reported relatively rapid onset of swelling of the lips and face several hours after taking lisinopril. We considered six cases of angioedema as probably drug related (cases no. 1, 2, 3, 4, 6, and 8) and three cases as possibly drug related (cases no. 5, 7, 9) and yielding a crude cumulative incidence of 1:328 (0.3%) or 1:219 (OS%), respectively. Of the six cases that were probably drug related, five occurred within three doses; the sixth case occurred within 2 weeks of the start of therapy. Three of the six patients were receiving no other medication at the time. The other three patients were receiving medication that they had taken previously without incident or that they were taking chronically. The three possibly related cases had been taking lisinopril for several months, but one was on no other medication. In the other two cases, lisinopril was the most recent addition to the medical regimen (the patients had been receiving the other medication for more than 1 year prior to the addition of lisinopril). The majority of the patients were treated with diphenhydramine alone and had no progression of edema. Lisinopril was discontinued. The edema resolved in 1 to 2 days. DISCUSSION
Angioedema has been reported to occur in association with captopril, enalapril, and lisinopril with a frequency of 0. 1%.3 Post marketing data appear to confirm this frequency for enalapri14 and captopril,5*6 but suggest a higher frequency for lisinopril (OS%).’ Our data also suggest a higher frequency for lisinopril than originally reported. Because this was not a surveillance study of all patients on lisinopril we may have been unaware of some cases of angioedema. Therefore, the incidence of angioedema associated with lisinopril could be even higher. During the same time period, 817 patients were prescribed captopril at our hospital. No cases of captopril-associated angioedema were seen by or reported to us, and no cases of adverse drug reactions were found in the hospital surveillance record. While this was not a comparative study of the two drugs, the same biases of overreporting and underre321
AMERICAN JOURNAL OF EMERGENCY MEDICINE n Volume 10, Number 4 m July 1992
322
TABLE1. Clinical Data on Patients Who Developed Angioedema After Taking Lisinopril
Age (yr)/Sex
Daily Dose (mg)
44/M
10
Lips, buccal/no
After third dose
None
2
52/M
10
Lips, buccal/no
After second dose
None
3
50/M
10
Lips, buccal, facial/no
After third dose
Ibuprofen, methocarbamol
4
62/M
10
Lips, facial/no
Within 2 wk
None
5’
67/M
10
Lips, facial/unknownt
6
66/M
10
Lips, facial, buccal/no
Multiple episodes after 2 mo on drug After first dose
7*
50/M
10
Lips, buccal/no
After 4 mo on drug
Hydrochlorthiazide, diltiazem, gemfibrozil Pilocarpine, betaxolol, colchicine None
8
56/M
20
After second dose
Ampicillin, ibuprofen
9
69/M
20
Lips, buccal, facial/? after first doset Tongue/no
After 10 mo on drug
Atenolol, aspirin, cimetidine, pentoxifylline
Case No.
Edema/Strider
Onset of Reaction
Other Medications
Treatment Diphenhydramine, observation, DC lisinopril Diphenhydramine, observation, DC lisinopril Diphenhydramine, observation, DC lisinopril Diphenhydramine, observation, DC lisinopril None
Diphenhydramine, observation, DC lisinoprii Diphenhydramine, observation, DC lisinopril None
Diphenhydramine, epinephrine, observation, DC lisinopril
ABBREVIATION:DC, discontinue. Possibly drug related; all others, probably drug related. t By history, not observed. l
porting should have applied. This also suggests that the incidence of angioedema may be higher with lisinopril than with captopril. We consider our cases probable or possible rather than definitely drug related because we did not rechallenge our patients with lisinopril, but a causal association is supported by the temporal relation of the reaction to the start of treatment and the absence of other likely causes in many of the patients. The time course of the reaction in our patients was similar to that in other studies.4.8 The mechanism of ACE inhibitor-associated angioedema is thought to be biochemical rather than immunologic.6 Bradykinin is believed to play a role in the pathogenesis of angioedema. It is inactivated by two proteases, kininase I (carboxypeptidase N) and kininase II (identical to ACE). Development of angioedema in patients receiving ACE inhibitors may be due to decreased destruction of local tissue bradykinin.’ Deficiency of carboxypeptidase N may also be associated with episodes of angioedema,” and Slater et al4 have speculated that susceptibility to ACE inhibitorassociated angioedema may be greater in patients with this deficiency. Several new ACE inhibitors recently have been released and more are expected. Given the low incidence of side effects associated with ACE inhibitors, it is anticipated that the number of patients treated with these agents will increase greatly. Because of this, episodes of angioedema will be seen with increasing frequency in emergency departments, and
physicians must be aware of this potentially complication.
life-threatening
REFERENCES 1. Gianos ME, Klaustermeyer WB, Kurohara M, et al: Enalapril induced angioedema. Am J Emerg Med 1990;8:124-126 2. Chin HL, Buchan DA: Severe angioedema after long-term use of an angiotensin-converting enzyme inhibitor. Ann Intern Med 1990;112:312-313 (letter) 3. US Physicians Desk Reference. Ordell, NJ, Medical Economics Books, 1990, pp 2129, 2175 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. Irvin JD, Viau JM: Safety profiles of the angiotensin converting enzyme inhibitors captopril and enalapril. Am J Med 1986;81(4C):46-50 6. Singer DRJ, Macgregor GA: Angioneurotic oedema associated with two angiotensin converting enzyme inhibitors. Br Med J 1986;293:1243 7. Cameron HA, Higgins TJC: Clinical experience with lisinopril. Observations on safety and tolerability. J Hum Hypertens 1989;3(1):177-186. 8. Wood SM, Mann RD, Rawlins MD: Angio-oedema and urticaria associated with angiotensin converting enzyme inhibitors. Br Med J 1987;294:91-92 9. Ferner RE, Simpson JM, Rawlins MD: Effects of intradermal bradykinin after inhibition of angiotensin converting enzyme. Br Med J 1987;294:1119-1120 10. Mathews KP, Pan PM, Gardner NJ, et al: Familial carboxypeptidase N deficiency. Ann Intern Med 1980;93:443-445
Angioedema Associated With Lisinopril RICHARD S. REES, MD, JEFFREY BERGMAN, RINA RAMIREZ-ALEXANDER, Angioedema has been reported to occur in association with all angiotensin-converting enzyme inhibitors used in the United States. We reviewed nine cases of angioedema associated with llsinopril use seen in the emergency department at our hospital among 1,970 patients that had been prescribed lisinopril from March 1989 to May 1990. Cases were considered as probably (six cases) or possibly (three cases) drug related, depending on the temporal relationship of the initiation of therapy and the onset of angloedema. All of the cases had edema of the lips, buccal mucosa, and or face. None presented with laryngeal edema or stridor. The angioedema resolved within 1 to 2 days with diphenhydramine treatment and discontinuation of lisinopril. Our data suggest that the incidence of angioedema associated with lisinopril is greater than that associated with captopril or enalapril. (Am J Emerg Med 1!!2;10:321-322. Copyright 0 1992 by W.8. Saunders Company)
Angioedema has been reported to occur in association with all angiotensin-converting enzyme (ACE) inhibitors. Although this is an infrequent complication, it can be life threatening. ‘J Until March 1, 1989, all three ACE inhibitors available for use in the United States were on our hospital formulary. Thereafter, enalapril was deleted from the formulary (to reduce pharmacy costs). As a result, large numbers of patients were subsequently started on lisinopril. From that time until May 1990 we saw nine cases of angioedema associated with lisinopril in the emergency department. These
cases
are the subjects
of this report.
PATIENTS AND METHODS From March 1989 to May 1990 a computer search revealed that 1,970 patients were prescribed lisinopril at our hospital. After the first case of angioedema associated with lisinopril was seen in the emergency department, the staff was requested to report all subsequent cases. Cases were considered probably drug related if there was a close temporal relationship between initiation of therapy and onset of angioedema. Cases were considered possibly drug related in patients taking lisinopril who had no prior history of angioedema. RESULTS
Clinical data for the nine cases are shown in Table 1. All of the patients were men and all were being treated for hyper-
From the Departments of Medicine and Ambulatory Care, the Department of Veterans Affairs Medical Center, New York, NY; and the NYU School of Medicine, New York, NY. Manuscriot received November 7. 1991: acceoted November . 25,199l. . Address reprint requests to Dr Rees, Medical Service, Department of Veterans Affairs Medical Center, 423 E 23rd St, New York, NY 10010. Key Words: Angioedema, lisinopril, angiotensin-converting enzyme inhibitors. Copyright 0 1992 by W.B. Saunders Company 0735-6757/92/l 004-0010$5.0010
MD, MD
tension. None of the patients had a prior history of allergy or angioedema. All of the patients had edema of the lips, buccal mucosa, and/or face, except patient no. 9 who had edema of the tongue only. None of the patients had obvious laryngeal edema or stridor, although patient no. 8 reported that he experienced “throat tightening and swelling” after the first dose. All of the patients were examined during the acute reaction except for patients no. 5 and 8 who reported to the emergency department after the angioedema had resolved. Their descriptions, however, were classic for angioedema in that they both reported relatively rapid onset of swelling of the lips and face several hours after taking lisinopril. We considered six cases of angioedema as probably drug related (cases no. 1, 2, 3, 4, 6, and 8) and three cases as possibly drug related (cases no. 5, 7, 9) and yielding a crude cumulative incidence of 1:328 (0.3%) or 1:219 (OS%), respectively. Of the six cases that were probably drug related, five occurred within three doses; the sixth case occurred within 2 weeks of the start of therapy. Three of the six patients were receiving no other medication at the time. The other three patients were receiving medication that they had taken previously without incident or that they were taking chronically. The three possibly related cases had been taking lisinopril for several months, but one was on no other medication. In the other two cases, lisinopril was the most recent addition to the medical regimen (the patients had been receiving the other medication for more than 1 year prior to the addition of lisinopril). The majority of the patients were treated with diphenhydramine alone and had no progression of edema. Lisinopril was discontinued. The edema resolved in 1 to 2 days. DISCUSSION
Angioedema has been reported to occur in association with captopril, enalapril, and lisinopril with a frequency of 0. 1%.3 Post marketing data appear to confirm this frequency for enalapri14 and captopril,5*6 but suggest a higher frequency for lisinopril (OS%).’ Our data also suggest a higher frequency for lisinopril than originally reported. Because this was not a surveillance study of all patients on lisinopril we may have been unaware of some cases of angioedema. Therefore, the incidence of angioedema associated with lisinopril could be even higher. During the same time period, 817 patients were prescribed captopril at our hospital. No cases of captopril-associated angioedema were seen by or reported to us, and no cases of adverse drug reactions were found in the hospital surveillance record. While this was not a comparative study of the two drugs, the same biases of overreporting and underre321
AMERICAN JOURNAL OF EMERGENCY MEDICINE n Volume 10, Number 4 m July 1992
322
TABLE1. Clinical Data on Patients Who Developed Angioedema After Taking Lisinopril
Age (yr)/Sex
Daily Dose (mg)
44/M
10
Lips, buccal/no
After third dose
None
2
52/M
10
Lips, buccal/no
After second dose
None
3
50/M
10
Lips, buccal, facial/no
After third dose
Ibuprofen, methocarbamol
4
62/M
10
Lips, facial/no
Within 2 wk
None
5’
67/M
10
Lips, facial/unknownt
6
66/M
10
Lips, facial, buccal/no
Multiple episodes after 2 mo on drug After first dose
7*
50/M
10
Lips, buccal/no
After 4 mo on drug
Hydrochlorthiazide, diltiazem, gemfibrozil Pilocarpine, betaxolol, colchicine None
8
56/M
20
After second dose
Ampicillin, ibuprofen
9
69/M
20
Lips, buccal, facial/? after first doset Tongue/no
After 10 mo on drug
Atenolol, aspirin, cimetidine, pentoxifylline
Case No.
Edema/Strider
Onset of Reaction
Other Medications
Treatment Diphenhydramine, observation, DC lisinopril Diphenhydramine, observation, DC lisinopril Diphenhydramine, observation, DC lisinopril Diphenhydramine, observation, DC lisinopril None
Diphenhydramine, observation, DC lisinoprii Diphenhydramine, observation, DC lisinopril None
Diphenhydramine, epinephrine, observation, DC lisinopril
ABBREVIATION:DC, discontinue. Possibly drug related; all others, probably drug related. t By history, not observed. l
porting should have applied. This also suggests that the incidence of angioedema may be higher with lisinopril than with captopril. We consider our cases probable or possible rather than definitely drug related because we did not rechallenge our patients with lisinopril, but a causal association is supported by the temporal relation of the reaction to the start of treatment and the absence of other likely causes in many of the patients. The time course of the reaction in our patients was similar to that in other studies.4.8 The mechanism of ACE inhibitor-associated angioedema is thought to be biochemical rather than immunologic.6 Bradykinin is believed to play a role in the pathogenesis of angioedema. It is inactivated by two proteases, kininase I (carboxypeptidase N) and kininase II (identical to ACE). Development of angioedema in patients receiving ACE inhibitors may be due to decreased destruction of local tissue bradykinin.’ Deficiency of carboxypeptidase N may also be associated with episodes of angioedema,” and Slater et al4 have speculated that susceptibility to ACE inhibitorassociated angioedema may be greater in patients with this deficiency. Several new ACE inhibitors recently have been released and more are expected. Given the low incidence of side effects associated with ACE inhibitors, it is anticipated that the number of patients treated with these agents will increase greatly. Because of this, episodes of angioedema will be seen with increasing frequency in emergency departments, and
physicians must be aware of this potentially complication.
life-threatening
REFERENCES 1. Gianos ME, Klaustermeyer WB, Kurohara M, et al: Enalapril induced angioedema. Am J Emerg Med 1990;8:124-126 2. Chin HL, Buchan DA: Severe angioedema after long-term use of an angiotensin-converting enzyme inhibitor. Ann Intern Med 1990;112:312-313 (letter) 3. US Physicians Desk Reference. Ordell, NJ, Medical Economics Books, 1990, pp 2129, 2175 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. Irvin JD, Viau JM: Safety profiles of the angiotensin converting enzyme inhibitors captopril and enalapril. Am J Med 1986;81(4C):46-50 6. Singer DRJ, Macgregor GA: Angioneurotic oedema associated with two angiotensin converting enzyme inhibitors. Br Med J 1986;293:1243 7. Cameron HA, Higgins TJC: Clinical experience with lisinopril. Observations on safety and tolerability. J Hum Hypertens 1989;3(1):177-186. 8. Wood SM, Mann RD, Rawlins MD: Angio-oedema and urticaria associated with angiotensin converting enzyme inhibitors. Br Med J 1987;294:91-92 9. Ferner RE, Simpson JM, Rawlins MD: Effects of intradermal bradykinin after inhibition of angiotensin converting enzyme. Br Med J 1987;294:1119-1120 10. Mathews KP, Pan PM, Gardner NJ, et al: Familial carboxypeptidase N deficiency. Ann Intern Med 1980;93:443-445
