Angiotensin-converting enzyme (ACE) inhibitor-induced acute pancreatitis: in search of the evidence.

Drug-induced pancreatitis is estimated to be responsible for nearly 2% of cases of acute pancreatitis. (1) Angiotensin-converting enzyme (ACE) inhibitors are some of the most widely prescribed medications. The occurrence of acute pancreatitis with several different ACE inhibitors including captopril, (2-3) lisinopril, (4-8) quinapril, (9) ramipril, (10-11) perinodpril, (12) enalapril (13-17) has been described in case reports. Similarly, pancreatitis has also been reported with telmisartan, an angiotensin-receptor blocker. (18)

In this issue of the Journal, Kanbay et al add to the accumulating evidence of association between pancreatitis and ACE inhibitors. (19) They describe another possible case of recurrent acute pancreatitis

with lisinopril. However, the determination of a causal association between ACE inhibitors and pancreatitis requires a multidisciplinary approach including clinical, pharmacological and epidemiologic methods. (20)

Clinically, the temporal relationship between the drug and the occurrence of pancreatitis, as well as the evidence of recurrence on re-challenge (8,16-17,19) in several case reports, supports the association between ACE inhibitors and pancreatitis. However, case reports are limited by their lack of a standardized method of reporting, and the presence of potential confounders.

On pharmacological grounds, the occurrence of localized angioedema of the pancreas has been proposed as a biologic basis for this reaction as a result of interference with the metabolism of kinins by ACE inhibitors. However, pancreatitis has occurred mainly at therapeutic doses, from several hours to several months after initiation of drug therapy, which argues against an angioedema-like effect. The severity of the reaction has ranged from mild in the majority of cases to fulminant (4,11) and necrotizing (15) in others. Besides, it is difficult to identify any particular susceptible groups at risk for this reaction. In fact, animal studies show that a combination of ACE inhibitors and angiotensin receptor blockers can actually attenuate pancreatic inflammation in rats. (21)

Epidemiologic approaches have included the use of pharmacovigilance databases and observational studies. Enalapril was found to have a probable causal relationship to pancreatitis in 21 years of pharmacovigilance reporting from the Netherlands. (22) However, these spontaneous reports do not reflect the true magnitude of the problem, as they lack a denominator. In contrast, a retrospective cohort study in Ontario, Canada found that the use of ACE inhibitors was not associated with a significant risk of acute pancreatitis among elderly patients. (23)

In light of the conflicting evidence and lack of quantitative information about ACE inhibitor-induced pancreatitis, epidemiologic studies to assess the risk of ACE inhibitor-induced acute pancreatitis are urgently needed. We also need an improved methodology of reporting harms. Systematic reviews and randomized controlled trials tend to focus on efficacy and seldom pay much attention to adverse effects. (24) We require complementary data gathering approaches from different sources of adverse events, including published case reports from the literature, spontaneous reports from pharmacovigilance databases, and systematic reviews of randomized controlled trials to estimate the true magnitude of this problem. (25)

Meanwhile, clinicians and researchers need to move beyond the traditional focus on the detection of this reaction, and face the new hurdles of characterizing it in greater detail based on frequency, dose responsiveness, time course, and patients' susceptibility factors. (24) Clinicians faced with the challenge of balancing the benefits and harms of ACE inhibitors at the bedside need to be reminded that the existence of a possible adverse drug reaction should be part of the differential diagnosis in cases of acute pancreatitis with an unexplained etiology.

References

1. Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. J Clin Gastroenterol 2005;39:709-716.

2. Jeandidier N. Klewansky M, Pinget M. Captopril-induced acute pancreatitis. Diabetes Care 1995;18:410-411.

3. Iliopoulou A, Giannakopoulos G, Pagoy H, Christos T, Theodore S. Acute pancreatitis due to captopril treatment. Dig Dis Sci 2001;46:1882-1883.

4. Standridge JB. Fulminant pancreatitis associated with lisinopril therapy. South Med J 1994;87:179-181.

5. Marinella MA, Billi JE. Lisinopril therapy associated with acute pancreatitis. West J Med 1995;163:77-78.

6. Kanbay M, Sekuk H, Yilmaz U, et al. Acute pancreatitis associated with combined lisinopril and atorvastatin therapy. Dig Dis 2005;23:92-94.

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9. Arjomand H, Kemp DG. Quinapril and pancreatitis. Am J Gastroenterol 1999;94:290-291.

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11. Anagnostopoulos GK, Kostopoulos P, Tsiakos S, et al. Fulminant pancreatitis associated with ramipril therapy. Pancreas 2003;27:278-279.

12. Gallego-Rojo FJ, Gonzalez-Calvin JL, Guilarte J, et al. Perindopril-induced acute pancreatitis. Dig Dis Sci 1997;42:1789-91.

13. Tilkemeier P, Thompson PD. Acute pancreatitis possibly related to enalapril. N Engl J Med 1988;318:1275-1276.

14. Martin T, Taupignon A, Graf E, et al. [Pancreatitis and hepatitis in a patient treated with enalapril maleate. A case report] Therapie 1989;44:449-450.

15. Gonzalez Ramallo VJ, Muino Miguez A, Torres Segovia FJ. Necrotizing pancreatitis and enalapril. Eur J Med 1992;1:123.

16. Maringhini A, Termini A, Patti R, et al. Enalapril-associated acute pancreatitis: recurrence after rechallenge. Am J Gastroenterol 1997;92:166-167.

17. Carnovale A, Esposito P, Bassano P, et al. Enalapril-induced acute recurrent pancreatitis. Dig Liver Dis 2003;35:55-57.

18. Baffoni L, Durante V, Grossi M. Acute pancreatitis induced by telmisartan overdose. Ann Pharmacother 2004;38:1088.

19. Kanbay M, Selcuk H, Yilmaz U. Recurrent acute pancreatitis secondary to lisinopril. South Med J 2006;99:1388-1389.

20. Diemont WL. Is this reaction caused by this drug? Neth J Med 2005;63:242-243.

21. Yamada T, Kuno A, Ogawa K, et al. Combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker synergistically suppresses chronic pancreatitis in rats. J Pharmacol Exp Ther 2005;313:36-45.

22. Eland IA, van Puijenbroek EP, Sturkenboom MJ, et al. Drug-associated acute pancreatitis: twenty-one years of spontaneous reporting in The Netherlands. Am J Gastroenterol 1999;94:2417-2422.

23. Cheng RM, Mamdani M, Jackevicius CA, et al. Association between ACE inhibitors and acute pancreatitis in the elderly. Ann Pharmacother 2003;37:994-998.

24. Loke YK. Assessing the benefit-harm balance at the bedside. BMJ 2004;329:7-8.

25. Loke YK, Derry S, Aronson JK. A comparison of three different sources of data in assessing the frequencies of adverse reactions to amiodarone. Br J Clin Pharmacol 2004;57:616-621.

Even though people may be well known, they hold in their hearts the
emotions of a simple person for the moments that are the most important
of those we know on earth: birth, marriage and death.
--Jackie Kennedy

Sonal Singh, MD

From the Section of General Internal Medicine, Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC and the MPH Program, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

Reprint requests to Sonal Singh, MD, Department of Medicine, Wake Forest University, Medical Centre Boulevard, Winston-Salem, North Carolina 27157; Email: [e-mail]

Accepted April 20, 2006.