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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. 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, lisinopril, quinapril, ramipril, perinodpril, enalapril has been described in case reports. Similarly, pancreatitis has also been reported with telmisartan, an angiotensin-receptor blocker. In this issue of the Journal, Kanbay et al add to the accumulating evidence of association between pancreatitis and ACE inhibitors. 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. Clinically, the temporal relationship between the drug and the occurrence of pancreatitis, as well as the evidence of recurrence on re-challenge 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 and necrotizing 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. 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. 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. In light of the conflicting evidence and lack of quantitative information about ACE inhibitor-induced pancreatitis, epidemiologic studies to assess the risk of ACE inhibitorinduced 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. 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. 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. 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.