Amiodarone use and the risk of acute pancreatitis: Influence of different exposure definitions on risk estimation

Abstract

Background: The antiarrhythmic drug amiodarone has an extremely long half-life of approximately 60 days, yet this is hardly considered in observational studies of adverse effects of amiodarone, such as acute pancreatitis. Objectives: To investigate the robustness of the association between amiodarone and the risk of acute pancreatitis against different exposure definitions. Methods: All incident amiodarone users in the Dutch PHARMO database between 2005 and 2015 and two comparison groups were included: (1) incident users of a different type of antiarrhythmic drug and (2) age-and sex-matched subjects starting a non-antiarrhythmic drug. Different definitions were applied to amiodarone exposure, including dichotomized, continuous, and categorized cumulative definitions with lagged effects to account for the long half-life of amiodarone. For each exposure definition, Cox proportional hazards regression analysis was used to estimate the risk of acute pancreatitis associated with amiodarone use, while adjusting for confounding. Results: This study included 15 378 starters of amiodarone, 21 394 starters of other antiarrhythmic drugs, and 61 579 starters of nonantiarrhythmic drugs. Compared with starters of other antiarrhythmic drugs, the adjusted hazard ratios (HRs) for the dichotomized definitions of exposure ranged between 1.21 and 1.43, for the continuous definitions of exposure between HR 1.13 and 1.22, and for the categorized cumulative definitions between HR 0.52 and 1.72. The HRs observed in the comparison with non-antiarrhythmic drugs users were generally higher: For the dichotomized exposure definitions, they ranged between 1.67 and 1.82, for the continuous exposure definitions between 1.39 and 1.70, and for the categorized cumulative exposure definitions between 0.68 and 2.55. Accounting for lagged effects had little impact on estimated HRs estimates. Conclusions: This study demonstrates the the relative insensitivity to of the association between amiodarone and the risk of acute pancreatitis against a broad range of different exposure definitions. Accounting for lagged effects had little impact, possibly because treatment switching was uncommon in this population.