Hempenius M, Groenwold RHH, de Boer A, Klungel OH, Gardarsdottir H. Pharmacoepidemiol Drug Saf. 2019 Aug 2; 28 1563-1571.
PURPOSE: The antiarrhythmic drug amiodarone has a long half-life of 60 days, which is often ignored in observational studies. This study aimed to investigate the impact of different exposure definitions on the association between amiodarone use andthe risk of acute pancreatitis. METHOD: Using data from the Dutch PHARMO Database Network, incident amiodarone users were compared to incident users of a different type of antiarrhythmic drug. Eighteen different definitions were applied to define amiodarone exposure, including dichotomized, continuous and categorized cumulative definitions with lagged effects to account for the half-life of amiodarone. For each exposure definition, a Cox proportional hazards model was used to estimate the hazard ratio (HR) of hospitalization for acute pancreatitis. RESULTS: This study included 15,378 starters of amiodarone and 21,394 starters of other antiarrhythmic drugs. Adjusted HRs for acute pancreatitis ranged between 1.21-1.43 for dichotomized definitions of exposure to amiodarone, between 1.13-1.22 for dose definitions (per DDD) and between 0.52-1.72 for cumulative dose definitions, depending on the category. Accounting for lagged effects had little impact on estimated HRs. CONCLUSIONS: This study demonstratesthe relative insensitivity of the association between amiodarone and the risk of acute pancreatitis against a broad range of different exposure definitions. Accounting for possible lagged effects had little impact, possibly because treatment switching and discontinuation was uncommon in this population.