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

Abstract

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 and the 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 demonstrates the 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.

Keywords: amiodarone; drug therapy; pancreatitis; pharmacoepidemiology; research design.

Figure 1

Illustration of different exposure definitions in a drug exposure study. Top left panel shows dispensing pattern. Other panels show the result of different exposure definitions. Washout periods are set at 60 d.

Figure 2

Hazard ratios (HRs) of exposure to amiodarone compared with exposure to another antiarrhythmic drug and the risk of acute pancreatitis. ^†HR expressed for being exposed vs nonexposed. ^‡HR expressed per 1 daily defined dose (DDD). ^§HR expressed for steady‐state dose. ^¶HR expressed for this category vs nonuse or past‐use (past‐use is not applicable when no reset was applied). HRs adjusted for age, sex, diabetes mellitus, hypertriglyceridemia, biliary stones, antiarrhythmic drugs, acetaminophen, opiates, atorvastatin, furosemide, hydrochlorothiazide, doxycycline, and steroids.