Timing of concomitant drug use in pharmacoepidemiological studies

Abstract

Background: Both antidepressants (AD) and benzodiazepines (BZD) have been associated with an increased risk for hip fracture. However, the hazard function is not constant over exposure time and differs for these two medication classes. Hence, the timing of initiation of co-use will determine the overall hazard function. Objectives: The aim of this study was to describe timing of BZD co-medication use among AD users. Methods: The study population included patients from the Netherlands Information Network of General Practice who initiated ADs between 2002 and 2009. AD-treatment episodes were constructed for each patient assuming the start of a new episode when 90 days elapsed between the theoretical end-date of a prior AD prescription (Rx) and the start-date of the next AD Rx. Within the first AD episode, three groups of BZD co-use were defined: “simultaneous” (simultaneous start of AD and BZD, no BZD during 182 days prior to start), “before” and “during” starters. These groups were described according to intensity of BZD use (number of Rxs), mono/polytherapy of AD and duration of AD episode. Results: The study population consisted of 16,617 AD users. The mean age was 50 years (SD = 18) and 63.2% were female. The median duration of the AD episode was 80 days (IQR = 259). Of 28.5% of patients used both AD and BZD. Of these, 57.2% started BZD before the AD, 19.0% were “simultaneous” starters and 23.8% started BZD during their first AD episode. In general, “simultaneous” starters were younger (mean = 45.3 vs. 56.4 years) yet had less intensity of BZD use (mean = 4.3 vs. 7.5 Rxs) compared to “before” starters. “After” starters were slightly older (mean = 48.0 vs. 45.3 years), had more AD polytherapy (20.2% vs. 14.9%) however less intensive BZD use (mean = 3.7 vs. 4.3 Rxs) compared to “simultaneous” starters. Conclusions: Timing of initiating BZD use in AD users is important, as each BZD co-use group is expected to have a different overall hazard function for hip fracture as opposed to when co-medication is defined as constant over time. To calculate accurate hazard function, it is important to take into consideration the timing of initiation of co-medication use in pharmacoepidemiological studies.