Impact of treatment discontinuation definitions on comparative retention studies: a simulation-based case study in spondyloarthritis

Background: In comparative effectiveness research, treatment retention - i.e., the time from treatment start to treatment discontinuation - is an important indicator of treatment effectiveness for chronic illnesses. There is no agreement on the event that defines discontinuation. Commonly used are “last dose received”, “decision to discontinue”, or “first dose missed”, as well as mixtures of these in multi-source studies. For drugs administered less frequently than once daily as is the case for many disease-modifying anti-rheumatic drugs (DMARDs) used for the treatment of spondyloarthritis, retention as determined by these events can vary considerably. Our goal was to quantify the impact of the different definitions of discontinuation on conclusions drawn from treatment comparisons and to recommend a standardised definition. Methods: We utilised model-based simulations and real-world data from spondyloarthritis patients treated with tumour necrosis factor (TNF) inhibitors, DMARDs with a wide range of dosing intervals, in Europe. We compared the estimation of the hazard ratio of discontinuation between treatments with varying differences in dosing intervals for the different definitions of discontinuation. To accommodate interval-censored events we used linear transformation models. Results: The simulation revealed increasing differences in the estimated treatment hazard ratio based on time to “last dose received” or “first dose missed” compared to “decision to discontinue” with increasing differences in the dosing interval (up to 55 days). These differences were, however, small and further diminished with mixed events. No bias was observed when the time to “decision to discontinue” was analysed as interval-censored between the times to “last dose received” and “first dose missed” instead of as exactly observed. No clinically meaningful differences in estimated hazard ratios between TNF inhibitors with different dosing intervals (56 versus 7 days) were observed in the real-world data. Conclusions: The impact of the different treatment discontinuation definitions on comparative retention were found to be negligible. Nonetheless, we recommend to define retention as the time from treatment start to the decision to discontinue treatment. Is the timing of the decision unknown, retention can be analysed as interval-censored between the last dose received and the first dose missed using transformation models. Trial registration: Not applicable.