Replication of rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation in a cohort study using electronic primary care database

Abstract

Background: Imitating the design of a randomized controlled trial in an observational study is one of the recent methodological approaches that has been developed to improve the usefulness of observational studies in assessing drug effectiveness (efficacy of drugs in routine clinical care); however, the usefulness of this approach has not been investigated from non-inferiority perspective. Objectives: To imitate the design of the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) non-inferiority trial in an observational study. Methods: A retrospective cohort study was conducted using the British Clinical Practice Research Datalink (CPRD). Applying the eligibility criteria of the trial, patients who were diagnosed with non-valvular AF and were prescribed either rivaroxaban or warfarin (incident users) from October 2008 were included and followed to the end of the study period (December 2017). Non-inferiority of rivaroxaban to warfarin in the prevention of the composite endpoint of stroke or systemic embolism was assessed using a non-inferiority margin of hazard ratio (HR) 1.46 (the margin that was used in the triak). Cox-proportional hazards regression was used to estimate the study outcomes adjusting for time-fixed and time-varying confounders. Results: We included 25,473 incident users of rivaroxaban (n = 4,008) or warfarin (n = 21,465). Similar to the trial, non-inferiority in the primary outcome was demonstrated: HR1.04 (95% confidence interval [CI] 0.84 to 1.30) in the intention-to-treat population and in another two analysis populations. The target population of the trial is mostly treated in the real-world settings (i.e. the proportion of patients who did not meet the exclusion criteria was small), thus affecting the precision of analysis in the latter. Finally, the event rate of the primary outcome in warfarin group was lower compared with that in the trial and this may affect the applicability of the trial's non-inferiority margin in our study. Conclusions: imitating the design of a non-inferiority trial in observational study led to consistent results with that of the trial in similar patient population, however, an adjustment for the trial's non-inferiority margin is needed to take into account the variation in the effect of the active comparator in observational settings.