Comparison of oral anticoagulants for stroke prevention in atrial fibrillation using the UK Clinical Practice Research Datalink Aurum: A reference trial (ARISTOTLE) emulation study

Abstract

Background Stroke prevention treatment guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provides an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs, however there remains uncertainty on the validity of the methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in the original trials. We used linked UK primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban vs warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results. Methods and findings Patients with AF in a UK primary care database Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 Jan 2013 to 31 Jul 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) time in therapeutic range (TTR). The analysis sample comprised 8734 apixaban users and propensity-score matched 8734 warfarin users in CPRD. Results [Hazard Ratio (95% Confidence Interval)] confirmed apixaban non-inferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) vs trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) vs trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for Stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year) whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year) Analysis by TTR suggested non-inferiority of apixaban in those with TTR < 0.75 [Stroke/SE 0.94 (0.75,1.19), all-cause death 0.99 (0.87,1.12)]. However, apixaban was associated with increased hazards compared with well-controlled warfarin treatment (TTR >= 0.75) [Stroke/SE 1.49 (1.13,1.97), all-cause death 1.75 (1.49,2.06)]. The main limitation of the study’s methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm. Conclusions Analysis of non-interventional data generated results demonstrating non-inferiority of apixaban vs warfarin consistent with the pre-specified benchmarking criteria. Unlike in ARISTOTLE superiority of apixaban vs warfarin was not seen which may be linked to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. The methodological template developed can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or under-represented in trials and also provides a framework which can be adapted to investigate treatment effects for other conditions.