Comparison of oral anticoagulants for stroke prevention in atrial fibrillation using the UK Clinical Practice Research Datalink Aurum: A reference trial (ARISTOTLE) emulation study
Authors: Powell Emma Maud , Gungabissoon Usha , Tazare John , Smeeth Liam , Baptiste Paris J , Bin Hammad Turki M , Wong Angel YS , Douglas Ian J , Wing Kevin 
Published: March 2024

ABSTRACTBackgroundStroke 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 findingsPatients 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.ConclusionsAnalysis 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.AUTHOR SUMMARYWhy Was This Study Done?Stroke prevention treatment guidelines for patients with atrial fibrillation (AF) are based on results from randomised controlled trials (RCTs), we do not know if these results are relevant to patients that would not have been eligible to be included in the RCTs.This study used routinely collected health data from the UK to emulate an RCT that compared apixaban to warfarin, ARISTOTLE, and also looked at whether the benefit of apixban compared with warfarin was impacted by the quality of warfarin therapy (measured by time in therapeutic range, TTR).Emulating an RCT for stroke prevention in patients with AF should help to understand how transferable RCT results are to ‘real-world’ practices and whether this methodological approach can help to improve treatment options and outcomes for patient groups currently underrepresented in clinical trials.What Did the Researchers Do and Find?The researchers looked at patients with AF in a UK primary care data prescribed apixaban or warfarin and applied a “reference trial emulation” approach, in which the ARISTOTLE trial eligibility, selection and analysis approaches were applied to UK primary care data and results benchmarked against those of ARISTOTLE.Patients prescribed apixaban had similar rates of outcomes to those prescribed warfarin in our cohort and our results were successfully benchmarked against ARISTOTLE. Unlike ARISTOTLE we did not see superiority of apixaban vs warfarin [Hazard ratio (95% confidence interval)] for time to stroke or systemic embolism: 0.98 (0.82,1.19) in our cohort vs 0.79 (0.66,0.95) in ARISTOTLE.We also found the benefit of apixaban vs warfarin differed depending on the quality of warfarin therapy with apixaban superior to poorly controlled warfarin therapy (TTR < 0.75) [Stroke/SE 0.94 (0.75,1.19), Death 0.99 (0.87,1.12)] whereas apixaban was not superior to well-controlled warfarin (TTR ≥ 0.75) [Stroke/SE 1.49 (1.13,1.97), Death 1.75 (1.49,2.06)].What Do These Findings Mean?ur results support the NICE guidelines on selecting treatment for stroke prevention in patients with AF and also provide reassurance on continuing warfarin in patients with high TTR.can use UK primary health care data to emulate a reference trial of treatments for the prevention of stroke in AF.can use the data and methods to look at how well treatments work in patients that would not have been included in RCTs such as those with multimorbidity or patient groups under-represented in RCTs such as ethnic minority groups and older patients.limitations include the possibility of residual confounding, a risk patients doing well on warfarin were over-represented in our cohort, and a lower proportion of Asian participants in our cohort compared with ARISTOTLE.