# Comparison of oral anticoagulants for stroke prevention in atrial fibrillation using the UK clinical practice research Datalink Aurum: A reference trial (ARISTOTLE) emulation study

## TL;DR

This study uses real-world UK data to emulate a trial comparing apixaban and warfarin for stroke prevention in atrial fibrillation, finding apixaban noninferior but not superior to warfarin.

## Contribution

The study introduces a methodological template for using real-world data to evaluate anticoagulants in underrepresented patient groups.

## Key findings

- Apixaban showed noninferiority to warfarin for stroke/systemic embolism and death in real-world data.
- Apixaban was superior to poorly controlled warfarin for major bleeding but not to well-controlled warfarin.
- Results were consistent with trial benchmarks but did not show apixaban superiority, possibly due to differences in patient populations.

## Abstract

Stroke prevention 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 provide 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 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 trials.

We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results.

Patients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 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) TTR.

The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus 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 similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study’s methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR.

Analysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions.

Emma Maud Powell and colleagues use target trial emulation to demonstrate how real world data can extend our knowledge of anticoagulation treatment effects using non-interventional methods.

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 United Kingdom to emulate an RCT that compared apixaban to warfarin, ARISTOTLE, and also looked at whether the benefit of apixaban 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.

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 versus warfarin [hazard ratio (95% confidence interval)] for time to stroke or systemic embolism: 0.98 (0.82,1.19) in our cohort versus 0.79 (0.66,0.95) in ARISTOTLE.

We also found the benefit of apixaban versus warfarin differed for some outcomes depending on the quality of warfarin therapy with apixaban (i) superior only to poorly controlled warfarin therapy for major bleeding [TTR < 0.75: 0.74 (0.63, 0.86), TTR ≥ 0.75: 1.08 (0.90, 1.30)] (ii) associated with an increased risk of death compared only to well-controlled warfarin therapy [TTR ≥ 0.75: 1.20 (1.04, 1.37), TTR < 0.75: 0.94 (0.84, 1.06)].

Our 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.

We can use UK primary health care data to emulate a reference trial of treatments for the prevention of stroke in AF.

We 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 underrepresented in RCTs such as ethnic minority groups and older patients.

Study limitations include the possibility of residual confounding, a risk patients doing well on warfarin were overrepresented in our cohort, a lower proportion of Asian participants in our cohort compared with ARISTOTLE, and the likelihood of residual selection bias/misclassification in the TTR analysis.