Teoh, MEL; (2024) Real-world effectiveness of oral anticoagulants in the prevention of stroke: emulation and extension of the ARISTOTLE trial using UK EHRs. PhD thesis, London School of Hygiene & Tropical Medicine. DOI: https://doi.org/10.17037/PUBS.04674716
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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 the 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. This thesis sought to validate non-interventional methodology for comparison of treatment effectiveness of oral anticoagulants in AF by emulating the pivotal ARISTOTLE trial (apixaban vs warfarin) in linked UK primary care data before extending the analysis to study groups excluded from, or underrepresented in ARISTOTLE. METHODS: This thesis used a novel method involving simultaneous equations and sampling to select a subset of patients with AF in CPRD Aurum prescribed apixaban or warfarin that matched the ARISTOTLE participants on baseline characteristics using only publicly available summaries. Recently developed methods for inclusion of prevalent users were explored, and a sampling method used with a modification to mimic the process of screening into an RCT. ARISTOTLE outcomes were assessed during 2.5 years of patient follow-up and results benchmarked before extending the analysis to patient groups under-represented in or excluded from ARISTOTLE. RESULTS: I was able to select a subset of patients in CPRD Aurum that matched ARISTOTLE participants on summary baseline characteristics and included prevalent users. The analysis sample comprised 8734 apixaban users and propensity-score matched 8734 warfarin users in CPRD. Results demonstrated non-Inferiority of apixaban vs warfarin consistent with the prespecified benchmarking criteria. Unlike in ARISTOTLE superiority of apixaban vs warfarin was not seen which may be linked to the higher proportion of patients with well-controlled warfarin and lower proportion of Asian patients compared to ARISTOTLE. After benchmarking results to ARISTOTLE, I extended the analysis to look at an underrepresented group (people aged ³ 75 years) and an excluded patient group (increased bleeding risk). In the people aged ³ 75 years consistent results were seen compared with people aged < 75 years and with the ARISTOTLE emulation with similar risks of stroke/SE and all-cause death for apixaban vs warfarin along with a trend for a lower risk of major bleeding on apixaban compared with warfarin. The increased bleeding risk group also showed results consistent with the ARISTOTLE emulation for key outcomes. CONCLUSIONS: Emulation of a reference trial in oral anticoagulants for atrial fibrillation can aid understanding of results in non-interventional data and increase confidence in the methods used facilitating the extension to patient groups of interest excluded or underrepresented in the trial. The framework can be adapted to investigate treatment effects for other conditions.
Item Type | Thesis |
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Thesis Type | Doctoral |
Thesis Name | PhD |
Contributors | Wing, K; Douglas, I and Gungabissoon, U |
Faculty and Department | Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology |
Research Group | Electronic Health Records Research Group |
Funder Name | Medical Research Council |
Grant number | MR/N013638/1 |
Copyright Holders | Maud Emma Louise Teoh |
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Filename: 2024_EPH_PhD_Teoh_M.pdf
Licence: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
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