Emulating a target trial to assess effect modification: an application to obesity in the comparative effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation using electronic health records

Anticoagulation therapy is recommended for patients with non-valvular atrial fibrillation (NVAF) and an increased risk of stroke. Although apixaban showed superiority over warfarin in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, little is known about their effects in overweight and obese patients, with concerns that obesity might undermine apixaban’s effects due to the fixed dosing across body mass index (BMI) groups. We emulated a target trial similar to the ARISTOTLE study using Clinical Practice Research Datalink (CPRD) linked data to estimate the 36-month risk ratios (RR) and risk differences of the effects of apixaban compared to warfarin in NVAF patients in a composite of stroke/systemic embolism (SE), major bleeding and all-cause mortality. In 55,826 patients, apixaban did not differ across groups of BMI in stroke/SE with RR (95% CI) of 1.15 (0.81, 1.62) in normal weight, 1.06 (0.70, 1.61) in overweight and 1.23 (0.69, 2.17) in obese patients. In major bleeding, apixaban was not superior to warfarin in the normal weight group (RR (95% CI) 1.10 (0.76, 1.60) but superior in overweight (RR (95% CI) 0.73 (0.57, 0.93) and obese (RR (95 % CI) 0.67 (0.52, 0.87) groups. In NVAF, the effectiveness and safety of apixaban compared to warfarin were consistent across BMI groups. ### Competing Interest Statement T.Bin Hammad has nothing to disclose. E. Powell is employed at Compass Pathways and is funded by the MRC for this work. P. Baptiste is supported by a GSK studentship. I. Douglas reports grants, and holds stocks in GSK, outside the submitted work. K. Wing has nothing to disclose. ### Funding Statement This work was partly supported by the Saudi Food and Drug Authority (SFDA) as a part of a Master of Science (MSc) project for Turki Bin Hammad. The SFDA had no role in the design, review or writing of the manuscript. The views expressed in this paper are those of the author and not do not necessarily reflect those of the SFDA or its stakeholders. Guaranteeing the accuracy and the validity of the data is a sole responsibility of the research team. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the MSc Research Ethics Committee (Ethics Ref: 27537) at the London School of Hygiene & Tropical Medicine and the Independent Scientific Advisory Committee for MHRA Database Research (approved amendment to 19_066). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data from the Clinical Practice Research Datalink (CPRD), Hospital Episodes Statistics-Admitted Patient Care (HES-APC) and mortality data from the Office for National Statistics (ONS) were obtained after ethical approval and cannot be made publicly available.