Overestimation of anticoagulant benefit in patients with atrial fibrillation and low life expectancy: evidence from 12 randomized trials

Background Patients with atrial fibrillation (AF) have a high rate of all-cause mortality that is only partially attributable to vascular outcomes. While the competing risk of death may affect expected anticoagulant benefit, guidelines do not account for it. We sought to determine if using a competing risks framework materially affects the guideline-endorsed estimate of absolute risk reduction attributable to anticoagulants. Methods We conducted a secondary analysis of 12 RCTs that randomized patients with AF to oral anticoagulants or either placebo or antiplatelets. For each participant, we estimated the absolute risk reduction (ARR) of anticoagulants to prevent stroke or systemic embolism using two methods. First, we estimated the ARR using a guideline-endorsed model (CHA2DS2-VASc) and then again using a Competing Risk Model that uses the same inputs as CHA2DS2-VASc but accounts for the competing risk of death and allows for non-linear growth in benefit over time. We compared the absolute and relative differences in estimated benefit and whether the differences in estimated benefit varied by life expectancy. Results 7933 participants had a median life expectancy of 8 years (IQR 6, 12), determined by comorbidity-adjusted life tables. 43% were randomized to oral anticoagulation (median age 73 years, 36% women). The guideline-endorsed CHA2DS2-VASc model estimated a larger ARR than the Competing Risk Model (median ARR at 3 years, 6.9% vs. 5.2%). ARR differences varied by life expectancies: for those with life expectancies in the highest decile, 3-year ARR difference (CHA2DS2-VASc model – Competing Risk Model 3-year risk) was −1.2% (42% relative underestimation); for those with life expectancies in the lowest decile, 3-year ARR difference was 5.9% (91% relative overestimation). Conclusion Anticoagulants were exceptionally effective at reduced stroke risk. However, anticoagulant benefits were misestimated with CHA2DS2-VASc, which does not account for the competing risk of death nor decelerating treatment benefit over time. Overestimation was most pronounced in patients with the lowest life expectancy and when benefit was estimated over a multi-year horizon. ### Competing Interest Statement Dr. Shah, Dr. Jeon, Dr. Boscardin, and Dr. Covinsky reported funding from the National Institute on Aging/National Institutes of Health related to the conduct of this study (noted below). Dr. Fang reported grants from the National Heart, Lung, and Blood Institute/National Institutes of Health during the conduct of the study (K24HL141354) and grants from Patient-Centered Outcomes Research Institute outside the submitted work. Dr. Singer was supported, in part, by the Eliot B. and Edith C. Shoolman Fund of Massachusetts General Hospital. He has received research support from Bristol Myers Squibb and consultancy fees from Bristol-Myers Squibb, Fitbit, Medtronic, and Pfizer. Professor Hobbs is, in part, supported by the NIHR (ARC OTV and MIC) and has received occasional consultancy fees from Bayer, BMS Pfizer, Novartis, and AZ unconnected to this study. ### Funding Statement This study was funded by the NIA (K76AG074919, P30AG044281). ### 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 Committee on Human Research at the University of California, San Francisco, and the Partners Human Research Committee at Massachusetts General Hospital approved the analysis for this study and waived the requirement for patient consent (Protocol 21-35046 and 2022P001783, respectively). 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 Researchers can apply to the AF Investigators for data access.