Risk-benefit assessment of oral anticoagulation in atrial fibrillation using virtual clinical trials

Abstract Background: Oral anticoagulation (OAC) reduces stroke risk in patients with atrial fibrillation (AF), and screening can enable earlier AF detection and OAC initiation. However, the population-level trade-off between stroke prevention and OAC-related major bleeding for different types of AF and OAC therapy remains uncertain, and large randomized trials to resolve this are costly and time-consuming. Methods: A state-transition Markov-like model was developed to: 1) simulate the lifetime course of AF, stroke, major bleeding, and death in different virtual populations; 2) quantify benefits (stroke reduction) and harms (major bleeding) of systematic AF screening with screening-triggered OAC across CHA2DS2-VA scores; and 3) compare rhythm-guided, time-delimited ("pill-in-pocket") OAC with continuous OAC. Results: The model synthesized information from multiple clinical sources and reproduced stroke and bleeding incidence across clinical scenarios. At CHA?DS?-VA=2, long-term continuous rhythm monitoring (LT-CRM) with OAC lowered stroke risk (HR, 0.92 [95%CI, 0.88-0.96]) but raised bleeding risk (HR, 1.17 [95%CI, 1.07-1.27]) versus no screening. Time-to-benefit was shorter than time-to-harm for CHA?DS?-VA?4, but longer for CHA?DS?-VA=0. Pill-in-pocket OAC vs continuous OAC showed no difference in stroke/mortality (HR, 1.03, 95%CI [0.91-1.16]) but lower bleeding risk (HR, 0.81, 95%CI: 0.68-0.96]) in patients with elevated bleeding risk, but not at baseline. Sensitivity analyses revealed that the risk-benefit profiles of screening or pill-in-pocket OAC strategy further depend on OAC adherence and bleeding risks. Conclusions: Our model highlights a trade-off between stroke reduction and bleeding for systematic screening-initiated OAC, with net benefit for CHA?DS?-VA?4. We provide the first virtual implementation of an ongoing rhythm-guided OAC trial, showing that pill-in-pocket OAC may lower bleeding risk compared to continuous OAC, highlighting the potential of virtual clinical trials to guide clinical trial design.