Abstract Background and Aims The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation. Methods These pre-specified analyses of the NOAH-AFNET 6 (n = 2534 patients) and ARTESiA (n = 4012 patients) trials compared anticoagulation with no anticoagulation in patients with DDAF with or without vascular disease, defined as prior stroke/transient ischaemic attack, coronary or peripheral artery disease. Efficacy outcomes were the primary outcomes of both trials, a composite of stroke, systemic arterial embolism (SE), myocardial infarction, pulmonary embolism or cardiovascular death, and stroke or SE. Safety outcomes were major bleeding or major bleeding and death. Results In patients with vascular disease (NOAH-AFNET 6, 56%; ARTESiA, 46%), stroke, myocardial infarction, systemic or pulmonary embolism, or cardiovascular death occurred at 3.9%/patient-year with and 5.0%/patient-year without anticoagulation (NOAH-AFNET 6), and 3.2%/patient-year with and 4.4%/patient-year without anticoagulation (ARTESiA). Without vascular disease, outcomes were equal with and without anticoagulation (NOAH-AFNET 6, 2.7%/patient-year; ARTESiA, 2.3%/patient-year in both randomized groups). Meta-analysis found consistent results across both trials (I2heterogeneity = 6%) with a trend for interaction with randomized therapy (pinteraction = .08). Stroke/SE behaved similarly. Anticoagulation equally increased major bleeding in vascular disease patients [edoxaban, 2.1%/patient-year; no anticoagulation, 1.3%/patient-year; apixaban, 1.7%/patient-years; no anticoagulation, 1.1%/patient-year; incidence rate ratio 1.55 (1.10–2.20)] and without vascular disease [edoxaban, 2.2%/patient-year; no anticoagulation, 0.6%/patient-year; apixaban, 1.4%/patient-year; no anticoagulation, 1.1%/patient-year; incidence rate ratio 1.93 (0.72–5.20)]. Conclusions Patients with DDAF and vascular disease are at higher risk of stroke and cardiovascular events and may derive a greater benefit from anticoagulation than patients with DDAF without vascular disease.