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Background Vitamin K, through its role in the vitamin K-dependent activation of matrix-GLA-protein, has been suggested to have a lung-protective effect, though the mechanism is unknown. Chronic obstructive pulmonary disease (COPD) patients treated with vitamin K antagonists (VKAs) may lose this protection, thereby increasing their risk of an acute exacerbation of COPD (AE-COPD) and death. We examined this hypothesis in a nationwide cohort of COPD patients treated with VKA. COPD patients treated with direct oral anticoagulant (DOAC) served as controls.Objective To assess the association between VKA treatment and the 1-year risk of AE-COPD-related hospitalisation and all-cause mortality in patients with COPD and atrial fibrillation or flutter.Methods This nationwide, observational, register-based cohort study applied Cox proportional hazard regression models, adjusting for established confounders. HRs with 95% CIs were reported. Sensitivity analyses included complete-case analysis and inverse probability of treatment weighting (IPTW).Results A total of 7091 COPD patients were included, of whom 3455 (48.7%) received VKA treatment. A total of 1955 patients reached the endpoint, including 820 in the VKA-treated group. In the primary analysis, VKA treatment was associated with a lower risk of AE-COPD hospitalisation or death (adjusted HR of 0.87 (95% CI 0.78 to 0.98), p=0.024). The association remained in the sensitivity analyses but lost statistical significance. Complete-case analysis: adjusted HR of 0.88 (CI 0.76 to 1.01), p=0.079. IPTW analysis: HR of 0.85 (CI 0.72 to 1.01), p=0.070.Interpretation VKA treatment was associated with a reduction in risk of AE-COPD hospitalisation and mortality compared to DOAC. Sensitivity analysis was consistent with the main analysis; however, it did not reach statistical significance.