Mortality Following Recurrent Venous Thromboembolism and Major Bleeding Stratified by Active Cancer Status

Recurrent venous thromboembolism (VTE) and major bleeding are serious complications after acute VTE. However, their independent impact on subsequent mortality in the era of direct oral anticoagulants remains unclear, particularly with respect to differences between patients with and without active cancer. The aim of this study was to evaluate the associations of recurrent VTE and major bleeding with subsequent mortality in the overall cohort and subgroups stratified by active cancer. We analyzed 5,197 patients with VTE from the COMMAND VTE Registry-2 using multivariable Cox proportional hazards models with recurrent VTE and major bleeding as time-updated covariates. In the overall cohort, 283 patients developed recurrent VTE, 470 developed major bleeding, and 1,323 died. Recurrent VTE and major bleeding were associated with mortality (adjusted HR: 1.65, 95% CI: 1.28-2.12, P < 0.001; adjusted HR: 3.33, 95% CI: 2.83-3.91, P < 0.001, respectively). Among patients with active cancer, both recurrent VTE and major bleeding were associated with mortality (adjusted HR: 1.95, 95% CI: 1.45-2.62, P < 0.001; adjusted HR: 2.96, 95% CI: 2.42-3.61, P < 0.001, respectively). Among patients without active cancer, only major bleeding was associated with mortality (adjusted HR: 3.78, 95% CI: 2.88-4.97, P < 0.001), whereas recurrent VTE was not associated with mortality (adjusted HR: 0.93, 95% CI: 0.55-1.56, P = 0.78). In contemporary real-world patients with VTE in the era of direct oral anticoagulants, major bleeding was associated with increased subsequent mortality in both patients with and without active cancer, whereas recurrent VTE was associated with increased mortality in patients with active cancer, with no significant association observed in those without active cancer.