Impact of recurrent venous thromboembolism and major bleeding events on subsequent mortality in patients with and without active cancer: Insights from the COMMAND VTE Registry-2

Background Recurrent venous thromboembolism (VTE) and major bleeding are serious complications after acute VTE. However, their independent impact on subsequent mortality in the contemporary era of direct oral anticoagulants (DOACs) remains unclear, particularly with respect to differences between patients with and without active cancer. Purpose To evaluate the association of recurrent VTE and major bleeding events with mortality in a large, real-world cohort of patients with VTE, overall and stratified by the presence of active cancer. Methods We used data from the COMMAND VTE Registry-2, which enrolled 5,197 consecutive patients with acute symptomatic VTE at 31 centers in Japan between January 2015 and August 2020. After excluding 4 patients with simultaneous recurrent VTE and major bleeding, 5,193 patients were analyzed. The risks of subsequent mortality associated with recurrent VTE, and major bleeding were estimated using time-updated multivariable Cox proportional hazards models in the overall cohort and stratified by the presence or absence of active cancer. Interaction testing was conducted to evaluate heterogeneity of effect. Results The mean age was 67.7 ± 15.7 years; 2,134 (41%) were male, and 1,506 (29%) had active cancer. During a median follow-up of 1002 days (IQR 515–1594), 266 patients developed recurrent VTE events, 458 developed major bleeding events, and 1,294 died. In the overall cohort, both recurrent VTE and major bleeding were independently associated with subsequent mortality (recurrent VTE: adjusted HR 1.63, 95%CI 1.26–2.11, P < 0.001; major bleeding: adjusted HR 3.35, 95%CI 2.85–3.93, P < 0.001). Among patients with active cancer, recurrent VTE (adjusted HR 1.87, 95% CI 1.40–2.51) and major bleeding (adjusted HR 2.95, 95% CI 2.42–3.59) were both significantly associated with mortality. In contrast, among patients without active cancer, recurrent VTE was not significantly associated with mortality (adjusted HR 1.14, 95% CI 0.67–1.92), whereas major bleeding remained strongly associated with mortality (adjusted HR 4.35, 95% CI 3.33–5.68). There was significant heterogeneity in the association between major bleeding and mortality according to the presence or absence of active cancer (P for interaction = 0.02), whereas statistical evidence of heterogeneity was not demonstrated for recurrent VTE (P for interaction = 0.10). Conclusion In contemporary real-world patients with VTE, major bleeding demonstrated a differential prognostic impact between patients with and without active cancer, with a stronger relative association observed among patients without active cancer. In contrast, although recurrent VTE was associated with increased mortality in patients with active cancer, but not in those without, and this difference did not reach statistical significance.