Elevated on-treatment D-dimer level is associated with major bleeding during extended anticoagulation for venous thromboembolism

Abstract

Assessing optimal anticoagulant duration in venous thromboembolism (VTE) requires balancing the risks of recurrent VTE and anticoagulant-associated bleeding with fixed-duration or indefinite anticoagulation. In unprovoked VTE, elevated on-treatment D-dimer level is a predictor of recurrent thromboembolism after anticoagulant cessation, but its impact on anticoagulant-associated bleeding is unknown. We performed a post-hoc pooled analysis of two prospective cohorts (BLEEDRISK and REVERSE-2 studies) that enrolled unprovoked VTE patients who continued anticoagulation after ≥3 months of initial treatment. We calculated incidence rates of major bleeding, intracranial hemorrhage and fatal bleeding by D-dimer quartiles, then determined hazard ratios with the lowest D-dimer quartile as reference. Among 3,337 participants, incidence rates of anticoagulant-associated major bleeding from the lowest to highest D-dimer quartile were 0.45, 0.91, 1.43 and 2.20 events per 100 person-years respectively. Accounting for age, sex and anticoagulant type, individuals in the highest D-dimer quartile had a 2.7-fold higher risk of anticoagulant-associated major bleeding compared to the lowest quartile (adjusted hazard ratio [aHR] 2.70, 95% CI 1.35 – 5.41, p=0.005). This association remained robust after additional adjustment for hemoglobin, creatinine and concurrent anti-platelet use in the BLEEDRISK cohort. We did not observe differences in risks of intracranial hemorrhage or fatal bleeding by D-dimer quartiles. Elevated on-treatment D-dimer levels predicted higher risks of major bleeding during indefinite anticoagulation. Given the established relationship between elevated on-treatment D-dimer levels and recurrent VTE after time-limited anticoagulation, our findings underscore the need for additional risk stratification tools in this population to personalize anticoagulant treatment that maximizes its net clinical benefit.