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

Haematologica

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.

Authors 17

1. Harry Wang

   University of Ottawa · Ottawa Hospital Research Institute

   Affiliation as printed

   Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa

2. Michael J. Kovacs

   Western University

   Affiliation as printed

   Department of Medicine, Western University, London, Ontario

3. Alejandro Lazo‐Langner

   Western University

   Affiliation as printed

   Department of Medicine, Western University, London, Ontario

4. David R. Anderson

   Dalhousie University

   Affiliation as printed

   Department of Medicine, Dalhousie University, Halifax

5. Susan Rebecca Kahn

   McGill University

   Affiliation as printed

   Department of Medicine, McGill University, Montreal

6. Lana A. Castellucci

   University of Ottawa · Ottawa Hospital Research Institute

   Affiliation as printed

   Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa

7. Jeannot Schmidt

   Centre Hospitalier Universitaire de Clermont-Ferrand

   Affiliation as printed

   Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont

8. Antoine Élias

   Centre Hospitalier Intercommunal Toulon-La Seyne-sur-Mer

   Affiliation as printed

   Centre Hospitalier Intercommunal Toulon La Seyne-sur-Mer, Toulon

9. Marc Righini

   University Hospital of Geneva

   Affiliation as printed

   Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, Geneva

10. Thomas L. Ortel

    Duke University

    Affiliation as printed

    Department of Medicine, Duke University, Durham, North Carolina

11. Menno Volkert Huisman Aachen Dept of Medicine - Thrombosis and Hemostasis

    Leiden University Medical Center

    Affiliation as printed

    Department of Medicine - Thrombosis and Hemostasis, Leiden University Medical Center, Leiden

12. Marc Carrier

    University of Ottawa · Ottawa Hospital Research Institute

    Affiliation as printed

    Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa

13. Ranjeeta Mallick

    University of Ottawa · Ottawa Hospital Research Institute

    Affiliation as printed

    School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada; Ottawa Methods Centre, Ottawa Hospital Research Institute, Ottawa

14. MSc Marc A. Rodger

    McGill University

    Affiliation as printed

    Department of Medicine, McGill University, Montreal

15. Grégoire Le Gal

    University of Ottawa · Ottawa Hospital Research Institute

    Affiliation as printed

    Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa

16. Philip S. Wells

    University of Ottawa · Ottawa Hospital Research Institute

    Affiliation as printed

    Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa

17. Yan Xu

    University of Ottawa · Ottawa Hospital Research Institute

    Affiliation as printed

    Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa. yaxu@toh.ca