Faizan Khan1, Tobias Tritschler2, Miriam Kimpton3, Philip S Wells3, Clive Kearon4, Jeffrey I Weitz4, Harry R Büller5, Gary E Raskob6, Walter Ageno7, Francis Couturaud8, Paolo Prandoni9, Gualtiero Palareti9, Cristina Legnani9, Paul A Kyrle10, Sabine Eichinger10, Lisbeth Eischer10, Cecilia Becattini11, Giancarlo Agnelli11, Maria Cristina Vedovati11, Geert-Jan Geersing12, Toshihiko Takada12, Benilde Cosmi13, Drahomir Aujesky2, Letizia Marconi14, Antonio Palla14, Sergio Siragusa15, Charlotte A Bradbury16, Sameer Parpia17, Ranjeeta Mallick18, Anthonie W A Lensing19, Martin Gebel19, Michael A Grosso20, Kednapa Thavorn1, Brian Hutton1, Gregoire Le Gal3, Dean A Fergusson21, Marc A Rodger22. 1. University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (F.K., K.T., B.H.). 2. Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (T.T., D.A.). 3. Ottawa Hospital Research Institute, University of Ottawa, and The Ottawa Hospital, Ottawa, Ontario, Canada (M.K., P.S.W., G.L.). 4. McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (C.K., J.I.W.). 5. Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands (H.R.B.). 6. University of Oklahoma Health Sciences Center, Hudson College of Public Health, Oklahoma City, Oklahoma (G.E.R.). 7. University of Insubria, Varese, Italy (W.A.). 8. Brest University Hospital, Brest, France (F.C.). 9. Arianna Foundation on Anticoagulation, Bologna, Italy (P.P., G.P., C.L.). 10. Medical University of Vienna, Vienna, Austria (P.A.K., S.E., L.E.). 11. University of Perugia, Perugia, Italy (C.B., G.A., M.C.V.). 12. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (G.G., T.T.). 13. Sant'Orsola-Malpighi University Hospital, Bologna, Italy (B.C.). 14. University of Pisa, Pisa, Italy (L.M., A.P.). 15. University of Palermo, Palermo, Italy (S.S.). 16. University of Bristol, Bristol, United Kingdom (C.A.B.). 17. McMaster University, Hamilton, Ontario, Canada (S.P.). 18. Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.M.). 19. Bayer, Wuppertal, Germany (A.W.L., M.G.). 20. Daiichi Sankyo, Basking Ridge, New Jersey (M.A.G.). 21. University of Ottawa, Ottawa Hospital Research Institute, and The Ottawa Hospital, Ottawa, Ontario, Canada (D.A.F.). 22. Ottawa Hospital Research Institute, Ottawa, Ontario, and McGill University, Montreal, Quebec, Canada (M.A.R.).
Abstract
BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).
BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).
Authors: Paul L den Exter; Scott C Woller; Helia Robert-Ebadi; Camila Masias; Pierre-Emmanuel Morange; David Castelli; John-Bjarne Hansen; Geert-Jan Geersing; Deborah M Siegal; Kerstin de Wit; Frederikus A Klok Journal: J Thromb Haemost Date: 2022-06-23 Impact factor: 16.036