Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism

Lana A Castellucci¹, Vivien M Chen^{2

3

4}, Michael J Kovacs⁵, Alejandro Lazo-Langner⁵, Peter Greenstreet⁶, Susan Kahn⁷, Benoit Côté⁸, Sam Schulman⁹, Kerstin de Wit^{10

11}, James Douketis¹², Deepa Suryanarayan¹³, Tony Wan¹⁴, Erik Yeo¹⁵, Genevieve Le Templier¹⁶, Huyen A Tran^{17

18}, Abbey Willcox^{17

18

19}, Helen J Crowther²⁰, Ritam Prasad²¹, Sudeep Shivakumar²², Etimbuk Umana²³, Fionnuala Ni Ainle²³, Tobias Tritschler²⁴, Stefano Barco^{25

26}, Jean-Philippe Galanaud²⁷, Marc Blondon²⁸, Lisa Baumann Kreuziger²⁹, Susan Solymoss³⁰, Clive Kearon³¹, Erin Thomas¹, Tim Ramsay⁶, Gregoire Le Gal¹, Marc Rodger³²; COBRRA Trial Investigators

Collaborators, Affiliations

Collaborators

COBRRA Trial Investigators:
Lana A Castellucci, Vivien Chen, Susan Kahn, Kerstin de Wit, Sudeep Shivakumar, Gregoire Le Gal, Marc Rodger, Michael Kovacs, Huyen Tran, John Simes, Rachael Morton, Timothy Brighton, Caroline Reddel, Marc Blondon, Lisa Baumann Kreuziger, Sameer Parpia, Tobias Tritschler, Fionnuala Ní Áinle, Jean-Philippe Galanaud, Stefano Barco, P S Wells, M Forgie, A Karovitch, D Scarvelis, L Duffett, C Code, J Shaw, T F Wang, M Kimpton, T James, Y Xu, D Siegal, A Delluc, M Carrier, C Gonsalves, E Gandara, K Thavorn, N Langlois, R Rodriguez, T Salvi, M Hill, A M Clement, A Pecarskie, Y He, S Schulman, J Eikelboom, V Bhagirath, N Chan, M Zondag, D Matino, P Gross, E Kruja, J Douketis, R Gaa, C Wu, S Takach-Lapner, J Patterson, M Hnatiuk, L Rackel, S Couban, D Anderson, K Robinson, D White, W Hasegawa, M M Keating, N Forward, I Sharif, M Elsawy, C Fraga, A Trottier, J Richards, B Scott, T Wan, P Rahmani, J Jayaraman, E Yeo, Z Liederman, J Abdulrehman, E Kaplovitch, M Dzyuba, V Tagalakis, M Koolian, M Blostein, A Hirsch, E Shulikovsky, A Lazo-Langner, J Kovacs, D Suryanarayan, T Robinson, B Côté, M Émond, V Mai, G Roberge, A Nadeau, I Chagnon, J P Makhzum, G Marcotte, G Le Templier, S Côté-Bigras, M Gérard, V Naessens, C Seguin, J Popov, M Warner, K Mendelew, S Solymoss, H Rana, E Umana, B Bassa, T Breslin, J Kaulsay, C McDermott, P Doran, C Carpenter, S Bannon, P Giacalone, A Kelly, P Varghese, C Durivage, J Curnow, A Bennett, C Dix, D H Robinson, A Willcox, C Ward, F Passam, K T Htun, H J Crowther, P Reberio, M S Lim, S McRae, D Pepperell, R Prasad, S Engelbrecht, D Lenton, S Ng

Affiliations

¹ Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa.
² Department of Haematology and Australian and New Zealand Army Corps Research Institute, Concord Repatriation and General Hospital, Sydney.
³ Sydney Concord Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney.
⁴ National Health and Medical Research Council Clinical Trials Centre, Sydney.
⁵ Department of Medicine, Division of Hematology, Western University, London, ON, Canada.
⁶ Ottawa Methods Centre, Ottawa Hospital Research Institute, Ottawa.
⁷ Department of Medicine, Jewish General Hospital, Montreal.
⁸ Department of Internal Medicine, Hôpital de l'Enfant-Jésus, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, QC, Canada.
⁹ Hamilton General Hospital, Hamilton, ON, Canada.
¹⁰ Department of Emergency Medicine, Queen's University, Kingston, ON, Canada.
¹¹ Canada Division of Emergency Medicine, Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹² Department of Medicine, St. Joseph's Healthcare Hamilton and McMaster University, Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
¹³ Department of Medicine, Division of Hematology, University of Calgary, Calgary, AB, Canada.
¹⁴ Department of Medicine, University of British Columbia, Vancouver, Canada.
¹⁵ Thrombosis and Hemostasis Program, Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto.
¹⁶ Department of Medicine, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
¹⁷ Clinical Haematology Department, Alfred Hospital, Melbourne, VIC, Australia.
¹⁸ Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
¹⁹ Department of Haematology, Austin Hospital, Melbourne, VIC, Australia.
²⁰ Department of Haematology, Blacktown Hospital, Blacktown, NSW, Australia.
²¹ Hunter Clot Clinic, NSW Health Pathology, Calvary Mater Newcastle, Waratah, NSW, Australia.
²² Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada.
²³ Royal College of Surgeons in Ireland, School of Medicine, University College Dublin, Dublin.
²⁴ Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
²⁵ Department of Vascular Medicine, University Hospital Zurich, Zurich, Switzerland.
²⁶ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
²⁷ Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto.
²⁸ Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, Geneva.
²⁹ Versiti Blood Research Insititute, Versiti, Milwaukee.
³⁰ McGill University Health Centre, Montreal.
³¹ Department of Medicine, McMaster University, Hamilton, ON, Canada.
³² Department of Medicine, McGill University, Montreal.

PMID: 41812192
DOI: 10.1056/NEJMoa2510703

Clinical Trial

Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism

Lana A Castellucci et al. N Engl J Med. 2026.

. 2026 Mar 12;394(11):1051-1060.

doi: 10.1056/NEJMoa2510703.

Authors

Collaborators

COBRRA Trial Investigators:
Lana A Castellucci, Vivien Chen, Susan Kahn, Kerstin de Wit, Sudeep Shivakumar, Gregoire Le Gal, Marc Rodger, Michael Kovacs, Huyen Tran, John Simes, Rachael Morton, Timothy Brighton, Caroline Reddel, Marc Blondon, Lisa Baumann Kreuziger, Sameer Parpia, Tobias Tritschler, Fionnuala Ní Áinle, Jean-Philippe Galanaud, Stefano Barco, P S Wells, M Forgie, A Karovitch, D Scarvelis, L Duffett, C Code, J Shaw, T F Wang, M Kimpton, T James, Y Xu, D Siegal, A Delluc, M Carrier, C Gonsalves, E Gandara, K Thavorn, N Langlois, R Rodriguez, T Salvi, M Hill, A M Clement, A Pecarskie, Y He, S Schulman, J Eikelboom, V Bhagirath, N Chan, M Zondag, D Matino, P Gross, E Kruja, J Douketis, R Gaa, C Wu, S Takach-Lapner, J Patterson, M Hnatiuk, L Rackel, S Couban, D Anderson, K Robinson, D White, W Hasegawa, M M Keating, N Forward, I Sharif, M Elsawy, C Fraga, A Trottier, J Richards, B Scott, T Wan, P Rahmani, J Jayaraman, E Yeo, Z Liederman, J Abdulrehman, E Kaplovitch, M Dzyuba, V Tagalakis, M Koolian, M Blostein, A Hirsch, E Shulikovsky, A Lazo-Langner, J Kovacs, D Suryanarayan, T Robinson, B Côté, M Émond, V Mai, G Roberge, A Nadeau, I Chagnon, J P Makhzum, G Marcotte, G Le Templier, S Côté-Bigras, M Gérard, V Naessens, C Seguin, J Popov, M Warner, K Mendelew, S Solymoss, H Rana, E Umana, B Bassa, T Breslin, J Kaulsay, C McDermott, P Doran, C Carpenter, S Bannon, P Giacalone, A Kelly, P Varghese, C Durivage, J Curnow, A Bennett, C Dix, D H Robinson, A Willcox, C Ward, F Passam, K T Htun, H J Crowther, P Reberio, M S Lim, S McRae, D Pepperell, R Prasad, S Engelbrecht, D Lenton, S Ng

Affiliations

¹ Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa.
² Department of Haematology and Australian and New Zealand Army Corps Research Institute, Concord Repatriation and General Hospital, Sydney.
³ Sydney Concord Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney.
⁴ National Health and Medical Research Council Clinical Trials Centre, Sydney.
⁵ Department of Medicine, Division of Hematology, Western University, London, ON, Canada.
⁶ Ottawa Methods Centre, Ottawa Hospital Research Institute, Ottawa.
⁷ Department of Medicine, Jewish General Hospital, Montreal.
⁸ Department of Internal Medicine, Hôpital de l'Enfant-Jésus, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, QC, Canada.
⁹ Hamilton General Hospital, Hamilton, ON, Canada.
¹⁰ Department of Emergency Medicine, Queen's University, Kingston, ON, Canada.
¹¹ Canada Division of Emergency Medicine, Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹² Department of Medicine, St. Joseph's Healthcare Hamilton and McMaster University, Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
¹³ Department of Medicine, Division of Hematology, University of Calgary, Calgary, AB, Canada.
¹⁴ Department of Medicine, University of British Columbia, Vancouver, Canada.
¹⁵ Thrombosis and Hemostasis Program, Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto.
¹⁶ Department of Medicine, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
¹⁷ Clinical Haematology Department, Alfred Hospital, Melbourne, VIC, Australia.
¹⁸ Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
¹⁹ Department of Haematology, Austin Hospital, Melbourne, VIC, Australia.
²⁰ Department of Haematology, Blacktown Hospital, Blacktown, NSW, Australia.
²¹ Hunter Clot Clinic, NSW Health Pathology, Calvary Mater Newcastle, Waratah, NSW, Australia.
²² Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada.
²³ Royal College of Surgeons in Ireland, School of Medicine, University College Dublin, Dublin.
²⁴ Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
²⁵ Department of Vascular Medicine, University Hospital Zurich, Zurich, Switzerland.
²⁶ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
²⁷ Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto.
²⁸ Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, Geneva.
²⁹ Versiti Blood Research Insititute, Versiti, Milwaukee.
³⁰ McGill University Health Centre, Montreal.
³¹ Department of Medicine, McMaster University, Hamilton, ON, Canada.
³² Department of Medicine, McGill University, Montreal.

PMID: 41812192
DOI: 10.1056/NEJMoa2510703

Abstract

Background: Apixaban and rivaroxaban are the oral anticoagulants most frequently used to treat acute venous thromboembolism. However, uncertainty remains about the difference in bleeding risk between the two medications.

Methods: In an international trial with a prospective, randomized, open-label, blinded end-point design, we assigned, in a 1:1 ratio, eligible patients with acute symptomatic pulmonary embolism or proximal deep-vein thrombosis to receive apixaban or rivaroxaban for 3 months. Apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily, and rivaroxaban was given at a dose of 15 mg twice daily for 21 days followed by 20 mg daily. The primary outcome was clinically relevant bleeding, a composite of major bleeding or clinically relevant nonmajor bleeding, as defined according to the International Society on Thrombosis and Haemostasis, during the 3-month trial period. Secondary outcomes included death from any cause.

Results: A total of 2760 patients underwent randomization: 1370 to the apixaban group and 1390 to the rivaroxaban group. A primary-outcome event occurred in 44 of 1345 patients (3.3%) in the apixaban group and 96 of 1355 patients (7.1%) in the rivaroxaban group (relative risk, 0.46; 95% confidence interval [CI], 0.33 to 0.65; P<0.001). Death from any cause occurred in 1 patient (0.1%) in the apixaban group and in 4 patients (0.3%) in the rivaroxaban group (relative risk, 0.25; 95% CI, 0.03 to 2.26). Serious adverse events unrelated to bleeding or venous thrombosis occurred in 36 patients (2.7%) in the apixaban group and in 30 patients (2.2%) in the rivaroxaban group.

Conclusions: Among patients with acute venous thromboembolism, the risk of clinically relevant bleeding was significantly lower with apixaban than with rivaroxaban during the 3-month treatment period. (Funded by the Canadian Institutes of Health Research and others; COBRRA ClinicalTrials.gov number, NCT03266783.).

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Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism

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Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism

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