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CC BY 4.0 · TH Open 2022; 06(03): e177-e183
DOI: 10.1055/s-0042-1750379
Original Article

Rivaroxaban Plus Aspirin for Extended Thromboprophylaxis in Acutely Ill Medical Patients: Insights from the MARINER Trial

Alex C. Spyropoulos 
1   The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, The Feinstein Institute for Medical Research, New York, New York, United States
2   Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, New York, United States
,
Mark Goldin
3   Northwell Health, Great Neck, New York, United States
,
Walter Ageno
4   Department of Medicine and Surgery, University of Insubria, Varese, Italy
5   University of Insubria, Varese, Italy
,
Gregory W. Albers
6   Stanford Stroke Center, Stanford Medical Center, Stanford University, Palo Alto, California, United States
,
C. Gregory Elliott
7   Department of Medicine, University of Utah and Intermountain Healthcare, Salt Lake City, Utah, United States
,
William R. Hiatt
8   Division of Cardiology, University of Colorado School of Medicine
9   CPC Clinical Research, Aurora, Colorado, United States
,
Jonathan L. Halperin
10   Cardiovascular Institute, Mount Sinai Medical Center, New York, New York, United States
,
Gregory Maynard
11   University of California at Davis, Sacramento, California, United States
,
P. Gabriel Steg
12   Université de Paris, Assistance Publique–Hôpitaux de Paris, and INSERM U-1148, Paris, France
,
Jeffrey I. Weitz
13   McMaster University
14   The Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Theodore E. Spiro
15   Bayer US, LLC, Whippany, New Jersey, United States
,
Wentao Lu
16   Cardiovascular Clinical Development, Janssen Research and Development, LLC, Raritan, New Jersey, United States
,
Jessica Marsigliano
16   Cardiovascular Clinical Development, Janssen Research and Development, LLC, Raritan, New Jersey, United States
,
Gary E. Raskob
17   Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
,
Elliot S. Barnathan 
16   Cardiovascular Clinical Development, Janssen Research and Development, LLC, Raritan, New Jersey, United States
› Author Affiliations Funding/Acknowledgments Janssen Research & Development LLC sponsored the MARINER study.
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Abstract

Background The MARINER trial evaluated whether postdischarge thromboprophylaxis with rivaroxaban could reduce the primary outcome of symptomatic venous thromboembolism (VTE) or VTE-related death in acutely ill medical patients at risk for VTE. Although aspirin use was not randomized, approximately half of the enrolled patients were receiving aspirin at baseline. We hypothesized that thromboprophylaxis with once-daily rivaroxaban (10 mg or, if creatinine clearance was 30–49 mL/min, 7.5 mg) plus aspirin (R/A) would be superior to placebo without aspirin (no thromboprophylaxis [no TP]).

Methods We compared the primary and major secondary outcomes in the intention-to-treat population in four subgroups defined at baseline: (1) R/A (N = 3,159); (2) rivaroxaban alone (N = 2,848); (3) aspirin alone (N = 3,046); and (4) no TP (N = 2,966). Major bleeding (MB) and nonmajor clinically relevant (NMCR) bleeding were assessed in the safety population on treatment plus 2 days.

Results Patients on R/A had reduced symptomatic VTE and VTE-related death compared with no TP (0.76 vs 1.28%, p = 0.042), and experienced less symptomatic VTE and all-cause mortality (p = 0.005) and all-cause mortality alone (p = 0.01) compared with no TP. Event incidences for rivaroxaban alone (0.91%) or aspirin alone (0.92%) were similar. MB was low in all groups but lowest in the no TP group. NMCR bleeding was increased with R/A compared with no TP (p = 0.009).

Limitations Aspirin use was not randomized.

Conclusion Extended postdischarge thromboprophylaxis with R/A was associated with less symptomatic VTE and VTE-related death compared with no TP in previously hospitalized medical patients at risk for VTE. NMCR bleeding was increased with R/A compared with no TP. These post hoc findings need confirmation in a prospective trial.

Keywords

aspirin - combined modality therapy - hospitalization - rivaroxaban - venous thromboembolism

Author Contributions

All authors have contributed equally to the manuscript: (1) conception and design of the work, and analysis and interpretation of the data; (2) drafting the work or revising it critically for important intellectual content including: Introduction, Methods, Results, and Discussion; (3) final approval of the version to be published; and (4) agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.




Publication History

Received: 09 March 2022

Accepted: 25 April 2022

Article published online:
11 July 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Hull RD, Merali T, Mills A, Stevenson AL, Liang J. Venous thromboembolism in elderly high-risk medical patients: time course of events and influence of risk factors. Clin Appl Thromb Hemost 2013; 19 (04) 357-362
    CrossrefPubMedGoogle Scholar
  • 2 Spyropoulos AC, Anderson Jr FA, FitzGerald G. et al; IMPROVE Investigators. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140 (03) 706-714
    CrossrefPubMedGoogle Scholar
  • 3 Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146 (04) 278-288
    CrossrefPubMedGoogle Scholar
  • 4 Bajaj NS, Vaduganathan M, Qamar A. et al. Extended prophylaxis for venous thromboembolism after hospitalization for medical illness: a trial sequential and cumulative meta-analysis. PLoS Med 2019; 16 (04) e1002797
    CrossrefPubMedGoogle Scholar
  • 5 Kahn SR, Lim W, Dunn AS. et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e195S-e226S
    CrossrefPubMedGoogle Scholar
  • 6 Schünemann HJ, Cushman M, Burnett AE. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018; 2 (22) 3198-3225
    CrossrefPubMedGoogle Scholar
  • 7 Cohen AT, Harrington RA, Goldhaber SZ. et al; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016; 375 (06) 534-544
    CrossrefPubMedGoogle Scholar
  • 8 Spyropoulos AC, Ageno W, Albers GW. et al; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med 2018; 379 (12) 1118-1127
    CrossrefPubMedGoogle Scholar
  • 9 Anderson DR, Dunbar M, Murnaghan J. et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med 2018; 378 (08) 699-707
    CrossrefPubMedGoogle Scholar
  • 10 Anderson DR, Dunbar MJ, Bohm ER. et al. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med 2013; 158 (11) 800-806
    CrossrefPubMedGoogle Scholar
  • 11 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
    CrossrefPubMedGoogle Scholar
  • 12 Bonaca MP, Bauersachs RM, Anand SS. et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020; 382 (21) 1994-2004
    CrossrefPubMedGoogle Scholar
  • 13 Gibson CM, Korjian S, Chi G. et al; APEX Investigators. Comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely ill medical patients: an APEX trial substudy. J Am Heart Assoc 2017; 6 (07) e006015
    CrossrefPubMedGoogle Scholar
  • 14 Tomkowski WZ, Davidson BL. Thromboprophylaxis by rivaroxaban, aspirin, both, or placebo after hospitalization for medical illness. Thromb Res 2019; 180: 62-63
    CrossrefPubMedGoogle Scholar
  • 15 Ageno W, Lopes RD, Goldin M. et al. Rivaroxaban for extended thromboprophylaxis in acutely ill medical patients 75 years of age or older. J Thromb Haemost 2021; 19 (11) 2772-2780
    CrossrefPubMedGoogle Scholar
  • 16 Gibson CM, Chi G, Halaby R. et al; APEX Investigators. Extended-duration betrixaban reduces the risk of stroke versus standard-dose enoxaparin among hospitalized medically ill patients: an APEX trial substudy (acute medically ill venous thromboembolism prevention with extended duration betrixaban). Circulation 2017; 135 (07) 648-655
    CrossrefPubMedGoogle Scholar
  • 17 Spyropoulos AC, Ageno W, Albers GW. et al. Post-discharge prophylaxis with rivaroxaban reduces fatal and major thromboembolic events in medically ill patients. J Am Coll Cardiol 2020; 75 (25) 3140-3147
    CrossrefPubMedGoogle Scholar