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

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

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 14 Tomkowski WZ, Davidson BL. Thromboprophylaxis by rivaroxaban, aspirin, both, or placebo after hospitalization for medical illness. Thromb Res 2019; 180: 62-63
• 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
• 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
• 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