CC BY-NC-ND 4.0 · Thromb Haemost 2020; 120(03): 515-524
DOI: 10.1055/s-0039-1701009
Stroke, Systemic or Venous Thromboembolism
Georg Thieme Verlag KG Stuttgart · New York

Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials

Jeffrey I. Weitz
1   The Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Gary E. Raskob
2   College of Public Health, University of Oklahoma, Oklahoma City, Oklahoma, United States
,
Alex C. Spyropoulos
3   The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, New York, United States
4   The Feinstein Institute for Medical Research, New York, New York, United States
5   Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, New York, United States
,
Theodore E. Spiro
6   Thrombosis and Hematology Therapeutic Area, Clinical Development, Pharmaceuticals, Bayer U.S. LLC, Whippany, New Jersey, United States
,
Yoriko De Sanctis
7   Statistics and Data Insights, Bayer U.S. LLC, Whippany, New Jersey, United States
,
Jianfeng Xu
8   Janssen Research and Development LLC, Raritan, New Jersey, United States
,
Wentao Lu
8   Janssen Research and Development LLC, Raritan, New Jersey, United States
,
Eunyoung Suh
8   Janssen Research and Development LLC, Raritan, New Jersey, United States
,
Domenick Argenti
8   Janssen Research and Development LLC, Raritan, New Jersey, United States
,
Haitao Yang
8   Janssen Research and Development LLC, Raritan, New Jersey, United States
,
John Albanese
8   Janssen Research and Development LLC, Raritan, New Jersey, United States
,
Concetta Lipardi
8   Janssen Research and Development LLC, Raritan, New Jersey, United States
,
Elliot S. Barnathan
8   Janssen Research and Development LLC, Raritan, New Jersey, United States
› Author Affiliations
Funding Bayer U.S. LLC and Janssen Research & Development LLC sponsored the MAGELLAN and MARINER trials and the analysis reported here.
Further Information

Publication History

04 October 2019

04 December 2019

Publication Date:
23 January 2020 (online)

Abstract

Patients with renal impairment are at higher risk of thrombosis and bleeding than those with normal renal function. The optimal rivaroxaban dose for thromboprophylaxis in acutely ill medical patients with renal impairment is unknown. MARINER and MAGELLAN were multicenter, randomized clinical trials of rivaroxaban in acutely ill medical patients. Efficacy and safety outcomes in patients with renal impairment in MARINER (7.5 mg once daily) were compared with those in patients with normal renal function in MARINER (10 mg once daily) and in a subpopulation of MAGELLAN that excluded patients at high risk for bleeding at baseline (10 mg once daily). Compared with enoxaparin/placebo in the MAGELLAN subpopulation, the relative risk (RR) of symptomatic venous thromboembolism (VTE) and VTE-related death with rivaroxaban 10 mg in patients with renal impairment (RR = 0.62; 95% confidence interval [CI] 0.27–1.44) was similar to that in those with normal renal function (RR = 0.78; 95% CI 0.44–1.40), while in MARINER, the 7.5 mg dose did not reduce the risk in patients with renal impairment (hazard ratio = 1.00; 95% CI 0.52–1.92). Major bleeding with rivaroxaban 10 mg once daily was higher in patients with renal impairment than in those with normal renal function in MAGELLAN (1.54% vs. 0.98%) and in the MAGELLAN subpopulation (0.94% vs. 0.61%). At a dose of 10 mg once daily, rivaroxaban is effective for thromboprophylaxis in acutely ill medical patients with impaired or normal renal function. The safety of this regimen is enhanced without loss of efficacy by excluding patients at high risk for bleeding, but not by using a reduced-dose strategy.

Trial Registration ClinicalTrials.gov identifiers: NCT00571649 for the MAGELLAN trial, NCT02111564 for the MARINER trial.

Authors' Contributions

All authors contributed equally to the manuscript: (1) conception and design of the work, 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 the questions related to the accuracy or integrity of any part.


 
  • References

  • 1 Tadlock MD, Chouliaras K, Kennedy M. , et al. The origin of fatal pulmonary emboli: a postmortem analysis of 500 deaths from pulmonary embolism in trauma, surgical, and medical patients. Am J Surg 2015; 209 (06) 959-968
  • 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 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
  • 4 Cohen AT, Alikhan R, Arcelus JI. , et al. Assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients. Thromb Haemost 2005; 94 (04) 750-759
  • 5 Geerts WH, Bergqvist D, Pineo GF. , et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6, Suppl): 381S-453S
  • 6 Jalal DI, Chonchol M, Targher G. Disorders of hemostasis associated with chronic kidney disease. Semin Thromb Hemost 2010; 36 (01) 34-40
  • 7 Ribic C, Crowther M. Thrombosis and anticoagulation in the setting of renal or liver disease. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 188-195
  • 8 Cohen AT, Spiro TE, Büller HR. , et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (06) 513-523
  • 9 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
  • 10 Cohen AT, Spiro TE, Büller HR. , et al. Extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study protocol. J Thromb Thrombolysis 2011; 31 (04) 407-416
  • 11 Raskob GE, Spyropoulos AC, Zrubek J. , et al. The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications. Thromb Haemost 2016; 115 (06) 1240-1248
  • 12 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16 (01) 31-41
  • 13 Spyropoulos AC, Lipardi C, Xu J. , et al. Improved Benefit Risk Profile of Rivaroxaban in a Subpopulation of the MAGELLAN Study. Clin Appl Thromb Hemost 2019; 25: 1076029619886022
  • 14 Mehran R, Rao SV, Bhatt DL. , et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
  • 15 Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50 (10) 675-686
  • 16 Eriksson BI, Borris L, Dahl OE. , et al; ODIXa-HIP Study Investigators. Oral, direct factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4 (01) 121-128
  • 17 Eriksson BI, Borris LC, Dahl OE. , et al; ODIXa-HIP Study Investigators. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114 (22) 2374-2381
  • 18 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22 (04) 719-748
  • 19 Cox DR. Regression models and life-tables. J R Stat Soc B 1972; 34 (02) 187-220
  • 20 Wattanakit K, Cushman M, Stehman-Breen C, Heckbert SR, Folsom AR. Chronic kidney disease increases risk for venous thromboembolism. J Am Soc Nephrol 2008; 19 (01) 135-140
  • 21 Trujillo-Santos J, Schellong S, Falga C. , et al; RIETE Investigators. Low-molecular-weight or unfractionated heparin in venous thromboembolism: the influence of renal function. Am J Med 2013; 126 (05) 425-434.e1
  • 22 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