Medically Ill Patient Assessment of Rivaroxaban Versus Placebo IN Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER) Trial: Primary Results Alex C. Spyropoulos *, Walter Ageno, Gregory W. Albers, C. Gregory Elliott, Jonathan L. Halperin, William R. Hiatt, Gregory A. Maynard, P. Gabriel Steg, Jeffrey I. Weitz, Eunyoung Suh, Theodore E. Spiro, Elliot S. Barnathan, Gary E. Raskob* On behalf of the MARINER Investigators * Study Co-Chairs
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Medically Ill Patient Assessment of Rivaroxaban Versus Placebo IN Reducing Post-Discharge
Alex C. Spyropoulos*, Walter Ageno, Gregory W. Albers, C. Gregory Elliott, Jonathan L. Halperin, William R. Hiatt, Gregory A. Maynard, P. Gabriel Steg,
Jeffrey I. Weitz, Eunyoung Suh, Theodore E. Spiro, Elliot S. Barnathan, Gary E. Raskob*
On behalf of the MARINER Investigators* Study Co-Chairs
Background• A significant proportion of ~20 million patients in the US and EU hospitalized annually
for medical illness remain at risk for venous thromboembolism (VTE) after hospital discharge, but the role of extended thromboprophylaxis is controversial– Over 400,000 VTE and fatal PE events annually with an incidence of 3% in at-risk patients– The rate of symptomatic VTE more than doubles over the first 21 days and is associated
with a five-fold increase of fatal PE up to 6 weeks post-discharge– Previous trials of extended thromboprophylaxis have shown either excess bleeding or
benefit based on mainly reducing asymptomatic deep vein thrombosis• The MARINER trial was designed to optimize the benefit/risk profile of extended
prophylaxis with rivaroxaban at discharge in an at-risk medically ill population using clinically meaningful endpoints– VTE enrichment strategy – Reduced dosing in subjects with moderate renal insufficiency/key exclusionary criteria
Spyropoulos AC et al Chest 2011; 140:706-14 Guyatt GH, et al. Chest 2012;141(suppl):e185s-e194s
Anderson FA, Jr. et al. Am J Hematol 2007;82(9):777-82Cohen AT et al. Thromb Haemost 2007;98(4):756-64Heit JA et al. Arch Intern Med 2002;162(11):1245-8
ObjectivesPrimary Objective
• Prevention of symptomatic venous thromboembolism (VTE: lower extremity deep vein thrombosis [DVT] and non-fatal pulmonary embolism [PE])
and VTE-related death (death due to PE or death in which PE cannot be ruled out as the cause)
Secondary Objectives
• VTE-related death • Symptomatic VTE • The composite of symptomatic VTE and all-cause
mortality • The composite of symptomatic VTE, myocardial
infarction, non-hemorrhagic stroke and CV death • All-cause mortality
Principal Safety Objective
• Major bleeding using International Society of Thrombosis and Haemostasis (ISTH) bleeding criteria
VTE-related death 43 (0.72) 46 (0.77) 0.93 (0.62, 1.42) 0.751
Death (PE) 3 (0.05) 5 (0.08) 0.60 (0.14, 2.51) 0.485
Death (PE cannot be ruled out) 40 (0.67) 41 (0.68) 0.98 (0.63, 1.51) 0.912
[1] Hazard ratio (95% CI) and p-value are from the Cox proportional hazard model, stratified by baseline creatinine clearance (CrCl) (30-<50mL/min vs. ≥50mL/min), with treatment as the only covariate.[2] P-value (two-sided) for superiority of rivaroxaban versus placebo from the Cox proportional hazard model.
Primary Efficacy Outcome: By Dose Stratum/Baseline Renal Function
%
Rivaroxaban 10 mg (N=4909)
Placebo (N=4913)
Rivaroxaban 7.5mg (N=1098)
Placebo (N=1099)
2.5
2
1.5
1
0.5
0
0.650.98
1.64 1.64
Symptomatic VTE and VTE-related Death up to Day 45
Secondary Efficacy Outcomes up to Day 45Symptomatic VTE and
All-Cause MortalitySymptomatic VTE, MI,
Ischemic Stroke and CV Death All-Cause Mortality
27% Reduction
Bleeding Outcomes (On Treatment + 2 Days)
Rivaroxaban(N=5982)
Placebo(N=5980) Rivaroxaban vs Placebo
n (%) n (%)Hazard Ratio(95% CI) [1]
p-value [2]
Major bleeding 17 (0.28) 9 (0.15) 1.88 (0.84, 4.23) 0.124
A fall in hemoglobin of >=2g/dL 14 (0.23) 6 (0.10) 2.33 (0.89, 6.05) 0.084
A transfusion of >=2 units of packed RBC 11 (0.18) 3 (0.05) 3.66 (1.02, 13.10) 0.047
A critical site 3 (0.05) 2 (0.03) 1.50 (0.25, 8.97) 0.657
A fatal outcome 2 (0.03) 0 (0.0) NA (NA, NA)
Non-major clinically relevant bleeding 85 (1.42) 51 (0.85) 1.66 (1.17, 2.35) 0.004[1] Hazard ratio (95% CI) and p-value are from the Cox proportional hazard model, stratified by baseline CrCl (30-<50 mL/min vs. ≥50 mL/min), with treatment as the only covariate.[2] P-value (two-sided) for superiority of rivaroxaban versus placebo from the Cox proportional hazard model.
Conclusions – MARINER • Rivaroxaban did not significantly reduce the composite of symptomatic VTE and VTE-
related death in an at-risk medically ill population post-hospital discharge (ARR=0.27%)– There appeared to be no effect on VTE-related death
• Secondary outcomes revealed:– A 56% reduction in symptomatic VTE – A 27% reduction in symptomatic VTE and all-cause mortality
• Rivaroxaban 10mg in subjects without significant renal impairment (CrCL ≥ 50ml/min) appeared more effective than reduced dose in subjects with moderate renal impairment
• The incidence of major bleeding with rivaroxaban was low (0.28%) with no significant increase in major, critical, or fatal bleeding
The results of the MARINER study are now available at NEJM.org
Jim Douketis (Chair)Alexander G. Turpie,Sam SchulmanClive KearonLori-Ann LinkinsSebastian Schellong
Kenneth Bauer (Chair)William GeertsRobin Roberts
Independent Data Monitoring Committee
National Lead InvestigatorsPatricia Casais, Alexander Gallus, Jeff Karrasch, Sabine Eichinger-Hasenauer, Vitaly Krivenchuk, Almira Hadzovic-Dzuvo, Stevan Trbojevic, Renato Lopes, Valentina Mincheva, Marc Carrier, Rodolfo Dennis, Neven Tudoric, Jindrich Spinar, Henrik Nielsen, Toomas Marandi, Tamaz Shaburishvili, Jan Beyer-Westendorf, Panos Vardas, Zoltan Boda, Benjamin Brenner, Franco Piovella, Dainis Krievins, Birute Petrauskiene, Violeta Dejanova-Ilijevska, Luis Ramon Virgen Carrillo, Saskia Middeldorp, Reynaldo Pastor Castillo Leon, Adam Torbicki, Marta Saraiva de Sousa, Maria Dorobantu, Constantin Militaru, Igor Yavelov, Biljana Vuckovic, Jindrich Spinar, Helmuth Reuter, Matthys Basson, Manuel Monreal, Serdar Kucukoglu, Alexander Parkhomenko, Raza Alikhan, David Rosenberg, Roger Yusen, Alok Khorana, Victor Tapson, Charles Pollack, Monica Hazelrigg
The >1000 MARINER Investigators and Coordinators and the > 12,000 patients and their families