M edically Ill Patient A ssessment of R ivaroxaban Versus Placebo IN - - PowerPoint PPT Presentation
M edically Ill Patient A ssessment of R ivaroxaban Versus Placebo IN Reducing Post-Discharge Venous Thrombo- E mbolism R isk ( MARINER ) Trial: Primary Results Alex C. Spyropoulos* , Walter Ageno, Gregory W. Albers, C. Gregory Elliott, Jonathan L.
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
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
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):777-82 Cohen AT et al. Thromb Haemost 2007;98(4):756-64 Heit JA et al. Arch Intern Med 2002;162(11):1245-8
Primary Objective
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
mortality
infarction, non-hemorrhagic stroke and CV death
Principal Safety Objective
Secondary Safety Objective
Placebo
Rivaroxaban 10 mg/day (CrCl ≥ 50ml/min) 7.5mg/day (CrCl 30-<50ml/min) Day 45
Day 75 ~12,000 Medically Ill hospitalized for 3-10 days*
Design: Randomized, double-blind placebo-controlled, event driven trial
*3-14 days prior to INT-5
Discharge Screening Treatment Follow-up
1:1 Stratified by Renal Function and Country
Power: 90%, Two sided alpha 0.05 to target 161 events (Placebo 2.5%, 40% RRR)
Key inclusion criteria*
u
Patients ≥ 40 years hospitalized for 3-10 days with thromboprophylaxis (LMWH or UFH) prior to randomization for one of the following acute medical conditions
u
Heart failure
u
Acute respiratory insufficiency or acute exacerbation of COPD
u
Acute ischemic stroke
u
Acute infectious diseases
u
Inflammatory diseases, including rheumatic disease
u
Total modified IMPROVE VTE Risk Score ≥ 4 OR total modified IMPROVE VTE Risk Score 2 or 3 and D dimer > 2x ULN during index hospitalization
Key exclusion criteria*
u
Bleeding Risks
u
Any bleeding within 3 months
u
Surgery, biopsy or trauma 4 weeks prior or planned
u
Active gastroduodenal ulcer
u
Active cancer
u
Required anticoagulation after discharge
u
Use of dual antiplatelet therapy during the index hospitalization
u
Concomitant Medications
u
Combined P-gp and strong CYP3A4 inhibitors
u
Combined P-gp and strong CYP3A4 inducers
* Reflects I/E Criteria as of INT-7
VTE Risk Factor Points Previous VTE 3 Known thrombophilia 2 Lower-limb paralysis 2 History of cancer* 2 Immobilization ≥1 day* 1 ICU/CCU stay 1 Age >60 years 1
Spyropoulos AC et al Chest 2011; 140:706-14
*Modified for the MARINER clinical trial ICU = intensive care unit; CCU = critical care unit.
MARINER was conducted in 36 countries at 671 sites
Canada N=43 United States N=291 Colombia N=140 Peru N=65 Brazil N=92 Argentina N=242 South Africa N=208 UK N=8 Spain N=384 Netherlands N=17 Germany N=17 Italy N=147 Israel N=111 Denmark N=7 Czech RepN=231 Russia N=1142 Ukraine N=854 Hungary N=549 Australia N=88 Poland N=619 Romania N=324 Mexico N=32 Portugal N=13 Estonia N=11 Latvia N=308 Lithuania N=164 Belarus N=133 Austria N=14 Turkey N=70 Georgia N=1762 Greece N=131 Bulgaria N=1428 Croatia N=270 Bosnia and Herzegovina N=597 Serbia N=609 Macedonia N=902
12,024 Patients randomized 12,019 Patients included in the Intention to Treat Analysis 6,007 Assigned to receive Rivaroxaban 6,012 Assigned to receive placebo 2 Without written informed consent 3 Without Health Authority Approval 19 Outcome Status at Day 45 unknown 1 Lost to follow up 18 Withdrew consent 24 Outcome Status at Day 45 unknown 4 Lost to follow up 20 Withdrew consent 525 Discontinued study treatment prematurely 540 Discontinued study treatment prematurely 5982 Treated with rivaroxaban 5980 Treated with placebo 11,962 Patients included in the Safety Analysis 32 Not treated 25 Not treated
Characteristic Rivaroxaban (n= 6007) Placebo (n=6012)
Age (Mean-yr) 69.7 69.7 ≥ 75 yr (%) 35.9 35.6 Male Sex (%) 52.1 52.5 Race (% White) 96.3 96.6 Weight (mean kg) 80.8 80.6 Creatinine Clearance (ml/min) 30 - < 50 (%); 7.5mg Dose Stratum 18.3 18.3 ≥50 (%); 10mg Dose Stratum 81.7 81.7 Diabetes (%) 29.1 27.9 History of Cancer (%) 8.1 8.9 Baseline aspirin use (%) 52.6 50.7
Characteristic Rivaroxaban (n= 6007) Placebo (n=6012)
Reason for Index Hospitalization (%) Heart Failure 40.6 39.9 Acute Resp Insuff or Exac of COPD 26.2 26.8 Acute Infectious Disease 17.5 17.4 Acute Ischemic Stroke 14.3 14.4 Inflammatory Disease 1.4 1.5 Duration of Index Hosp. (days, mean) 6.7 6.7 Duration of thromboprophylaxis (days, mean) 6.2 6.2 Modified IMPROVE Risk Score (%) 2 34.9 35.8 3 31.4 29.6 ≥ 4 33.6 34.5 D-Dimer >2x Upper Limit of Normal (%) 70.4 70.5
%
Rivaroxaban (N=6007) Placebo (N=6012)
1.6 1.4 1.2 1 0.8 0.6 0.4 0.2
0.83 1.1
Symptomatic VTE and VTE related Death up to Day 45
50 66
HR 0.76 (95% CI 0.52-1.09) 24% RRR 0.27% ARR
P=0.136
Rivaroxaban (N=6007) Placebo (N=6012) Rivaroxaban vs Placebo
Outcomes n (%) n (%) Hazard Ratio (95% CI) [1] p-value [2]
Primary efficacy outcome (Sx VTE and VTE-related death) 50 (0.83) 66 (1.10) 0.76 (0.52, 1.09) 0.136 Symptomatic lower extremity DVT 4 (0.07) 13 (0.22) 0.31 (0.10, 0.94) 0.039 Symptomatic non-fatal PE 7 (0.12) 15 (0.25) 0.47 (0.19, 1.14) 0.096 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
[2] P-value (two-sided) for superiority of rivaroxaban versus placebo from the Cox proportional hazard model.
%
Rivaroxaban 10 mg (N=4909) Placebo (N=4913) Rivaroxaban 7.5mg (N=1098) Placebo (N=1099)
2.5 2 1.5 1 0.5 0.65 0.98 1.64 1.64
P=0.075 P=0.994
10 mg QD (CrCl ≥50ml/min) 7.5 mg QD (CrCl 30-< 50ml/min)
32 48 18 18
56% Reduction
Symptomatic VTE and All-Cause Mortality Symptomatic VTE, MI, Ischemic Stroke and CV Death All-Cause Mortality
27% Reduction
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.
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
– A 56% reduction in symptomatic VTE – A 27% reduction in symptomatic VTE and all-cause mortality
appeared more effective than reduced dose in subjects with moderate renal impairment
increase in major, critical, or fatal bleeding
Clinical Events Committee
Jim Douketis (Chair) Alexander G. Turpie, Sam Schulman Clive Kearon Lori-Ann Linkins Sebastian Schellong Kenneth Bauer (Chair) William Geerts Robin Roberts
Independent Data Monitoring Committee
National Lead Investigators
Patricia 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