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. 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 Anderson FA, Jr. et al. Am J Hematol 2007;82(9):777-82 Spyropoulos AC et al Chest 2011; 140:706-14 Cohen AT et al. Thromb Haemost 2007;98(4):756-64 Guyatt GH, et al. Chest 2012;141(suppl):e185s-e194s Heit JA et al. Arch Intern Med 2002;162(11):1245-8

Objectives Primary Objective Secondary Objectives • • Prevention of symptomatic venous VTE-related death • thromboembolism (VTE: lower extremity deep Symptomatic VTE • vein thrombosis [DVT] and non-fatal pulmonary The composite of symptomatic VTE and all-cause embolism [PE]) mortality • The composite of symptomatic VTE, myocardial and VTE-related death (death due to PE or death in infarction, non-hemorrhagic stroke and CV death • which PE cannot be ruled out as the cause) All-cause mortality Principal Safety Objective • Major bleeding using International Society of Thrombosis and Haemostasis (ISTH) bleeding criteria Secondary Safety Objective • Non-major clinically relevant bleeding

MARINER - Study Design Design: Randomized, double-blind placebo-controlled, event driven trial Rivaroxaban 10 mg/day (CrCl ≥ 50ml/min) 7.5mg/day (CrCl 30-<50ml/min) 1:1 ~12,000 Medically Ill Stratified by R hospitalized Renal Function for 3-10 days* and Country Placebo Discharge Screening Treatment Follow-up *3-14 days prior to INT-5 Day 45 Day 75 Power: 90%, Two sided alpha 0.05 to target 161 events (Placebo 2.5%, 40% RRR)

Key Inclusion and Exclusion Criteria Key inclusion criteria* Key exclusion criteria* u Patients ≥ 40 years hospitalized for 3-10 days with u Bleeding Risks thromboprophylaxis (LMWH or UFH) prior to u Any bleeding within 3 months randomization for one of the following acute medical u Surgery, biopsy or trauma 4 weeks prior or conditions planned u Heart failure u Active gastroduodenal ulcer u Acute respiratory insufficiency or acute u Active cancer exacerbation of COPD u Required anticoagulation after discharge u Acute ischemic stroke u Use of dual antiplatelet therapy during the index u Acute infectious diseases hospitalization u Inflammatory diseases, including rheumatic u Concomitant Medications disease u Combined P-gp and strong CYP3A4 inhibitors u Combined P-gp and strong CYP3A4 inducers 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 * Reflects I/E Criteria as of INT-7

IMPROVE VTE Risk Score 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 *Modified for the MARINER clinical trial ICU = intensive care unit; CCU = critical care unit. Spyropoulos AC et al Chest 2011; 140:706-14

MARINER Randomized 12,024 subjects MARINER was conducted in 36 countries at 671 sites Lithuania Serbia Ukraine Estonia Latvia Denmark UK Poland N=164 Belarus N=609 N=854 N=11 N=308 N=7 N=8 N=619 N=133 Bulgaria N=1428 Russia Canada Netherlands N=1142 N=43 N=17 Spain N=384 United States N=291 Portugal N=13 Germany N=17 Mexico N=32 Italy N=147 Austria N=14 Turkey Colombia N=140 Czech RepN=231 N=70 Georgia Croatia N=270 N=1762 Brazil Israel Bosnia and N=92 Peru N=65 N=111 Herzegovina N=597 Australia Hungary N=549 N=88 South Africa Romania Macedonia N=208 Argentina N=324 N=902 N=242 Greece N=131

Study Flow 12,024 Patients randomized 2 Without written informed consent 3 Without Health Authority Approval 12,019 Patients included in the Intention to Treat Analysis 6,007 Assigned to receive Rivaroxaban 6,012 Assigned to receive placebo 25 Not treated 32 Not treated 5982 Treated with 11,962 Patients included 5980 Treated rivaroxaban in the Safety Analysis with placebo 19 Outcome Status at 24 Outcome Status at 525 Discontinued 540 Discontinued Day 45 unknown Day 45 unknown study treatment study treatment 1 Lost to follow up 4 Lost to follow up prematurely prematurely 18 Withdrew consent 20 Withdrew consent

Baseline Characteristics (1) 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

Baseline Characteristics (2) 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

Study Results

Primary Efficacy Outcome Symptomatic VTE and VTE related Death up to Day 45 1.6 P=0.136 1.4 1.1 HR 0.76 1.2 (95% CI 0.52-1.09) 1 0.83 24% RRR % 0.27% ARR 0.8 0.6 0.4 0.2 50 66 0 Rivaroxaban (N=6007) Placebo (N=6012)

Primary Efficacy Outcome up to Day 45

Components of the Primary Efficacy Outcome up to Day 45 Rivaroxaban Placebo (N=6007) (N=6012) Rivaroxaban vs Placebo p-value [2] Hazard Ratio Outcomes n (%) n (%) (95% CI) [1] Primary efficacy outcome 50 (0.83) 66 (1.10) 0.76 (0.52, 1.09) 0.136 (Sx VTE and VTE-related death) 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 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 Symptomatic VTE and VTE-related Death up to Day 45 7.5 mg QD (CrCl 30-< 50ml/min) 10 mg QD (CrCl ≥50ml/min) 2.5 P=0.994 2 1.64 1.64 1.5 % P=0.075 0.98 1 0.65 0.5 32 48 18 18 0 Rivaroxaban 10 mg Placebo Rivaroxaban 7.5mg Placebo (N=4909) (N=4913) (N=1098) (N=1099)

Secondary Efficacy Outcomes up to Day 45 VTE-related Death Symptomatic VTE 56% Reduction

Secondary Efficacy Outcomes up to Day 45 Symptomatic VTE and Symptomatic VTE, MI, All-Cause Mortality Ischemic Stroke and CV Death All-Cause Mortality 27% Reduction

Bleeding Outcomes (On Treatment + 2 Days) Rivaroxaban Placebo (N=5982) (N=5980) Rivaroxaban vs Placebo Hazard Ratio n (%) n (%) p-value [2] (95% CI) [1] 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.