1. Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome – Thrombolysis in Myocardial Infarction 51 Trial (ATLAS-ACS 2 TIMI 51): A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Rivaroxaban in Subjects with Acute Coronary Syndrome C. Michael Gibson, M.S., M.D., Jessica Mega, M.P.H., M.D., & Eugene Braunwald, M.D. on behalf of the ATLAS ACS 2 TIMI 51 Investigators Funded by a Research Grant from Johnson and Johnson and Bayer to Brigham & Women’s Hospital. Dr. Gibson has received honoraria & consulting fees from J&J and Bayer.

2. BACKGROUND: Thrombin In ACS There is excess thrombin generation that persists for 6 months following an index ACS event. 1 Thrombin is the most potent stimulant of platelet aggregation. 2 recurrent Reduction of thrombin generation by warfarin reduces recurrent MI by 44% in a meta-analysis of 10 ACS trials. 3 Rivaroxaban is a direct factor Xa inhibitor which blocks initiation of the final common pathway leading to thrombin generation. Based upon safety and efficacy in Phase II, 5.0 mg bid and 2.5 mg bid doses of Rivaroxaban were chosen for Phase III evaluation in ATLAS TIMI 51. 4 1. Merlini PA et al. Circulation. 1994;90:61-68. 2. Coughlin S. Thrombin signaling and protease-activated receptors. Nature 2000;407(6801):258-64. 3. Rothberg MB et al Ann Intern Med. 2005 Aug 16;143(4):241-50. 4. Lancet. 2009;374(9683):29-38.

3. TRIAL ORGANIZATION Trial Leadership: TIMI Study Group Chairman: Eugene Braunwald, Principal Investigator: C. Michael Gibson Investigator: Jessica Mega, Statisticians: Sabina Murphy, Charles Contant Executive Committee Jean-Pierre Bassand, Deepak Bhatt, Christoph Bode, Keith Fox, Marc Cohen, Shinya Goto, David Schneider, Freek Verheugt Sponsors: Johnson & Johnson and Bayer Health Care J&J: Paul Burton, Peter DiBattiste, Alexei N. Plotnikov, Linda DeCaprio, Xiang Sun Bayer: Nancy Cook Bruns, Scott Berkowitz, Frank Misselwitz Data Safety Monitoring Board Douglas Weaver (Chair), Christian Hamm, Judith S. Hochman, Jeffrey Anderson, Hiroyuki Daida, Statistician: Allan Skene

4. Recent ACS: STEMI, NSTEMI, UA No increased bleeding risk, No warfarin, No ICH, No prior stroke if on ASA + Thienopyridine Stabilized 1-7 Days Post-Index Event PRIMARY ENDPOINT: EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.) SAFETY: TIMI major bleeding not associated with CABG Event driven trial of 1,002 events in 15,342 patients** RIVAROXABAN 5.0 mg BID N=5,176 ASA + Thieno, n=4,827 ASA, n=349 Stratified by Thienopyridine use at MD Discretion + ASA 75 to 100 mg/day Placebo N=5,176 ASA + Thieno, n=4,821 ASA, n=355 RIVAROXABAN 2.5 mg BID n=5,174 ASA + Thieno, n=4,825 ASA, n=349 * Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke ** 184 subjects were excluded from the efficacy analyses prior to unblinding

5. 44 Countries766 Sites 44 Countries766 Sites NATIONAL LEAD INVESTIGATORS RUSSIA (1756) ARGENTINA (404) CHILE (213) TURKEY (119) M. Ruda M. Amuchastegui R. Corbalan Z. Yigit INDIA (1469) JAPAN (400) FRANCE (213) SERBIA (117) V. Chopra S. Goto S. Goto G. Montalescot Z. Vasiljevic POLAND (1062) NETHERLANDS (377) CANADA (190) PORTUGAL (115) M. Tendera T. Oude Ophuis M. van Hessen M. Le May P. Theroux J. Morais CHINA (901) ISRAEL (353) SLOVAKIA (178) LATVIA (100) R. Gao S. Meisel T. Duris A. Erglis BULGARIA (792) GERMANY (332) LITHUANIA (177) DENMARK (99) N. Gotcheva E. Giannitsis B. Petrauskiene S. Eggert Jensen UNITED STATES (684) ROMANIA (304) TUNISIA (177) NEW ZEALAND (98) C.M. Gibson D. Vinereanu H. Haouala H. White UKRAINE (629) COLOMBIA (269) BELGIUM (173) MALAYSIA (97) A. Parkhomenko R. Botero F. Van de Werf K. Hian Sim BRAZIL (529) MEXICO (254) EGYPT (159) GREECE (69) J. Nicolau G. Llamas A. Mowafy A. Mowafy AUSTRALIA (510) UNITED KINGDOM (254) KOREA, REPUBLIC OF (150) CROATIA (62) P. Aylward I. Squire K. Seung M. Bergovec CZECH REPUBLIC (485) ITALY (235) SWEDEN (144) MOROCCO (57) P. Widimsky D. Ardissino M. Dellborg HUNGARY (412) SPAIN (230) THAILAND (140) PHILIPPINES (38) R. Kiss A. Betriu P. Sritara

6. PlaceboRivaroxaban 2.5 mg BID Rivaroxaban 5.0 mg BID Age, mean (SD)61.5 (± 9.4)61.8 (± 9.2)61.9 (± 9.0) Sex, male n (%)75.0%74.9%74.2% Prior MI, n (%)27.3%26.3%27.1% Diabetes, n (%)31.8%32.3%31.8% STEMI, n (%)50.9%50.3%49.9% NSTEMI, n (%)25.6%25.5%25.8% UA, n (%)23.6%24.2%24.3% PCI at Index Hosp, n (%)59.9%60.2%60.0% BASELINE CHARACTERISTICS

7. STATISTICAL ANALYSIS The primary efficacy endpoint of CV death, MI and stroke* (ischemic + hemorrhagic) was evaluated sequentially**: Pre-Specified Analysis: Rivaroxaban 2.5 + 5.0 mg BID doses pooled together across both thienopyridine strata (all Rivaroxaban vs all Placebo) Rivaroxaban 2.5 mg BID and 5.0 mg BID doses separately across both thienopyridine strata (p<0.05) The primary method of analysis was a log rank test stratified by thienopyridine use in the mITT # population with confirmation in an ITT ## analysis * Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke ** Same testing procedure was conducted independently for ASA+Thienopyridine # mITT, a ll randomized subjects and end point events, which are observed from randomization up to the earliest date of the completion of the treatment period (i.e, global treatment end date), or 30 days after early discontinuation of the study drug or 30 days following randomization for those subjects who were randomly assigned to treatment but not treated ## ITT, a ll randomized subjects and end point events, which are observed from randomization up to the global treatment end date If p < 0.0499982 interim adjusted

8. Months After Randomization PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke* (Ischemic + Hemg.) Rivaroxaban (both doses) HR 0.84 (0.74-0.96) ARR 1.7% mITT p = 0.008 ITT p = 0.002 NNT = 59 10.7% 8.9% Estimated Cumulative Rate (%) Placebo *: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; ARR=Absolute Relative Reduction; NNT=Number needed to treat; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID. 5113 4307 3470 2664 1831 1079 421 10229 8502 6753 5137 3554 2084 831 Placebo Rivaroxaban 2 Yr KM Estimate No. at Risk

9. STENT THROMBOSIS* ARC Definite, Probable, Possible Months After Randomization Rivaroxaban (both doses) HR 0.69 (0.51- 0.93) mITT p = 0.016 ITT p = 0.008 2.9% 2.3% Estimated Cumulative incidence (%) Estimated Cumulative incidence (%) Placebo 2 Yr KM Estimate ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012 * End point events are as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

10. Months Estimated Cumulative incidence (%) HR 0.85 mITT p=0.028 ITT P=0.010 Placebo Rivaroxaban 5 mg BID 024 8.8% 10.7% Rivaroxaban at 5 mg PO BID was associated with a numerical but not statistically significant reduction in mortality. * First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC Two year Kaplan-Meier estimates, Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches. PRIMARY EFFICACY ENDPOINT: 5.0 mg BID CV Death / MI / Stroke* (Ischemic + Hemg.) 12

11. 024 Rivaroxaban 2.5 mg BID All Cause Death PRIMARY EFFICACY ENDPOINT*: 2.5 mg PO BID 0 24 Cardiovascular Death Months CV Death / MI / Stroke* Estimated Cumulative incidence (%) HR 0.84 mITT p=0.020 ITT p=0.007 HR 0.66 mITT p=0.002 ITT p=0.005 10.7% 9.1% 0 24 Placebo Months 4.5% 2.9% 4.1% 2.7% Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID Placebo HR 0.68 mITT p=0.002 ITT p=0.004 NNT = 63 Placebo * First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat. NNT = 71NNT = 63 12 12% 5%

12. Placebo 024 Rivaroxaban 2.5 mg BID All Cause Death PRIMARY EFFICACY ENDPOINTS: 2.5 mg PO BID In Patients Treated with ASA + Thienopyridine 0 24 Cardiovascular Death Months CV Death / MI / Stroke* Estimated Cumulative incidence (%) 0 24 Months HR 0.85 mITT p=0.039 ITT p=0.011 HR 0.62 mITT p<0.001 ITT p<0.001 2.7% 4.5% 4.2% 2.5% 10.4% 9.0% Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID Placebo HR 0.64 mITT p<0.001 ITT p<0.001 NNT = 56 *: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC Two year Kaplan-Meier estimates, Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat. NNT = 71 NNT = 59 12 12% 5%

13. PRIMARY EFFICACY SUBGROUP RESULTS ( mITT ) ASA ASA + thienopyridine 0.86 (0.75 -0.98) 0.34 0.69 (0.45 -1.05) STEMI NSTEMI UA 0.85 (0.70- 1.03) 0.85 (0.68- 1.06) 0.82 (0.62- 1.07) 0.96 <65 Years 65 Years 0.83 (0.70- 0.99) 0.84 (0.70- 1.01) 0.94 Male Female 0.87 (0.75- 1.01) 0.77 (0.60- 0.99) 0.40 Weight <60 kg Weight60 to <90 kg Weight90 kg 0.83 (0.56- 1.25) 0.85 (0.72- 0.99) 0.83 (0.64- 1.08) 0.98 Prior MI No Prior MI 0.83 (0.68- 1.01) 0.85 (0.72- 1.01) 0.80 0.5 0.8 1.25 2.0 1.0 Diabetes Mellitus No Diabetes Mellitus 0.96 (0.77- 1.20) 0.78 (0.67- 0.92) 0.14 CreatinineCl<50mL/min CreatinineCl>50mL/min 0.88 (0.62- 1.26) 0.84 (0.73- 0.96) 0.82 0.57 (0.33- 0.97) North America South America Western Europe Eastern Europe Asia Other 0.89 (0.59- 1.34) 0.90 (0.59- 1.37) 0.83 (0.69- 1.00) 0.86 (0.63- 1.17) 0.92 (0.60- 1.39) 0.80 Overall 0.84 (0.74 0.96) HR (95% CI) P interaction Rivaroxaban BetterPlacebo Better

14. Analysis Placebo2.5 mg Rivaroxaban 5.0 mg Rivaroxaban 2 Yr KM Estimate 0.6%1.8% HR 3.46 2.4% HR 4.47 SAFETY ENDPOINTS 1-10 Days After Last Dose 1.8%1.4% p=NS 2.2% p=NS Post-Treatment Ischemic Events # Treatment-Emergent Non CABG TIMI Major Bleeding*Treatment-Emergent 1.6%1.3% p=NS 1.4% p=NS ## Liver Function Test (ALT > 3xULN) ## There was no excess of either combined ALT > 3x ULN and Total Bilirubin > 2x ULN cases among patients treated with Rivaroxaban, or SAEs. *: First occurrence of Non-CABG TIMI major bleeding events occurred between first dose to 2 days post last dose as adjudicated by the CEC across thienopyridine use strata; Two year Kaplan-Meier estimates, *: First occurrence of Non-CABG TIMI major bleeding events occurred between first dose to 2 days post last dose as adjudicated by the CEC across thienopyridine use strata; Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine are provided; Stratified log-rank p-values are provided; #: Raw percentage for CV death/MI/stroke (ischemic, hemorrhagic, uncertain) ; ##: Raw percentage of subjects with abnormal value measured between first dose to 2 days post last dose among subjects with normal baseline measurement. p<0.001

15. TREATMENT-EMERGENT FATAL BLEEDS AND ICH n=4n=5 n=8 n=9 n=6 n=15 *Among patients treated with aspirin + thienopyridine, there was an increase in fatal bleeding among patients treated with 5.0 mg of Rivaroxaban (15/5110) vs 2.5 mg of Rivaroxaban (5/5115) (p=0.02) * p=0.009 Riva Vs Placebo p=NS for Riva vs Placebo n=5 n=18 n=14 p=NS for Riva vs Placebo p=0.044 for 2.5 mg vs 5.0 mg

16. SUMMARY- SAFETY There was a dose dependent increase in bleeding associated with rivaroxaban (2.5 mg ↓ 5.0 mg).There was a dose dependent increase in bleeding associated with rivaroxaban (2.5 mg ↓ 5.0 mg). No evidence of drug induced liver injury or rebound (post-treatment) ischemic events Although ICH was increased with rivaroxaban, there was no excess risk of fatal ICH or fatal bleeding associated with rivaroxaban compared to placebo.

17. SUMMARY-EFFICACY The primary efficacy endpoint of CV death, MI and stroke was reduced when added to standard therapy for both rivaroxaban doses combined, and for the 2.5 and 5.0 mg BID doses separately CV and all cause death were reduced for both rivaroxaban doses combined, and for the 2.5 mg BID dose in both mITT and ITT analyses

18. SUMMARY-EFFICACY (cont.) When 2.5 mg PO BID of rivaroxaban was added to ASA + thienopyridine, cardiovascular death was reduced by 38% and all cause death by 36% One death prevented if 56 patients treated for two years with 2.5 mg BID of Rivaroxaban