ACS is a major public health challenge In the US:  Over 1.5 million people experience ACS annually 1 In the EU:  ACS is the most common cause of death, accounting for more than 741,000 deaths each year 2  The 6-month post-discharge mortality rate is: 3  3.6% in patients with UA  4.8% in patients with STEMI  6.2% in patients with NSTEMI 1. American Heart Association, 2008; 2. British Heart Foundation Health Promotion Research Group, 2008; 3. Goldberg et al, 2004

Event rate of CV death, MI or stroke at 12 months post event remains ~10% *Major bleeding: non-CABG-related TIMI major bleeding 1. Antiplatelet Trialists' Collaboration, 1994; 2. Antithrombotic Trialists' Collaboration, 2002; 3. Wiviott et al, 2007; 4. Wallentin et al, *2.2* *2.4* None –25% 15.0 ASA 1,2 –20% 12.1 ASA + clopidogrel 3 ASA + –19% 9.9 prasugrel ASA + clopidogrel 4 Event rate (%) –16% ASA ticagrelor 4 CV death, MI or stroke Major bleeding

Anticoagulants and antiplatelets have different yet complementary mechanisms of action Rivaroxaban Apixaban Edoxaban Anticoagulants Antiplatelets ASA Clopidogrel Prasugrel Ticagrelor GPIIb/IIIa inhibitors Fibrinogen Fibrin Clot Platelets Factor Xa GPIIb/IIIa Thromboxane ADP Inflammation Cellular proliferation Collagen + other mediators Activated platelet Coagulation cascade Mackman, 2008 Platelet aggregation Thrombin

Rivaroxaban has the potential to further improve secondary prevention of ACS  Oral administration  Predictable pharmacology  Rapid onset of action  Fixed dose  Balanced dual mode of elimination  Low potential for drug–drug or food–drug interactions*  No routine coagulation monitoring Roehrig et al, 2005; Perzborn et al, 2005; Kubitza et al, 2005; 2006a,b,c; 2007a,b * For full details, see the rivaroxaban Summary of Product Characteristics, available at Rivaroxaban binds directly to the active site of Factor Xa (K i 0.4 nM) Rivaroxaban

2.5 and 5 mg bid rivaroxaban doses were chosen for phase III based on data from ATLAS ACS TIMI 46 Gibson, 2008; Data on file at Johnson & Johnson; Mega et al, ASA plus thienopyridine 3.8% 2.0% 1.2% 0.2% HR=0.55 (0.27–1.11) p= ASA 11.9% 6.6% 1.2% 0.0% HR=0.54 (0.27–1.08) p= Placebo TIMI major bleeding Rivaroxaban 2.5 and 5 mg TIMI major bleedingRivaroxaban 2.5 and 5 mg death, MI, stroke Placebo death, MI, stroke Incidence (%) Time after start of treatment (days)

ATLAS ACS 2 TIMI 51 Rivaroxaban 2.5 mg bid n=4825 Rivaroxaban 2.5 mg bid n=4825 Placebo n=4821 Placebo n=4821 Rivaroxaban 5 mg bid n=4827 Rivaroxaban 5 mg bid n=4827 Event-driven study – 1002 events Stratum 2: ASA + thienopyridine (93%) Rivaroxaban 2.5 mg bid n=349 Rivaroxaban 2.5 mg bid n=349 Placebo n=355 Placebo n=355 Rivaroxaban 5 mg bid n=349 Rivaroxaban 5 mg bid n=349 Physician's decision to add thienopyridine or not N=15,526* ASA dose = 75–100 mg/day Stratum 1: ASA alone (7%) Mega et al, 2011 *184 patients were excluded from the efficacy analyses prior to unblinding because of trial misconduct at three sites

Main inclusion and exclusion criteria Inclusion criteria  Diagnosis of STEMI, NSTEMI, or UA with at least one of the following:  ≥0.1 mV ST-segment deviation  TIMI risk score ≥4  Patients aged ≥18 years; <55 years only with either:  Diabetes mellitus or  Prior MI  Patients received ASA 75–100 mg/day alone or ASA plus a thienopyridine  Based on national/local dosing guidelines Exclusion criteria  Increased bleeding risk, e.g.  Low platelet count  History of intracranial haemorrhage  Active internal bleeding  Prior stroke or TIA in stratum 2 patients  Atrial fibrillation: except single episodes >2 years previously in patients aged <60 years with no evidence of cardiopulmonary disease Gibson et al, 2011

Study endpoints/analyses  Primary efficacy endpoint: composite of cardiovascular death, MI and stroke (ischaemic, haemorrhagic or uncertain)  Main safety endpoint: incidence of major bleeding not associated with CABG surgery (according to TIMI bleeding definition)  Primary analysis: log-rank test stratified by thienopyridine use in mITT population with confirmation in an ITT analysis  mITT: all randomized patients and events from randomization up to earliest date of completion of treatment period (i.e. global treatment end date), 30 days after early discontinuation of study drug, or 30 days after randomization (patients randomized but not treated)  ITT: all randomized patients and events observed from randomization up to global treatment end date Gibson et al, 2011

Patient characteristics Rivaroxaban 2.5 mg bid (n=5174) Rivaroxaban 5 mg bid (n=5176) Placebo (n=5176) Mean age, years (SD)62 (9) Male sex, % Median weight, kg78 Median CrCl, ml/min85 86 Medical history, % Prior MI2627 Hypertension6768 Diabetes mellitus32 Index diagnosis, % STEMI50 51 NSTEMI26 UA24 PCI or CABG for index6160 Mega et al, 2011

Primary efficacy endpoint (CV death/MI/stroke) Both rivaroxaban doses, both strata Number at risk Placebo Rivaroxaban10, Months after randomization HR=0.84 (0.74–0.96) ARR=1.7% mITT p=0.008 ITT p=0.002 NNT= % 8.9% 2-year Kaplan–Meier estimate Estimated cumulative rate (%) Rivaroxaban Placebo Mega et al, 2011

Primary efficacy analysis: patient subgroups Both rivaroxaban doses, both strata Mega et al, 2011 ASA ASA + thienopyridine 0.86 ( ) ( ) STEMI NSTEMI UA 0.85 ( ) 0.85 ( ) 0.82 ( ) 0.96 <65 years ≥65 years 0.83 ( ) 0.84 ( ) 0.94 Male Female 0.87 ( ) 0.77 ( ) 0.40 Weight <60 kg Weight60 to <90 kg Weight≥90 kg 0.83 ( ) 0.85 ( ) 0.83 ( ) 0.98 Prior MI No prior MI 0.83 ( ) 0.85 ( ) Diabetes mellitus No diabetes mellitus 0.96 ( ) 0.78 ( ) 0.14 CrCl <50 ml/min CrCl ≥50 ml/min 0.88 ( ) 0.84 ( ) ( ) North America South America Western Europe Eastern Europe Asia Other 0.89 ( ) 0.90 ( ) 0.83 ( ) 0.86 ( ) 0.92 ( ) 0.80 Overall 0.84 ( ) HR (95% CI) P interaction Favours rivaroxabanFavours placebo

Primary efficacy endpoint Separate rivaroxaban doses, both strata Rivaroxaban 2.5 mg bid (n=5114) Rivaroxaban 5 mg bid (n=5115) Placebo (n=5113) Composite primary endpoint K–M estimate at 2 years9.1%8.8%10.7% HR versus placebo (95% CI)0.84 (0.72–0.97)0.85 (0.73–0.98) p value versus placebo CV death K–M estimate at 2 years2.7%4.0%4.1% HR versus placebo (95% CI) 0.66 (0.51–0.86)0.94 (0.75–1.20) p value versus placebo MI K–M estimate at 2 years6.1%4.9%6.6% HR versus placebo (95% CI)0.90 (0.75–1.09)0.79 (0.65–0.97) p value versus placebo Stroke (haemorrhagic and ischaemic) K–M estimate at 2 years1.4%1.7%1.2% HR versus placebo (95% CI) 1.13 (0.74–1.73)1.34 (0.90–2.02) p value versus placebo Mega et al, 2011

Components of primary endpoint Rivaroxaban 2.5 mg bid, both strata 0 Months Cardiovascular death NNT= % 2.7% Placebo Rivaroxaban 2.5 mg bid HR=0.66 mITT p=0.002 ITT p= All-cause death Months 4.5% 2.9% 240 Placebo Rivaroxaban 2.5 mg bid HR=0.68 mITT p=0.002 ITT p= NNT=63 Months CV death/MI/stroke Cumulative incidence (%) HR=0.84 mITT p=0.02 ITT p= % 9.1% Rivaroxaban 2.5 mg bid Placebo NNT=63 Mega et al, 2011; Gibson et al, 2011

2-year Kaplan–Meier estimate HR=0.69 (0.51–0.93) RRR=31% mITT p=0.02 ITT p= % 2.3% Months after randomization Rivaroxaban Placebo Estimated cumulative incidence (%) Stent thrombosis* Both rivaroxaban, both strata *Stent thrombosis events: definite, probable or possible (Academic Research Consortium definitions) Mega et al, 2011 Rivaroxaban 2.5 mg bid Rivaroxaban 5 mg bid 2-year K–M estimate2.2%2.3% HR versus placebo (95% CI)0.65 (0.45–0.94)0.73 (0.51–1.04) p value vs placebo (mITT)

Principal safety endpoint Separate rivaroxaban doses, both strata Rivaroxaban 2.5 mg bid (n=5115) Rivaroxaban 5 mg bid (n=5110) Placebo (n=5125) Non-CABG TIMI major bleed K–M estimate at 2 years1.8%2.4%0.6% p value versus placebo<0.001 ICH K–M estimate at 2 years0.4%0.7%0.2% p value versus placebo Fatal bleeding K–M estimate at 2 years0.1%0.4%0.2% p value versus placebo Fatal ICH K–M estimate at 2 years0.1%0.2%0.1% p value versus placebo–– Mega et al, 2011

Treatment-emergent fatal bleeding events and ICH Separate rivaroxaban doses, both strata Rivaroxaban vs placebo p=NS Rivaroxaban vs placebo p=0.009 Rivaroxaban vs placebo p=NS 2-year Kaplan–Meier estimate (%) Mega et al, 2011

Other safety endpoints Separate rivaroxaban doses, both strata Rivaroxaban 2.5 mg bid (n=5115) Rivaroxaban 5 mg bid (n=5110) Placebo (n=5125) Post-treatment ischaemic events* Raw percentage 1.4%2.2%1.8% p value versus placebop=NS Liver function test (ALT >3× ULN) # Raw percentage 1.3%1.4%1.6% p value versus placebop=NS Other adverse events (raw percentages) Dyspnoea1.1%1.3%1.5% Cough1.2%1.1%1.4% * *CV death/MI/stroke (ischaemic, haemorrhagic, uncertain) events occurring 1–10 days after last rivaroxaban dose; # Abnormal values from first dose to 2 days post last dose in patients with normal baseline values Mega et al, 2011

ATLAS ACS 2 TIMI 51: summary  Compared with placebo, rivaroxaban (2.5 or 5 mg bid) on top of ASA or ASA plus clopidogrel showed:  Significant reductions in the rates of death, MI, and stroke  Benefits in all types of ACS patients (UA, NSTEMI and STEMI )  More than a 30% reduction in risk of both CV and all-cause mortality (2.5 mg bid)  No increase in fatal bleeding and fatal ICH  A non-bleeding safety profile similar to placebo  The addition of anticoagulation with rivaroxaban may represent a new treatment strategy in patients after recent ACS Mega et al, 2011