1. Recent ACS: STEMI, NSTEMI, UA Stabilized 1-7 Days Post-Index Event Exclusions: increased bleeding risk, warfarin use, ICH, prior stroke if on ASA + thienopyridine PRIMARY ENDPOINTS: EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin) SAFETY: TIMI major bleeding not associated with CABG Rivaroxaban 5.0 mg BID n=5,176 Stratified by Thienopyridine Use at MD Discretion ASA 75 to 100 mg/day Placebo n=5,176 Rivaroxaban 2.5 mg BID n=5,174 Event driven trial with 1,002 primary efficacy events Mega et al, N Engl J Med. 2011 Nov 13 ATLAS ACS 2: Design

2. 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 (%)75.074.974.2 Prior MI, (%)27.326.327.1 Diabetes, (%)31.832.331.8 STEMI, (%)50.950.349.9 NSTEMI, (%)25.625.525.8 UA, (%)23.624.224.3 Revasc at Index, (%)60.760.4 ASA+Thienopyridine, (%)93.193.3 PRE HOSPITAL HOSPITAL ATLAS ACS 2: Baseline Characteristics Mega et al, N Engl J Med. 2011 Nov 13

3. Maanden na randomisatie Rivaroxaban (beide doseringen) HR 0.84 (0.74-0.96) mITT p = 0.008 ITT p = 0.002 ARR 1.8% NNT = 56 10.7% 8.9% Geschatte cumulatieve incidentie (%) Placebo 5113 4307 3470 2664 1831 1079 421 10229 8502 6753 5137 3554 2084 831 Placebo Rivaroxaban 2 Yr KM Estimate No. at Risk ATLAS ACS 2: Primair Eindpunt Mega et al, N Engl J Med. 2011 Nov 13

4. 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 ATLAS ACS 2: Stent Thrombosis ARC Definite / Probable / Possible Mega et al, N Engl J Med. 2011 Nov 13

5. Months Estimated Cumulative Incidence (%) Placebo Rivaroxaban 5 mg BID 0 8.8% 10.7% 24 Cardiovascular DeathCV Death / MI / Stroke HR 0.94 mITT p=0.63 ITT p=0.57 Months 0 24 4.0% 4.1% Placebo Rivaroxaban 5 mg BID HR 0.85 mITT p=0.028 ITT p=0.010 NNT=53 Mega et al, N Engl J Med. 2011 Nov 13 ATLAS ACS 2: Efficacy endpoints Dose 5.0 mg BID

6. 024 Rivaroxaban 2.5 mg BID All Cause Death 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 NNT = 71NNT = 63 12 12% 5% Mega et al, N Engl J Med. 2011 Nov 13 ATLAS ACS 2: Efficacy Endpoints Very Low Dose 2.5 mg BID

7. Placebo 024 Rivaroxaban 2.5 mg BID All Cause Death 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 NNT = 71 NNT = 59 12 12% 5% Mega et al, N Engl J Med. 2011 Nov 13 ATLAS ACS 2 Efficacy Endpoints Very Low Dose 2.5 mg BID Patients Treated with ASA + Thienopyridine

8. n=4n=5 n=8 n=9 n=6 n=15 p=NS for all comparisons n=5 n=18 n=14 p=NS for Riva vs Placebo p=NS for Riva 5 vs Placebo p=NS for Riva 2.5 vs Placebo p=0.044 for Riva 2.5 vs 5 p=0.009 for Riva vs Placebo p= 0.005 Riva 5 vs Placebo P=0.037 for Riva 2.5 vs Placebo p=0.44 for Riva 2.5 vs 5 Percent (%) Mega et al, N Engl J Med. 2011 Nov 13 ATLAS ACS 2: Treatment- Emergent Fatal Bleeds and ICH

9. ATLAS ACS 2: Conclusion Very low dose anticoagulation with rivaroxaban (2.5 mg BID), in addition to antiplatelet therapies, represents an effective strategy to reduce cardiovascular events in patients with a recent ACS. Mega et al, N Engl J Med. 2011 Nov 13