Recent ACS: STEMI, NSTEMI, UAStabilized 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

Rivaroxaban5.0 mg BID

n=5,176

Stratified by Thienopyridine Use at MD Discretion

ASA 75 to 100 mg/day

Placebon=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

Placebo Rivaroxaban2.5 mg BID

Rivaroxaban5.0 mg BID

Age, mean (SD) 61.5 (± 9.4) 61.8 (± 9.2) 61.9 (± 9.0)

Sex, male (%) 75.0 74.9 74.2

Prior MI, (%) 27.3 26.3 27.1

Diabetes, (%) 31.8 32.3 31.8

STEMI, (%) 50.9 50.3 49.9

NSTEMI, (%) 25.6 25.5 25.8

UA, (%) 23.6 24.2 24.3

Revasc at Index, (%) 60.7 60.4 60.4

ASA+Thienopyridine, (%) 93.1 93.3 93.3

PRE

HO

SPIT

ALH

OSP

ITAL

ATLAS ACS 2: Baseline Characteristics

Mega et al, N Engl J Med. 2011 Nov 13

Maanden na randomisatie

Rivaroxaban(beide doseringen)

HR 0.84 (0.74-0.96)

mITT p = 0.008ITT p = 0.002

ARR 1.8%NNT = 56

10.7%

8.9%

Ges

chatt

e cu

mul

atiev

e in

cide

ntie

(%)

Placebo

5113 4307 3470 2664 1831 1079 421

10229 8502 6753 5137 3554 2084 831

PlaceboRivaroxaban

2 Yr KM Estimate

No. at Risk

ATLAS ACS 2: Primair Eindpunt

Mega et al, N Engl J Med. 2011 Nov 13

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%

Esti

mat

ed C

umul

ative

Inci

denc

e (%

)

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

0

5

10

1 Months

Estim

ated

Cum

ulati

ve In

cide

nce

(%)

Placebo

Rivaroxaban5 mg BID

0

8.8%

10.7%

24

Cardiovascular DeathCV Death / MI / Stroke

HR 0.94

mITTp=0.63

ITTp=0.57

Months0 24

4.0%

4.1%Placebo

Rivaroxaban5 mg BID

HR 0.85

mITTp=0.028

ITTp=0.010

NNT=53

Mega et al, N Engl J Med. 2011 Nov 13

ATLAS ACS 2: Efficacy endpointsDose 5.0 mg BID

0 24

Rivaroxaban2.5 mg BID

All Cause Death

0 24

Cardiovascular Death

Months

CV Death / MI / Stroke

Estim

ated

Cum

ulati

ve in

cide

nce

(%)

HR 0.84

mITTp=0.020

ITTp=0.007

HR 0.66

mITTp=0.002

ITTp=0.005

10.7%

9.1%

0 24

Placebo

Months Months

4.5%

2.9%

4.1%

2.7%

Rivaroxaban2.5 mg BID

Rivaroxaban2.5 mg BID

Placebo HR 0.68

mITTp=0.002

ITTp=0.004

NNT = 63

Placebo

NNT = 71NNT = 6312 12 12

12%5% 5%

Mega et al, N Engl J Med. 2011 Nov 13

ATLAS ACS 2: Efficacy EndpointsVery Low Dose 2.5 mg BID

Placebo

0 24

Rivaroxaban2.5 mg BID

All Cause Death

0 24

Cardiovascular Death

Months

CV Death / MI / Stroke

Estim

ated

Cum

ulati

ve in

cide

nce

(%)

0 24Months Months

HR 0.85

mITT p=0.039

ITTp=0.011

HR 0.62

mITTp<0.001

ITTp<0.001

2.7%

4.5%

4.2%

2.5%

10.4%

9.0%

Rivaroxaban2.5 mg BID

Rivaroxaban2.5 mg BID

PlaceboPlacebo HR 0.64

mITTp<0.001

ITTp<0.001

NNT = 56NNT = 71 NNT = 5912 12 12

12%5% 5%

Mega et al, N Engl J Med. 2011 Nov 13

ATLAS ACS 2 Efficacy EndpointsVery Low Dose 2.5 mg BIDPatients Treated with ASA + Thienopyridine

0,2 0,20,10,1

0,4

0,1

0,4

0,7

0,2

0

0,2

0,4

0,6

0,8

1

1,2

Fatal ICH Fatal ICH

Placebo

2.5 mg Rivaroxaban

5.0 mg Rivaroxaban

n=4 n=5 n=8n=9 n=6 n=15

p=NS for all comparisons

n=5 n=18n=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

Perc

ent (

%)

Mega et al, N Engl J Med. 2011 Nov 13

ATLAS ACS 2: Treatment- Emergent Fatal Bleeds and ICH

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