AAnti-Xa nti-Xa TTherapy to herapy to LLower ower

Cardiovascular Events in Addition to Standard Therapy in Cardiovascular Events in Addition to Standard Therapy in SSubjects with ubjects with AAcute cute CCoronary oronary SSyndrome – Thrombolysis in yndrome – Thrombolysis in

Myocardial Infarction 51 Trial (ATLAS-ACS 2 TIMI 51): Myocardial Infarction 51 Trial (ATLAS-ACS 2 TIMI 51): A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of

Rivaroxaban in Subjects with Acute Coronary SyndromeRivaroxaban in Subjects with Acute Coronary Syndrome

C. Michael Gibson, M.S., M.D., Jessica Mega, M.P.H., M.D., C. Michael Gibson, M.S., M.D., Jessica Mega, M.P.H., M.D., & Eugene Braunwald, M.D.& Eugene Braunwald, M.D.

on behalf of the ATLAS ACS 2 TIMI 51 Investigatorson behalf of the ATLAS ACS 2 TIMI 51 Investigators

Funded by a Research Grant from Johnson and Johnson and Bayer to Brigham & Women’s 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.Hospital. Dr. Gibson has received honoraria & consulting fees from J&J and Bayer.

BACKGROUND: BACKGROUND: Thrombin In ACSThrombin 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

• Reduction of thrombin generation by warfarin reduces recurrentrecurrent 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.

TRIAL ORGANIZATIONTRIAL ORGANIZATION Trial Leadership: TIMI Study Group

Chairman: Eugene Braunwald, Principal Investigator: C. Michael GibsonInvestigator: Jessica Mega, Statisticians: Sabina Murphy, Charles Contant

Executive CommitteeJean-Pierre Bassand, Deepak Bhatt, Christoph Bode, Keith Fox, Marc Cohen, Shinya Goto, David Schneider, Freek Verheugt

Sponsors: Johnson & Johnson and Bayer Health CareJ&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

Recent ACS: STEMI, NSTEMI, UARecent ACS: STEMI, NSTEMI, UANo increased bleeding risk, No warfarin, No ICH, No No increased bleeding risk, No warfarin, No ICH, No

prior stroke if on ASA + Thienopyridineprior stroke if on ASA + ThienopyridineStabilized 1-7 Days Post-Index EventStabilized 1-7 Days Post-Index Event

PRIMARY ENDPOINT:PRIMARY ENDPOINT:EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.)EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.)

SAFETY: TIMI major bleeding not associated with SAFETY: TIMI major bleeding not associated with CABGCABG

Event driven trial of 1,002 events in 15,342 patients**

RIVAROXABAN5.0 mg BID

N=5,176ASA + Thieno, n=4,827

ASA, n=349

Stratified by Thienopyridine use at MD Discretion+ ASA 75 to + ASA 75 to 100 mg/day100 mg/day

PlaceboN=5,176

ASA + Thieno, n=4,821ASA, n=355

RIVAROXABAN2.5 mg BID

n=5,174ASA + 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

44 Countries44 Countries 766 Sites766 Sites

NATIONAL LEAD INVESTIGATORS

RUSSIA (1756)RUSSIA (1756)  

ARGENTINA (404)ARGENTINA (404)  

CHILE (213)CHILE (213)  

TURKEY (119)TURKEY (119)M. Ruda M. Ruda    M. Amuchastegui M. Amuchastegui    R. CorbalanR. Corbalan    Z. YigitZ. Yigit

INDIA (1469)INDIA (1469)    JAPAN (400)JAPAN (400)    FRANCE (213)FRANCE (213)    SERBIA (117)SERBIA (117)V. ChopraV. Chopra    S. Goto S. Goto     G. Montalescot G. Montalescot    Z. VasiljevicZ. Vasiljevic

POLAND (1062)POLAND (1062)    NETHERLANDS (377)NETHERLANDS (377)    CANADA (190)CANADA (190)    PORTUGAL (115)PORTUGAL (115)M. Tendera M. Tendera   

T. Oude Ophuis T. Oude Ophuis M. van HessenM. van Hessen

   M. Le May M. Le May P. Theroux P. Theroux

   J. MoraisJ. Morais

CHINA (901)CHINA (901)    ISRAEL (353)ISRAEL (353)    SLOVAKIA (178)SLOVAKIA (178)    LATVIA (100)LATVIA (100)R. Gao R. Gao    S. Meisel S. Meisel    T. Duris T. Duris    A. ErglisA. Erglis

BULGARIA (792)BULGARIA (792)    GERMANY (332)GERMANY (332)    LITHUANIA (177)LITHUANIA (177)    DENMARK (99)DENMARK (99)N. Gotcheva N. Gotcheva    E. Giannitsis E. Giannitsis    B. PetrauskieneB. Petrauskiene    S. Eggert JensenS. Eggert Jensen

UNITED STATES (684)UNITED STATES (684)    ROMANIA (304)ROMANIA (304)    TUNISIA (177)TUNISIA (177)    NEW ZEALAND (98)NEW ZEALAND (98)C.M. GibsonC.M. Gibson    D. VinereanuD. Vinereanu    H. HaoualaH. Haouala    H. WhiteH. White

UKRAINE (629)UKRAINE (629)    COLOMBIA (269)COLOMBIA (269)    BELGIUM (173)BELGIUM (173)    MALAYSIA (97)MALAYSIA (97)A. ParkhomenkoA. Parkhomenko    R. BoteroR. Botero    F. Van de WerfF. Van de Werf    K. Hian SimK. Hian Sim

BRAZIL (529)BRAZIL (529)    MEXICO (254)MEXICO (254)    EGYPT (159)EGYPT (159)    GREECE (69)GREECE (69)J. NicolauJ. Nicolau    G. LlamasG. Llamas    A. Mowafy A. Mowafy       

AUSTRALIA (510)AUSTRALIA (510)  

UNITED KINGDOM (254)UNITED KINGDOM (254)   KOREA, REPUBLIC OF KOREA, REPUBLIC OF

(150)(150)  

CROATIA (62)CROATIA (62)P. Aylward P. Aylward    I. SquireI. Squire    K. SeungK. Seung    M. BergovecM. Bergovec

CZECH REPUBLIC (485)CZECH REPUBLIC (485)    ITALY (235)ITALY (235)    SWEDEN (144)SWEDEN (144)    MOROCCO (57)MOROCCO (57)P. Widimsky P. Widimsky    D. ArdissinoD. Ardissino    M. DellborgM. Dellborg      

HUNGARY (412)HUNGARY (412)    SPAIN (230)SPAIN (230)    THAILAND (140)THAILAND (140)    PHILIPPINES (38)PHILIPPINES (38)R. Kiss R. Kiss    A. BetriuA. Betriu    P. SritaraP. Sritara      

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 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

STATISTICAL ANALYSISSTATISTICAL 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, all 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, all randomized subjects and end point events, which are observed from randomization up to the global treatment end date

If p < 0.0499982 interim adjusted

Months After RandomizationMonths After Randomization

PRIMARY EFFICACY ENDPOINT: PRIMARY EFFICACY ENDPOINT: CVCV Death / MI / Stroke* (Ischemic + Hemg.) Death / MI / Stroke* (Ischemic + Hemg.)

RivaroxabanRivaroxaban(both doses)(both doses)

HR 0.84 HR 0.84 (0.74-0.96)(0.74-0.96)ARR 1.7%ARR 1.7%

mITT mITT p = 0.008p = 0.008ITT ITT p = 0.002p = 0.002

NNT = 59NNT = 59

10.7%10.7%

8.9%8.9%

Estim

ated

Cum

ulat

ive

Rat

e (%

)Es

timat

ed C

umul

ativ

e R

ate

(%) PlaceboPlacebo

*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strataTwo 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.

51135113 43074307 34703470 26642664 18311831 10791079 4214211022910229 85028502 67536753 51375137 35543554 20842084 831831

PlaceboPlaceboRivaroxabanRivaroxaban

2 Yr KM Estimate

No. at Risk

STENT THROMBOSIS* ARC Definite, Probable, Possible

Months After RandomizationMonths After Randomization

RivaroxabanRivaroxaban(both doses)(both doses)

HR 0.69HR 0.69 (0.51- 0.93)(0.51- 0.93)

mITT mITT p = 0.016p = 0.016

ITT ITT p = 0.008p = 0.008

2.9%2.9%

2.3%2.3%

Est

imat

ed C

umul

ativ

e in

cide

nce

(%)

Estim

ated

Cum

ulat

ive

inci

denc

e (%

)

PlaceboPlacebo

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* End point events are as adjudicated by the CEC across thienopyridine use strataTwo 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.

0

5

10

Months

Estim

ated

Cum

ulat

ive

inci

denc

e (%

)

HR 0.85

mITTp=0.028

ITTP=0.010

Placebo

Rivaroxaban5 mg BID

0 24

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* First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CECTwo 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 PRIMARY EFFICACY ENDPOINT: 5.0 mg BIDBID

CV Death / MI / Stroke* (Ischemic + Hemg.) CV Death / MI / Stroke* (Ischemic + Hemg.)

12

0 24

Rivaroxaban2.5 mg BID

All Cause Death

PRIMARY EFFICACY ENDPOINT*: 2.5 mg PO BID PRIMARY EFFICACY ENDPOINT*: 2.5 mg PO BID

0 24

Cardiovascular Death

Months

CV Death / MI / Stroke*

Estim

ated

Cum

ulat

ive

inci

denc

e (%

) 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

* First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata* First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strataTwo 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 = 6312 12 12

12%5% 5%

Placebo

0 24

Rivaroxaban2.5 mg BID

All Cause Death

PRIMARY EFFICACY ENDPOINTS: 2.5 mg PO BID PRIMARY EFFICACY ENDPOINTS: 2.5 mg PO BID In Patients Treated with ASA + ThienopyridineIn Patients Treated with ASA + Thienopyridine

0 24

Cardiovascular Death

Months

CV Death / MI / Stroke*

Estim

ated

Cum

ulat

ive

inci

denc

e (%

)

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 = 56

*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CECTwo 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 = 5912 12 12

12%5% 5%

PRIMARY EFFICACY SUBGROUP RESULTS (mITT)

ASAASA + thienopyridine 0.86 (0.75 -0.98)

0.340.69 (0.45 -1.05)

STEMINSTEMIUA

0.85 (0.70- 1.03)0.85 (0.68- 1.06)0.82 (0.62- 1.07)

0.96

<65 Years65 Years

0.83 (0.70- 0.99)

0.84 (0.70- 1.01)

0.94

MaleFemale

0.87 (0.75- 1.01)

0.77 (0.60- 0.99)0.40

Weight <60 kgWeight 60 to <90 kgWeight 90 kg

0.83 (0.56- 1.25)

0.85 (0.72- 0.99)

0.83 (0.64- 1.08)

0.98

Prior MINo Prior MI

0.83 (0.68- 1.01)

0.85 (0.72- 1.01)0.80

0.5 0.8 1.25 2.01.0

Diabetes MellitusNo Diabetes Mellitus

0.96 (0.77- 1.20)

0.78 (0.67- 0.92)0.14

Creatinine Cl <50 mL /minCreatinine Cl >50 mL /min

0.88 (0.62- 1.26)

0.84 (0.73- 0.96)0.82

0.57 (0.33- 0.97)North AmericaSouth AmericaWestern EuropeEastern EuropeAsiaOther

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) Pinteraction

Rivaroxaban Better Placebo Better

AnalysisPlacebo 2.5 mg

Rivaroxaban5.0 mg

Rivaroxaban2 Yr KM Estimate 0.6% 1.8%

HR 3.462.4%

HR 4.47

SAFETY ENDPOINTS

1-10 Days After Last 1-10 Days After Last DoseDose

1.8% 1.4%p=NS

2.2%p=NS

Post-Treatment Ischemic Events#

Treatment-Emergent Non CABG TIMI Major Bleeding*

Treatment-EmergentTreatment-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 *: 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, 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<0.001p<0.001

TREATMENT-EMERGENT TREATMENT-EMERGENT FATAL BLEEDS AND ICHFATAL BLEEDS AND ICH

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

Placebo2.5 mg Rivaroxaban5.0 mg Rivaroxaban

n=4 n=5 n=8n=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=18n=14

p=NS for Rivavs Placebo

p=0.044 for 2.5 mg vs 5.0 mg

SUMMARY- SAFETYSUMMARY- SAFETY

• There was a dose dependent increase in bleeding There was a dose dependent increase in bleeding associated with rivaroxaban (2.5 mg ↓ 5.0 mg).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.

SUMMARY-EFFICACYSUMMARY-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

SUMMARY-EFFICACY (cont.)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