c. michael gibson, ms, md - timi study · pdf filec. michael gibson, ms, md on behalf of the...

AAntinti--XaXa TTherapy to herapy to LLower ower Cardiovascular Events in Cardiovascular Events in AAddition to Standard Therapy in ddition to Standard Therapy in pypySSubjects with ubjects with AAcute cute CCoronary oronary SSyndrome yndrome -- ThrombolysisThrombolysis in in

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

RivaroxabanRivaroxaban in Subjects with Acute Coronary Syndromein Subjects with Acute Coronary Syndrome

C. Michael Gibson, MS, MDC. Michael Gibson, MS, MDon 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.

BACKGROUNDBACKGROUNDTHROMBUS

ATLAS ACS-TIMI 46N =3,491

6 HR 0.69 (95% CI, 0.50 - 0.96)

0 03

5.5%Placebo4

,

4

roke

(%)

P = 0.03

3

ding

(%)

2

3.9%Rivaroxaban (combined)

eath

, MI,

or s

tr

1.51.8 1.82

MI M

ajor

Ble

ed

0

De

0.1

0.71TIM

Days after randomization300

0

60 90 120 150 1800

Lancet 2009;374(9683):29-38.

Placebo 5 mg 10 mg 15 mg 20 mg

Rivaroxaban

TRIAL ORGANIZATIONTRIAL ORGANIZATIONTrial Leadership: TIMI Study Group

Chairman: Eugene Braunwald, Principal Investigator: C. Michael GibsonI ti t J i M St ti ti i S bi M h Ch l C t tInvestigator: 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 BoardDouglas Weaver (Chair) , Christian Hamm, Judith S. Hochman, Jeffrey Anderson, g ( ) , , , y ,Hiroyuki Daida, Statistician: Allan Skene

Recent ACS: STEMI, NSTEMI, UARecent ACS: STEMI, NSTEMI, UAStabilized 1Stabilized 1--7 Days Post7 Days Post--Index EventIndex Event

Exclusions: increased bleeding risk, warfarin use, ICH, Exclusions: increased bleeding risk, warfarin use, ICH, prior stroke if on ASA + thienopyridine prior stroke if on ASA + thienopyridine

Stratified by Thienopyridine Use at MD Discretion

ASA 75 to 100 mg/day

Rivaroxaban5.0 mg BIDPlacebo

n=5 176

Rivaroxaban 2.5 mg BID

n=5,176n=5,176 n=5,174

PRIMARY ENDPOINTS:PRIMARY ENDPOINTS:EFFICACY: CV Death, MI, Stroke EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin)(Ischemic, Hemorrhagic, or Uncertain Origin)

SAFETY: TIMI major bleeding not associated with CABGSAFETY: TIMI major bleeding not associated with CABGSAFETY: TIMI major bleeding not associated with CABGSAFETY: TIMI major bleeding not associated with CABG

Event driven trial with 1,002 primary efficacy events

NATIONAL LEAD INVESTIGATORSRUSSIA (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. YigitINDIA (1469)INDIA (1469) JAPAN (400)JAPAN (400) FRANCE (213)FRANCE (213) SERBIA (117)SERBIA (117)

V ChopraV Chopra S GotoS Goto G MontalescotG Montalescot Z VasiljevicZ VasiljevicV. ChopraV. Chopra S. GotoS. Goto G. Montalescot G. Montalescot Z. VasiljevicZ. VasiljevicPOLAND (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 GR G S M i lS M i l T D iT D i A E liA E liR. 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. GiannitsisE. Giannitsis

H. Katus H. Katus B. PetrauskieneB. Petrauskiene S. Eggert JensenS. Eggert JensenUNITED 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. WhiteUKRAINE (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. MowafyA. 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

44 Countries44 Countries 766 Sites766 Sites

yy ggHUNGARY (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

BASELINE CHARACTERISTICSPlacebo Rivaroxaban

2.5 mg BIDRivaroxaban5.0 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

SPIT

AL

Prior MI, (%) 27.3 26.3 27.1

Diabetes, (%) 31.8 32.3 31.8PRE

HO

STEMI, (%) 50.9 50.3 49.9

NSTEMI, (%) 25.6 25.5 25.8

AL

UA, (%) 23.6 24.2 24.3

Revasc at Index, (%) 60.7 60.4 60.4HO

SPIT

A

ASA+Thienopyridine, (%) 93.1 93.3 93.3

STATISTICAL ANALYSISSTATISTICAL ANALYSISPrePre--specified Primary Efficacy Analysisspecified Primary Efficacy Analysisp y y yp y y y

Rivaroxaban(2.5 mg BID and 5 mg BID)

vs.Placebo

If <0.05, then proceed

Rivaroxaban5 mg BID

vs.

Rivaroxaban2.5 mg BID

vs.PlaceboPlacebo

• The primary method of analysis was a log rank test stratified by thienopyridine p y y g y pyuse in the mITT population with confirmation in an ITT analysis

PRIMARY EFFICACY ENDPOINT: PRIMARY EFFICACY ENDPOINT: CVCV Death / MI / StrokeDeath / MI / Stroke

10.7%10.7%(%)

(%) PlaceboPlacebo

2 Yr KM Estimate

8.9%8.9%

Inci

denc

e

Inci

denc

e

RivaroxabanRivaroxaban(b th d )(b th d )

HR 0.84 HR 0.84 (0.74(0.74--0.96)0.96)

0 0080 008umul

ativ

e I

umul

ativ

e I

(both doses)(both doses) mITT mITT p = 0.008p = 0.008ITT ITT p = 0.002p = 0.002

ARR 1.8%ARR 1.8%timat

ed C

utim

ated

Cu

Months After RandomizationMonths After Randomization

NNT = 56NNT = 56Est

Est

N t Ri k Months After RandomizationMonths After Randomization51135113 43074307 34703470 26642664 18311831 10791079 4214211022910229 85028502 67536753 51375137 35543554 20842084 831831

PlaceboPlaceboRivaroxabanRivaroxaban

No. at Risk

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.

STENT THROMBOSIS ARC Definite / Probable / Possible

2 Y KM E ti t

2.9%2.9%

ce (%

)ce

(%)

PlaceboPlacebo

2 Yr KM Estimate

2.3%2.3%

e In

cide

nce

Inci

denc

HR 0.69HR 0.69umul

ativ

eum

ulat

ive

RivaroxabanRivaroxaban(both doses)(both doses)

(0.51(0.51-- 0.93)0.93)

mITTmITT p = 0.016p = 0.016mat

ed C

um

ated

Cu

ITT ITT p = 0.008p = 0.008Esti

Esti

ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012

Months After RandomizationMonths After Randomization

EFFICACY ENDPOINTS:EFFICACY ENDPOINTS:Low Dose 5.0 mg BIDLow Dose 5.0 mg BIDgg

Cardiovascular DeathCV Death / MI / Stroke

10

ence

(%)

Placebo

8.8%

10.7% HR 0.94

mITTp=0.63 4.0%

4.1%PlaceboHR 0.85

mITTp=0.028

ulat

ive

Inci

de ITTp=0.57

ITTp=0.010

5

mat

ed C

umu

Rivaroxaban5 mg BID

Rivaroxaban5 mg BID

0

Estim

0 24 0 24

g

NNT=53

1 Months0 24Months0 24

EFFICACY ENDPOINTS:EFFICACY ENDPOINTS:Very Low Dose 2.5 mg BIDVery Low Dose 2.5 mg BID

All Cause DeathCardiovascular DeathCV Death / MI / Stroke

ce (%

) HR 0.84

mITT

HR 0.66

mITT10.7%

Placebo4.5%4.1%

Placebo HR 0.68

mITT0 002

Placebo12%5% 5%

ativ

e in

cide

n p=0.020ITT

p=0.007

p=0.002ITT

p=0.005

9.1%

2.9%2.7%

p=0.002ITT

p=0.004

Rivaroxaban2 5 mg BIDat

ed C

umul

a

Rivaroxaban2 5 mg BID

Rivaroxaban2 5 mg BID

0 24

2.5 mg BID

0 24Months

Estim

a

0 24Months Months

2.5 mg BID2.5 mg BIDNNT = 63NNT = 71NNT = 63

12 12 12Months Months Months

EFFICACY ENDPOINTS:EFFICACY ENDPOINTS:Very Low Dose 2.5 mg BIDVery Low Dose 2.5 mg BID

P ti t T t d ith ASA Thi idiP ti t T t d ith ASA Thi idi

All Cause DeathCardiovascular DeathCV Death / MI / Stroke

Patients Treated with ASA + Thienopyridine Patients Treated with ASA + Thienopyridine

Placebo

nce

(%)

HR 0.85

mITT p=0.039

HR 0.62

mITTp<0.001

4.5%4.2%

10.4%

PlaceboPlacebo HR 0.64

mITTp<0.001

12%5% 5%

ativ

e in

cide

n

ITTp=0.011

ITTp<0.001

2.7%2 5%

9.0%ITT

p<0.001

Rivaroxaban2 5 BIDat

ed C

umul

a 2.5%

Rivaroxaban2 5 BID

Rivaroxaban2 5 BID

0 24

2.5 mg BID

0 24Months

Estim

a

0 24Months Months

2.5 mg BID2.5 mg BIDNNT = 56NNT = 71 NNT = 59

12 12 12

PRIMARY EFFICACY SUBGROUP RESULTSHR (95% CI) Pinteraction

All Rivaroxaban vs. Placebo

ASAASA + thienopyridine 0.86 (0.75 -0.98)

0.340.69 (0.45 -1.05)

<65 Years65 Y

0.83 (0.70 - 0.99) 0.94

Overall 0.84 (0.74 0.96)

STEMINSTEMIUA

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

0.96

65 Years 0.84 (0.70 - 1.01)

Male 0.87 (0.75 - 1.01) 0.40Female 0.77 (0.60 - 0.99)

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 MI 0 83 (0 68 1 01) 0 80Prior MINo Prior MI

0.83 (0.68 - 1.01)

0.85 (0.72 - 1.01)0.80

Diabetes MellitusNo Diabetes Mellitus

0.96 (0.77 - 1.20)

0.78 (0.67 - 0.92)0.14

Creatinine Cl <50 mL /min 0.88 (0.62 - 1.26) 0.82Creatinine Cl >50 mL /min 0.84 (0.73 - 0.96)

0.82

0.57 (0.33 - 0.97)North AmericaSouth AmericaWestern EuropeEastern EuropeA i

0.89 (0.59 - 1.34)0.90 (0.59 - 1.37)0.83 (0.69 - 1.00)0 86 (0 63 1 17)

0.80

0.5 0.8 1.25 2.01.0

AsiaOther

0.86 (0.63 - 1.17)0.92 (0.60 - 1.39)

Rivaroxaban Better Placebo Better

SAFETY ENDPOINTST t t E t N CABG TIMI M j Bl di *

AnalysisPlacebo 2.5 mg

Rivaroxaban5.0 mg

Rivaroxaban

Treatment-Emergent Non CABG TIMI Major Bleeding*

2 Yr KM Estimate 0.6% 1.8%HR 3.46

2.4%HR 4.47

p<0.001

ALT > 3X ULNALT > 3X ULN 1 6% 1 3% 1 4%

Liver Function Test (ALT > 3xULN) ##

p<0.001

ALT > 3X ULNALT > 3X ULN 1.6% 1.3%p=NS

1.4%p=NS

There was no excess of either combined ALT > 3x ULN and Total Bilirubin > 2x ULN cases among patients treated with Rivaroxaban, or SAEs.

11--1010 Days After Last Days After Last DoseDose

1.8% 1.4% 2.2%

Post-Treatment CVD / MI / Stroke##

DoseDose p=NS p=NS

*: 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 of subjects with abnormal value measured between first dose to 2 days post last dose among subjects with normal baseline measurement; ##: Raw percentage.

TREATMENTTREATMENT--EMERGENT EMERGENT FATAL BLEEDS AND ICHFATAL BLEEDS AND ICH

1.2Placebop=NS for Riva vs Placebo p=0.009 for Riva vs Placebo

0 8

1 2.5 mg Rivaroxaban5.0 mg Rivaroxaban

p=NS for Riva 5 vs Placebop=NS for Riva 2.5 vs Placebop=0.044 for Riva 2.5 vs 5

p= 0.005 Riva 5 vs PlaceboP=0.037 for Riva 2.5 vs Placebop=0.44 for Riva 2.5 vs 5

00

0.7

0.6

0.8

p=NS for all

nt (%

)

0.2 0.20 10 1

0.4

0 1

0.4

0.20 2

0.4comparisons

Per

cen

0.10.1 0.1

0

0.2

Fatal ICH Fatal ICH

n=4 n=5 n=8n=9 n=6 n=15 n=5 n=18n=14

Fatal ICH Fatal ICH

SUMMARYSUMMARY

•• Rivaroxaban reduced the risk of cardiovascular death, Rivaroxaban reduced the risk of cardiovascular death, myocardial infarction, or stroke in patients across themyocardial infarction, or stroke in patients across themyocardial infarction, or stroke in patients across the myocardial infarction, or stroke in patients across the spectrum of ACS.spectrum of ACS.

• Rates of major bleeding and ICH were higher with rivaroxaban; however, there was no excess risk of fatal ICH or fatal bleeding with rivaroxaban compared to placeboor fatal bleeding with rivaroxaban compared to placebo (particularly with 2.5 mg BID).

• One death would be prevented if 56 patients on antiplatelet therapies were treated for two years with rivaroxaban 2.5 mg BID.

CONCLUSIONCONCLUSION

• Very low dose anticoagulation with rivaroxaban (2 5 mg BID) in addition torivaroxaban (2.5 mg BID), in addition to antiplatelet therapies, represents an effective strategy to reduce cardiovasculareffective strategy to reduce cardiovascular events in patients with a recent ACS.

The full article is available online at www.nejm.org.