C. Michael Gibson, MS, MD C. Michael Gibson, MS, MD on behalf of - - PowerPoint PPT Presentation

Anti nti-

• Xa

Xa Therapy to herapy to Lower

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Cardiovascular Events in Cardiovascular Events in Addition to Standard Therapy in ddition to Standard Therapy in py py Subjects with ubjects with Acute cute Coronary

• ronary Syndrome

yndrome -

• Thrombolysis

Thrombolysis in in Myocardial Infarction 51 Trial (ATLAS ACS 2 Myocardial Infarction 51 Trial (ATLAS ACS 2 -

• TIMI 51):

TIMI 51):

A Randomized Double A Randomized Double Blind Placebo Controlled Study to Evaluate the Efficacy and Safety of Blind Placebo Controlled Study to Evaluate the Efficacy and Safety of A Randomized, Double A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Rivaroxaban Rivaroxaban in Subjects with Acute Coronary Syndrome in Subjects with Acute Coronary Syndrome

• C. Michael Gibson, MS, MD
• C. Michael Gibson, MS, MD
• n behalf of the ATLAS ACS 2 TIMI 51 Investigators
• n 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

THROMBUS

ATLAS ACS-TIMI 46 N =3,491

6 HR 0.69 (95% CI, 0.50 - 0.96) 0 03 5.5% Placebo

4

,

4 roke (%) P = 0.03

3

ding (%) 2 3.9% Rivaroxaban (combined) eath, MI, or str 1.5 1.8 1.8

2

MI Major Bleed De 0.1 0.7

1

TIM Days after randomization 30 60 90 120 150 180

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

Placebo 5 mg 10 mg 15 mg 20 mg

Rivaroxaban

TRIAL ORGANIZATION TRIAL ORGANIZATION

Trial Leadership: TIMI Study Group

Chairman: Eugene Braunwald, Principal Investigator: C. Michael Gibson I ti t J i M St ti ti i S bi M h Ch l C t t Investigator: Jessica Mega, Statisticians: Sabina Murphy, Charles Contant

Executive Committee

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

Sponsors: Johnson & Johnson and Bayer Health Care

J&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, g ( ) , , , y , Hiroyuki Daida, Statistician: Allan Skene

Recent ACS: STEMI, NSTEMI, UA Recent ACS: STEMI, NSTEMI, UA

Stabilized 1 Stabilized 1-

• 7 Days Post

7 Days Post-

• Index Event

Index 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

Rivaroxaban

5.0 mg BID

Placebo

n=5 176

Rivaroxaban

2.5 mg BID

n=5,176 n=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 CABG SAFETY: TIMI major bleeding not associated with CABG SAFETY: TIMI major bleeding not associated with CABG SAFETY: TIMI major bleeding not associated with CABG

Event driven trial with 1,002 primary efficacy events

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. Corbalan
• R. Corbalan
• Z. Yigit
• Z. Yigit

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

• V. Chopra
• V. Chopra
• S. Goto
• S. Goto
• G. Montalescot
• G. Montalescot
• Z. Vasiljevic
• Z. 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 Hessen
• M. van Hessen
• M. Le May
• M. Le May
• P. Theroux
• P. Theroux
• J. Morais
• J. Morais

CHINA (901) CHINA (901) ISRAEL (353) ISRAEL (353) SLOVAKIA (178) SLOVAKIA (178) LATVIA (100) LATVIA (100) R G R G S M i l S M i l T D i T D i A E li A E li

• R. Gao
• R. Gao
• S. Meisel
• S. Meisel
• T. Duris
• T. Duris
• A. Erglis
• A. 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
• H. Katus
• H. Katus
• B. Petrauskiene
• B. Petrauskiene
• S. Eggert Jensen
• S. Eggert Jensen

UNITED STATES (684) UNITED STATES (684) ROMANIA (304) ROMANIA (304) TUNISIA (177) TUNISIA (177) NEW ZEALAND (98) NEW ZEALAND (98) C.M. Gibson C.M. Gibson

• D. Vinereanu
• D. Vinereanu
• H. Haouala
• H. Haouala
• H. White
• H. White

UKRAINE (629) UKRAINE (629) COLOMBIA (269) COLOMBIA (269) BELGIUM (173) BELGIUM (173) MALAYSIA (97) MALAYSIA (97)

• A. Parkhomenko
• A. Parkhomenko
• R. Botero
• R. Botero
• F. Van de Werf
• F. Van de Werf
• K. Hian Sim
• K. Hian Sim

BRAZIL (529) BRAZIL (529) MEXICO (254) MEXICO (254) EGYPT (159) EGYPT (159) GREECE (69) GREECE (69)

• J. Nicolau
• J. Nicolau
• G. Llamas
• G. 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. Squire
• I. Squire
• K. Seung
• K. Seung
• M. Bergovec
• M. Bergovec

CZECH REPUBLIC (485) CZECH REPUBLIC (485) ITALY (235) ITALY (235) SWEDEN (144) SWEDEN (144) MOROCCO (57) MOROCCO (57)

• P. Widimsky
• P. Widimsky
• D. Ardissino
• D. Ardissino
• M. Dellborg
• M. Dellborg

44 Countries 44 Countries 766 Sites 766 Sites

y g HUNGARY (412) HUNGARY (412) SPAIN (230) SPAIN (230) THAILAND (140) THAILAND (140) PHILIPPINES (38) PHILIPPINES (38)

• R. Kiss
• R. Kiss
• A. Betriu
• A. Betriu
• P. Sritara
• P. Sritara

BASELINE CHARACTERISTICS

Placebo Rivaroxaban 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 (%) 75.0 74.9 74.2

SPITAL

Prior MI, (%) 27.3 26.3 27.1 Diabetes, (%) 31.8 32.3 31.8

PRE 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 60.4

HOSPITA

ASA+Thienopyridine, (%) 93.1 93.3 93.3

STATISTICAL ANALYSIS STATISTICAL ANALYSIS

Pre Pre-

• specified Primary Efficacy Analysis

specified Primary Efficacy Analysis p y y y p y y y

Rivaroxaban

(2.5 mg BID and 5 mg BID)

vs. Placebo

If <0.05, then proceed

Rivaroxaban

5 mg BID

vs. Rivaroxaban

2.5 mg BID

vs. Placebo Placebo

• The primary method of analysis was a log rank test stratified by thienopyridine

p y y g y py use in the mITT population with confirmation in an ITT analysis

PRIMARY EFFICACY ENDPOINT: PRIMARY EFFICACY ENDPOINT:

CV CV Death / MI / Stroke Death / MI / Stroke

10.7% 10.7%

(%) (%)

Placebo Placebo

2 Yr KM Estimate

8.9% 8.9%

Incidence Incidence

Rivaroxaban Rivaroxaban

(b th d ) (b th d ) HR 0.84 HR 0.84 (0.74 (0.74-

• 0.96)

0.96) 0 008 0 008

umulative I umulative I

(both doses) (both doses)

mITT mITT p = 0.008

p = 0.008

ITT ITT p = 0.002

p = 0.002 ARR 1.8% ARR 1.8%

timated Cu timated Cu

Months After Randomization Months After Randomization NNT = 56 NNT = 56

Est Est

N t Ri k

Months After Randomization Months After Randomization

5113 5113 4307 4307 3470 3470 2664 2664 1831 1831 1079 1079 421 421 10229 10229 8502 8502 6753 6753 5137 5137 3554 3554 2084 2084 831 831 Placebo Placebo Rivaroxaban Rivaroxaban

• 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 (%)

Placebo Placebo

2 Yr KM Estimate

2.3% 2.3%

e Incidenc e Incidenc

HR 0.69 HR 0.69

umulative umulative

Rivaroxaban Rivaroxaban

(both doses) (both doses) (0.51 (0.51-

• 0.93)

0.93)

mITT mITT p = 0.016

p = 0.016 mated Cu mated Cu

ITT ITT p = 0.008

p = 0.008 Esti Esti ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012 Months After Randomization Months After Randomization

EFFICACY ENDPOINTS: EFFICACY ENDPOINTS: Low Dose 5.0 mg BID Low Dose 5.0 mg BID g

Cardiovascular Death CV Death / MI / Stroke

10

ence (%)

Placebo

8.8% 10.7% HR 0.94 mITT p=0.63 4.0% 4.1%

Placebo

HR 0.85 mITT p=0.028

ulative Incide

ITT p=0.57 ITT p=0.010

5

mated Cumu

Rivaroxaban 5 mg BID Rivaroxaban 5 mg BID

Estim 24 24

g NNT=53

1

Months

24

Months

24

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

All Cause Death Cardiovascular Death CV Death / MI / Stroke

ce (%)

HR 0.84 mITT HR 0.66 mITT

10.7%

Placebo

4.5% 4.1%

Placebo

HR 0.68 mITT 0 002

Placebo

12% 5% 5%

ative inciden

p=0.020

ITT p=0.007

p=0.002

ITT p=0.005

9.1% 2.9% 2.7%

p=0.002

ITT p=0.004

Rivaroxaban 2 5 mg BID

ated Cumula

Rivaroxaban 2 5 mg BID Rivaroxaban 2 5 mg BID

24

2.5 mg BID

24

Months Estima

24

Months Months

2.5 mg BID 2.5 mg BID

NNT = 63 NNT = 71 NNT = 63

12 12 12 Months Months Months

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

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

All Cause Death Cardiovascular Death CV 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 mITT p<0.001

4.5% 4.2% 10.4%

Placebo Placebo

HR 0.64 mITT p<0.001

12% 5% 5%

ative inciden ITT p=0.011 ITT p<0.001

2.7% 2 5% 9.0%

ITT p<0.001

Rivaroxaban 2 5 BID

ated Cumula

2.5%

Rivaroxaban 2 5 BID Rivaroxaban 2 5 BID

24

2.5 mg BID

24

Months Estima

24

Months Months

2.5 mg BID 2.5 mg BID

NNT = 56 NNT = 71 NNT = 59

12 12 12

PRIMARY EFFICACY SUBGROUP RESULTS

HR (95% CI) Pinteraction

All Rivaroxaban vs. Placebo

ASA ASA + thienopyridine

0.86 (0.75 -0.98)

0.34

0.69 (0.45 -1.05)

<65 Years 65 Y

0.83 (0.70 - 0.99)

0.94

Overall

0.84 (0.74 0.96)

STEMI NSTEMI UA

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)

0.40

Female

0.77 (0.60 - 0.99)

Weight <60 kg Weight 60 to <90 kg Weight 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 80

Prior MI No Prior MI

0.83 (0.68 - 1.01) 0.85 (0.72 - 1.01)

0.80

Diabetes Mellitus No 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)

0.82

Creatinine Cl >50 mL /min

0.84 (0.73 - 0.96)

0.82

0.57 (0.33 - 0.97)

North America South America Western Europe Eastern Europe A 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 2.0 1.0

Asia Other

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

Rivaroxaban Better Placebo Better

SAFETY ENDPOINTS

T t t E t N CABG TIMI M j Bl di *

Analysis

Placebo 2.5 mg Rivaroxaban 5.0 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 ULN ALT > 3X ULN

1 6% 1 3% 1 4%

Liver Function Test (ALT > 3xULN) #

p<0.001 ALT > 3X ULN ALT > 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. 1-

• 10

10 Days After Last Days After Last Dose Dose

1.8% 1.4% 2.2%

Post-Treatment CVD / MI / Stroke##

Dose Dose

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.

TREATMENT TREATMENT-

• EMERGENT

EMERGENT FATAL BLEEDS AND ICH FATAL BLEEDS AND ICH

1.2

Placebo

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

0 8 1

2.5 mg Rivaroxaban 5.0 mg Rivaroxaban

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= 0.005 Riva 5 vs Placebo P=0.037 for Riva 2.5 vs Placebo p=0.44 for Riva 2.5 vs 5

0.7 0.6 0.8

p=NS for all

nt (%)

0.2 0.2 0 1 0 1 0.4 0 1 0.4 0.2 0 2 0.4

comparisons

Percen

0.1 0.1 0.1 0.2 Fatal ICH Fatal ICH

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

Fatal ICH Fatal ICH

SUMMARY SUMMARY

• Rivaroxaban reduced the risk of cardiovascular death,

Rivaroxaban reduced the risk of cardiovascular death, myocardial infarction, or stroke in patients across the myocardial infarction, or stroke in patients across the myocardial 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

• r fatal bleeding with rivaroxaban compared to placebo
• r 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.

CONCLUSION CONCLUSION

• Very low dose anticoagulation with

rivaroxaban (2 5 mg BID) in addition to rivaroxaban (2.5 mg BID), in addition to antiplatelet therapies, represents an effective strategy to reduce cardiovascular effective strategy to reduce cardiovascular events in patients with a recent ACS.

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