ST-Elevation Myocardial Infarction

(1)

STEMI

Rivaroxaban in Patients following a

ST-Elevation Myocardial Infarction

Jessica L. Mega, Eugene Braunwald, Sabina A. Murphy,

Alexei Plotnikov, Paul Burton, Robert Gabor Kiss,

,

Alexandr Parkhomenko, Michal Tendera,

Petr Widimsky, & C. Michael Gibson

(2)

Disclosures

ATLAS ACS 2-TIMI 51 was supported by research grants from

Johnson & Johnson and Bayer Healthcare.

Received grants for clinical research or research supplies via the

TIMI Study Group and Brigham and Women's Hospital from:

TIMI Study Group and Brigham and Women s Hospital from:

Bayer Healthcare, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Johnson &

Johnson, Sanofi-Aventis, Accumetrics, Nanosphere, NIH/NHLBI

p

Served as a consultant for:

(3)

ACS AND THROMBIN GENERATION

300 300

Acute Coronary Syndromes

250 250 200 200

n

M

n

M)

)

y

n=28

200 200 150 150

h

rombin (

h

rombin (

nn

Control

Coronary

Artery

Disease

n=25

100 100 50 50

T

h

T

h

n 25

0 0 0 0 200200 400400 600600 800800 10001000 12001200

Ti

(

d )

Ti

(

d )

Adapted from Brummel-Ziedins, et al. J Thromb Haem2008;6:104–110

Time (seconds)

(4)

THROMBIN INDUCES THROMBOSIS AND

HEMOSTASIS

Platelet Aggregation

Coagulation

IXa Pl t l t PAR 1 3 4 Platelet Fibrinogen IIb/IIIa IIb/IIIa

X

+ VIII + Ca++ Tissue Factor + VII Ib Platelet PAR-1,3,4 Ia Vessel Wall Collagen PAR-1 Receptor activation

X

RIVAROXABAN

Oral Factor

Xa

Platelet

Adhesion

THROMBIN

Prothrombin

Oral Factor

Xa Inhibitor

Xa

Fibrinogen

Fibrin Formation

(5)

ATLAS ACS 2-TIMI 51: STEMI

STEMI

I ATLAS ACS 2 TIMI 51

i

b

• In ATLAS ACS 2-TIMI 51, rivaroxaban

reduced recurrent CV events across the

spectrum of ACS

spectrum of ACS.

• The present analysis reports the results of

the pre-specified subgroup of STEMI

patients, in whom long-term anticoagulant

therapy has been of particular interest

(6)

STUDY DESIGN

STEMI

7817 STEMI Patients

(From a total of 15526

(From a total of 15526 Patients with Recent

Patients with Recent ACS)

ACS)

Stabilized

Stabilized 1

1--7 Days

7 Days Following the Index Event

Following the Index Event –

– Median 4.7 Days

Median 4.7 Days

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

Rivaroxaban

Placebo

Rivaroxaban

2.5 mg BID

N=2601

Rivaroxaban

5 mg BID

N=2584

Placebo

N=2632

PRIMARY

PRIMARY ENDPOINTS:

ENDPOINTS:

EFFICACY: CV Death MI

EFFICACY: CV Death MI Stroke

Stroke

((Ischemic Hemorrhagic or Uncertain)

Ischemic Hemorrhagic or Uncertain)

EFFICACY: CV Death, MI,

EFFICACY: CV Death, MI, Stroke

Stroke

((Ischemic, Hemorrhagic, or Uncertain)

Ischemic, Hemorrhagic, or Uncertain)

SAFETY: TIMI major bleeding not associated with

(7)

ANALYSIS

STEMI

• KM event rates at 24 mos.

• Log-rank test stratified by intent to use a

thienopyridine.

• Efficacy data for the intention to treat (ITT)

analysis to provide complete accounting of

events, as well for modified ITT (mITT). The

mITT events are a subset of ITT events.

• Observed follow-up time >94% and similar in

each treatment group.

g

p

(8)

NATIONAL LEAD INVESTIGATORS

ARGENTINA M. Amuchastegui AUSTRALIA P Aylward DENMARK S. Eggert Jensen EGYPT J&J/Bayer LATVIA A. Erglis LITHUANIA B Petrauskiene RUSSIA M. Ruda SERBIA Z V ilij i P. Aylward BELGIUM F. Van de Werf BRAZIL J. Nicolau J&J/Bayer FRANCE G. Montalescot GERMANY E. Giannitsis/H. Katus GREECE B. Petrauskiene MALAYSIA K.H. Sim MEXICO G. Llamas Esperon Z. Vasilijevic SLOVAKIA T. Duris SPAIN A. Betriu BULGARIA N. Gotcheva CANADA P. Theroux/M. Le May CHILE GREECE J&J/Bayer HUNGARY R. Gabor Kiss INDIA MOROCCO J&J/Bayer NETHERLANDS

T. Oude Ophuis/M. van Hessen

NEW ZEALAND SWEDEN M. Dellborg THAILAND P. Sritara TUNISIA CHILE R. Corbalan CHINA R. Gao COLOMBIA R B t V. Chopra ISRAEL S. Meisel ITALY D Ardissino NEW ZEALAND H.White PHILIPPINES J&J/Bayer POLAND M T d TUNISIA H. Haouala TURKEY Z. Yigit UKRAINE R. Botero CROATIA M. Bergovec CZECH REPUBLIC P. Widimsky D. Ardissino JAPAN J&J/Bayer KOREA K. B. Seung M. Tendera PORTUGAL J. Morais ROMANIA D. Vinereanu A. Parkhomenko UNITED KINGDOM I. Squire UNITED STATES C. M. Gibson

44 Countries

766 Sites

(9)

BASELINE

CHARACTERISTICS

STEMI

Placebo

Rivaroxaban

2 5

BID

Rivaroxaban

5 0

BID

CHARACTERISTICS

2.5 mg BID

5.0 mg BID

Age, mean (SD)

60.8 (8.9)

61.5 (8.8)

61.3 (8.6)

Male Sex

78%

79%

Prior MI

17%

16%

17%

Diabetes

30%

29%

Hypertension

59%

58%

Hypercholesterolemia

40%

41%

Thienopyridine

(Clopidogrel or Ticlopidine)

97%

96%

97%

(10)

PRIMARY EFFICACY ENDPOINT

STEMI

10%

Placebo

N=2599

ITT: HR 0.81 (95% CI 0.67-0.97)

P=0.019

Stroke

10.6%

8%

h

, MI, or

8.4%

4%

6%

Rivaroxaban

N=5128

a

r Deat

h

2%

4%

o

vascul

a

0%

%

Cardi

o

0

90

180

270

360

450

540

630

720 Days

mITT: HR 0.85 (95% CI 0.70-1.03)

P=0.09

(11)

PRIMARY EFFICACY ENDPOINT:

30 Days

STEMI

2%

Placebo

ITT: HR 0.71 (95% CI 0.51-0.99)

P=0.042

Stroke

2.3%

2%

h

, MI, or

1.7%

1%

Rivaroxaban

a

r Deat

h

o

vascul

a

0%

0

5

10

15

20

25

30 Cardi

o

0

5

10

15

20

25

30 Days

mITT: HR 0.71 (95% CI 0.51-0.99)

P=0.042

(12)

PRIMARY EFFICACY ENDPOINT:

While on Aspirin and Thienopyridine

STEMI

10%

12%

Placebo

ITT: HR 0.78 (95% CI 0.64-0.94)

P=0.010

Stroke

11.8%

8%

h

, MI, or

7.9%

6%

Rivaroxaban

a

r Deat

h

2%

4%

o

vascul

a

0%

2%

Cardi

o

0

90

180

270

360

450

540

630

720 Days

mITT: HR 0.82 (95% CI 0.67-1.01)

P=0.061

(13)

EFFICACY ENDPOINTS: 5 mg BID

STEMI

10%

ITT: HR 0.81 (95% CI 0.66-1.00) P=0.051

CV Death, MI, or Stroke

5% ITT: HR 0.92 (95% CI 0.67-1.28) P=0.64

CV Death

10.6% 4.2% 8% Placebo 4% Placebo 4.2% 4 0% 6% Rivaroxaban 5 BID 3% Rivaroxaban 5 BID 8.2% 4.0% 2% 4% 5 mg BID 1% 2% 5 mg BID 0% 2% 0% 1% 0 90 180 270 360 450 540 630 720

Days

mITT: HR 0.86 (95% CI 0.69-1.07) P=0.17 0 90 180 270 360 450 540 630 720 mITT: HR 0.94 (95% CI 0.66-1.33) P=0.73

(14)

EFFICACY ENDPOINTS: 2.5 mg BID

STEMI

10%

CV Death, MI, or Stroke

ITT: HR 0.81 (95% CI 0.65-1.00)

P 0 047

CV Death

All-cause Death

5% ITT: HR 0.60 (95% CI 0.42-0.87) P 0 006 5% ITT: HR 0.63 (95% CI 0.45-0.89) P 0 008 10.6% 4.7% 8% Placebo P=0.047 4% P=0.006 4% Placebo P=0.008 4.2% 6% 3% Placebo 3% 8.7% 3.0% 4% Rivaroxaban 2.5 mg BID 2% Rivaroxaban 2 5 BID 2% Rivaroxaban 2 5 BID 2.5% 0% 2% 0% 1% 2.5 mg BID 0% 1% 2.5 mg BID 0% 0 90 180 270 360 450 540 630 720 mITT: HR 0.85 (95% CI 0.68-1.06) P=0.14 0% 0 90 180 270 360 450 540 630 720 mITT: HR 0.58 (95% CI 0.39-0.86) P=0.006 0% 0 90 180 270 360 450 540 630 720 mITT: HR 0.60 (95% CI 0.41-0.87) P=0.007

(15)

EFFICACY ENDPOINTS: 2.5 mg BID

While on Aspirin and Thienopyridine

STEMI

4% 4%

12%

CV Death, MI, or Stroke

ITT: HR 0.79 (95% CI 0.63-1.00)

P 0 048

CV Death

All-cause Death

ITT: HR 0.51 (95% CI 0.32-0.82) P 0 005 ITT: HR 0.52 (95% CI 0.33-0.82) P 0 004 11.8% 3 8% 4.2% 3% 4% 3% 4% 8% 10% Placebo P=0.048 P=0.005 Placebo P=0.004 3.8% 2% 3% 2% 3% 6% 8% Placebo 9.0% 2.0% 1% 2% 1% 2% 4% Rivaroxaban 2.5 mg BID 1.7% 0% 1% 0% 1% 0% 2% Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID 0% 0 90 180 270 360 450 540 630 720 0% 0 90 180 270 360 450 540 630 720 0% 0 90 180 270 360 450 540 630 720 mITT: HR 0.83 (95% CI 0.65-1.06) P=0.13 mITT: HR 0.45 (95% CI 0.27-0.77) P=0.003 mITT: HR 0.48 (95% CI 0.29-0.79) P=0.004

(16)

4%

PRIMARY SAFETY ENDPOINT

STEMI

4%

2.5 mg BID vs Placebo: HR 3.63 (95% CI 1.73-7.61) P<0.001

e

ding

3%

5 mg BID vs Placebo: HR 5.47 (95% CI 2.68-11.17) P<0.001

a

jor Ble

e

Rivaroxaban 5 mg BID N=2552

2.7%

2%

A

BG M

a

Ri b

1.7%

1%

I non-C

A

_Rivaroxaban 2.5 mg BID N=2566

0%

Placebo N=2607

TIM

0.6%

0

90

180

270

360

450

540

630

720 Days

(17)

OTHER SAFETY ENDPOINTS

STEMI

6%

7%

Placebo

e

ars

2.5 mg vs 5 mg P=0 019

5%

6%

Rivaroxaban 2.5 mg BID

Rivaroxaban 5 mg BID

a

tes at

2 Y

e

_P=0.019 4.51%

3%

4%

e

r Event R

a

2.5 mg vs 5 mg P=0.018 2.46%

1%

2%

a

plan-Mei

e

1.08% 0 12% 0.40%

0%

Non-CABG TIMI Major or Minor Bleeding

Fatal Bleeding

K

a

_0.12% 0.04%

2.5 mg vs Placebo P<0.001

5 mg vs Placebo P<0.001

2.5 mg vs Placebo P=0.33

5 mg vs Placebo P=0.12

(18)

SUMMARY

STEMI

• In patients with a recent STEMI:

–

Rivaroxaban reduced recurrent

cardiovascular events. This benefit

d

l

d

id

t i

ti

t

emerged early and was evident in patients

treated with aspirin and clopidogrel.

–

Rivaroxaban increased the rate of major

bleeding, but there was no significant

increase in fatal bleeding.

–

Rivaroxaban 2.5 mg BID resulted in a

survival benefit and less bleeding than 5

mg BID.

(19)

CONCLUSION

STEMI

Treatment with very low dose

rivaroxaban (2 5 mg BID) offers an

rivaroxaban (2.5 mg BID) offers an

effective strategy to reduce

thrombotic events in patients

following a STEMI.