ACS is a major public health challenge

In the US:

Over 1.5 million people experience ACS annually1

In the EU:

ACS is the most common cause of death, accounting for more than 741,000 deaths each year2

The 6-month post-discharge mortality rate is:3 3.6% in patients with UA 4.8% in patients with STEMI 6.2% in patients with NSTEMI

1. American Heart Association, 2008; 2. British Heart Foundation Health Promotion Research Group, 2008; 3. Goldberg et al, 2004

Event rate of CV death, MI or stroke at 12 months post event remains ~10%

*Major bleeding: non-CABG-related TIMI major bleeding

1. Antiplatelet Trialists' Collaboration, 1994; 2. Antithrombotic Trialists' Collaboration, 2002; 3. Wiviott et al, 2007; 4. Wallentin et al, 2009

20.0 2.8*2.2*0.8 1.3

1.8* 2.4*0

5

10

15

20

25

None

–25%

15.0

ASA1,2

–20%

12.1

ASA +clopidogrel3

ASA +

–19%

9.9

prasugrel3

11.7

ASA +clopidogrel4

Eve

nt

rate

(%

)

–16%

ASA +

9.8

ticagrelor4

CV death, MI or stroke

Major bleeding

Anticoagulants and antiplatelets have different yet complementary mechanisms of action

RivaroxabanApixabanEdoxaban

Anticoagulants Antiplatelets

ASA

ClopidogrelPrasugrelTicagrelor

GPIIb/IIIa inhibitors

Fibrinogen

Fibrin

Clot

Platelets

FactorXa

GPIIb/IIIa

Thromboxane

ADP

InflammationCellular

proliferation

Collagen + other mediators

Activatedplatelet

Coagulationcascade

Mackman, 2008

Platelet aggregation

ThrombinThrombin

Rivaroxaban has the potential to further improve secondary prevention of ACS

Oral administration

Predictable pharmacology Rapid onset of action Fixed dose Balanced dual mode of

elimination

Low potential for drug–drug or food–drug interactions*

No routine coagulation monitoring

Roehrig et al, 2005; Perzborn et al, 2005; Kubitza et al, 2005; 2006a,b,c; 2007a,b

*For full details, see the rivaroxaban Summary of Product Characteristics, available at http://www.xarelto.com

Rivaroxaban binds directly to the active site of Factor Xa (Ki 0.4 nM)

Rivaroxaban

N NO

NH

O

SCl

O

O

O

2.5 and 5 mg bid rivaroxaban doses were chosen for phase III based on data from ATLAS ACS TIMI 46

Gibson, 2008; Data on file at Johnson & Johnson; Mega et al, 2009

5

4

3

2

1

0

ASA plus thienopyridine

3.8%

2.0%

1.2%

0.2%

HR=0.55(0.27–1.11)

p=0.03

90 1800

15

12

9

6

3

0

ASA

11.9%

6.6%

1.2%0.0%

HR=0.54(0.27–1.08)

p=0.17

90 1800

Placebo TIMI major bleeding

Rivaroxaban 2.5 and 5 mg TIMI major bleeding Rivaroxaban 2.5 and 5 mg death, MI, stroke

Placebo death, MI, stroke

Inci

den

ce (

%)

Time after start of treatment (days)

ATLAS ACS 2 TIMI 51

Rivaroxaban2.5 mg bid

n=4825

Rivaroxaban2.5 mg bid

n=4825

Placebon=4821

Placebon=4821

Rivaroxaban

5 mg bidn=4827

Rivaroxaban

5 mg bidn=4827

Event-driven study – 1002 eventsEvent-driven study – 1002 events

Stratum 2: ASA +thienopyridine (93%)

Stratum 2: ASA +thienopyridine (93%)

Rivaroxaban2.5 mg bid

n=349

Rivaroxaban2.5 mg bid

n=349

Placebon=355

Placebon=355

Rivaroxaban

5 mg bidn=349

Rivaroxaban

5 mg bidn=349

Physician's decision to add thienopyridine or not

N=15,526*N=15,526*

ASA dose =75–100 mg/day

Stratum 1: ASA alone (7%)

Stratum 1: ASA alone (7%)

Mega et al, 2011

*184 patients were excluded from the efficacy analyses prior to unblinding because of trial misconduct at three sites

Main inclusion and exclusion criteria

Inclusion criteria Diagnosis of STEMI, NSTEMI, or

UA with at least one of the following: ≥0.1 mV ST-segment deviation TIMI risk score ≥4

Patients aged ≥18 years; <55 years only with either: Diabetes mellitus or Prior MI

Patients received ASA 75–100 mg/day alone or ASA plus a thienopyridine Based on national/local

dosing guidelines

Exclusion criteria Increased bleeding risk, e.g.

Low platelet count History of intracranial

haemorrhage Active internal bleeding

Prior stroke or TIA in stratum 2 patients Atrial fibrillation: except single

episodes >2 years previously in patients aged <60 years with no evidence of cardiopulmonary disease

Gibson et al, 2011

Study endpoints/analyses

Primary efficacy endpoint: composite of cardiovascular death, MI and stroke (ischaemic, haemorrhagic or uncertain)

Main safety endpoint: incidence of major bleeding not associated with CABG surgery (according to TIMI bleeding definition)

Primary analysis: log-rank test stratified by thienopyridine use in mITT population with confirmation in an ITT analysis mITT: all randomized patients and events from randomization up to

earliest date of completion of treatment period (i.e. global treatment end date), 30 days after early discontinuation of study drug, or 30 days after randomization (patients randomized but not treated)

ITT: all randomized patients and events observed from randomization up to global treatment end date

Gibson et al, 2011

Patient characteristics

Rivaroxaban2.5 mg bid(n=5174)

Rivaroxaban5 mg bid(n=5176)

Placebo(n=5176)

Mean age, years (SD) 62 (9) 62 (9) 62 (9)

Male sex, % 75 74 75

Median weight, kg 78 78 78

Median CrCl, ml/min 85 85 86

Medical history, %

Prior MI 26 27 27

Hypertension 67 68 68

Diabetes mellitus 32 32 32

Index diagnosis, %

STEMI 50 50 51

NSTEMI 26 26 26

UA 24 24 24

PCI or CABG for index 61 60 60

Mega et al, 2011

Primary efficacy endpoint (CV death/MI/stroke)Both rivaroxaban doses, both strata

Number at riskPlacebo 5113 4307 3470 2664 1831 1079 421Rivaroxaban 10,229 8502 6753 5137 3554 2084 831

Months after randomization

HR=0.84 (0.74–0.96)ARR=1.7%

mITT p=0.008ITT p=0.002

NNT=56

10.7%

8.9%

2-year Kaplan–Meier estimate

Est

imat

ed c

um

ula

tive

rat

e (%

)

Rivaroxaban

Placebo

12

00 16

10

8

6

4

2

201284 24

Mega et al, 2011

Primary efficacy analysis: patient subgroupsBoth rivaroxaban doses, both strata

Mega et al, 2011

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 years≥65 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

CrCl <50 ml/minCrCl ≥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

Favours rivaroxaban Favours placebo

Primary efficacy endpointSeparate rivaroxaban doses, both strata

Rivaroxaban2.5 mg bid(n=5114)

Rivaroxaban5 mg bid(n=5115)

Placebo(n=5113)

Composite primary endpoint

K–M estimate at 2 years 9.1% 8.8% 10.7%

HR versus placebo (95% CI) 0.84 (0.72–0.97) 0.85 (0.73–0.98)

p value versus placebo 0.02 0.03

CV death

K–M estimate at 2 years 2.7% 4.0% 4.1%

HR versus placebo (95% CI) 0.66 (0.51–0.86) 0.94 (0.75–1.20)

p value versus placebo 0.002 0.63

MI

K–M estimate at 2 years 6.1% 4.9% 6.6%

HR versus placebo (95% CI) 0.90 (0.75–1.09) 0.79 (0.65–0.97)

p value versus placebo 0.27 0.02

Stroke (haemorrhagic and ischaemic)

K–M estimate at 2 years 1.4% 1.7% 1.2%

HR versus placebo (95% CI) 1.13 (0.74–1.73) 1.34 (0.90–2.02)

p value versus placebo 0.56 0.15

Mega et al, 2011

Components of primary endpointRivaroxaban 2.5 mg bid, both strata

0

Months

Cardiovascular death

NNT=71

5

0 24

4.1%

2.7%

Placebo

Rivaroxaban2.5 mg bid

HR=0.66

mITT p=0.002ITT p=0.005

181260

5

All-cause death

Months

4.5%

2.9%

240

Placebo

Rivaroxaban2.5 mg bid

HR=0.68

mITT p=0.002ITT p=0.004

18126

NNT=63

Months

CV death/MI/stroke

Cu

mu

lati

ve i

nci

de

nce

(%

)

HR=0.84

mITT p=0.02ITT p=0.007

10.7%

9.1%

Rivaroxaban2.5 mg bid

Placebo

13

0240 18126

NNT=63

Mega et al, 2011; Gibson et al, 2011

2-year Kaplan–Meier estimate

HR=0.69(0.51–0.93)RRR=31%

mITT p=0.02ITT p=0.008

2.9%

2.3%

Months after randomization

Rivaroxaban

Placebo

Est

imat

ed c

um

ula

tive

inci

den

ce (

%)

2

00 4 8 12 16 2420

3

1

Stent thrombosis*Both rivaroxaban, both strata

*Stent thrombosis events: definite, probable or possible (Academic Research Consortium definitions)Mega et al, 2011

Rivaroxaban2.5 mg bid

Rivaroxaban5 mg bid

2-year K–M estimate 2.2% 2.3%

HR versus placebo (95% CI) 0.65 (0.45–0.94) 0.73 (0.51–1.04)

p value vs placebo (mITT) 0.02 0.08

Principal safety endpointSeparate rivaroxaban doses, both strata

Rivaroxaban2.5 mg bid(n=5115)

Rivaroxaban5 mg bid(n=5110)

Placebo(n=5125)

Non-CABG TIMI major bleed

K–M estimate at 2 years 1.8% 2.4% 0.6%p value versus placebo <0.001 <0.001

ICH

K–M estimate at 2 years 0.4% 0.7% 0.2%p value versus placebo 0.04 0.005

Fatal bleeding

K–M estimate at 2 years 0.1% 0.4% 0.2%p value versus placebo 0.45 0.20

Fatal ICH

K–M estimate at 2 years 0.1% 0.2% 0.1%p value versus placebo – –

Mega et al, 2011

0.2 0.20.10.1

0.4

0.1

0.4

0.7

0.2

0.0

0.2

0.4

0.6

0.8

1.0

Fatal bleeding events ICH Fatal ICH

Placebo 2.5 mg rivaroxaban 5.0 mg rivaroxaban

Treatment-emergent fatal bleeding events and ICHSeparate rivaroxaban doses, both strata

Rivaroxaban vs placebop=NS

Rivaroxaban vs placebop=0.009

Rivaroxaban vs placebop=NS

2-ye

ar K

apla

n–M

eier

est

imat

e (%

)

Mega et al, 2011

Other safety endpointsSeparate rivaroxaban doses, both strata

Rivaroxaban2.5 mg bid

(n=5115)

Rivaroxaban5 mg bid

(n=5110)

Placebo

(n=5125)

Post-treatment ischaemic events*

Raw percentage 1.4% 2.2% 1.8%

p value versus placebo p=NS p=NS

Liver function test (ALT >3× ULN)#

Raw percentage 1.3% 1.4% 1.6%

p value versus placebo p=NS p=NS

Other adverse events (raw percentages)

Dyspnoea 1.1% 1.3% 1.5%

Cough 1.2% 1.1% 1.4%

**CV death/MI/stroke (ischaemic, haemorrhagic, uncertain) events occurring 1–10 days after last rivaroxaban dose; #Abnormal values from first dose to 2 days post last dose in patients with normal baseline values

Mega et al, 2011

ATLAS ACS 2 TIMI 51: summary

Compared with placebo, rivaroxaban (2.5 or 5 mg bid) on top of ASA or ASA plus clopidogrel showed: Significant reductions in the rates of death, MI , and stroke Benefits in all types of ACS  patients (UA, NSTEMI and STEMI ) More than a 30% reduction in risk of both CV and all-cause mortality

(2.5 mg bid) No increase in fatal bleeding and fatal ICH  A non-bleeding safety profile similar to placebo

The addition of anticoagulation with rivaroxaban may represent a new treatment strategy in patients after recent ACS

Mega et al, 2011