ACS is a major public health challenge

1
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 is3
• 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
2
Event rate of CV death, MI or stroke at 12 months
post event remains 10
25
CV death, MI or stroke
Major bleeding
20
25
15
20
Event rate ()
16
19
10
5
1.3
0.8
20.0
2.8
2.2
1.8
2.4
15.0
12.1
9.9
11.7
9.8
0
None
ASA1,2
ASA
ASA
ASA
ASA
clopidogrel3
prasugrel3
clopidogrel4
ticagrelor4
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
3
Anticoagulants and antiplatelets have different
yet complementary mechanisms of action
Coagulationcascade
Platelets
Anticoagulants
Collagen other mediators
Antiplatelets
RivaroxabanApixabanEdoxaban
ASA
FactorXa
Thromboxane
ClopidogrelPrasugrelTicagrelor
ADP
InflammationCellular proliferation
Thrombin
Thrombin
Activatedplatelet
GPIIb/IIIa inhibitors
Fibrinogen
GPIIb/IIIa
Platelet aggregation
Fibrin
Clot
Mackman, 2008
4
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 drugdrug or fooddrug
  interactions
• No routine coagulation monitoring

Rivaroxaban binds directly to the active site of
Factor Xa (Ki 0.4 nM)
For full details, see the rivaroxaban Summary of
Product Characteristics, available at
http//www.xarelto.com
Roehrig et al, 2005 Perzborn et al, 2005
Kubitza et al, 2005 2006a,b,c 2007a,b
5
2.5 and 5 mg bid rivaroxaban doses were chosen
for phase III based on data from ATLAS ACS TIMI
46
Rivaroxaban 2.5 and 5 mg TIMI major bleeding
Rivaroxaban 2.5 and 5 mg death, MI, stroke
Placebo TIMI major bleeding
Placebo death, MI, stroke
5
15
ASA plus thienopyridine
ASA
11.9
4
12
3.8
HR0.54(0.271.08)
HR0.55(0.271.11)
3
9
Incidence ()
6.6
2.0
2
6
p0.17
1.2
1
3
p0.03
1.2
0.2
0
0
0.0
90
180
0
90
180
0
Time after start of treatment (days)
Gibson, 2008 Data on file at Johnson Johnson
Mega et al, 2009
6
ATLAS ACS 2 TIMI 51
N15,526
Physician's decision to add thienopyridine or not
Stratum 2 ASA thienopyridine (93)
Stratum 1 ASA alone (7)
ASA dose 75100 mg/day
Rivaroxaban 2.5 mg bid n349
Placebo n355
Rivaroxaban 5 mg bid n349
Rivaroxaban 2.5 mg bid n4825
Placebo n4821
Rivaroxaban 5 mg bid n4827
Event-driven study 1002 events
184 patients were excluded from the efficacy
analyses prior to unblinding because of trial
misconduct at three sites
Mega et al, 2011
7
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 lt55 years only with
  either
• Diabetes mellitus or
• Prior MI
• Patients received ASA 75100 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 gt2
  years previously in patients aged lt60 years with
  no evidence of cardiopulmonary disease

Gibson et al, 2011
8
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
9
Patient characteristics
Mega et al, 2011
10
Primary efficacy endpoint (CV death/MI/stroke)Bot
h rivaroxaban doses, both strata
HR0.84 (0.740.96) ARR1.7 mITT p0.008 ITT
p0.002 NNT56
Months after randomization
Mega et al, 2011
11
Primary efficacy analysis patient subgroupsBoth
rivaroxaban doses, both strata
P
HR (95 CI)
interaction
Overall
0.96)
0.84 (0.74
ASA ASA thienopyridine
0.69 (0.45 -1.05)
0.34
0.86 (0.75 -0.98)
lt65 years
0.94
0.83 (0.70
- 0.99)
65 years
0.84 (0.70
- 1.01)
STEMI
0.85 (0.70
- 1.03)
0.96
NSTEMI
0.85 (0.68
- 1.06)
UA
0.82 (0.62
- 1.07)
Male
0.87 (0.75
- 1.01)
0.40
Female
0.77 (0.60
- 0.99)
0.98
Weight lt60 kg
0.83 (0.56
- 1.25)
Weight
60 to lt90 kg
0.85 (0.72
- 0.99)
Weight
90 kg
0.83 (0.64
- 1.08)
Prior MI
0.83 (0.68
- 1.01)
0.80
No prior MI
0.85 (0.72
- 1.01)
Diabetes mellitus
0.96 (0.77
- 1.20)
0.14
No diabetes mellitus
0.78 (0.67
- 0.92)
CrCl lt50 ml/min
0.88 (0.62
- 1.26)
0.82
CrCl 50 ml/min
0.84 (0.73
- 0.96)
0.57 (0.33
- 0.97)
North America
0.80
South America
0.89 (0.59
- 1.34)
Western Europe
0.90 (0.59
- 1.37)
Eastern Europe
0.83 (0.69
- 1.00)
Asia
0.86 (0.63
- 1.17)
Other
0.92 (0.60
- 1.39)
0.5
0.8
1.25
2.0
1.0
Mega et al, 2011
Favours rivaroxaban
Favours placebo
12
Primary efficacy endpointSeparate rivaroxaban
doses, both strata
Mega et al, 2011
13
Components of primary endpointRivaroxaban 2.5 mg
bid, both strata
Mega et al, 2011 Gibson et al, 2011
14
Stent thrombosisBoth rivaroxaban, both strata
2-year KaplanMeier estimate
3
2.9
Placebo
2.3
HR0.69(0.510.93) RRR31 mITT p0.02 ITT
p0.008
2
Rivaroxaban
Estimated cumulative incidence ()
1
0
0
4
8
12
16
24
20
Months after randomization
Stent thrombosis events definite, probable or
possible (Academic Research Consortium
definitions)
Mega et al, 2011
15
Principal safety endpointSeparate rivaroxaban
doses, both strata
Mega et al, 2011
16
Treatment-emergent fatal bleeding events and
ICHSeparate rivaroxaban doses, both strata
Rivaroxaban vs placebopNS
Rivaroxaban vs placebop0.009
Rivaroxaban vs placebopNS
2-year KaplanMeier estimate ()
Mega et al, 2011
17
Other safety endpointsSeparate rivaroxaban
doses, both strata
CV death/MI/stroke (ischaemic, haemorrhagic,
uncertain) events occurring 110 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
18
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