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The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

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Page 1: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

The EINSTEIN PE Study

'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

Page 2: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

Effective PE Treatment Matters

PE is a potentially fatal consequence of DVT PE is frequently asymptomatic, and along with DVT, is associated with

delayed diagnosis, making prompt treatment difficult1

More than 90% of deaths occur in untreated patients, because of unrecognized symptoms of PE2

1. Ageno et al, 2008; 2. Torbicki et al, 2008

DVT PE0

5

10

15

20

25 23

16

Pro

po

rtio

n o

f p

ati

en

ts

(%)

Diagnosis of VTE >10 days from onset of symptoms (%)2

Page 3: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

'Xarelto': Simple and Effective Single-Drug Approach for VTE Treatment

'Xarelto' is fast-acting and has minimal drug–druginteractions1

'Xarelto' has no need for routine monitoring or frequent dose adjustment1

1. Perzborn et al, 2011; 2. Kubitza et al, 2013

'Xarelto' acts as fast as enoxaparin and can be given at the initiation of DVT and PE treatment

'Xarelto' exerts similarpharmacodynamic effects to enoxaparin2

40

30

20

10

00

4 8 12 16 20 24A

nti

-Fac

tor

Xa

acti

vity

(n

g/m

l en

oxa

par

in)

Time (hours)

Enoxaparin (n=10)'Xarelto' (n=11)

Page 4: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

The EINSTEIN PE Study Design Included an Initial Intensified Regimen of 'Xarelto'

A single-drug approach with 'Xarelto' was used in the pivotal EINSTEIN PE study - the largest ever conducted in the acute treatment of PE, involving haemodynamically stable patients

An intensified dose of 'Xarelto' (15 mg bid) was given for the first 21 days to provide protection when patients are at highest risk of recurrence

After 21 days, 'Xarelto' 20 mg od was given to provide continued protection against VTE recurrence

Primary efficacy outcome: symptomatic recurrent VTE (composite of recurrent DVT, non-fatal PE or fatal PE)

Principal safety outcome: composite of major or clinically relevant non-major bleeding

The EINSTEIN–PE Investigators, 2012

15 mg bidObjectively confirmed PE

with or without symptomatic DVT

N=4832

'Xarelto' Day 1 Day 21

Enoxaparin (1.0 mg/kg) bid for at least 5 days,

plus VKA target INR 2.5 (INR range 2.0–3.0)

Predefined treatment period of 3, 6 or 12 months

20 mg od

'Xarelto'

R

30

-da

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ob

se

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d

Page 5: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

'Xarelto' Enoxaparin/VKA

n (%) n (%)

First symptomatic recurrent VTE 50 (2.1) 44 (1.8)

Recurrent DVT 18 (0.7) 17 (0.7)

Recurrent DVT + PE 0 2 (<0.1)

Non-fatal PE 22 (0.9) 19 (0.8)

Fatal PE/unexplained death where PE cannot be ruled out 10 (0.4) 6 (0.3)

Effective PE Treatment Matters

3.0

2.5

2.0

1.5

1.0

0.0

0.5

0 30 60 90 120 150 180 210 240 270 300 330 360Time to event (days)

'Xarelto' (N=2419)

Enoxaparin/VKA (N=2413)

HR=1.12 (95% CI 0.75–1.68)

p=0.003 (non-inferiority)

p=0.57 (superiority)

Cu

mu

lati

ve e

ven

t ra

te (

%)

'Xarelto' also showed consistent efficacy across subgroups

The EINSTEIN–PE Investigators, 2012

Intention-to-treat population

'Xarelto' and standard of care had similar efficacy in the reduction of symptomatic recurrent VTE

Page 6: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

Safety Matters: Similar Rates of Clinically Relevant Bleeding

'Xarelto' n/N (%)

Enoxaparin/VKAn/N (%)

HR (95% CI)p-value

249/2412 (10.3)

274/2405(11.4)

0.90 (0.76–1.07) p=0.23

0 30 60 90 120 150 180 210 240 270 300 330 360

1514

10

131211

9876543210

Time to event (days)

'Xarelto' (N=2412)

Enoxaparin/VKA (N=2405)

Cu

mu

lati

ve e

ven

t ra

te (

%)

'Xarelto' also showed consistent safety across subgroups

The EINSTEIN–PE Investigators, 2012

Safety population

Major or clinically relevant non-major bleeding

Page 7: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

3.0

2.5

2.0

1.5

1.0

0

0.5

0 30 60 90 120 150 180 210 240 270 300 330 360Cu

mu

lati

ve e

ven

t ra

te (

%)

Time to event (days)

'Xarelto' (N=2412)

Enoxaparin/VKA (N=2405)

Significant Reduction: Halving the Risk of Major Bleeding

'Xarelto' Enoxaparin/VKAHR (95% CI)p-valuen (%) n (%)

Major bleeding 26 (1.1) 52 (2.2) 0.49 (0.31–0.79) p=0.003

Fatal 2 (<0.1) 3 (0.1)

Non-fatal critical site 7 (0.3) 26 (1.1)

Intracranial 1 (<0.1) 10 (0.4)

Retroperitoneal 1 (<0.1) 7 (0.3)

The EINSTEIN–PE Investigators, 2012

Safety population

'Xarelto' reduced major bleeding by 51%compared with standard of care, with large reductions in

critical site bleeding

Page 8: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

'Xarelto' can be Used in a Wide Range of Haemodynamically Stable PE Patients

Efficacy and safety outcomes were consistent across key patient subgroups, including elderly patients and those with renal impairment

'Xarelto' was effective regardless of the severity of PE, whether it was anatomically limited (≤25% of vasculature of a single lobe) or extensive (multiple lobes and >25% of entire pulmonary vasculature)

'Xarelto' was associated with a similar rate of adverse events compared with standard of care· This included serious adverse events and treatment-emergent adverse

events There was no evidence of liver toxicity in patients who received

'Xarelto'

The EINSTEIN–PE Investigators, 2012

Page 9: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

Patients Matter: Improved Treatment Satisfaction with 'Xarelto'

A subanalysis of patients in EINSTEIN PE showed that 'Xarelto' was associated with improved treatment satisfaction in patients with PE, compared with standard of care1

· This included a reduction in patient-reported anticoagulation burden and an increase in convenience1

1. Prins et al, 2012

'Xarelto' offers increased patient satisfaction, potentially improving compliance compared with

standard of care

Page 10: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

'Xarelto': Simple PE Management from Hospital to Home

'Xarelto' is the only novel oral anticoagulant investigated in a dedicated PE study

Similar efficacy and safety outcomes compared with standard of care

Significant reduction in major bleeding events by 51% compared with standard of care, including intracranial

haemorrhage and retroperitoneal bleeding

Consistent efficacy and safety results across key patient subgroups

EINSTEIN PE confirmed the benefits of the simple, single-drug approach with 'Xarelto' in haemodynamically

stable PE patients

Page 11: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

Pack Shot

Page 12: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism
Page 13: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

BACK-UP SLIDES

Page 14: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

'Xarelto' (N=2419)

Enoxaparin/VKA(N=2413)

Male patients (%) 54.1 51.7

Age, mean, years 57.9 57.5

Weight, kg

≤50 kg 1.6 1.8

>50–100 kg 84.1 83.3

>100 kg 14.3 14.9

Creatinine clearance (%)

<30 ml/min 0.2 <0.1

30–49 ml/min 8.6 7.9

50–79 ml/min 26.3 24.6

≥80 ml/min 64.3 67.0

Patient Characteristics: Similar in Both Study Arms in EINSTEIN PE

The EINSTEIN–PE Investigators, 2012

Intention-to-treat population

Page 15: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

'Xarelto' (N=2419)

Enoxaparin/VKA(N=2413)

Intended treatment duration (%)3 months 5.3 5.16 months 57.3 57.512 months 37.4 37.5

Anatomical extent baseline PE (%)Limited (single lobe, ≤25% of vasculature)

12.8 12.4

Intermediate 57.5 59.0Extensive (multiple lobes, >25% of entire vasculature)

24.7 23.9

Pretreatment with LMWH/heparin/fondaparinux ≤48 h (%)

92.5 92.1

Active cancer (%) 4.7 4.5Unprovoked PE (%) 64.7 64.3

Patient and Treatment Characteristics: Similar in Both Study Arms in EINSTEIN PE

The EINSTEIN–PE Investigators, 2012

Intention-to-treat population

Page 16: The EINSTEIN PE Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Pulmonary Embolism

Bleeding Management in Clinical Practice

If bleeding events occur while patients are receiving 'Xarelto', they can be managed easily by measures used in clinical practice1,2

· There is no specific reversal agent currently available for 'Xarelto'; however, studies are ongoing3–5

1. Siegal et al, 2012; 2. Bauer KA, 2012; 3. Eerenberg et al, 2012; 4. Marlu et al, 2012; 5. Lu et al, 2013

Bleeding during anticoagulant treatment with

'Xarelto'

Minor bleeding e.g. gum or nose bleed

Major bleeding

Bleeding that cannot be controlled by

general or supportive measures

General measures Delay next dose or discontinue treatment

Supportive measures Mechanical compression Fluid replacement Haemodynamic support or blood products

Consider haemostatic procoagulant agents Prothrombin complex concentrate Activated prothrombin complex Factor VIIa