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The EINSTEIN DVT Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Deep Vein Thrombosis

The EINSTEIN DVT Study 'Xarelto' for the Acute and Continued Treatment of Symptomatic Deep Vein Thrombosis

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The EINSTEIN DVT Study

'Xarelto' for the Acute and Continued Treatment of Symptomatic Deep Vein Thrombosis

Effective VTE Treatment Matters

Patients who experience acute VTE (DVT or PE) are at risk of recurrent episodes and complications such as post-thrombotic syndrome

PE is a potentially fatal consequence of VTE, and is frequently asymptomatic An estimated 540,000 VTE-related deaths occur annually in Europe1

1. Cohen et al, 2007

*In EuropeCombined deaths VTE-related deaths*

0

100,000

200,000

300,000

400,000

500,000

600,000

209,926

543,454

AIDSBreast cancerProstate cancer

Transport accident

Persistent Threat of VTE Recurrence

Patients who experience a thromboembolic event are at continued risk of recurrent VTE

This risk of recurrence is highest in the first 6–12 months after the initial episode, and may continue for as long as 10 years1

Recurrent episodes are observed in >20% of patients 12 months after discontinuation of anticoagulation2

Prompt, effective treatment of VTE is vital to prevent VTE recurrence

1. Heit et al, 2000; 2. Kearon et al, 1999

Cumulative event rate of recurrent VTE after discontinuation of therapy in

patients with unprovoked VTE2

Cu

mu

lati

ve e

ven

t ra

te

40

Time after discontinuation (months)

30

20

10

00

4 8 12 16 20 24

>20% of patients had a recurrence within 12 months of discontinuing 3 months’ warfarin treatment

Point of treatment discontinuation

'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)

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

A single-drug approach with 'Xarelto' was used in EINSTEIN DVT 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 Investigators, 2010

15 mg bidObjectively confirmed DVT

without symptomatic PE

N=3449

'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

y

ob

se

rva

tio

n

pe

rio

d

Effective DVT Treatment Matters

Time to event (days)

Cu

mu

lati

ve e

ven

t ra

te (

%)

0 30 60 90 120 150 180 210 240 270 300 330 3600

1.0

2.0

3.0'Xarelto' (N=1731)

Enoxaparin/VKA (N=1718)4.0

HR=0.68 (95% CI 0.44–1.04)

p<0.001 for non-inferiority

p=0.08 for superiority

The EINSTEIN Investigators, 2010

Intention-to-treat population

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

Safety Matters: Similar Rates of Clinically Relevant Bleeding

Enoxaparin/VKA (N=1711)

'Xarelto' (N=1718)

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

0Cu

mu

lati

ve e

ven

t ra

te (

%)

2

4

6

8

10

12

14

HR=0.97 (95% CI 0.76–1.22)

p=0.77

The EINSTEIN Investigators, 2010

Safety population

'Xarelto' and standard of care had similar rates of major and clinically relevant non-major bleeding

'Xarelto' Enoxaparin/VKA

n (%) n (%)

First major/clinically relevant non-major bleeding

139 (8.1) 138 (8.1)

Major bleeding 14 (0.8) 20 (1.2)

Contributing to death 1 (<0.1) 5 (0.3)

In a critical site 3 (0.2) 3 (0.2)

'Xarelto' can be Used in a Wide Range of Patients With DVT

Efficacy and safety outcomes were consistent across key patient subgroups including age, sex, body weight, renal function and active cancer

'Xarelto' was associated with a similar rate of adverse events, including vascular events, compared with standard of care

There was no evidence of liver toxicity in patients who received 'Xarelto'

The EINSTEIN Investigators, 2010

'Xarelto' (N=1731), %

Enoxaparin/VKA(N=1718), %

HR (95% CI) p-value

Net clinical benefit*

2.9 4.20.67

(0.47–0.95)0.03

Favourable Benefit–Risk Balance Matters

The EINSTEIN Investigators, 2010

*Defined as the composite of the primary efficacy outcome and major bleeding

Enoxaparin/VKA 'Xarelto' 0

1

2

3

4

54.2

2.9

Inci

den

ce (

%) RRR

33%(p=0.03)

Patients Matter: Improved Treatment Satisfaction with 'Xarelto'

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

· This included a reduction in patient-reported anticoagulation burden1

1. Bamber et al, 2013

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

standard of care

'Xarelto': Simple DVT Management from Hospital to Home

EINSTEIN DVT supports simplified VTE treatment with a single-drug approach with 'Xarelto'

Similar efficacy and safety outcomes compared with standard of care

Consistent efficacy and safety outcomes irrespective of age, sex, body weight, renal function and cancer

Superior net clinical benefit compared with standard of care

Simplified, effective treatment of DVT

Pack Shot

BACK-UP SLIDES

'Xarelto' (N=1731)

Enoxaparin/VKA(N=1718)

Male patients (%) 57.4 56.3

Age, mean (years) 55.8 56.4

Weight (%)

≤50 kg 2.1 2.9

>50–100 kg 83.4 82.8

>100 kg 14.2 14.3

Creatinine clearance (%)

<30 ml/min 0.3 0.5

30–<50 ml/min 6.6 7.0

50–<80 ml/min 22.7 23.2

≥80 ml/min 68.9 68.1

Patient Characteristics: Similar in Both Study Arms in EINSTEIN DVT

The EINSTEIN Investigators, 2010

Intention-to-treat population

'Xarelto' (N=1731)

Enoxaparin/VKA(N=1718)

Intended treatment duration (%)

3 months 12.0 11.8

6 months 62.6 63.0

12 months 25.4 25.1

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

73.0 71.0

Active cancer (%) 6.8 5.2

Unprovoked VTE (%) 60.9 63.0

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

The EINSTEIN Investigators, 2010

Intention-to-treat population

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