the einstein ext study 'xarelto' for the long-term prevention of recurrent venous...

The EINSTEIN EXT Study

'Xarelto' for the Long-Term Prevention of Recurrent Venous Thromboembolism

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

Long-term treatment of VTE is an important factor in preventing recurrent events

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

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ven

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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

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4 8 12 16 20 24A

nti

-Fac

tor

Xa

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vity

(n

g/m

l en

oxa

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in)

Time (hours)

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

The EINSTEIN EXT Study Design

Compared 'Xarelto' (as a once-daily 20 mg dose) with placebo for the long-term prevention of recurrent symptomatic VTE

Patients enrolled were those for whom the decision to continue or stop treatment was unclear, and who had previously received anticoagulation with 'Xarelto' or a VKA

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

Principal safety outcome: major bleeding

The EINSTEIN Investigators, 2010

Confirmed symptomatic DVT or PE completing

6–12 months of 'Xarelto' or VKA in the

EINSTEIN programmeN=1197

Placebo

Predefined treatment period of 6 or 12 months

'Xarelto' 20 mg od

R

30

-da

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Confirmed symptomatic DVT or PE completing 6–12 months of VKA

~53%

~47%

Day 1

Effective Long-Term Treatment Matters

ITT population; *some patients had more than one event


Time to event (days)

10

5

21C

um

ula

tive

eve

nt

rat

e (%

)

34

9

678

00 30 60 90 120 150 180 210 240 270 300 330 360

HR=0.184; p<0.0001 (superiority)RRR=82%

'Xarelto' N=602

PlaceboN=594

'Xarelto' showed a relative risk reduction of 82%

'Xarelto' (N=602) Placebo (N=594)n (%) n (%)

Symptomatic recurrent VTE* 8 (1.3) 42 (7.1)

Recurrent DVT 5 (0.8) 31 (5.2)

Non-fatal PE 2 (0.3) 13 (2.2)

Fatal PE 0 0 1 (0.2)

Unexplained death (where PE cannot be excluded)

1 (0.2) 0 0

'Xarelto' (N=598)

Placebo (N=590) p-value

n (%) n (%)

Major bleeding 4 (0.7) 0 0 0.11

Bleeding contributing to death 0 0 0 0

Bleeding in a critical site 0 0 0 0

Associated with fall in haemoglobin 2 g/dl and/or transfusion 4 (0.7) 0 0

Gastrointestinal bleeding 3 (0.5) 0 0

Menorrhagia 1 (0.2) 0 0

Major or clinically relevant non-major bleeding 36 (6.0) 7 (1.2) <0.001

Clinically relevant non-major bleeding 32 (5.4) 7 (1.2)

Safety Matters: No Significant Increase in Major Bleeding

Safety population


ITT population

'Xarelto' (N=602) Placebo (N=594)

n (%) n (%)

Cardiovascular outcomes 4 (0.7) 4 (0.7)

STEMI 1 (0.2) 0 0

Unstable angina 3 (0.5) 1 (0.2)

Transient ischaemic attack 0 0 1 (0.2)

Ischaemic stroke 0 0 1 (0.2)

Non-CNS systemic embolism 0 0 1 (0.2)

Total mortality 1 (0.2) 2 (0.3)

PE, or unexplained death where PE cannot be excluded 1 (0.2) 1 (0.2)

Cancer 0 0 1 (0.2)

Safety Matters: Low Rates of Mortality and Cardiovascular Outcomes


'Xarelto' (N=602), %

Placebo (N=594), % HR (95% CI) p-value

Net clinical benefit* 2.0 7.1 0.28 (0.15–0.53) <0.001

Favourable Benefit–Risk Balance Matters


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

A total of 34 recurrent events were prevented, at the cost of 4 major bleeding events

RRR

72%(p<0.001)

Placebo 'Xarelto'0

2

4

6

8

Inc

ide

nc

e (

%)

7.1

2.0

'Xarelto': Simple Sustained Protection from Hospital to Home

EINSTEIN EXT confirmed the benefits of the simple, single-drug approach with 'Xarelto' for long-term treatment of DVT/PE

No significant increase in major bleeding events or vascular events

Significant reductions in recurrent VTE compared with placebo – an 82% relative risk reduction

An acceptable benefit–risk balance for patients receiving long-term treatment in whom there is no clear decision whether to

continue or stop anticoagulation

Pack Shot

BACK-UP SLIDES

'Xarelto' (N=602)

Placebo(N=594)

Males (%) 58.8 57.1

Age, mean (years) 58.2 58.4

Weight (%)

≤50 kg 1.7 0.8

>50–100 kg 81.6 82.2

>100 kg 14.1 14.6

Creatinine clearance (ml/min) (%)

<30 0 0.8

30–<49 6.1 7.4

50–<80 22.3 20.5

≥80 62.0 62.8

Index event* (%)

DVT 64.1 59.9

PE 35.9 40.1

Active cancer (%) 4.7 4.4

Unprovoked VTE (%) 73.1 74.2

Patient Characteristics: Similar in Both Study Arms in EINSTEIN EXT


ITT population; *index event not confirmed in all patients

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

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