EINSTEIN DVT and EINSTEIN PE Pooled Analysis

'Xarelto' for the Treatment of Symptomatic Venous Thromboembolism

Effective and Safe Treatment of DVT and PE Across a Wide Range of Patients

Effective and safe treatment of DVT and PE can be challenging, particularly in high-risk subgroups of patients, including:· Frail and elderly patients1

· Patients with renal impairment2 · Patients with cancer2

1. Silverstein et al, 2007; 2. Van Es et al, 2011

These patients may be at increased risk of bleeding and/or venous thromboembolism

EINSTEIN DVT and PE Pooled Analysis

Two phase III studies with similar designs1,2

1. The EINSTEIN Investigators, 2010; 2. The EINSTEIN–PE Investigators, 2012

Allowed prespecified pooling of >8000 patients, which provided robustness for: • Subgroup analyses

• Evaluation of rare safety events

Objectively confirmed DVT

without symptomatic PE

Objectively confirmed PE with

or without symptomatic DVT

15 mg bidN=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

N=4832

Effective VTE Treatment Matters

0.5

3.0

2.5

2.0

1.5

1.0

0.0

'Xarelto' N=4150

Enoxaparin/VKAN=4131

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

Cu

mu

lati

ve e

ven

t ra

te (

%)

HR=0.89 (95% CI 0.66–1.19);

p non-inferiority <0.001

p superiority =0.41

Changed p value from <0.0001

Updated reference from Buller ASH to Prins 2013 throughout

Prins et al, 2013

ITT population

Cu

mu

lati

ve e

ven

t ra

te (

%)

'Xarelto' N=4130

Enoxaparin/VKAN=4116

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

14

10

12

8

6

4

2

0

Time to event (days)

'Xarelto' n/N (%)

Enoxaparin/VKAn/N (%)

HR (95% CI)p-value

388/4130 (9.4)

412/4116(10.0)

0.93 (0.81–1.06) p=0.27

Safety Matters: Similar Rates of Clinically Relevant Bleeding

Prins et al, 2013

Safety population

Safety Matters: Significant Reductions in Major Bleeding

0.5

3.0

2.5

2.0

1.5

1.0

0.0

'Xarelto' N=4130

Enoxaparin/VKAN=4116

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

Cu

mu

lati

ve

ev

en

t ra

te (

%)

Safety population

Prins et al, 2013

'Xarelto' (N=4130)

Enoxaparin/VKA (N=4116) HR (95% CI)

p-valuen (%) n (%)

Major bleeding 40 (1.0) 72 (1.7) 0.54 (0.37–0.79) p=0.002

Fatal 3 (<0.1) 8 (0.2)

In a critical site 10 (0.2) 27 (0.7)

Retroperitoneal 1 (<0.1) 7 (0.2)

Intracranial 3 (<0.1) 9 (0.2)

Changed critical site bleeding events in SOC group from 29 to 27, retroperitoneal bleeding from 8 to 7 and intracranial bleeding from 10 to 9 (as per paper)

'Xarelto' can be Used in a Wide Range of Patients with VTE

'Xarelto' versus enoxaparin/VKA in age, weight, gender and renal function subgroups showed:

Prins et al, 2013

Similar rates of VTE recurrence andclinically relevant bleeding

Similar or lower rates of major bleeding

The pooled paper does not specifically mention these separate subgroups – may we suggest deleting, as all relevant data is presented in the following slides?

Outcome

'Xarelto' Enoxaparin/VKAHR

(95% CI)n/N (%) n/N (%)

Recurrent VTE

Fragile 21/791 (2.7) 30/782 (3.8) 0.68(0.39–1.18)

Non-fragile 65/3359 (1.9) 65/3349 (1.9) 0.98(0.69–1.38)

Major bleeding

Fragile 10/788 (1.3) 35/779 (4.5) 0.27 (0.13–0.54)

Non-fragile 30/3342 (0.9) 37/3337 (1.1) 0.80(0.49–1.29)

‘Xarelto’: Effective and Well-tolerated in Fragile Patients with VTE

*Age >75 years or CrCl <50 ml/min or body weight ≤50 kg

Prins et al, 2013

'Xarelto' reduces the risk of major bleeding in

fragile patients by 73% versus standard of care

Changed lower CI value from 0.70 to 0.69 for recurrent VTE in non-fragile pts (as per paper)

Outcome 'Xarelto' Enoxaparin/VKA

HR(95% CI)n/N (%) n/N (%)

Recurrent VTE

Cancer* 16/316 (5.1) 20/281 (7.1) 0.69(0.36–1.33)

No cancer 70/3834 (1.8) 75/3850 (1.9) 0.93(0.67–1.29)

Major bleeding

Cancer* 9/316 (2.8) 14/278 (5.0) 0.53(0.23–1.23)

No cancer‡ 31/3820 (0.8) 58/3832 (1.5) 0.53 (0.34–0.82)

‘Xarelto’: Effective and Well-tolerated in Patients with Cancer and VTE

Prins et al, 2013

*Patients with known active cancer at baseline or who developed cancer during the study‡In this analysis, six DVT patients were randomized to rivaroxaban but received enoxaparin/VKA

Originally included data for cancer at baseline. Has been updated to show data for cancer overall

Anatomical extent of VTE at baseline

Incidence of recurrent VTE

'Xarelto' Enoxaparin/VKA

n/N (%) n/N (%)

Limited(≤25% of vasculature of a single lobe, popliteal vein only)

10/799 (1.3) 19/815 (2.3)

Intermediate 48/1873 (2.2) 49/1881 (2.6)

Extensive(multiple lobes and >25% of entire pulmonary vasculature; involving common femoral/ iliac vein)

35/1364 (2.6) 26/1327 (2.0)

'Xarelto': Effective for All Clot Severities

Prins et al, 2013

Updated as per data in paper

'Xarelto': Simple Effective VTE Management from Hospital to Home

EINSTEIN DVT and EINSTEIN PE pooled analysis confirmed the benefits of the simple, single-drug approach with 'Xarelto'

A 46% risk reduction in major bleeding events overall, and a 73% risk reduction in fragile patients

Consistent efficacy and safety across key patient subgroups, irrespective of fragility, cancer or clot severity

One simple treatment approach for a range of patients with DVT or PE, from hospital to home

Improved benefit–risk profile of anticoagulation compared with standard of care

Pack Shot

BACK-UP SLIDES

Efficacy and Safety Outcomes in the EINSTEIN DVT and PE Pooled Analysis

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

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

Subgroup analyses included:· Age · Weight · Gender· Renal function· Fragility· Active cancer· Clot severity

Prins et al, 2013

Suggest removing age, weight, gender and renal function as not specifically mentioned in paper?

Patient Characteristics: Similar in Both Study Arms in the EINSTEIN Pooled Analysis

Rivaroxaban(N=4151)

Enoxaparin/VKA(N=4131)

Males (%) 56 54

Age, mean, years 57 57

Unprovoked VTE (%) 63 64

Previous VTE (%) 19 20

Active cancer (%) 6 5

Updated to align with the paper (weight,CrCl and index VTE event are not included)

Prins et al, 2013

ITT 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