the einstein pe study 'xarelto' for the acute and continued treatment of symptomatic...
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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
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(%)
Diagnosis of VTE >10 days from onset of symptoms (%)2
'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
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4 8 12 16 20 24A
nti
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Xa
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Time (hours)
Enoxaparin (n=10)'Xarelto' (n=11)
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
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'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
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%)
'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
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
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
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%)
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
'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
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
'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
Pack Shot
BACK-UP SLIDES
'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
'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
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