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
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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