1. EINSTEIN DVT and EINSTEIN PE Pooled Analysis
'Xarelto' for the Treatment of Symptomatic Venous Thromboembolism

2. 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
These patients may be at increased risk of bleeding and/or venous thromboembolism
Effective and Safe Treatment of VTE Remains Clinically Challenging in Certain Patient Groups
For elderly patients, effective and safe treatment of VTE can be challenging owing to a likelihood of co-morbidities and the need for concomitant medications, and an increased risk of bleeding, partly because of physiological changes1
Patients with renal impairment, including the elderly, are at increased risk of bleeding and VTE.3 Owing to varying levels of renal excretion with the novel oral anticoagulants,3 optimal dosing and maintaining an acceptable benefit–risk balance is an important consideration for physicians
Approximately 20% of all cases of VTE occur in patients with cancer4 and patients with cancer-associated VTE are at increased risk of hospital readmission and mortality within 6 months of initial hospitalization5
Anticoagulant treatment in patients with cancer-associated VTE can be difficult because of the need for treatment interruption, and the influence of nausea and drug interactions on normally therapeutic levels of anticoagulation6
Clinical data are limited in these and other patients, such as those with low body weight; therefore, adequate clinical surveillance is crucial, while ensuring that patients receive treatment that is simple, safe and effective
Abbreviations
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism
References
Silverstein RL et al. Blood 2007;110:3097–3101
Van Es J et al. J Thromb Haemost 2011;9 Suppl 1:265–274
Poulsen BK et al. Drugs 2012;72:1739–1753
Lyman GH. Cancer 2011;117:1334–1349
Levitan N et al. Medicine (Baltimore) 1999;78:285–291
Kearon C et al. Chest 2012;141(Suppl):e419S–e494S
1. Silverstein et al, 2007; 2. Van Es et al, 2011

3. EINSTEIN DVT and PE Pooled Analysis
Two phase III studies with similar designs1,2
Objectively confirmed DVT without symptomatic PE
Objectively confirmed PE with or without symptomatic DVT
15 mg bid
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 R
30-day observation period
N=4832
The EINSTEIN DVT and EINSTEIN PE Pooled Analysis
The pooled analysis was prespecified before commencement of the individual trials, with an aim of providing meaningful clinical data on patient subgroups
The study designs were similar to enable data pooling: EINSTEIN DVT and EINSTEIN PE were both event-driven, non-inferiority studies that investigated the efficacy and safety of 'Xarelto' compared with standard of care in a total of 8282 randomized patients (1 patient was excluded in EINSTEIN PE because of invalid informed consent) with confirmed acute symptomatic DVT and PE, respectively1,2
Patients received 'Xarelto' (15 mg bid for 21 days; followed by 20 mg od), or subcutaneous enoxaparin followed by a VKA (either warfarin or acenocoumarol) for 3, 6 or 12 months. The VKA dose was adjusted to maintain an INR of 2.0–3.01,2
Rationale for the dosing regimen stemmed from dose-finding studies, which showed that an intensified 'Xarelto' dose was well-tolerated and effective in the treatment of acute symptomatic DVT, as suggested by a reduction in thrombus burden3,4
Because the dose selected for the phase III studies was based on data from patients with DVT, EINSTEIN PE included a dose confirmation stage in the first 400 patients, to ensure that the selected dose was also effective for the treatment of patients with PE
Ineligible patients in EINSTEIN PE included those in whom pulmonary embolectomy had been performed, or who received thrombolytic therapy
Abbreviations
bid, twice daily; DVT, deep vein thrombosis; INR, international normalized ratio; od, once daily; PE, pulmonary embolism; R, randomization; VKA, vitamin K antagonist; VTE, venous thromboembolism
References
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297
Agnelli G et al. Circulation 2007;116:180–187
Büller H et al. Blood 2008;112:2242–2247
Allowed prespecified pooling of >8000 patients, which provided robustness for:
Subgroup analyses
Evaluation of rare safety events
1. The EINSTEIN Investigators, 2010; 2. The EINSTEIN–PE Investigators, 2012

4. Effective VTE Treatment Matters
0.5
3.0
2.5
2.0
1.5
1.0
0.0
'Xarelto'
N=4150
Enoxaparin/VKA
N=4131 30 60 90
120
150
180
210
240
270
300
330
360
Time to event (days)
Cumulative event rate (%)
HR=0.89 (95% CI 0.66–1.19);
p non-inferiority <0.001
p superiority =0.41
Changed p value from <0.0001
'Xarelto' Showed Similar Efficacy to Standard of Care in the Reduction of Recurrent VTE
Recurrent VTE occurred in 2.1% and 2.3% of patients receiving 'Xarelto' and enoxaparin/VKA, respectively. This was shown to be statistically non-inferior for 'Xarelto' (p<0.0001), yet did not reach statistical significance for superiority (p=0.41)1
Recurrent DVT and PE events occurred at similar rates between patients who received 'Xarelto' and enoxaparin/VKA (recurrent DVT: 0.8% and 1.1%, respectively; recurrent PE: 1.0% and 0.9%, respectively)1
Less than 0.1% of patients in each treatment group had both a recurrent DVT and a recurrent PE1
The number of deaths and cases of fatal PE were similar between patients who received 'Xarelto' compared with enoxaparin/VKA1
Abbreviations
CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; ITT, intention-to-treat; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE,  venous thromboembolism
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
Updated reference from Buller ASH to Prins 2013 throughout
ITT population
Prins et al, 2013

5. Safety Matters: Similar Rates of Clinically Relevant Bleeding
Cumulative event rate (%)
'Xarelto'
N=4130
Enoxaparin/VKA
N=4116 30 60 90
120
150
180
210
240
270
300
330
360 14 10 12 8 6 4 2
Time to event (days)
'Xarelto' n/N (%)
Enoxaparin/VKA n/N (%)
HR (95% CI) p-value
388/4130 (9.4)
412/4116 (10.0)
0.93 (0.81–1.06) p=0.27
'Xarelto' Showed Similar Rates of Clinically Relevant Bleeding to Standard of Care
Composite rates of major or clinically relevant non-major bleeding occurring during treatment were similar between patients receiving 'Xarelto' and enoxaparin/VKA (9.4% vs 10%, respectively; p=0.27)1
Abbreviations
CI, confidence interval; HR, hazard ratio; VKA, vitamin K antagonist
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
Safety population
Prins et al, 2013

6. Safety Matters: Significant Reductions in Major Bleeding
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)
0.5
3.0
2.5
2.0
1.5
1.0
0.0
'Xarelto'
N=4130
Enoxaparin/VKA
N=4116 30 60 90
120
150
180
210
240
270
300
330
360
Time to event (days)
Cumulative event rate (%)
'Xarelto' (N=4130)
Enoxaparin/VKA (N=4116)
HR (95% CI) p-value 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 27
(0.7)
Retroperitoneal 1 7
Intracranial 9
'Xarelto' Showed a Significant Reduction in Major Bleeding Compared with Standard of Care
Rates of major bleeding were significantly lower in patients who received 'Xarelto' compared with enoxaparin/VKA (1.0% vs 1.7%, respectively; p=0.002), translating to a 46% relative risk reduction1
There were fewer cases of critical site bleeding in patients receiving 'Xarelto' compared with enoxaparin/VKA, which included intracranial bleeding (3 vs 9, respectively)1
Rates of fatal bleeding were also lower with 'Xarelto' therapy compared with enoxaparin/VKA (3 vs 8, respectively)1
Abbreviations
CI, confidence interval; HR, hazard ratio; VKA, vitamin K antagonist
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
Safety population
Prins et al, 2013

7. 'Xarelto' can be Used in a Wide Range of Patients with VTE
The pooled paper does not specifically mention these separate subgroups – may we suggest deleting, as all relevant data is presented in the following slides?
'Xarelto' versus enoxaparin/VKA in age, weight, gender and renal function subgroups showed:
Similar rates of VTE recurrence and
clinically relevant bleeding
Similar or lower rates of major bleeding
'Xarelto' Showed Consistent Efficacy and Safety across Key Patient Subgroups
Regardless of the patient population studied, 'Xarelto' was shown to be consistently effective in the reduction of recurrent VTE and was well tolerated1
Abbreviations
VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
Prins et al, 2013

8. ‘Xarelto’: Effective and Well-tolerated in Fragile Patients with VTE
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
(%)
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
0.98 (0.69–1.38)
Major bleeding
10/788
(1.3)
35/779
(4.5)
0.27 (0.13–0.54)
30/3342
(0.9)
37/3337
(1.1)
0.80 (0.49–1.29)
'Xarelto' Showed an Improvement in Recurrent VTE and a Significant Reduction in Major Bleeding in Fragile Patients Compared with Standard of Care
Fragile patients were defined as elderly (age >75 years) or those with moderate or severe renal impairment (CrCl <50 ml/min) or patients with low body weight (≤50 kg)1
The rate of recurrent VTE was numerically lower in patients who received 'Xarelto' compared with enoxaparin/VKA (2.7% vs 3.8%, respectively)1
'Xarelto' was associated with a significant reduction in major bleeding compared with enoxaparin/VKA in fragile patients (1.3% vs 4.5%, respectively), which translated to a 73% relative risk reduction1
Abbreviations
CI, confidence interval; CrCl, creatinine clearance; HR, hazard ratio; VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
'Xarelto' reduces the risk of major bleeding in fragile patients by 73% versus standard of care
*Age >75 years or CrCl <50 ml/min or body weight ≤50 kg
Prins et al, 2013

9. ‘Xarelto’: Effective and Well-tolerated in Patients with Cancer and VTE
Originally included data for cancer at baseline. Has been updated to show data for cancer overall
Outcome
'Xarelto'
Enoxaparin/VKA
HR (95% CI)
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
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' Showed Reductions in Efficacy and Safety Outcomes in Patients with Cancer Compared with Standard of Care
Recurrent VTE occurred in 5.1% and 7.1% of patients with cancer who received 'Xarelto' and enoxaparin/VKA, respectively1
Rates of major bleeding were numerically lower, occurring in 2.8% and 5.0% of patients with cancer who received 'Xarelto' and enoxaparin/VKA, respectively1
Abbreviations
CI, confidence interval; HR, hazard ratio; VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
*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
Prins et al, 2013

10. 'Xarelto': Effective for All Clot Severities
Updated as per data in paper
Anatomical extent of VTE at baseline
Incidence of recurrent VTE
'Xarelto'
Enoxaparin/VKA
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
26/1327
(2.0)
'Xarelto' Showed Similar Efficacy to Standard of Care in the Reduction of Recurrent VTE Regardless of the Extent of Thrombosis
In patients with anatomically limited thrombosis, recurrent VTE occurred in 1.3% and 2.3% of patients who received 'Xarelto' and enoxaparin/VKA, respectively1
Rates of recurrent VTE were also similar between 'Xarelto' and enoxaparin/VKA treatment groups in those presenting with an intermediate clot burden (2.2% and 2.6%, respectively) and extensive clot burden (2.6% vs 2.0%, respectively)1
Abbreviations
VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
Prins et al, 2013

11. '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'
Improved benefit–risk profile of anticoagulation compared with standard of care
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
'Xarelto' Provides Simple Management from Hospital to Home
In the EINSTEIN DVT and PE pooled analysis, a single-drug approach with 'Xarelto' was shown to be non-inferior to enoxaparin/VKA in the reduction of recurrent VTE
'Xarelto' was associated with similar rates of clinically relevant bleeding, and a significant reduction in major bleeding
Data from the pooled analysis of >8000 patients has shown that 'Xarelto' can be used effectively in a wide range of patients with DVT and/or PE
It should be considered that there are still some patients with VTE for whom 'Xarelto' should not be used, including those with haemodynamically unstable PE, or those who require an invasive procedure such as thrombectomy or thrombolysis
In the treatment of DVT and/or PE, a simple, single-drug approach with 'Xarelto' is likely to provide:
Effective and well-tolerated treatment in patients, including those who are elderly, fragile, have cancer-associated VTE or who present with extensive thrombosis
Fewer clinical restrictions for physicians when making difficult treatment choices
A similar treatment approach in many patients, regardless of the clinical manifestation of VTE
Immediate and continued anticoagulation, protecting the patient from risk of recurrent events
A favourable benefit–risk profile in a wide range of patients with DVT and PE
Abbreviations
DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism
One simple treatment approach for a range of patients with DVT or PE, from hospital to home

12. Pack Shot

14. Back-up slides

15. 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
Suggest removing age, weight, gender and renal function as not specifically mentioned in paper?
Outcome measures in the EINSTEIN DVT and EINSTEIN PE Pooled Analysis
The primary efficacy and principal safety outcomes were the same as those employed in the individual EINSTEIN DVT and PE trials1
Bleeding was defined as major if it was clinically overt and associated with a fall in the haemoglobin level of ≥20 g/l, or if it led to transfusion of ≥2 units of red cells, or if it was intracranial or retroperitoneal, occurred in another critical site or contributed to death2,3
Bleeding was defined as non-major (but clinically relevant) if it was overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of study treatment or associated with any other discomfort such as pain or impairment of activities of daily life2,3
Subgroups included were those considered to be at higher risk or VTE or bleeding, and who may be clinically challenging for physicians
For the subgroup analysis of varying clot severity, the extent of DVT or PE was defined as limited if proximal DVT was limited to the popliteal vein or if a single lobe PE involved ≤25% of the vasculature of that lobe, or extensive if proximal DVT involved the common femoral and/or iliac vein, or if PE involved multiple lobes or >25% of the entire pulmonary vasculature1
Abbreviations
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297
Prins et al, 2013

16. Patient Characteristics: Similar in Both Study Arms in the EINSTEIN Pooled Analysis
Updated to align with the paper (weight,CrCl and index VTE event are not included)
Rivaroxaban (N=4151)
Enoxaparin/VKA (N=4131)
Males (%) 56 54
Age, mean, years 57
Unprovoked VTE (%) 63 64
Previous VTE (%) 19 20
Active cancer (%) 6 5
Patient Characteristics in the EINSTEIN DVT and EINSTEIN PE Pooled Analysis
Overall, similar characteristics were observed between patients who received rivaroxaban or standard of care, which included patients with unprovoked VTE or active cancer1
Abbreviations
DVT, deep vein thrombosis; ITT, intention-to-treat; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
ITT population
Prins et al, 2013

17. 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
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
Bleeding Management in Clinical Practice
Bleeding complications are a recognized risk associated with all anticoagulant use, and clinical vigilance is required to enable effective, rapid bleeding control
In phase III clinical trials of 'Xarelto', rates of bleeding were similar to or lower than standard of care. In the EINSTEIN DVT and PE pooled analysis, rates of major bleeding were significantly reduced in patients who received 'Xarelto' compared with enoxaparin/VKA6
Several effective approaches are available if bleeding occurs while a patient is receiving 'Xarelto'. These include local compression, surgical intervention, fluid replacement or blood product replacement until haemostasis is restored, along with delay or discontinuation of anticoagulation1,2
An agent is not yet available for specific reversal of 'Xarelto' anticoagulant activity, or for any of the novel oral anticoagulants
PCC, activated PCC and recombinant Factor VIIa have all been investigated for the reversal of 'Xarelto' activity in studies involving healthy volunteers with promising results;3,4 however, further studies are still ongoing
A universal Factor Xa reversal agent is in development,5 which includes a phase II study in humans (ClinicalTrials.gov identifier: NCT )
Abbreviations
PCC, prothrombin complex concentrate; VKA, vitamin K antagonist
References
Siegal DM et al. Eur Heart J 2013;34:489–498b
Bauer KA. Am J Hematol 2012;87 Suppl 1:S119–126
Eerenberg ES et al. Circulation 2011;124:1573–1579
Marlu R et al. Thromb Haemost 2012;108:217–224
Lu G et al. Nat Med 2013;19:446–451
Prins MH et al. Thromb J 2013 Sep 20;11(1):21
1. Siegal et al, 2012; 2. Bauer KA, 2012; 3. Eerenberg et al, 2012; 4. Marlu et al, 2012; 5. Lu et al, 2013