1. The EINSTEIN DVT Study
'Xarelto' for the Acute and Continued Treatment of Symptomatic Deep Vein Thrombosis

2. Effective VTE Treatment Matters
Patients who experience acute VTE (DVT or PE) are at risk of recurrent episodes and complications such as post-thrombotic syndrome
PE is a potentially fatal consequence of VTE, and is frequently asymptomatic
An estimated 540,000 VTE-related deaths occur annually in Europe1
543,454
A crucial need for effective VTE treatment
VTE continues to be associated with considerable mortality and morbidity worldwide, occurring in 70–113 individuals per 100,000 in the Western world annually,2 and the risk of VTE increases with age3
Early diagnosis is important to prevent progression of DVT and PE
Associated symptoms include swelling, leg pain or tenderness for DVT, and dyspnoea, chest pain and syncope for PE. Symptoms can be non-specific, or even absent, making diagnosis difficult.4,5 Diagnostic tools and clinical probability scores, such as the Wells score, should be used to confirm or exclude DVT or PE4,6,7
Complications of VTE include post-thrombotic syndrome, which can impact upon patient’s quality of life,8 and chronic thromboembolic pulmonary hypertension, which, although rare, is associated with mortality rates of 4–20%4
Abbreviations
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism
References
Cohen AT et al. Thromb Haemost 2007;98:756–764
White RH. Circulation 2003;107(23 Suppl 1):I4–I8
Anderson FA, Jr et al. Arch Intern Med 1991;151:933–938
Torbicki A et al. Eur Heart J 2008;29:2276–2315
Blann AD et al. BMJ 2006;332;215–219
Wells PS et al. Lancet 1997;350:1795–1798
Wells PS et al. Thromb Haemost 2000;83:416–420
van Korlaar IM et al. Thromb Res 2004;114:11–18
209,926
Transport accident
Prostate cancer
Breast cancer
AIDS
*In Europe
1. Cohen et al, 2007

3. 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
Cumulative event rate of recurrent VTE after discontinuation of therapy in patients with unprovoked VTE2
Cumulative event rate 40
Time after discontinuation (months) 30 20 10 4 8 12 16 24
>20% of patients had a recurrence within 12 months of discontinuing 3 months’ warfarin treatment
Point of treatment discontinuation
Recurrent VTE is a Continuing Risk
Prompt, sustained treatment of VTE is fundamental, owing to a high risk of recurrent events following an initial DVT, or excess symptomatic events3 or potentially fatal events,4 as shown in patients who did not receive adequate anticoagulation
A study of patients who experienced an initial VTE showed the incidence of recurrence increased from 0.2% at 7 days to 17.6% at 10 years after the initial event; this risk of recurrence was highest during the first 6–12 months of treatment, yet never completely diminished1
Abbreviations
DVT, deep vein thrombosis; VTE, venous thromboembolism
References
Heit JA et al. Arch Intern Med 2000;160:761–768
Kearon C et al. N Engl J Med 1999;340:901–990
Brandjes DP et al. N Engl J Med 1992;327:1485–1489
Barritt DW et al. Lancet 1960;1:1309–1312
Prompt, effective treatment of VTE is vital to prevent VTE recurrence
1. Heit et al, 2000; 2. Kearon et al, 1999

4. 'Xarelto': Simple and Effective Single-Drug Approach for VTE Treatment
'Xarelto' is fast-acting and has minimal drug–drug interactions1
'Xarelto' has no need for routine monitoring or frequent dose adjustment1
'Xarelto' exerts similar pharmacodynamic effects to enoxaparin2 40 30 20 10 4 8 12 16 24
Anti-Factor Xa activity (ng/ml enoxaparin)
Time (hours)
Enoxaparin (n=10)
'Xarelto' (n=11)
'Xarelto‘ as an alternative treatment option for VTE
Traditional approaches for VTE treatment involve initial heparin therapy for 5–10 days, overlapping with and followed by a VKA3,4
Drawbacks are associated with dual-drug therapy and include the need for parenteral administration of LMWH, and the need for coagulation monitoring and dose adjustment with VKAs. VKAs also have a narrow therapeutic window and exhibit multiple drug and food interactions5
'Xarelto' is an oral, direct Factor Xa inhibitor that has been investigated in phase III clinical trials, and has many of the characteristics required in an ideal anticoagulant:
A rapid onset of action similar to enoxaparin,2 with maximum plasma concentrations occurring 2–4 hours after tablet intake6
No requirement for routine coagulation monitoring or frequent dose adjustments based on age, gender, body weight or renal function6
Minimal food and drug interactions6
'Xarelto' has been investigated for the treatment and secondary prevention of DVT and PE in the EINSTEIN programme,7,8 and based on these clinical outcomes has received regulatory approval in the EU, US and Canada for the treatment and secondary prevention of DVT and PE
Abbreviations
DVT, deep vein thrombosis; LMWH, low molecular weight heparin; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism
References
Perzborn E et al. Nat Rev Drug Discov 2011;10:61–75
Kubitza D et al. Clin Pharmacol Drug Dev 2013; 2:270–277
Kearon C et al. Chest 2012;141:e419S–e494S
Torbicki A et al. Eur Heart J 2008;29:2276–2315
Eriksson BI et al. Ann Rev Med 2011;62:41–57
Bayer Pharma AG. Xarelto (rivaroxaban) Summary of Product Characteristics 2013
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297
'Xarelto' acts as fast as enoxaparin and can be given at the initiation of DVT and PE treatment
1. Perzborn et al, 2011; 2. Kubitza et al, 2013

5. The EINSTEIN DVT Study Design Included an Initial Intensified Regimen of 'Xarelto'
A single-drug approach with 'Xarelto' was used in EINSTEIN DVT
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
15 mg bid
Objectively confirmed DVT without symptomatic PE
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
The EINSTEIN DVT Study
EINSTEIN DVT was an event-driven, non-inferiority study that investigated the efficacy and safety of 'Xarelto' compared with standard of care in 3449 randomized patients with confirmed acute symptomatic DVT, without symptomatic PE1
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
The 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 burden2,3
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 death1
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 life1
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
Agnelli G et al. Circulation 2007;116:180–187
Büller H et al. Blood 2008;112:2242–2247
The EINSTEIN Investigators, 2010

6. Effective DVT Treatment Matters
Time to event (days)
Cumulative event rate (%) 30 60 90
120
150
180
210
240
270
300
330
360
1.0
2.0
3.0
'Xarelto' (N=1731)
Enoxaparin/VKA (N=1718)
4.0
HR=0.68 (95% CI 0.44–1.04)
p<0.001 for non-inferiority
p=0.08 for superiority
'Xarelto' Showed Similar Efficacy to Standard of Care in the Reduction of Recurrent VTE
Recurrent VTE occurred in 2.1% and 3.0% of patients receiving 'Xarelto' and enoxaparin/VKA, respectively, which was shown to be statistically non-inferior for 'Xarelto' (p<0.001), approaching significance for superiority (p=0.08)1
By day 21 (the end of 'Xarelto' bid dosing), the primary efficacy outcome had occurred in 1.2% of patients who received 'Xarelto' and in 1.7% of patients who received enoxaparin/VKA1
A total of 14 and 28 recurrent DVT events were confirmed in patients receiving 'Xarelto' and enoxaparin/VKA, respectively, whereas a total of 20 and 18 non-fatal PE events occurred in 'Xarelto' and enoxaparin/VKA treatment groups, respectively1
One case of fatal PE occurred, which was in the 'Xarelto' group1
Abbreviations
bid, twice daily; CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
'Xarelto' and standard of care had similar efficacy in the reduction of symptomatic recurrent VTE
Intention-to-treat population
The EINSTEIN Investigators, 2010

7. Safety Matters: Similar Rates of Clinically Relevant Bleeding
Enoxaparin/VKA (N=1711)
'Xarelto' (N=1718)
Time to event (days) 30 60 90
120
150
180
210
240
270
300
330
360
Cumulative event rate (%) 2 4 6 8 10 12 14
HR=0.97 (95% CI 0.76–1.22)
p=0.77
'Xarelto'
Enoxaparin/VKA n
(%)
First major/clinically relevant non-major bleeding
139
(8.1)
138
Major bleeding 14
(0.8) 20
(1.2)
Contributing to death 1
(<0.1) 5
(0.3)
In a critical site 3
(0.2)
'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 (8.1% in each group)1
Rates of major bleeding were numerically lower in patients who received 'Xarelto' compared with enoxaparin/VKA (0.8% vs 1.2%, respectively), which included similar rates of critical site bleeding and lower rates of fatal bleeding1
Rates of clinically relevant non-major bleeding were similar between 'Xarelto' and enoxaparin/VKA treatment groups (7.3% vs 7.0%, respectively)1
Abbreviations
CI, confidence interval; HR, hazard ratio; VKA, vitamin K antagonist
Reference
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
'Xarelto' and standard of care had similar rates of major and clinically relevant non-major bleeding
Safety population
The EINSTEIN Investigators, 2010

8. 'Xarelto' can be Used in a Wide Range of Patients With DVT
Efficacy and safety outcomes were consistent across key patient subgroups including age, sex, body weight, renal function and active cancer
'Xarelto' was associated with a similar rate of adverse events, including vascular events, compared with standard of care
There was no evidence of liver toxicity in patients who received 'Xarelto'
'Xarelto' Showed Consistent Efficacy and Safety Outcomes across Patient Subgroups
Impaired renal function, low or high body weight, older age and active cancer are all patient characteristics that may contribute to clinically challenging VTE treatment. 'Xarelto' was effective and well-tolerated across these and other patient subgroups1
Adverse event rates were similar between the 'Xarelto' and enoxaparin/VKA treatment groups (4.3% vs 3.9%, respectively)1
Vascular event rates were also similar during treatment (0.7% vs 0.8%, respectively); NSTEMI events and transient ischaemic stroke were the most common events in the 'Xarelto' and enoxaparin/VKA treatment groups, respectively1
Increases in liver enzymes (defined as the combination of an alanine aminotransferase level exceeding three times the upper limit of the normal range and a bilirubin level exceeding twice the upper limit of the normal range) were observed in 0.1% and 0.2% of patients in patients who received 'Xarelto' and enoxaparin/VKA, respectively1
Abbreviations
NSTEMI, non-ST elevation myocardial infarction; VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
The EINSTEIN Investigators, 2010

9. Favourable Benefit–Risk Balance Matters
'Xarelto' (N=1731), %
Enoxaparin/VKA (N=1718), %
HR (95% CI)
p-value
Net clinical benefit*
2.9
4.2
0.67 (0.47–0.95)
0.03
'Xarelto' Achieved a Significant Gain in Net Clinical Benefit
Net clinical benefit is a measure of benefits versus harms of a treatment and is an indicator of unwanted events; the lower the value, the bigger the improvement in clinical benefit
Net clinical benefit was a predefined secondary outcome, and was defined as the composite of the primary efficacy outcome (recurrent VTE) and major bleeding1
The net clinical benefit outcome occurred in 2.9% of patients who received 'Xarelto' and in 4.2% of patients who received enoxaparin/VKA1
This composite outcome suggests that anticoagulation with 'Xarelto' provides a favourable benefit–risk balance in terms of recurrent VTE and major bleeding1
Abbreviations
CI, confidence interval; HR, hazard ratio; RRR, relative risk reduction; VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
*Defined as the composite of the primary efficacy outcome and major bleeding
The EINSTEIN Investigators, 2010

10. Patients Matter: Improved Treatment Satisfaction with 'Xarelto'
A subanalysis of patients in EINSTEIN DVT showed that 'Xarelto' was associated with improved treatment satisfaction in patients with DVT, compared with standard of care1
This included a reduction in patient-reported anticoagulation burden1
'Xarelto' offers increased patient satisfaction, potentially improving compliance compared with standard of care
Treatment Satisfaction with 'Xarelto' Treatment in Patients with DVT
Appropriate measurement of treatment satisfaction with novel oral anticoagulants can be achieved through validated patient-reported outcomes
A subanalysis of EINSTEIN DVT involving >1400 patients was performed, which was the first study to evaluate a novel oral anticoagulant compared with standard of care from the patient perspective1
Patient satisfaction was measured using the Anti-Clot Treatment Scale (ACTS). 'Xarelto' was associated with improved treatment satisfaction and a reduction in patient-reported anticoagulation burden, compared with enoxaparin/VKA1
Use of a single-drug approach with 'Xarelto' in patients with DVT may, therefore, contribute to increased patient compliance and treatment adherence, in addition to simplifying treatment and improving health outcomes
Abbreviations
DVT, deep vein thrombosis; VKA, vitamin K antagonist
Reference
Bamber L et al. Thromb Haemost 2013;110:732–741
1. Bamber et al, 2013

11. 'Xarelto': Simple DVT Management from Hospital to Home
EINSTEIN DVT supports simplified VTE treatment with a single-drug approach with 'Xarelto'
Similar efficacy and safety outcomes compared with standard of care
Consistent efficacy and safety outcomes irrespective of age, sex, body weight, renal function and cancer
'Xarelto' Provides Simple Management from Hospital to Home
In EINSTEIN DVT, 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 rates of major bleeding and fatal bleeding were numerically lower
'Xarelto' has the potential to be used effectively in a wide range of patients with DVT
In the treatment of DVT, a simple, single-drug approach with 'Xarelto' is likely to provide:
Effective and well-tolerated treatment
Increased patient compliance, treatment adherence and patient satisfaction
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
Abbreviations
DVT, deep vein thrombosis; VKA, vitamin K antagonist; VTE, venous thromboembolism
Superior net clinical benefit compared with standard of care
Simplified, effective treatment of DVT

12. Pack Shot

14. Back-up slides

15. Patient Characteristics: Similar in Both Study Arms in EINSTEIN DVT
'Xarelto' (N=1731)
Enoxaparin/VKA (N=1718)
Male patients (%)
57.4
56.3
Age, mean (years)
55.8
56.4
Weight (%)
≤50 kg
2.1
2.9
>50–100 kg
83.4
82.8
>100 kg
14.2
14.3
Creatinine clearance (%)
<30 ml/min
0.3
0.5
30–<50 ml/min
6.6
7.0
50–<80 ml/min
22.7
23.2
≥80 ml/min
68.9
68.1
Patient Characteristics in EINSTEIN DVT
Overall, similar characteristics were observed between patients who received 'Xarelto' or enoxaparin/VKA1
A range of patients with DVT were represented in EINSTEIN DVT – a proportion of those enrolled had renal impairment, unprovoked VTE or active cancer1
Approximately 90% of patients studied received treatment for 6 months or longer1
It is also worth noting that initial heparin treatment was only administered for 2 days or less in ~70% of patients1
Abbreviations
DVT, deep vein thrombosis; VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
Intention-to-treat population
The EINSTEIN Investigators, 2010

16. Patient and Treatment Characteristics: Similar in Both Study Arms in EINSTEIN DVT
'Xarelto' (N=1731)
Enoxaparin/VKA (N=1718)
Intended treatment duration (%)
3 months
12.0
11.8
6 months
62.6
63.0
12 months
25.4
25.1
Pretreatment with LMWH/heparin/fondaparinux ≤48 h (%)
73.0
71.0
Active cancer (%)
6.8
5.2
Unprovoked VTE (%)
60.9
Patient Characteristics in EINSTEIN DVT
Overall, similar characteristics were observed between patients who received 'Xarelto' or enoxaparin/VKA1
A range of patients with DVT were represented in EINSTEIN DVT – a proportion of those enrolled had renal impairment, unprovoked VTE or active cancer1
Approximately 90% of patients studied received treatment for 6 months or longer1
It is also worth noting that initial heparin treatment was only administered for 2 days or less in ~70% of patients1
Abbreviations
LMWH, low molecular weight heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism
Reference
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
Intention-to-treat population
The EINSTEIN Investigators, 2010

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 EINSTEIN DVT, rates of major bleeding and fatal bleeding were numerically lower in patients who received 'Xarelto' compared with those who received 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
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
1. Siegal et al, 2012; 2. Bauer KA, 2012; 3. Eerenberg et al, 2012; 4. Marlu et al, 2012; 5. Lu et al, 2013