Rivaroxaban : Lesson Learned from

EINSTEIN Study

dr. Azhari Gani, SpPD-KKV, FCIC, FINASIM

EINSTEIN DVT: study design

Randomized, open-label, event-driven, non-inferiority study

Patients with confirmed acute symptomatic DVT without
symptomatic PE
88 primary efficacy outcomes needed

Treatment period: 3, 6 or 12 months

Day 1 Day 21
Rivaroxaban Rivaroxaban

30-day observation
N=3449

after treatment
Confirmed 15 mg bid 20 mg od

cessation
symptomatic
DVT without R
symptomatic
PE Enoxaparin (1.0 mg/kg) bid for at least 5 days,
plus VKA target INR 2.5 (INR range 2.03.0)

The EINSTEIN Investigators. N Engl J Med 2010

 EINSTEIN DVT:
primary efficacy outcome analysis
Rivaroxaban Enoxaparin/VKA
(N=1731) (N=1718)
n (%) n (%)
First symptomatic recurrent VTE 36 (2.1) 51 (3.0)
Recurrent DVT 14 (0.8) 28 (1.6)
Recurrent DVT + PE 1 (<0.1) 0 (0.0)
Non-fatal PE 20 (1.2) 18 (1.0)
Fatal PE/unexplained death where
4 (0.2) 6 (0.3)
PE cannot be ruled out
0.44 0.68 1.04

0 1.00 2.00
HR
Rivaroxaban Rivaroxaban Rivaroxaban
superior non-inferior inferior
p=0.08 for superiority (two-sided) p<0.001 for non-inferiority
(one-sided)
CI, confidence interval; HR, hazard ratio
ITT population The EINSTEIN Investigators. N Engl J Med 2010
EINSTEIN DVT:
primary efficacy outcome time to first event
4.0
Cumulative event rate (%)

Enoxaparin/VKA (N=1718)
3.0
Rivaroxaban (N=1731)

2.0

HR=0.68; p<0.001 (non-inferiority)

1.0 RR=32%

0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of subjects at risk

Rivaroxaban 1731 1668 1648 1621 1424 1412 1220 400 369 363 345 309 266
Enoxaparin/
1718 1616 1581 1553 1368 1358 1186 380 362 337 325 297 264
VKA

RR, relative risk

The EINSTEIN Investigators. N Engl J Med 2010
EINSTEIN DVT:
primary efficacy outcome by subgroup
Symptomatic recurrent VTE
Rivaroxaban Enoxaparin/VKA HR (95% CI)
n/N (%) n/N (%)
Overall 36/1731 (2.1) 51/1718 (3.0)
Age
<65 years 26/1145 (2.3) 30/1111 (2.7)
6575 years 6/371 (1.6) 11/382 (2.9)
>75 years 4/215 (1.9) 10/225 (4.4)
Weight
70 kg 12/494 (2.4) 21/524 (4.0)
>7090 kg 13/740 (1.8) 19/707 (2.7)
>90 kg 11/491 (2.2) 11/486 (2.3)
Gender
Male 17/993 (1.7) 24/967 (2.5)
Female 19/738 (2.6) 27/751 (3.6)

0.1 1 10

Favours rivaroxaban Favours enoxaparin/VKA

ITT population

The EINSTEIN Investigators. N Engl J Med 2010 (Supplementary Appendix)

EINSTEIN DVT:
primary efficacy outcome by subgroup
Symptomatic recurrent VTE
Rivaroxaban Enoxaparin/VKA HR (95% CI)
n/N (%) n/N (%)
Overall 36/1731 (2.1) 51/1718 (3.0)
Region
Western Europe 15/758 (2.0) 17/740 (2.3)
Eastern Europe 1/255 (0.4) 4/260 (1.5)
Australia and
6/179 (3.4) 9/179 (5.0)
New Zealand
North America 5/163 (3.1) 8/163 (4.9)
Asia 3/211 (1.4) 8/211 (3.8)

0.1 1 10

Favours rivaroxaban Favours enoxaparin/VKA

ITT population

The EINSTEIN Investigators. N Engl J Med 2010 (Supplementary Appendix)

EINSTEIN DVT:
principal safety outcome analysis
Rivaroxaban Enoxaparin/VKA
HR (95% CI)
(N=1718) (N=1711)

n (%) n (%) p-value

First major or non-major clinically 0.97 (0.761.22)

139 (8.1) 138 (8.1)
relevant bleeding p=0.77

0.65 (0.331.30)
Major bleeding 14 (0.8) 20 (1.2)
p=0.21

Contributing to death 1 (<0.1) 5 (0.3)

In a critical site 3 (0.2) 3 (0.2)

Associated with fall in haemoglobin

10 (0.6) 12 (0.7)
2 g/dl and/or transfusion of 2 units

Non-major clinically relevant bleeding 126 (7.3) 119 (7.0)

Patients could have one or more bleeding events

Safety population
The EINSTEIN Investigators. N Engl J Med 2010
EINSTEIN DVT: principal safety outcome (composite
of major or non-major clinically relevant bleeding)
14 Enoxaparin/VKA (N=1711)
12
Cumulative event rate (%)

10

8 Rivaroxaban (N=1718)
6

0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of subjects at risk
Rivaroxaban 1718 1585 1538 1382 1317 1297 715 355 338 304 278 265 140
Enoxaparin/
1711 1554 1503 1340 1263 1238 619 338 321 287 268 249 118
VKA

The EINSTEIN Investigators. N Engl J Med 2010

EINSTEIN DVT:
principal safety outcome by subgroup
Composite of major or non-major clinically relevant bleeding
Rivaroxaban Enoxaparin/VKA HR (95% CI)
n/N (%) n/N (%)
Overall 139/1718 (8.1) 138/1711 (8.1)
Age
<65 years 86/1134 (7.6) 79/1107 (7.1)
6575 years 34/369 (9.2) 39/381 (10.2)
>75 years 19/215 (8.8) 20/223 (9.0)
Weight
70 kg 48/492 (9.8) 42/522 (8.0)
>7090 kg 59/733 (8.0) 57/708 (8.1)
>90 kg 31/488 (6.4) 39/481 (8.1)
Gender
Male 75/987 (7.6) 74/963 (7.7)
Female 64/731 (8.8) 64/748 (8.6)

0.1 1 10

Favours rivaroxaban Favours enoxaparin/VKA

Safety population

The EINSTEIN Investigators. N Engl J Med 2010 (Supplementary Appendix)

EINSTEIN DVT: conclusions
In patients who had acute symptomatic proximal DVT, without
symptomatic PE, rivaroxaban showed:
Non-inferiority to LMWH/VKA for efficacy (HR=0.68; 95% CI 0.441.04;
p<0.001)
Similar findings for principal safety outcome between the two groups
Consistent efficacy and safety results irrespective of age, body weight,
gender, creatinine clearance and cancer
No evidence of liver toxicity
Oral rivaroxaban, could provide clinicians and patients with a simple,
single-drug approach for the acute treatment of DVT

The EINSTEIN Investigators. N Engl J Med 2010

Rivaroxaban
EINSTEIN Extension
EINSTEIN Extension: study background
Treatment for index venous thromboembolic event
6 or 12 months anticoagulation

Equipoise
Continue Should anticoagulation
be stopped
Stop treatment
anticoagulation
or continue?

Routine coagulation
monitoring, with dose
adjustment and
attendant risk of
bleeding

EINSTEIN Extension

The EINSTEIN Investigators. N Engl J Med 2010

EINSTEIN Extension:
study objective and design

Primary objective
To evaluate whether rivaroxaban is superior to placebo in
the long-term prevention of recurrent symptomatic VTE in
patients with symptomatic DVT or PE who completed 6 or
12 months of treatment with a VKA or rivaroxaban

Study design
Multicentre, randomized, double-blind, placebocontrolled,
eventdriven, superiority study for efficacy

The EINSTEIN Investigators. N Engl J Med 2010

EINSTEIN Extension: study design
Randomized, double-blind, placebo-controlled, event-driven (n=30),
superiority study

Confirmed
symptomatic Treatment period of 6 or 12 months
DVT or PE
completing Day 1
6 or 12
months of ~53%
rivaroxaban or
VKA in Rivaroxaban 20 mg od

observation
EINSTEIN N=1197

30-day

period
programme
R
Placebo

Confirmed
symptomatic
DVT or PE ~47%
completing
6 or 12 months
of VKA

The EINSTEIN Investigators. N Engl J Med 2010

EINSTEIN Extension: major outcomes
Primary efficacy outcome*1
Symptomatic recurrent VTE, i.e. composite of recurrent DVT, nonfatal
PE or fatal PE, or unexplained death where PE cannot
be excluded
Principal safety outcome*1,2
Major bleeding, defined as overt bleeding associated with:
A fall in haemoglobin of 2 g/dl, or
A transfusion of 2 units of packed red blood cells or whole blood, or
Occurrence at a critical site: intracranial, intraspinal, intraocular,
pericardial, intra-articular, intramuscular with compartment syndrome,
retroperitoneal, or
Death
*Adjudicated by a central independent adjudication committee
1. The EINSTEIN Investigators. N Engl J Med 2010
2. The EINSTEIN Investigators. N Engl J Med 2010 (Supplementary Appendix)
EINSTEIN Extension:
primary efficacy outcome and individual components
Rivaroxaban Placebo
(N=602) (N=594)
n (%) n (%)

Symptomatic recurrent VTE* 8 (1.3)# 42 (7.1)

Recurrent DVT 5 (0.8) 31 (5.2)

Non-fatal PE 2 (0.3) 13 (2.2)

Fatal PE 0 (0) 1 (0.2)

Unexplained death
1 (0.2) 0 (0)
(where PE cannot be excluded)

ITT population; *Some patients experienced more than

one event; #p<0.001
The EINSTEIN Investigators. N Engl J Med 2010
EINSTEIN Extension:
primary efficacy outcome analysis time to first event
13
12
Cumulative event rate (%)

11
10 Placebo (N=594)
9
8
7 HR=0.18; p<0.001
6 RRR=82%
5
4 Rivaroxaban (N=602)
3
2
1
0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)

Number of subjects at risk

Rivaroxaban 602 590 583 573 552 503 482 171 138 132 114 92 81

Placebo 594 582 570 555 522 468 444 164 138 133 110 93 85

RRR, relative risk reduction

The EINSTEIN Investigators. N Engl J Med 2010
EINSTEIN Extension: major bleeding
Rivaroxaban Placebo
(N=598) (N=590)
n (%) n (%)
Major bleeding 4 (0.7)* 0 (0)
Bleeding contributing to death 0 (0) 0 (0)
Bleeding in a critical site 0 (0) 0 (0)
Associated with fall in haemoglobin
4 (0.7) 0 (0)
2 g/dl and/or transfusion of 2 units
Gastrointestinal bleeding 3 (0.5) 0 (0)
Menorrhagia 1 (0.2) 0 (0)

Safety population; *p=0.11

The EINSTEIN Investigators. N Engl J Med 2010

EINSTEIN Extension: conclusions
In patients who had completed 6 or 12 months of anticoagulation,
rivaroxaban showed:
An 82% RRR in the recurrence of VTE (HR=0.18; p<0.001)
Absolute risk reduction 5.8%
Low incidence of major bleeding
Efficacy and safety results were consistent irrespective of bodyweight
and creatinine clearance
Oral rivaroxaban 20 mg od could provide clinicians and patients with
a simple and effective option for continued anticoagulant treatment

The EINSTEIN Investigators. N Engl J Med 2010

Overall summary
VTE is a serious and potentially life-threatening condition
Current standard of treatment usually requires initial parenteral
LMWH/UFH or fondaparinux followed by an oral VKA
Patients with VTE have a major risk of recurrent VTE that may persist for
many years2,3
Rivaroxaban demonstrated non-inferiority to LMWH/VKA for the treatment
of acute DVT, with a similar safety profile (EINSTEIN DVT)4
In patients who had completed 6 or 12 months of anticoagulation,
rivaroxaban showed an 82% relative risk reduction in the recurrence of
VTE (HR=0.18; p<0.001) vs placebo (EINSTEIN EXT)4
New oral anticoagulants may have the potential to improve benefitrisk
and simplify acute VTE treatment and secondary prevention

1. Schulman S. N Engl J Med 2003; 2. Prandoni P et al. Ann Intern Med 1996;
3. Heit JA et al. Arch Intern Med 2000; 4. The EINSTEIN Investigators. N Engl J Med 2010;
5. The EINSTEINPE Investigators. N Engl J Med 2012