Oral rivaroxaban for the treatment of symptomatic venous thromboembolism (a pooled analysis of the EINSTEIN DVT

Oral Rivaroxaban for the Treatment of
Symptomatic Venous Thromboembolism:
A Pooled Analysis of the EINSTEIN DVT
and EINSTEIN PE Studies
Anthonie WA Lensing
on behalf of the EINSTEIN Investigators


Bayer symposium - Da Nang, 13 October
Venous thromboembolism
 1-2 new cases per 1000 per year
 If no or inadequate anticoagulant treatment is given

recurrent thrombotic complications in 20-30%

 Heparin/vitamin K antagonist (VKA)

VKA has a slow onset of action; heparin is needed for the first
week of treatment

VKA has an unpredictable anticoagulant effect, requiring
– frequent INRs and dose adjustments
 Heparin/VKA recurrent VTE rate: ~ 3% at 6 mo


Rivaroxaban
Specific, direct factor Xa inhibitor
High oral bioavailability
Rapid onset of action
Half-life: 7–11 hours
Only 1/3 renally cleared

Small change in exposure with varying
bodyweight
Wide therapeutic window
Absorption limited if > 50 mg





Rivaroxaban



Can Rivaroxaban be given in a fixed
dose without the requirement for
monitoring and replace heparin and VKA
treatment in DVT/PE patients?



EINSTEIN DVT and EINSTEIN PE studies
Randomized, open-label, event-driven, non-inferiority studies of
identical design with a priori specified combined analyses



Primary efficacy outcome: recurrent VTE

Safety outcome: major bleeding

1. N Engl J Med 2010;363:2499 2. N Engl J Med 2012;366:1287–97
15 mg bid
DVT without
PE
1
N=3449
N=8282
Rivaroxaban
Day 1 Day 21
Enoxaparin bid for at least 5 days +
VKA, INR 2.0–3.0
PE with or
without DVT
2
N=4833
Predefined treatment period of 3, 6, or 12 months
20 mg od
30-day post-study
treatment period
Rivaroxaban
R
EINSTEIN DVT/PE:
primary efficacy outcome
Number of patients at risk
Rivaroxaban 4150 4018 3969 3924 3604 3579 3283 1237 1163 1148 1102 1034 938
Enoxaparin/VKA 4131 3932 3876 3826 3523 3504 3236 1215 1149 1109 1071 1019 939
0.5
3.0
2.5
2.0

1.5
1.0
0.0
Rivaroxaban
N=4150
Enoxaparin/VKA
N=4131
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Cumulative event rate (%)
Rivaroxaban
n/N (%)
Enoxaparin/VKA
n/N (%)
HR (95% CI)

86/4150
(2.1)
95/4131
(2.3)
0.89 (0.66–1.19)
EINSTEIN DVT/PE:
major bleeding
Number of patients at risk
Rivaroxaban 4130 3921 3862 3611 3479 3433 2074 1135 1095 1025 969 947 499
Enoxaparin/VKA 4116 3868 3784 3525 3394 3348 1835 1109 1065 990 950 916 409
0.5
3.0
2.5
2.0

1.5
1.0
0.0
Rivaroxaban
N=4130
Enoxaparin/VKA
N=4116
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Cumulative event rate (%)
Rivaroxaban
n/N (%)
Enoxaparin/VKA
n/N (%)
HR (95% CI)
p-value
40/4130
(1.0)
72/4116
(1.7)
0.54 (0.37–0.79)
p=0.002
Outcome
Rivaroxaban
(N=4130)
Enoxaparin/VKA
(N=4116)
HR (95% CI)
p-value
n % 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
Retroperitoneal 0 0 1 <0.1
Intracranial 2 <0.1 4 <0.1
Gastrointestinal/thorax 1 <0.1 3 <0.1
In a critical site 10 0.2 29 0.7
Retroperitoneal
1
<0.1 8 0.2
Intracranial
3
<0.1 10 0.2
Pericardial
0
0 2 <0.1
Other
6
0.1 7 0.2
Fall in hemoglobin ≥2 g/dl
and/or transfusions ≥2 units
27
0.7 37 0.9
Gastrointestinal
15
0.4 26 0.6
EINSTEIN DVT/PE:
types of major bleeding
*Some patients had >1 event

Einstein DVT/PE:
Clinical presentation of major bleeding
Major
bleeding
Rivaroxaban n=45
VKA n=79

Category 1

Controllable

18 (40.0%)

17 (21.5%)

Category 2

Requires
measures to
control, not serious
19 (42.2%)

34 (43.0%)

Category 3

Serious bleeding

7 (15.6%)

26 (32.9%)

Category 4

Fatal

1 (2.2%)

2 (2.5%)

Category 3+4 rivaroxaban vs VKA: odds ratio 0.39, 95% CI: 0.16-0.96; p=0.04)
Einstein DVT/PE - Major bleeding and
use of prohemostatic measures




Rivaroxaban
n=45
Enox/VKA
n=79
Vitamin K
1 30
FFP
4 11
Prothrombin
complex

2 9
rFVIIa

1 0
Outcome
Rivaroxaban Enoxaparin/VKA
HR (95% CI)
n/N % n/N %
Recurrent VTE
Non-fragile
65/3359 1.9 65/3349 1.9
0.98 (0.70–1.38)
Fragile 21/791 2.7 30/782 3.8 0.68 (0.39–1.18)
Major bleeding
Non-fragile
30/3342
0.9 37/3337 1.1 0.80 (0.49–1.29)
Fragile
10/788 1.3 35/779 4.5
0.27 (0.13–0.54)
EINSTEIN DVT/PE:
outcomes in fragile patients*
*Age >75 years, CrCl <50 ml/min, or body weight ≤50 kg
EINSTEIN DVT/PE:
Major bleeding and kidney function
0.8
1.4
0.9
1.0
3.0
4.0
0
2

4
6
8
10
12
14
>80
50−80
<50
Major bleeding (%)
Creatinine clearance (ml/min)
Rivaroxaban
Enoxaparin/VKA
p
trend
=0.92

p
trend
=0.01
Rivaroxaban Enoxaparin/VKA
n/N % n/N %
Limited
≤25% of vasculature of
a single lobe,
popliteal vein only
11/814 1.4 19/826 2.3
Intermediate

47/1941 2.4 50/1942 2.6

Extensive
multiple lobes and >25% of
entire pulmonary vasculature;
involving common femoral/
iliac vein
28/1218 2.3 25/1190

2.1
EINSTEIN DVT/PE:
Clot size and recurrent VTE
EINSTEIN PE:
Repeat CT scan at 3 weeks in 264 patients
Rivaroxaban

N=135

Enoxaparin/VKA

N=129

Complete resolution

59 (44%)

57 (44%)

Partial resolution

61 (45%)

58 (45%)

No change

15 (11%)

12 (9%)

Deteriorated

0

0

Van Es, et al. JTH, 11: 679–85
Venous thromboembolism and cancer
Long-term LMWH is recommended
LMWH is often not used based on medical,
economic and quality of life considerations

LMWH/VKA is often prescribed in practice

In EINSTEIN DVT/PE patients with cancer were not
excluded


Classification of DVT/PE patients with
cancer
Patients with cancer were classified as:


Active cancer at baseline (diagnosis or treatment < 6
months or recurrent or metastatic cancer)

Active cancer during the study (a new diagnosis of
cancer)

A history of cancer (all other)



EINSTEIN DVT/PE:
Analysis populations
Active cancer
at baseline
(n=462)
Active cancer
during study
(n=193)
History of
cancer
(n=469)
No known
cancer
(n=7157)
8281 patients randomized
EINSTEIN DVT/PE:
Outcomes

No known cancer
Rivaroxaban

Enoxaparin/VKA
HR (95% CI)
Recurrent VTE,
n (%) 65/3563 (1.8) 70/3594 (1.9)
0.93 (0.66–1.30)
Major bleeding, n (%)
31/3546 (0.9) 53/3582 (1.5)
0.58 (0.37–0.91)
Mortality, n (%)
33/3563 (0.9) 42/3594(1.2)
0.77 (0.49–1.22)
EINSTEIN DVT/PE:
Outcomes

History of cancer
Rivaroxaban
Enoxaparin/VKA
HR (95% CI)
Recurrent VTE,
n (%)
5/233 (2.1) 5/236 (2.1) 0.98 (0.28–3.43)
Major bleeding, n (%)

1/231 (0.4) 4/236 (1.7) 0.23 (0.03–2.06)
Mortality, n (%)

5/233 (2.1) 4/236 (1.7) 1.12 (0.30–4.22)
EINSTEIN DVT/PE:
Outcomes

Active cancer*
Rivaroxaban
Enoxaparin/VKA
HR (95% CI)
Recurrent VTE,
n (%)
16/354 (4.5) 20/301 (6.6) 0.67 (0.35–1.30)
Major bleeding, n (%)

8/353 (2.3) 15/298 (5.0) 0.42 (0.18–0.99)
Mortality, n (%)

58/354 (16.4) 53/301 (17.6) 0.93 (0.64–1.35)
*At baseline or diagnosed during the study

EINSTEIN DVT/PE in cancer:
Major bleeding and kidney function
2.4
2.2
2.1
2.7
5.0
13.0
0
2
4
6
8
10
12

14
>80
50−80
<50
Major bleeding (%)
Creatinine clearance (ml/min)
Rivaroxaban
Enoxaparin/VKA
p
trend
=0.92

p
trend
=0.01
EINSTEIN DVT/PE:
conclusions
In patients with acute symptomatic DVT and/or
PE, rivaroxaban showed:

Non-inferiority versus enoxaparin/VKA for efficacy
– Including cancer patients

Approximately 50% risk reduction for major bleeding
– Including cancer patients

Consistent efficacy and safety results irrespective of
age, body weight, gender, renal function, severity of
DVT/PE, and treatment of first/recurrent VTE


Single-drug approach: no LMWH needed