Neue Antikoagulantien bei spontaner
und Tumor-assoziierter VTE
Paul Kyrle
Univ. Klinik f. Innere Medizin I
AKH/Medizinische Universität Wien
Treatment of VTE: past, present and future
Heparin
Vitamin K antagonists
Heparin
Dabigatran/Edoxaban
Rivaroxaban/Apixaban
Treatment of VTE
up to
2 weeks
up to 3 - 6 months
acute
subacute
> 6 months
extended
RE-COVER - Dabigatran for acute/subacute VTE
Recurrent VTE and related death
Non-inferiority p<0.001
Schulman, N Engl J Med 2009
RE-COVER - Dabigatran for acute/subacute VTE
Bleeding
Schulman, N Engl J Med 2009
Oral Rivaroxaban for the Treatment of
Symptomatic Venous Thromboembolism:
A Pooled Analysis of the EINSTEIN DVT
and EINSTEIN PE Studies
Harry R Büller
on behalf of the EINSTEIN Investigators
EINSTEIN DVT and EINSTEIN PE studies
Randomized, open-label, event-driven, non-inferiority studies of
identical design with a priori specified combined analyses
Predefined treatment period of 3, 6, or 12 months
Confirmed
PE with or
without
symptomatic
DVT2
N=4833
Day 1
Day 21
Rivaroxaban
Rivaroxaban
15 mg bid
20 mg od
N=8282
R
Enoxaparin bid for at least 5 days +
VKA, INR 2.0–3.0
30-day post-study
treatment period
Confirmed
DVT without
symptomatic
PE1
N=3449

Primary efficacy outcome: first recurrent VTE

Principal safety outcome: first major or non-major clinically relevant bleeding
1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–510;
2. The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–97
EINSTEIN DVT and EINSTEIN PE pooled
analysis: patient characteristics
Males, %
Age, mean, years ± SD
Weight, n (%)
≤50 kg
>50–100 kg
≥100 kg
Creatinine clearance, ml/min (%)
<30
30–49
50–79
≥80
Index VTE, n (%)
DVT
PE
DVT and PE
Unprovoked VTE, n (%)
Previous VTE, n (%)
Active cancer, n (%)
ITT population
Rivaroxaban
(N=4150)
55
57±17
Enoxaparin/VKA
(N=4131)
54
57±17
75
3477
590
(1.8)
(84)
(14)
92
3432
605
(2.2)
(83)
(15)
10
322
1030
2748
(0.2)
(8)
(25)
(66)
11
311
992
2787
(0.3)
(8)
(24)
(67)
1699
1793
615
2003
791
232
(41)
(43)
(15)
(48)
(19)
(6)
1690
1804
597
2048
819
198
(41)
(44)
(15)
(50)
(20)
(5)
EINSTEIN DVT and EINSTEIN PE pooled
analysis: primary efficacy outcome
Cumulative event rate (%)
3.0
Enoxaparin/VKA
N=4131
2.5
2.0
Rivaroxaban
N=4150
1.5
HR=0.89; p non-inferiority <0.0001
1.0
Mean time in therapeutic range = 61.7%
0.5
0.0
0
30
60
90
120
150
180
210
240
270
300
330
360
Time to event (days)
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
ITT population
EINSTEIN DVT and EINSTEIN PE pooled
analysis: principal safety outcome
First major or clinically relevant non-major bleeding
Enoxaparin/VKA
N=4116
Cumulative event rate (%)
14
12
10
Rivaroxaban
N=4130
8
6
4
Rivaroxaban
n/N (%)
Enoxaparin/VKA
n/N (%)
HR (95% CI)
p-value
2
388/4130
(9.4)
412/4116
(10.0)
0.93 (0.81–1.06)
p=0.27
0
0
30
60
90
120
150
180
210
240
270
300
330
360
Time to event (days)
Number of patients at risk
Rivaroxaban
4130
3768
3671
3406
3270
3210
1928
1051
1009
936
878
853
453
Enoxaparin/VKA
4116
3738
3618
3330
3186
3125
1711
1025
981
907
857
823
369
Safety population
EINSTEIN DVT and EINSTEIN PE pooled
analysis: major bleeding
First major bleeding
Cumulative event rate (%)
3.0
2.5
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
2.0
Enoxaparin/VKA
N=4116
1.5
1.0
Rivaroxaban
N=4130
0.5
0.0
0
30
60
90
120
150
180
210
240
270
300
330
360
Time to event (days)
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
Safety population
Treatment of VTE - conclusion
up to
2 weeks
up to 3 - 6 months
acute
subacute
NOACS as safe
and effective
NOACS as
effective, but safer
> 6 months
extended
Risk of recurrence after unprovoked VTE
Kyrle, Rosendaal & Eichinger, Lancet 2010
EINSTEINext - Rivaroxaban for extended thromboprophylaxis after VTE
Study design
Confirmed
symptomatic DVT
or PE completing
6 or 12 months of
rivaroxaban or VKA
in EINSTEIN VTE
program
Confirmed
symptomatic DVT
or PE completing
6 or 12 months
of VKA
Treatment period of 6 or 12 months
~53%
N=1,197
Rivaroxaban 20 mg od
R
Day 1
~47%
Placebo
30-day observational period
Randomized, double-blind, placebo-controlled,
event-driven (n=30), superiority study
EINSTEIN Investigators, NEJM 2011
EINSTEIN-DVT - Rivaroxaban for acute DVT
Continued treatment
EINSTEIN Investigators, N Engl J Med 2010
EINSTEIN-DVT - Rivaroxaban for acute DVT
Continued treatment
no major bleeds
4 major bleeds
EINSTEIN Investigators, N Engl J Med 2010
AMPLIFY - Extended
Agnelli, NEJM 2012
AMPLIFY - Extended
Agnelli, NEJM 2012
RESONATE
RESONATE
Time to first VTE or VTE-related
death
Risk of first onset of any bleeding
Major bleeding
3
HR 0.52 (95% CI: 0.27–1.02)
Percentage
2,5
p = 0.058
2
1,5
48%
RRR
1.8%
1
0.9%
0,5
0
Dabigatran 150 mg bid
13/1430
RRR, relative risk reduction.
On treatment
Warfarin
25/1426
VKA in cancer patients
Prandoni, Blood 2002
VKA in cancer patients
Prandoni, Blood 2002
CLOT (Lee, NEJM 2003)
Major bleeding:
Dalteparin
19/338 (6%)
VKA
12/335 (4%)
p = 0.3
VTE and cancer  ACCP 2012
• LMWH over VKA (2B)
• VKA over NOACs (2C)
• Dalteparin
– once daily 200 IU/kg body weight s.c.
– dose reduction to 75 - 85% of therapeutic dose
after 4 weeks
EINSTEIN DVT and EINSTEIN PE pooled
analysis: outcomes in patients with cancer
Outcome
Rivaroxaban
Enoxaparin/VKA
HR
(95% CI)
n/N
%
n/N
%
6/232
2.6
8/198
4.0
0.62
(0.22–1.80)
80/3918
2.0
87/3933
2.2
0.91
(0.67–1.24)
6/232
2.6
8/196
4.1
0.61
(0.21–1.77)
34/3898
0.9
64/3920
1.6
0.53
(0.35–0.80)
Recurrent VTE
Cancer
No cancer
Major bleeding
Cancer
No cancer
Dabigatran in VTE cancer patients
RE-COVER
D
W
Advantages of NOACs in cancer patients with VTE
• oral route  better quality of life/adherence
• short half-life  better flexibility
• at least as effective and safe as VKA
Caveats für using NOACs in cancer patients with VTE
•
•
•
•
Small patient numbers in clinical trials
Generalizability of trial data (low-risk pts)
Oral route in pts with nausea, vomiting and diarrhea
Interaction with chemotherapy
• No on-going trials, neither with LMWH nor with NOACs
NOACs for treatment of VTE
Summary
•
•
•
•
•
as effective as LMWH/VKA
less (major) bleeding
single drug approach (rivaroxaban, apixaban)
effective in VTE long-term prevention (up to 1 year)
suitable for selected cancer patients