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Phase III studies of direct oral
anticoagulants for treatment and
prevention of VTE
Dabigatran, apixaban, edoxaban and
rivaroxaban


Phase III VTE acute treatment studies
Trial name

Design

Initial treatment
with heparin/
fondaparinux

Treatment
duration
(months)

Long-term
treatment
regimen

Active
comparator

EINSTEIN DVT

Open label

No

3, 6 or 12

od

Enoxaparin/VKA

EINSTEIN PE

Open label

No

3, 6 or 12

od

Enoxaparin/VKA

RE-COVER

Double blind

Yes

6

bid

UFH/LMWH/warfarin

RE-COVER II

Double blind

Yes

6

bid

UFH/LMWH/warfarin

Double blind

No

6

bid

Enoxaparin/warfarin

Double blind

Yes

3–12

od

UFH/LMWH/warfarin

Rivaroxaban

Dabigatran

Apixaban
AMPLIFY
Edoxaban

Hokusai-VTE

All studies had identical outcomes definitions and used the same independent adjudication committee


Treatment of acute VTE:
RE-COVER and RE-COVER II – study design
Predefined treatment period of 6 months
Symptomatic
VTE
RE-COVER

Dabigatran 150 mg bid
N=2564

R
Symptomatic
VTE

RE-COVER II

UFH/LMWH
VKA target INR 2.5 (range 2.0–3.0)

N=2568

Day 1

•

“Unselected” patient population

•

Dabigatran: thrombin inhibitor

Day 6


Treatment of acute VTE:
AMPLIFY – study design
Treatment period of 6 months
Apixaban
10 mg bid for 7 days,
then 5 mg bid for 6 months

Symptomatic
mainly
unprovoked DVT

or PE

R
N=5395

Standard therapy
Enoxaparin 1 mg/kg bid warfarin (INR 2.0–3.0)

•

Low bleeding risk population

•

Apixaban: Xa inhibitor

Agnelli G et al, N Engl J Med 2013


Treatment of acute VTE:
Hokusai-VTE – study design
Maximum treatment period of 12 months
Edoxaban
LMWH/UFH (at least 5 days) followed by
edoxaban 60 mg* od

Symptomatic
DVT and/or PE

R

N=8292

Standard care
LMWH/UFH (at least 5 days) and
warfarin (INR 2.0–3.0)

•

“Unselected” patient population

•

Edoxaban: Xa inhibitor

*30 mg od in patients with CrCl 30–50 ml/min, body weight ≤60 kg or receiving potent P-glycoprotein
inhibitors
The Hokusai-VTE Investigators, N Engl J Med 2013


Treatment of acute VTE:
EINSTEIN DVT/PE – study design
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
Day 1

Day 21
Rivaroxaban

Rivaroxaban

15 mg bid

20 mg od

N=8282

R
PE with or
without DVT
N=4833

Enoxaparin bid for at least 5 days +
VKA, INR 2.0–3.0

“Unselected” patient population
 Rivaroxaban: Xa inhibitor


1.

N Engl J Med 2010;363:2499 2. N Engl J Med 2012;366:1287–97

30-day post-study
treatment period

DVT without
PE1
N=3449

Treatment of acute VTE: RE-COVER 1 & 2
– efficacy and safety outcomes
Heparin/dabigatran
Events

N=2553
n (%)

Heparin/warfarin
N=2554

Pooled HR
(95% CI)

n (%)

Recurrent VTE
1.09 (0.76-1.57)
60 (2.4)

55 (2.2)

37 (1.4)

51 2.0

p<0.001
(non-inferiority)

Major Bleeding

Schulman S et al, N Engl J Med 2009

0.73 (0.48-1.11)


Treatment of acute VTE: AMPLIFY
– efficacy and safety outcomes
Events

Apixaban
N=2691
n (%)

Standard therapy
N=2704
n (%)

HR
(95% CI)

Recurrent VTE

59 (2.3)

71 (2.7)

0.84 (0.60–1.18)
p<0.001

(non-inferiority)

Major bleeding

15 (0.6)

49 (1.8)

0.31 (0.17–0.55)
p<0.001

Agnelli et al, 2013


Treatment of acute VTE: Hokusai-VTE
– efficacy and safety outcomes
Events

Heparin/edoxaban
(N=4118)
n (%)

Heparin/warfarin
(N=4122)
n (%)

Recurrent VTE
At end of study
period*

HR
(95% CI)
p<0.001
(non-inferiority)

130 (3.2)

146 (3.5)

0.89 (0.70–1.13)

On treatment

66 (1.6)

80 (1.9)

0.82 (0.60–1.14)

Major bleeding

56 (1.4)

66 (1.6)

0.84 (0.59–1.21)
p=0.35

*12 months after the start of treatment regardless of treatment duration
The Hokusai-VTE Investigators, N Engl J Med 2013

Treatment of acute VTE: EINSTEIN DVT/PE
– efficacy and safety outcomes
Events

Rivaroxaban
(N=4150)
n (%)

Standard therapy
(N=4131)
n (%)

HR
(95% CI)

Recurrent VTE

86 (2.1)

95 (2.3)

0.89 (0.66–1.19)
p<0.001
(non-inferiority)

Major bleeding

405 (1.0)

72 (1.7)

0.54 (0.37–0.79)
p<0.002

Agnelli et al, 2013


EINSTEIN DVT/PE:
types of major bleeding
Outcome

Major bleeding*
Fatal
Retroperitoneal
Intracranial
Gastrointestinal/thorax
In a critical site
Retroperitoneal
Intracranial
Pericardial
Other
Fall in hemoglobin ≥2 g/dl
and/or transfusions ≥2 units
Gastrointestinal

*Some patients had >1 event

Rivaroxaban

(N=4130)

Enoxaparin/VKA
(N=4116)

n

%

n

%

40

1.0

72

1.7

HR (95% CI)
p-value
0.54 (0.37–0.79)
p=0.002


EINSTEIN DVT/PE:
types of major bleeding
Outcome

Rivaroxaban
(N=4130)

Enoxaparin/VKA
(N=4116)

n

%

n

%

Major bleeding*

40

1.0

72

1.7

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

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

27

0.7

37

0.9

15

0.4

26

0.6

In a critical site

Fall in hemoglobin ≥2 g/dl
and/or transfusions ≥2 units
Gastrointestinal

*Some patients had >1 event

HR (95% CI)
p-value
0.54 (0.37–0.79)
p=0.002


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
Not serious but
19 (42.2%)
requires measures
to control

34 (43.0%)

Category 3
Serious

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:
Prohemostatic measures
Rivaroxaban n=45 Enox/VKA n=79
Vitamin K

1

30

FFP

4

11

Prothrombin 2
complex

9

rFVIIa

0

1

EINSTEIN DVT/PE:
outcomes in fragile patients*
Outcome

Rivaroxaban

Enoxaparin/VKA

HR (95% CI)

n/N

%

n/N

%

Fragile

21/791

2.7

30/782

3.8

0.68 (0.39–1.18)

Non-fragile

65/3359

1.9

65/3349

1.9

0.98 (0.70–1.38)

Fragile

10/788

1.3

35/779

4.5

0.27 (0.13–0.54)

Non-fragile

30/3342

0.9

37/3337

1.1

0.80 (0.49–1.29)

Recurrent VTE

Major bleeding

*Age >75 years, CrCl <50 ml/min, or body weight ≤50 kg


EINSTEIN DVT/PE:
Clot size and recurrent VTE
Rivaroxaban

Enoxaparin/VKA

n/N

%

n/N

%

11/814

1.4

19/826

2.3

Intermediate

47/1941

2.4

50/1942

2.6

Extensive

28/1218

2.3

25/1190

2.1

Limited
≤25% of a single lobe,
popliteal vein only

multiple lobes and >25% of
entire pulmonary vasculature;
involving common femoral/
iliac vein


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


EINSTEIN DVT/PE:
Outcomes in cancer patients
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)

58/354 (16.4)

53/301 (17.6)

0.93 (0.64–1.35)

Mortality, n (%)

*At baseline or diagnosed during the study


Overall summary: acute treatment studies
• All DOACs non-inferior to standard therapy
– important reductions in major bleeding with apixaban and
rivaroxaban single drug treatment
– No reduction in major bleeding for dabigatran and edoxaban dual
drug treatment

• Major bleeding is less severe with DOACs
– less fatal bleeds
– less critical organ bleeds (intracranial, retroperitoneal)

– presentation and course of major bleeding less severe with DOACs

• Results are consistent for subgroups