Neue Antikoagulantien bei spontaner

und Tumor-assoziierter VTE

Paul KyrleUniv. 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

acute subacute extended

up to 2 weeks up to 3 - 6 months > 6 months

Schulman, N Engl J Med 2009

Recurrent VTE and related death

RE-COVER - Dabigatran for acute/subacute VTE

Non-inferiority p<0.001

RE-COVER - Dabigatran for acute/subacute VTE

Schulman, N Engl J Med 2009

Bleeding

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

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

15 mg bid

Confirmed DVT without symptomatic

PE1

N=3449 N=8282Rivaroxaban

Day 1 Day 21

Enoxaparin bid for at least 5 days +

VKA, INR 2.0–3.0

Confirmed PE with or

without symptomatic

DVT2

N=4833

Predefined treatment period of 3, 6, or 12 months

20 mg od

30

-da

y p

os

t-s

tud

y

tre

atm

en

t p

eri

odRivaroxaban

R

Rivaroxaban(N=4150)

Enoxaparin/VKA(N=4131)

Males, % 55 54Age, mean, years ± SD 57±17 57±17Weight, n (%)

≤50 kg 75 (1.8) 92 (2.2)>50–100 kg 3477 (84) 3432 (83)≥100 kg 590 (14) 605 (15)

Creatinine clearance, ml/min (%)<30 10 (0.2) 11 (0.3)30–49 322 (8) 311 (8)50–79 1030 (25) 992 (24)≥80 2748 (66) 2787 (67)

Index VTE, n (%)DVT 1699 (41) 1690 (41)PE 1793 (43) 1804 (44)DVT and PE 615 (15) 597 (15)

Unprovoked VTE, n (%) 2003 (48) 2048 (50)Previous VTE, n (%) 791 (19) 819 (20)Active cancer, n (%) 232 (6) 198 (5)

EINSTEIN DVT and EINSTEIN PE pooled analysis: patient characteristics

ITT population

EINSTEIN DVT and EINSTEIN PE pooled analysis: 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

RivaroxabanN=4150

Enoxaparin/VKAN=4131

0 30 60 90 120 150 180 210 240 270 300 330 360

Time to event (days)

Cu

mu

lati

ve e

ven

t ra

te (

%)

HR=0.89; p non-inferiority <0.0001

Mean time in therapeutic range = 61.7%

ITT population

EINSTEIN DVT and EINSTEIN PE pooled analysis: principal safety outcome

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

Cu

mu

lati

ve e

ven

t ra

te (

%)

RivaroxabanN=4130

Enoxaparin/VKAN=4116

0 30 60 90 120 150 180 210 240 270 300 330 360

14

10

12

8

6

4

2

0

Time to event (days)

First major or clinically relevant non-major bleeding

Rivaroxabann/N (%)

Enoxaparin/VKAn/N (%)

HR (95% CI)p-value

388/4130 (9.4)

412/4116(10.0)

0.93 (0.81–1.06) p=0.27

Safety population

EINSTEIN DVT and EINSTEIN PE pooled analysis: 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

RivaroxabanN=4130

Enoxaparin/VKAN=4116

0 30 60 90 120 150 180 210 240 270 300 330 360

Time to event (days)

Cu

mu

lati

ve e

ven

t ra

te (

%)

First major bleeding

Rivaroxabann/N (%)

Enoxaparin/VKAn/N (%)

HR (95% CI)p-value

40/4130 (1.0)

72/4116(1.7)

0.54 (0.37–0.79) p=0.002

Safety population

Treatment of VTE - conclusion

acute subacute extended

up to 2 weeks up to 3 - 6 months > 6 months

NOACS as safe and effective

NOACS as effective, but safer

Risk of recurrence after unprovoked VTE

Kyrle, Rosendaal & Eichinger, Lancet 2010

Confirmed symptomatic DVT or PE completing 6 or 12 months of

rivaroxaban or VKA in EINSTEIN VTE

program

Rivaroxaban 20 mg od

PlaceboDay 1

R

N=1,197

Treatment period of 6 or 12 months

30-d

ay o

bse

rvat

ion

al p

erio

d

Confirmed symptomatic DVT or PE completing

6 or 12 months of VKA

~53%

~47%

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

EINSTEINext - Rivaroxaban for extended thromboprophylaxis after VTE

Study design

EINSTEIN Investigators, NEJM 2011

Continued treatment

EINSTEIN-DVT - Rivaroxaban for acute DVT

EINSTEIN Investigators, N Engl J Med 2010

Continued treatment

EINSTEIN-DVT - Rivaroxaban for acute DVT

EINSTEIN Investigators, N Engl J Med 2010

4 major bleeds

no major bleeds

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

0

0,5

1

1,5

2

2,5

3

Dabigatran 150 mg bid Warfarin13/1430

Major bleeding

0.9%

1.8%

HR 0.52 (95% CI: 0.27–1.02)

25/1426

Per

cen

tag

e

p = 0.058

On treatment

48% RRR

RRR, relative risk reduction.

VKA in cancer patients

Prandoni, Blood 2002

Prandoni, Blood 2002

VKA in cancer patients

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/VKAHR

(95% CI)n/N % n/N %

Recurrent VTE

Cancer 6/232 2.6 8/198 4.00.62

(0.22–1.80)

No cancer 80/3918 2.0 87/3933 2.2 0.91(0.67–1.24)

Major bleeding

Cancer 6/232 2.6 8/196 4.1 0.61(0.21–1.77)

No cancer 34/3898 0.9 64/3920 1.60.53

(0.35–0.80)

RE-COVER

Dabigatran in VTE cancer patients

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

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

NOACs for treatment of VTE