Neue Konzepte der Therapie venöser Thromboembolien
Paul KyrleUniv. Klinik f. Innere Medizin I
AKH/Medizinische Universität Wien
Therapie der VTE – verschiedene Möglichkeiten
Thrombolyse- hämodynamisch instabile PE, 4-Etagen tVT (?)
UFH- Niereninsuffizienz, hohes Blutungsrisiko
- Cave: HIT II (~ 2 %)
Fondaparinux NMH
Therapie der VTE mit NMH/VKA
gewichtsadaptiert („therapeutische Dosis“) 1 x oder 2 x tgl. s.c. mindestens 5 Tage bis INR mindestens 24 Stunden > 2
VKA ab Tag 1, mindestens 3 Monate (INR 2-3)
Treatment of VTE: past, present and future
Heparin Vitamin K antagonists
Heparin Dabigatran/Edoxaban
Rivaroxaban/Apixaban
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
Idraparinux vs. Heparin/VKA – van Gogh-PE
The van Gogh Investigators. N Engl J Med 2007;357:1094-1104
E R
Initial parenteraltherapy
Single-dummyperiod
Double-dummy period
6 monthsEnd of treatment
Until INR 2.0
Warfarin Warfarin(INR 2.0–3.0)
Dabigatran placebo
Warfarin placebo
DabigatranWarfarinplacebo
E= enrolmentR= randomization
LMWH/Dabigatran vs. LMWH/VKA for acute VTE
Schulman, N Engl J Med 2009
RE-COVER
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
EINSTEIN: Rivaroxaban for acute VTE
15 mg bid
Objectively confirmed
DVT without symptomatic
PEN=~2,900
Rivaroxaban
Day 1 Day 21
Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by
VKA to start ≤48 hours, target INR 2.5 (INR range 2–3)
Objectively confirmed PE
with or without symptomatic
DVT
EINSTEIN DVT/PETreatment period of 3, 6 or 12 months
20 mg od
N=~3,300
30
-da
y o
bs
erv
ati
on
p
eri
od
Rivaroxaban
R
Randomized, open-label, event-driven, non-inferiority study
EINSTEIN-DVT - Rivaroxaban for acute DVT
EINSTEIN Investigators, N Engl J Med 2010
Recurrent VTE and related death
HR=0.68 (95% CI: 0.44–1.04)
p<0.001 for non-inferiority
p=0.08 for superiority
Clinically significant bleeding
EINSTEIN-DVT - Rivaroxaban for acute DVT
EINSTEIN Investigators, N Engl J Med 2010
EINSTEIN-PE
Büller et a., NEJM 2012
EINSTEIN-PE
Büller et a., NEJM 2012
EINSTEIN-PE
Büller et a., NEJM 2012
Treatment of VTE
acute subacute extended
up to 2 weeks up to 3 - 6 months > 6 months
NOACS as safe and effective
NOACS as effective, but safer
Transient risk factors
Annualized event rate/pt-year (95% CI)
Any transient RF 3.3% (2.8 – 3.9)
Surgery 0.7% (0 – 1.5)
Nonsurgical RF 4.2% (2.8 – 5.6)
Iorio, Arch Intern Med 2012 (systematic review of 15 studies)
Risk of recurrence after unprovoked VTE
Kyrle, Rosendaal & Eichinger, Lancet 2010
Years after Discontinuation of Anticoagulation
Cum
ula
tive
Pro
babi
lity
of R
ecur
renc
e (%
) p < 0,001distal DVT
proximal DVT
symptomatic PE +/- DVT
RR (95% CI): distal 1 proximal 2,5 (1,6 – 3,9) PE 2,4 (1,5 – 3,7)
n = 151
n = 347
n = 333
Rezidivrisiko der VTE
Antikoagulation
- VKA
- NOAK Aspirin Therapie nach Risikostratifitierung
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
RE-MEDY™ study design
S, screening; R, randomization.
*Original protocol, 3–6 months of pre-treatment, then 18 months on study drug; amendment allowed 3–12 months of pre-treatment, then up to 36 months on study drug.
ConfirmedVTE
Anticoagulant
therapy
3–12 months*
S R
0–7 days until
INR ≤2.3
Screening/baseline
Dabigatran etexilate 150 mg bid
Warfarin placebo
Warfarin (INR 2.0–3.0)
Dabigatran placebo
Up to 36 months*End of treatment
Follow up 30 daysTreatment period
and “increasedrisk of
recurrence”
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.
RESONATE
RESONATE
Rezidivrisiko der VTE
Antikoagulation
- VKA
- NOAK Aspirin Therapie nach Risikostratifitierung
WARFASA
WARFASA
ASPIRE
ASPIRE
ASPIRE
WARFASA + ASPIRE
Rezidivrisiko der VTE
Antikoagulation
- VKA
- NOAK Aspirin Therapie nach Risikostratifitierung
Prediction rules for recurrent VTE
• Men continue and HER DOO2 • Vienna Prediction Model
• DASH Score
• Ottawa Score (cancer patients only)
Preselection of risk factors
• 929 patients with first unprovoked VTE
• impact on the recurrence risk independently confirmed
• simple assessment, reproducibility• clinical variables: age at venous thrombosis, sex,
location, BMI• laboratory variables: FV Leiden, prothrombin
mutation, D-Dimer
Eichinger, Circulation 2010
Vienna Prediction Model
RFs after forward selection
• sex• location (distal vs. proximal vs. PE)• D-Dimer 3 weeks after cessation of
anticoagulation
Eichinger, Circulation 2010
Vienna Prediction Model
http:/www.meduniwien.ac.at/user/georg.heinze/zipfile/
Circulation 2010;121:1630-1636 data supplement (free access)
Risk calculator
Vienna Prediction Model
Nomogram to predict recurrence: Vienna Prediction Model
Externe Validierung des VPM
Marcucci et al., ISTH 2013 Multizenterstudie Österreich (first patient in:
Jänner 2013)