Neue Konzepte der Therapie venöser Thromboembolien...Neue Konzepte der Therapie venöser...
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Neue Konzepte der Therapie venöser Thromboembolien Paul Kyrle Univ. Klinik f. Innere Medizin I AKH/Medizinische Universität Wien
Transcript of Neue Konzepte der Therapie venöser Thromboembolien...Neue Konzepte der Therapie venöser...
Neue Konzepte der Therapie venöser Thromboembolien
Paul Kyrle
Univ. 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
Vorführender
Präsentationsnotizen
There are 2 important consequences of recurrent venous thromboembolism. One complication is the development of the post-thrombotic syndrome, or worsening of an preexisting PTS if venous thrombosis occurs in the same leg. The PTS is often associated with serious consequences for patient, such as life-style alterations, loss of work or frequent hospitalizations. It also results in a considerable increase in health costs. Much more important, 5 to 10 percent of the patients with recurrent thrombosis die from pulmonary embolism. Therfore, prevention of recurrent VTE is of utmost clinical importance.
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)
Vorführender
Präsentationsnotizen
There are 2 important consequences of recurrent venous thromboembolism. One complication is the development of the post-thrombotic syndrome, or worsening of an preexisting PTS if venous thrombosis occurs in the same leg. The PTS is often associated with serious consequences for patient, such as life-style alterations, loss of work or frequent hospitalizations. It also results in a considerable increase in health costs. Much more important, 5 to 10 percent of the patients with recurrent thrombosis die from pulmonary embolism. Therfore, prevention of recurrent VTE is of utmost clinical importance.
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
Vorführender
Präsentationsnotizen
Figure 1. Cumulative Incidence of Venous Thromboembolic Events. The graphs show comparisons between the idraparinux group and the standard-therapy group for patients with deep-vein thrombosis (the DVT Study, Panel A) and those with pulmonary embolism (the PE Study, Panel B).
E R
Initial parenteral therapy
Single-dummy period
Double-dummy period
6 months End of treatment
Until INR ≥ 2.0
Warfarin Warfarin (INR 2.0–3.0)
Dabigatran placebo
Warfarin placebo
Dabigatran Warfarin placebo
E= enrolment R= 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
Vorführender
Präsentationsnotizen
Schulman, N Engl J Med 2009
EINSTEIN: Rivaroxaban for acute VTE
15 mg bid
Objectively confirmed DVT
without symptomatic
PE N=~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/PE Treatment period of 3, 6 or 12 months
20 mg od
N=~3,300
30-d
ay o
bser
vatio
n
pe
riod
Rivaroxaban
R
Randomized, open-label, event-driven, non-inferiority study
Vorführender
Präsentationsnotizen
References EINSTEIN DVT, PE, Extension Evaluation Study Information�available at: http://clinicaltrials.gov
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
ulat
ive
Pro
babi
lity
of R
ecur
renc
e (%
) p < 0,001 distal 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
Vorführender
Präsentationsnotizen
There are 2 important consequences of recurrent venous thromboembolism. One complication is the development of the post-thrombotic syndrome, or worsening of an preexisting PTS if venous thrombosis occurs in the same leg. The PTS is often associated with serious consequences for patient, such as life-style alterations, loss of work or frequent hospitalizations. It also results in a considerable increase in health costs. Much more important, 5 to 10 percent of the patients with recurrent thrombosis die from pulmonary embolism. Therfore, prevention of recurrent VTE is of utmost clinical importance.
Confirmed symptomatic DVT or PE completing 6 or 12 months of
rivaroxaban or VKA in EINSTEIN VTE
program
Rivaroxaban 20 mg od
Placebo Day 1
R
N=1,197
Treatment period of 6 or 12 months
30-d
ay o
bser
vatio
nal 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.
Confirmed VTE
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 days Treatment period
and “increased risk of
recurrence”
Time to first VTE or VTE-related death
Vorführender
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eingefügt
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
Perc
enta
ge
p = 0.058
On treatment
48% RRR
RRR, relative risk reduction.
RESONATE
RESONATE
Rezidivrisiko der VTE
Antikoagulation - VKA - NOAK
Aspirin Therapie nach Risikostratifitierung
Vorführender
Präsentationsnotizen
There are 2 important consequences of recurrent venous thromboembolism. One complication is the development of the post-thrombotic syndrome, or worsening of an preexisting PTS if venous thrombosis occurs in the same leg. The PTS is often associated with serious consequences for patient, such as life-style alterations, loss of work or frequent hospitalizations. It also results in a considerable increase in health costs. Much more important, 5 to 10 percent of the patients with recurrent thrombosis die from pulmonary embolism. Therfore, prevention of recurrent VTE is of utmost clinical importance.
WARFASA
WARFASA
ASPIRE
ASPIRE
ASPIRE
WARFASA + ASPIRE
Rezidivrisiko der VTE
Antikoagulation - VKA - NOAK
Aspirin Therapie nach Risikostratifitierung
Vorführender
Präsentationsnotizen
There are 2 important consequences of recurrent venous thromboembolism. One complication is the development of the post-thrombotic syndrome, or worsening of an preexisting PTS if venous thrombosis occurs in the same leg. The PTS is often associated with serious consequences for patient, such as life-style alterations, loss of work or frequent hospitalizations. It also results in a considerable increase in health costs. Much more important, 5 to 10 percent of the patients with recurrent thrombosis die from pulmonary embolism. Therfore, prevention of recurrent VTE is of utmost clinical importance.
Prediction rules for recurrent VTE
• Men continue and HER DOO2 • Vienna Prediction Model
• DASH Score
• Ottawa Score (cancer patients only)
Vorführender
Präsentationsnotizen
The NPV is about 92%. This means that these markers are probably well suited to identifying patients with a low recurrence risk.
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
Vorführender
Präsentationsnotizen
We developed nomograms that can be used to calculate risk scores and to estimate the probability of recurrence after 1 and 5 years Abbreviations DVT, deep vein thrombosis; PE, pulmonary embolism References 1. Eichinger et al. Circulation 2010;13;121(14):1630-6
Vorführender
Präsentationsnotizen
We developed nomograms that can be used to calculate risk scores and to estimate the probability of recurrence after 1 and 5 years Abbreviations DVT, deep vein thrombosis; PE, pulmonary embolism References 1. Eichinger et al. Circulation 2010;13;121(14):1630-6
Externe Validierung des VPM
Marcucci et al., ISTH 2013 Multizenterstudie Österreich (first patient in: Jänner
2013)
Vorführender
Präsentationsnotizen
There are 2 important consequences of recurrent venous thromboembolism. One complication is the development of the post-thrombotic syndrome, or worsening of an preexisting PTS if venous thrombosis occurs in the same leg. The PTS is often associated with serious consequences for patient, such as life-style alterations, loss of work or frequent hospitalizations. It also results in a considerable increase in health costs. Much more important, 5 to 10 percent of the patients with recurrent thrombosis die from pulmonary embolism. Therfore, prevention of recurrent VTE is of utmost clinical importance.
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