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Veröffentlicht von:Xaver Kessel Geändert vor über 10 Jahren
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Neue Konzepte der Therapie venöser Thromboembolien
Paul Kyrle Univ. Klinik f. Innere Medizin I AKH/Medizinische Universität Wien
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Therapie der VTE – verschiedene Möglichkeiten
Thrombolyse hämodynamisch instabile PE, 4-Etagen tVT (?) UFH Niereninsuffizienz, hohes Blutungsrisiko Cave: HIT II (~ 2 %) Fondaparinux NMH 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. 2
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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) 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. 3
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Treatment of VTE: past, present and future
Heparin Vitamin K antagonists Heparin Dabigatran/Edoxaban Rivaroxaban/Apixaban 4
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Treatment of VTE: past, present and future
Heparin Vitamin K antagonists Heparin Dabigatran/Edoxaban Rivaroxaban/Apixaban 5
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Treatment of VTE up to 2 weeks up to 3 - 6 months > 6 months acute
subacute extended 6
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Idraparinux vs. Heparin/VKA – van Gogh-PE
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). The van Gogh Investigators. N Engl J Med 2007;357: 7
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LMWH/Dabigatran vs. LMWH/VKA for acute VTE
RE-COVER LMWH/Dabigatran vs. LMWH/VKA for acute VTE Single-dummy period Double-dummy period Warfarin placebo Dabigatran Warfarin placebo Dabigatran placebo Warfarin Warfarin (INR 2.0–3.0) Initial parenteral therapy E R Until INR 2.0 6 months End of treatment E= enrolment R= randomization Schulman, N Engl J Med 2009
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Recurrent VTE and related death
RE-COVER - Dabigatran for acute/subacute VTE Recurrent VTE and related death Non-inferiority p<0.001 Schulman, N Engl J Med 2009
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Bleeding RE-COVER - Dabigatran for acute/subacute VTE
Schulman, N Engl J Med 2009 Schulman, N Engl J Med 2009
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EINSTEIN: Rivaroxaban for acute VTE
Randomized, open-label, event-driven, non-inferiority study EINSTEIN DVT/PE Treatment period of 3, 6 or 12 months Objectively confirmed DVT without symptomatic PE Rivaroxaban Rivaroxaban N=~2,900 15 mg bid 20 mg od References EINSTEIN DVT, PE, Extension Evaluation Study Information available at: 30-day observation period R Objectively confirmed PE with or without symptomatic DVT 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) N=~3,300 Day 1 Day 21 13 13
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Recurrent VTE and related death
EINSTEIN-DVT - Rivaroxaban for acute DVT 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 EINSTEIN Investigators, N Engl J Med 2010
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Clinically significant bleeding
EINSTEIN-DVT - Rivaroxaban for acute DVT Clinically significant bleeding EINSTEIN Investigators, N Engl J Med 2010
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EINSTEIN-PE Büller et a., NEJM 2012
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EINSTEIN-PE Büller et a., NEJM 2012
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EINSTEIN-PE Büller et a., NEJM 2012
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Xarelto: Zulassung bei Venenthrombose
Neue Antikoagulantien Xarelto: Zulassung bei Venenthrombose Behandlung von tiefen Venenthrombosen sowie VTE-Prophylaxe nach akuter tiefer Venenthrombose Dosierung: 2 x 15 mg tgl. für 3 Wochen, danach 1 x 20 mg tgl. 20
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NOACS as effective, but safer
Treatment of VTE up to 2 weeks up to months > 6 months acute subacute extended NOACS as safe and effective NOACS as effective, but safer 21
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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)
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Kyrle, Rosendaal & Eichinger, Lancet 2010
Risk of recurrence after unprovoked VTE Kyrle, Rosendaal & Eichinger, Lancet 2010
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Cumulative Probability of Recurrence (%)
distal DVT p < 0,001 proximal DVT RR (95% CI): distal proximal 2,5 (1,6 – 3,9) PE ,4 (1,5 – 3,7) symptomatic PE +/- DVT Cumulative Probability of Recurrence (%) n = 347 n = 333 n = 151 Years after Discontinuation of Anticoagulation
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Rezidivrisiko der VTE Antikoagulation VKA NOAK Aspirin
Therapie nach Risikostratifitierung 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. 25
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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 Rivaroxaban 20 mg od Placebo Day 1 R N=1,197 Treatment period of 6 or 12 months 30-day observational period 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 EINSTEIN Investigators, NEJM 2011
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EINSTEIN Investigators, N Engl J Med 2010
EINSTEIN-DVT - Rivaroxaban for acute DVT Continued treatment EINSTEIN Investigators, N Engl J Med 2010
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EINSTEIN Investigators, N Engl J Med 2010
EINSTEIN-DVT - Rivaroxaban for acute DVT Continued treatment 4 major bleeds no major bleeds EINSTEIN Investigators, N Engl J Med 2010
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AMPLIFY - Extended Agnelli, NEJM 2012
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AMPLIFY - Extended Agnelli, NEJM 2012
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Anticoagulant therapy 3–12 months*
RE-MEDY™ study design 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” *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. S, screening; R, randomization. 33
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Time to first VTE or VTE-related death
eingefügt 34
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Risk of first onset of any bleeding
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Major bleeding On treatment HR 0.52 (95% CI: 0.27–1.02) Percentage
48% RRR 1.8% 0.9% 13/1430 25/1426 On treatment RRR, relative risk reduction.
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REMEDY
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REMEDY
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RESONATE
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RESONATE
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Therapie nach Risikostratifitierung
Rezidivrisiko der VTE Antikoagulation VKA NOAK Aspirin Therapie nach Risikostratifitierung 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. 41
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WARFASA
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WARFASA
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ASPIRE
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ASPIRE
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ASPIRE
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WARFASA + ASPIRE
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Rezidivrisiko der VTE Antikoagulation VKA NOAK Aspirin
Therapie nach Risikostratifitierung 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. 50
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Prediction rules for recurrent VTE
Men continue and HER DOO2 Vienna Prediction Model DASH Score Ottawa Score (cancer patients only) The NPV is about 92%. This means that these markers are probably well suited to identifying patients with a low recurrence risk. 51
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Preselection of risk factors
Vienna Prediction Model 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
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RFs after forward selection
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
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Vienna Prediction Model
Risk calculator Circulation 2010;121: data supplement (free access)
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Nomogram to predict recurrence: Vienna Prediction Model
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
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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
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Externe Validierung des VPM
Marcucci et al., ISTH 2013 Multizenterstudie Österreich (first patient in: Jänner 2013) 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. 57
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