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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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Präsentation zum Thema: "Neue Konzepte der Therapie venöser Thromboembolien Paul Kyrle Univ. Klinik f. Innere Medizin I AKH/Medizinische Universität Wien."—  Präsentation transkript:

1 Neue Konzepte der Therapie venöser Thromboembolien Paul Kyrle Univ. Klinik f. Innere Medizin I AKH/Medizinische Universität Wien

2 Therapie der VTE – verschiedene Möglichkeiten Thrombolyse - hämodynamisch instabile PE, 4-Etagen tVT (?) UFH - Niereninsuffizienz, hohes Blutungsrisiko - Cave: HIT II (~ 2 %) Fondaparinux NMH

3 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)

4 Treatment of VTE: past, present and future Heparin Vitamin K antagonists Heparin Dabigatran/Edoxaban Rivaroxaban/Apixaban

5 Treatment of VTE: past, present and future Heparin Vitamin K antagonists Heparin Dabigatran/Edoxaban Rivaroxaban/Apixaban

6 Treatment of VTE acutesubacuteextended up to 2 weeks up to months> 6 months

7 Idraparinux vs. Heparin/VKA – van Gogh-PE The van Gogh Investigators. N Engl J Med 2007;357:

8

9 ER Initial parenteral therapy Single- dummy period Double-dummy period 6 months End of treatment Until INR 2.0 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

10 Schulman, N Engl J Med 2009 Recurrent VTE and related death RE-COVER - Dabigatran for acute/subacute VTE Non-inferiority p<0.001

11 RE-COVER - Dabigatran for acute/subacute VTE Schulman, N Engl J Med 2009 Bleeding

12

13 EINSTEIN: Rivaroxaban for acute VTE 15 mg bid Objectively confirmed DVT without symptomatic PE N=~2,900 Rivaroxaban Day 1Day 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, day observation period Rivaroxaban R Randomized, open-label, event-driven, non-inferiority study

14 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

15 Clinically significant bleeding EINSTEIN-DVT - Rivaroxaban for acute DVT EINSTEIN Investigators, N Engl J Med 2010

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17 EINSTEIN-PE Büller et a., NEJM 2012

18 EINSTEIN-PE Büller et a., NEJM 2012

19 EINSTEIN-PE Büller et a., NEJM 2012

20 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. Xarelto: Zulassung bei Venenthrombose Neue Antikoagulantien

21 Treatment of VTE acutesubacuteextended up to 2 weeks up to months > 6 months NOACS as safe and effective NOACS as effective, but safer

22 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)

23 Risk of recurrence after unprovoked VTE Kyrle, Rosendaal & Eichinger, Lancet 2010

24 Years after Discontinuation of Anticoagulation Cumulative Probability of Recurrence (%) 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

25 Rezidivrisiko der VTE Antikoagulation - VKA - NOAK Aspirin Therapie nach Risikostratifitierung

26 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 EINSTEINext - Rivaroxaban for extended thromboprophylaxis after VTE Study design EINSTEIN Investigators, NEJM 2011

27 Continued treatment EINSTEIN-DVT - Rivaroxaban for acute DVT EINSTEIN Investigators, N Engl J Med 2010

28 Continued treatment EINSTEIN-DVT - Rivaroxaban for acute DVT EINSTEIN Investigators, N Engl J Med major bleeds no major bleeds

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30 AMPLIFY - Extended Agnelli, NEJM 2012

31 AMPLIFY - Extended Agnelli, NEJM 2012

32

33 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* SR 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

34 Time to first VTE or VTE-related death

35 Risk of first onset of any bleeding

36 13/1430 Major bleeding 0.9% 1.8% HR 0.52 (95% CI: 0.27–1.02) 25/1426 Percentage p = On treatment 48% RRR RRR, relative risk reduction.

37 REMEDY

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39 RESONATE

40

41 Rezidivrisiko der VTE Antikoagulation - VKA - NOAK Aspirin Therapie nach Risikostratifitierung

42

43 WARFASA

44

45

46 ASPIRE

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48

49 WARFASA + ASPIRE

50 Rezidivrisiko der VTE Antikoagulation - VKA - NOAK Aspirin Therapie nach Risikostratifitierung

51 Prediction rules for recurrent VTE Men continue and HER DOO2 Vienna Prediction Model DASH Score Ottawa Score (cancer patients only)

52 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

53 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

54 Circulation 2010;121: data supplement (free access) Risk calculator Vienna Prediction Model

55 Nomogram to predict recurrence: Vienna Prediction Model

56

57 Externe Validierung des VPM Marcucci et al., ISTH 2013 Multizenterstudie Österreich (first patient in: Jänner 2013)


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