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 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

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

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

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

Treatment of VTE up to 2 weeks up to 3 - 6 months > 6 months acute subacute extended 6

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;357:1094-1104 7

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

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

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

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: http://clinicaltrials.gov 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

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

Clinically significant bleeding EINSTEIN-DVT - Rivaroxaban for acute DVT Clinically significant bleeding 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

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

NOACS as effective, but safer Treatment of VTE up to 2 weeks up to 3 - 6 months > 6 months acute subacute extended NOACS as safe and effective NOACS as effective, but safer 21

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)

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

Cumulative Probability of Recurrence (%) distal DVT p < 0,001 proximal DVT RR (95% CI): distal 1 proximal 2,5 (1,6 – 3,9) PE 2,4 (1,5 – 3,7) symptomatic PE +/- DVT Cumulative Probability of Recurrence (%) n = 347 n = 333 n = 151 Years after Discontinuation of Anticoagulation

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

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

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

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

AMPLIFY - Extended Agnelli, NEJM 2012

AMPLIFY - Extended Agnelli, NEJM 2012

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

Time to first VTE or VTE-related death eingefügt 34

Risk of first onset of any bleeding

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.

REMEDY

REMEDY

RESONATE

RESONATE

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

WARFASA

WARFASA

ASPIRE

ASPIRE

ASPIRE

WARFASA + ASPIRE

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

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

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

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

Vienna Prediction Model Risk calculator http:/www.meduniwien.ac.at/user/georg.heinze/zipfile/ Circulation 2010;121:1630-1636  data supplement (free access)

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

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) 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