Acute behandeling van longembolie. Peter Verhamme. Bloedings- en Vaatziekten UZ Leuven. Research support and/or honoraria:

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1 Acute behandeling van longembolie Peter Verhamme Bloedings- en Vaatziekten UZ Leuven Disclosures Research support and/or honoraria: Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Pfizer, BMS, Sanofi, Leo-pharma 1

2 Veneuze Tromboembolie Controversies in de behandeling van Longembolie Is behandeling van DVT en LE verschillend? NOACs voor LE? met of zonder LMWH? 2

3 Is behandeling van DVT en LE anders? Is behandeling van DVT en LE anders? Lessons from idraparinux DVT PE Recurrent VTE Idraparinux vs. Heparin/Vitamin K antagonist Open-label, non-inferiority study van Gogh Investigators. N Engl J Med 2007;357:

4 Is behandeling van DVT en LE anders? Lessons from Ximelagatran Ximelagatran: Eén dosis, geen LMWH Fiessinger et al., THRIVE Treatment Study Investigators. JAMA 2005;293: Treatment of VTE Initial treatment 5 days 3 weeks Continued treatment at least 3 months Secondary prevention long-term 4

5 Treatment of VTE Initial treatment 5 days 3 weeks LMWH + VKA (INR 2 3) Continued treatment at least 3 months Secondary prevention long-term Treatment of VTE Initial treatment 5 days 3 weeks LMWH + VKA (INR 2 3) + Dabigatran 150 mg BD + Edoxaban 60 mg OD Rivaroxaban 15 mg BD 3 weeks 20 mg OD Apixaban 10 mg BD 1 week 5 mg BD Continued treatment at least 3 months Secondary prevention long-term 1. Schulman et al. N Engl J Med 2009;361: ; 2. Schulman et al. Circulation 2014; 3. EINSTEIN Investigators. N Engl J Med 2010;363: ; 4. EINSTEIN PE Investigators. N Engl J Med 2012;366: ; 5. Agnelli et al.; AMPLIFY Investigators. N Engl J Med 2013;369: ; 6. The Hokusai-VTE Investigators. N Engl J Med 2013;369:

6 Treatment of VTE Initial treatment 5 days 3 weeks LMWH + VKA (INR 2 3) + Dabigatran 150 mg BD + Edoxaban 60 mg OD Rivaroxaban 15 mg BD 3 weeks 20 mg OD Apixaban 10 mg BD 1 week 5 mg BD Continued treatment at least 3 months Is it true for both DVT and PE? Secondary prevention long-term 1. Schulman et al. N Engl J Med 2009;361: ; 2. Schulman et al. Circulation 2014; 3. EINSTEIN Investigators. N Engl J Med 2010;363: ; 4. EINSTEIN PE Investigators. N Engl J Med 2012;366: ; 5. Agnelli et al.; AMPLIFY Investigators. N Engl J Med 2013;369: ; 6. The Hokusai-VTE Investigators. N Engl J Med 2013;369: Efficacy DVT/PE Van Es et al. Blood 2014;124:

7 And bleeding? Which types of major bleeding are reduced? What is the truth about gastrointestinal bleeding? Bleeding components Van Es et al. Blood 2014;124:

8 Treatment of VTE Initial treatment 5 days 3 weeks LMWH + VKA (INR 2-3) + Dabigatran 150 mg BD + Edoxaban 60 mg OD Rivaroxaban 15 mg BD 3 weeks 20 mg OD Apixaban 10 mg BD 1 week 5 mg BD Continued Treatment At least 3 months Are patients with serious PE included? Secondary Prevention Long-term Risk stratification of PE ESC guidelines on acute PE; EHJ

9 Simplified PESI score for assessing the likelihood of PE-related death Parameter Score Age 80 years 1 History of cancer 1 Chronic cardiopulmonary disease 1 Pulse 110 beats/min 1 Systolic blood pressure 100 mm Hg 1 Arterial oxyhaemoglobin saturation level 90% 1 1 point or more = high risk of early death Jiménez D, Arch Intern Med 2010;170: Risk stratification of PE ESC guidelines on acute PE; EHJ

10 S. Konstantidines et al. Nejm

11 S. Konstantidines et al. Nejm

12 The HOKUSAI-VTE Study edoxaban Symptomatic confirmed VTE event R Sham INR INR warfarin Day 1 5 Day months 6 months 12 months initial (LMW) heparin placebo warfarin placebo edoxaban The Hokusai-VTE Investigators. N Engl J Med 2013;369: HOKUSAI-VTE: Efficacy Outcomes Edoxaban (N=4118) Warfarin (N=4122) Hazard ratio (95% CI) P value First recurrent VTE (%) Overall study period ( ) <0.001 Non-inferiority Patients with index PE** Subgroup more severe PE (ProBNP) n/n (%) 15/ % 30/ % 0.73 ( ) 0.52 ( ) * Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin groups, respectively ** Denominator is number of patients with index PE: 1650 and 1669 in edoxaban and warfarin groups, respectively The Hokusai-VTE Investigators. N Engl J Med 2013;369:

13 What else does the clinician want to know? What is the efficacy/safety in the frail and elderly? Elderly Van Es et al. Blood 2014;124:

14 Controversies in the Management of Pulmonary Embolism Is treatment of PE different than of DVT? NOACs for PE: With or without LMWH? Will NOACs change treatment duration? Duration of therapy Unprovoked PE We recommend that after 3 months of anticoagulant therapy, all patients with unprovoked PE should be evaluated for the riskbenefit ratio of long-term therapy (Grade 1C). ACCP Guidelines, Chest 2008;133(6 Suppl) 14

15 HR (95%CI) efficacy active drug vs placebo 5/01/2016 Duration of therapy Unprovoked PE We recommend that after 3 months of anticoagulant therapy, all patients with unprovoked PE should be evaluated for the riskbenefit ratio of long-term therapy (Grade 1C). For patients with a first unprovoked PE in whom risk factors for bleeding are absent and for whom good anticoagulant monitoring is achievable, we recommend long-term treatment (Grade 1A). ACCP Guidelines, Chest 2008;133(6 Suppl) Secondary prevention of VTE DURAC II 1 LAFIT 2 PREVENT 3 Einstein THRIVE III 6 RE-SONATE 7 AMPLIFY (odds ratio) Ext 5 Ext 8 Warfarin Low dose Apixaban Warfarin Rivaroxaban Ximelagatran Dabigatran WARFASA 9 ASPIRE 10 ASA 1. Schulman S et al N Engl J Med 1997;336:393 8; 2. Kearon C et al. N Engl J Med 199;340:901 7; 3. Ridker PM et al N Engl J Med 2003;348: ; 4. The van Gogh Investigators N Engl J Med 2007;357: ; 5. The EINSTEIN Investigators N Engl J Med 2010;363: ; 6. Schulman S et al. N Engl J Med 2003;349: ; 7. Schulman S et al. N Engl J Med 2013;368:709 18; 8. Agnelli G et al. N Engl J Med 2013;368: ; 9. Becattini C et al. N Engl J Med 2012;366: ; 10. Brighton T et al. N Engl J Med 2012;367:

16 HR (95%CI) efficacy active drug vs placebo HR (95%CI) efficacy active drug vs placebo 5/01/2016 Secondary prevention of VTE DURAC II 1 LAFIT 2 PREVENT 3 Einstein THRIVE III 6 RE-SONATE 7 AMPLIFY (odds ratio) Ext 5 Ext 8 Warfarin Low dose Apixaban Warfarin Rivaroxaban Ximelagatran Dabigatran WARFASA 9 ASPIRE 10 ASA 1. Schulman S et al N Engl J Med 1997;336:393 8; 2. Kearon C et al. N Engl J Med 199;340:901 7; 3. Ridker PM et al N Engl J Med 2003;348: ; 4. The van Gogh Investigators N Engl J Med 2007;357: ; 5. The EINSTEIN Investigators N Engl J Med 2010;363: ; 6. Schulman S et al. N Engl J Med 2003;349: ; 7. Schulman S et al. N Engl J Med 2013;368:709 18; 8. Agnelli G et al. N Engl J Med 2013;368: ; 9. Becattini C et al. N Engl J Med 2012;366: ; 10. Brighton T et al. N Engl J Med 2012;367: Secondary prevention of VTE DURAC II 1 LAFIT 2 PREVENT 3 Einstein THRIVE III 6 RE-SONATE 7 AMPLIFY (odds ratio) Ext 5 Ext 8 Warfarin Low dose Apixaban Warfarin Rivaroxaban Ximelagatran Dabigatran WARFASA 9 ASPIRE 10 ASA 1. Schulman S et al N Engl J Med 1997;336:393 8; 2. Kearon C et al. N Engl J Med 199;340:901 7; 3. Ridker PM et al N Engl J Med 2003;348: ; 4. The van Gogh Investigators N Engl J Med 2007;357: ; 5. The EINSTEIN Investigators N Engl J Med 2010;363: ; 6. Schulman S et al. N Engl J Med 2003;349: ; 7. Schulman S et al. N Engl J Med 2013;368:709 18; 8. Agnelli G et al. N Engl J Med 2013;368: ; 9. Becattini C et al. N Engl J Med 2012;366: ; 10. Brighton T et al. N Engl J Med 2012;367:

17 Treatment of VTE Initial treatment 5 days 3 weeks Continued treatment at least 3 months Secondary prevention long-term LMWH + VKA (INR 2 3) NR Dabigatran 150 mg BD 150 mg/110 mg BD + Edoxaban 60 mg OD 60 mg/30 mg OD Rivaroxaban 15 mg BD 3 weeks 20 mg OD Apixaban 10 mg BD 1 week 5 mg BD 20 mg /15 mg /10 mg OD 5 mg / 2.5 mg BD Controversies in the Management of Pulmonary Embolism Is treatment of PE different than of DVT? NOACs for PE: With or without LMWH? Will NOACs change treatment duration? 17

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