UPDATE ON TREATMENT OF ACUTE VENOUS THROMBOSIS

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1 UPDATE ON TREATMENT OF ACUTE VENOUS THROMBOSIS Armando Mansilha MD, PhD, FEBVS 16 th National Congress of the Italian Society of Vascular and Endovascular Surgery Bologna, 2017

2 Disclosure I have the following potential conflicts of interest to report: Receipt of grants/research support Receipt of honoraria and travel support Participation in a company sponsored speakers bureau Employment in industry Shareholder in a healthcare company Owner of a healthcare company X I do not have any potential conflict of interest

3 Principles of VTE treatment PREVENT short-term and long-term sequelae PREVENT clot extension, including PE PREVENT Post-thrombotic syndrome Chronic thromboembolic pulmonary hypertension PREVENTION of recurrence

4 Stages of VTE treatment Active treatment Extended treatment Initial phase Long-term phase 5-7 days 3-6 months 3 months - indefinite Parenteral Oral anticoagulant Oral anticoagulant Oral anticoagulant Agnelli et al. Hematology 2013; , Kearon C, and Akl E A Blood 2014;123:

5 Wisconsin Alumni Research Foundation-arin + 50 Years of Experience Unpredictable Response Slow onset and off-set of action Routine Monitoring Multiple drug interactions Frequent dose adjustments Multiple diet interactions Narrow therapeutic window (INR 2-3) Warfarin resistance 1. Ansell J, et al. Chest 2008;133;160S-198S; 2. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22: ; Nutescu EA, et al. Cardiol Clin 2008; 26:

6 Oral Anticoagulation and Bleeding Risk

7 Mechanism of action of NOACs Brinkman. Thrombosis Journal (2015) 13:9; 1-14

8 VTE requires acute and extended treatment for prevention of recurrence Initial management Secondary prophylaxis (3 6 months) Extended prophylaxis (years) Parenteral AC* 5 days 1 Warfarin Parenteral AC* 5 days 1 Dabigatran 150 mg BID 2 Parenteral AC* 5 days 1 Edoxaban 60 mg OD 3 Rivaroxaban 15 mg BID 21 days 4 Rivaroxaban 20 mg OD Apixaban 10 mg BID 7 days 5 Apixaban 5 mg BID 6 months Apixaban 2.5 mg BID *LMWH, fondaparinux or UFH; Dabigatran 110 mg BID for aged 80 years, concomitant verapamil, or based on individual assessment of thromboembolic/bleeding risk; Edoxaban 30 mg OD for CrCl ml/min, weight 60 kg, certain concomitant P-gp inhibitors 1. Kearon et al. Chest 2012;141(2 Suppl):e419S-94S; 2. Pradaxa SPC; 3. Savaysa SPC; 4. Xarelto SPC; 5. Eliquis SPC. Current versions available online at:

9 Patients (%) Acute treatment of DVT/PE: NOACs non-inferior to warfarin for prevention of recurrent DVT/PE in their Phase III trials 3 HR: 1.09 (95% CI: ) HR: 0.89 (95% CI: ) HR: 0.84 (95% CI: ) HR: 0.82 (95% CI: ) % 2.2% 2.1% 2.3% 2.3% 2.7% 1.6% 1.9% NOAC Warfarin 0 RE-COVER / RE-COVER II* Dabigatran 1 EINSTEIN-DVT/ EINSTEIN-PE* Rivaroxaban 2 AMPLIFY Hokusai-VTE Apixaban 3 Edoxaban 4 Direct comparisons cannot be made as no head to head data is available *Pooled data; oral drug treatment period only; On treatment 1. Schulman S et al. Circulation 2014;129:764-72; 2. Prins MH et al. Thromb J 2013;11:21; 3. Agnelli G et al. N Engl J Med 2013;369: ; 4. The Hokusai-VTE Investigators. N Engl J Med 2013;369:

10 Patients (%) Acute treatment of DVT/PE: NOACs associated with less major bleeding versus warfarin in their Phase III trials * 3 HR: 0.60 (95% CI: ) HR: 0.54 (95% CI: ) HR: 0.31 (95% CI: ) HR: 0.84 (95% CI: ) % 1.6% 1.0% 1.7% 0.6% 1.8% 1.4% 1.6% NOAC Warfarin 0 RE-COVER / RE-COVER II* Dabigatran 1 EINSTEIN-DVT/ EINSTEIN-PE* Rivaroxaban 2 AMPLIFY Hokusai-VTE Apixaban 3 Edoxaban 4 Direct comparisons cannot be made as no head to head data is available *Statistically significant reductions for dabigatran, rivaroxaban, and apixaban vs warfarin, numerical reduction for edoxaban vs warfarin; Pooled data; oral drug treatment period only; Pooled analysis; On treatment 1. Schulman S et al. Circulation 2014;129:764-72; 2. Prins MH et al. Thromb J 2013;11:21; 3. Agnelli G et al. N Engl J Med 2013;369: ; 4. The Hokusai-VTE Investigators. N Engl J Med 2013;369:

11 VTE requires acute and extended treatment for prevention of recurrence Initial management Secondary prophylaxis (3 6 months) Extended prophylaxis (years) Parenteral AC* 5 days 1 Warfarin Parenteral AC* 5 days 1 Dabigatran 150 mg BID 2 Parenteral AC* 5 days 1 Edoxaban 60 mg OD 3 Rivaroxaban 15 mg BID 21 days 4 Rivaroxaban 20 mg OD Apixaban 10 mg BID 7 days 5 Apixaban 5 mg BID 6 months Apixaban 2.5 mg BID *LMWH, fondaparinux or UFH; Dabigatran 110 mg BID for aged 80 years, concomitant verapamil, or based on individual assessment of thromboembolic/bleeding risk; Edoxaban 30 mg OD for CrCl ml/min, weight 60 kg, certain concomitant P-gp inhibitors 1. Kearon et al. Chest 2012;141(2 Suppl):e419S-94S; 2. Pradaxa SPC; 3. Savaysa SPC; 4. Xarelto SPC; 5. Eliquis SPC. Current versions available online at:

12 Duration of Therapy Duration of therapy should be individualized after careful assessment of treatment benefit against risk of bleeding Short duration (at least 3 months): Proximal DVT associated with transient risk factors (e.g. recent surgery, trauma, immobilization) Distal DVT Extended treatment: Unprovoked DVT or DVT associated with permanent risk factors Prandoni P et al. Haematologica. 2007;92: P. de Jong et al. BJH, 2012;158: Kearon C, Akl EA, Comerota AJ, et al. Chest. 2012;141(suppl 2): e419s-e494s. 12

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14 Risk of Recurrence Provoking factor for VTE Major reversible risk factor Surgery - very low risk Non-surgical risk factors (trauma, immobilization, pregnancy, estrogens) - low risk Persistent or progressive risk factor (cancer) high risk Unprovoked VTE Several parameters can be evaluated - moderately high risk Previous VTE A second episode of VTE has a 50% higher risk of recurrence compared with the first one P. de Jong et al. BJH, 2012;158:

15 Risk of Recurrence unprovoked VTE Sex - Men have higher risk than women (HR 1.9) Site of VTE - Proximal DVT versus distal DVT higher risk (HR 2.08) D-Dimer (1 month after stopping anticoagulation) When positive the risk is higher (HR 2.27) Antiphospholipid syndrome Persistent LA or high titers of ACAS or B 2 GP1 higher risk Hereditary thrombophilias AT deficiency or multiple thrombophilias higher risk Post-thrombotic syndrome PTS Recurrence (ipsilateral DVT) P. de Jong et al. BJH, 2012;158:

16 Risk of Bleeding Patients characteristics Antithrombotics Older age (>75 ys) Previous bleeding Cancer Hypertension Diabetes Cerebrovascular disease Renal insufficiency Liver disease Poor INR control Antiplatelet agents NSAIDs Recent surgery Frequent falls P. de Jong et al. BJH, 2012;158:

17 Events (%) Primary Efficacy Outcome Recurrent symptomatic VTE and VTE-related deaths 10 8, % 7,1 6 5,6 4 NOAC Placebo 2 1,3 1,7 0 0,4 RE-SONATE EINSTEIN-EXT AMPLIFY-EXT 1. Schulman S et al. N Engl J Med 2013;368:709 18; 2. The EINSTEIN Investigators et al. N Engl J Med 2010;363: ; 3. Agnelli G et al. N Engl J Med 2013;368:

18 Safety outcome Major or CRNM bleedings 1. Schulman S et al. N Engl J Med 2013;368:709 18; 2. The EINSTEIN Investigators et al. N Engl J Med 2010;363: ; 3. Agnelli G et al. N Engl J Med 2013;368:

19 In extended prevention of VTE, dabigatran is the only NOAC to have up to 36 months follow-up data vs warfarin RE-COVER/II Dabigatran 150 mg BID vs warfarin 1,2 Initial parenteral therapy PRETREATMENT 3 12 months* RE-MEDY * Dabigatran 150 mg BID vs warfarin 3 PRETREATMENT 6 18 months* AMPLIFY Apixaban vs warfarin 4 AMPLIFY-EXT Apixaban vs placebo 5 RE-SONATE Dabigatran 150 mg BID vs placebo 3 EINSTEIN DVT/PE Rivaroxaban vs warfarin 6,7 EINSTEIN-EXT Rivaroxaban vs placebo 6 HOKUSAI-VTE Edoxaban vs warfarin 8 Time (months) *Original protocol, 3 6 months pretreatment, 18 months on study drug; amendment allowed 3 12 months pretreatment, then up to 36 months on study drug. 1. Schulman S et al. New Engl J Med 2009;361: ; 2. Schulman S et al. Circulation 2014;129:764-72; 3. Schulman S et al. N Engl J Med 2013;368:709-18; 4. Agnelli G et al. N Engl J Med 2013;369: ; 5. Agnelli G et al. N Engl J Med 2013;368: ; 6. Bauersachs R et al. N Engl J Med 2010;363: ; 7. Buller HR et al. N Engl J Med 2012; 366: ; 8. Hokusai-VTE Investigators. N Engl J Med 2013;369: UK/DBG e Aug 2015

20 Effect of Aspirin on Risk of Recurrence of VTE and Major Vascular Events 32-34% Warkentin TE. N Engl J Med 2012;367:

21 SURVET TRIAL Risk of clinically relevant bleeding vs placebo Adverse event Treatment Treatment duration (months) Major bleeding events SURVET 1 Sulodexide 24 0 Risk of clinically relevant bleeding vs comparator (HR [95% CI]) 0.97 [ ] p=0.98 ASPIRE+WARFASA 2 Aspirin 24 (48) 8 RE-SONATE 3 Dabigatran 6 2 EINSTEIN-EXT 4 Rivaroxaban 12 4 AMPLIFY-EXT 2 5 Apixaban (2.5 mg) 12 2 AMPLIFY-EXT 2 5 Apixaban (5 mg) 12 1 CI = Confidence Interval HR = Hazard Ratio LSU = Lipasemic Units 1.50 [ ] 2.92 [ ] 5.19 [ ] 1.20 [ ] 1.62 [ ] p=0.28 p=0.001 p< Andreozzi GM, et al. Circulation. 2015;132: Simes J, et al. Circulation. 2014;130: Schulman S, et al. N Engl J Med. 2013;368(8): The EINSTEIN Investigators. N Engl J Med. 2010:363: Agnelli G, et al. N Engl J Med. 2013;368(8):

22 Extended Treatment vs Indefinite Treatment Thrombosis Bleeding Evaluation of the patient at least once a year: Benefits of therapy - risk of recurrence Risks of therapy - risk of bleeding The patient has not developed contra-indications to therapy (severe renal impairment or severe liver disease, medications) Patient has not changed his preference Baglin et al. J Throm Hemost,10,

23 Conclusions NOACs are non-inferior to warfarin for active VTE treatment - prevention of recurrent or fatal VTE and present a favourable safety profile - significant reductions in major or clinically-relevant non major bleedings with NOACs vs warfarin. NOACs can be used for extended treatment with high efficacy and low bleeding risk. Easier management Not approved for: VTE associated with cancer VTE associated with high-risk thrombophilia (AFS) Contra-indications: Pregnant women Patients with severe renal impairment or severe liver disease

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25 UPDATE ON TREATMENT OF ACUTE VENOUS THROMBOSIS Armando Mansilha MD, PhD, FEBVS 16 th National Congress of the Italian Society of Vascular and Endovascular Surgery Bologna, 2017