UPDATE ON TREATMENT OF ACUTE VENOUS THROMBOSIS

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

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

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

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; 471-47, Kearon C, and Akl E A Blood 2014;123:1794-1801

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; 22:129-137; Nutescu EA, et al. Cardiol Clin 2008; 26:169-187. 5

Oral Anticoagulation and Bleeding Risk

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

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 15 50 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: http://www.medicines.org.uk/emc/

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: 0.76 1.57) HR: 0.89 (95% CI: 0.66 1.19) HR: 0.84 (95% CI: 0.60 1.18) HR: 0.82 (95% CI: 0.60 1.14) 2 1 2.4% 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;369:799-808; 4. The Hokusai-VTE Investigators. N Engl J Med 2013;369:1406-15

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: 0.36 0.99) HR: 0.54 (95% CI: 0.37 0.79) HR: 0.31 (95% CI: 0.17 0.55) HR: 0.84 (95% CI: 0.59 1.21) 2 1 1.0% 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;369:799-808; 4. The Hokusai-VTE Investigators. N Engl J Med 2013;369:1406-15

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;92:199-205. P. de Jong et al. BJH, 2012;158:433-441. 1. Kearon C, Akl EA, Comerota AJ, et al. Chest. 2012;141(suppl 2): e419s-e494s. 12

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;158:433-441

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;158:433-441

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;158:433-441

Events (%) Primary Efficacy Outcome Recurrent symptomatic VTE and VTE-related deaths 10 8,8 8 80 92% 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;363:2499 510; 3. Agnelli G et al. N Engl J Med 2013;368:699 708

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;363:2499 510; 3. Agnelli G et al. N Engl J Med 2013;368:699 708

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) 6 12 18 24 30 48 *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;361:2342-52; 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;369:799-808; 5. Agnelli G et al. N Engl J Med 2013;368:699-708; 6. Bauersachs R et al. N Engl J Med 2010;363:2499-510; 7. Buller HR et al. N Engl J Med 2012; 366:1287-97; 8. Hokusai-VTE Investigators. N Engl J Med 2013;369:1406-15 UK/DBG-151106e Aug 2015

Effect of Aspirin on Risk of Recurrence of VTE and Major Vascular Events 32-34% Warkentin TE. N Engl J Med 2012;367:2039-2041.

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 [0.14 6.88] 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 [0.72 3.14] 2.92 [1.52 5.60] 5.19 [2.13 11.7] 1.20 [0.69 2.10] 1.62 [0.96 2.73] p=0.28 p=0.001 p<0.001 - - 1. Andreozzi GM, et al. Circulation. 2015;132:1891-7. 2. Simes J, et al. Circulation. 2014;130:1060-71. 3. Schulman S, et al. N Engl J Med. 2013;368(8):709-18. 4. The EINSTEIN Investigators. N Engl J Med. 2010:363:2499-510. 5. Agnelli G, et al. N Engl J Med. 2013;368(8):699-708.

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, 698-702

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

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