Duration of Anticoagulation? Peter Verhamme MD, PhD Department of Cardiovascular Medicine University of Leuven Belgium

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2 Duration of Anticoagulation? Peter Verhamme MD, PhD Department of Cardiovascular Medicine University of Leuven Belgium

3 Disclosures Honoraria and research support: Daiichi-Sankyo, Boehringer Ingelheim, Bayer HealthCare, Pfizer, Sanofi, Ionis Pharmaceuticals, Leo-Pharma, Bristol-Myers Squibb

4 Case: Recurrent VTE 41-year-old man Proximal DVT 2 years ago; R/ VKA Recurrent distal DVT; R/ NOAC Thrombophilia (FVLeiden) and familial history of VTE Frequent long-haul flights

5 Case: Recurrent VTE Your choice? 1. Stop Anticoagulation 2. VKA 3. ASA 100mg 4. LMWH 5. NOAC treatment dose 6. NOAC prophylactic dose

6 Case: Recurrent VTE 41-year-old man Proximal DVT 2 years ago; R/ VKA Recurrent distal DVT; R/ NOAC Thrombophilia (FVLeiden) and familial history of VTE Frequent long-haul flights

7 Case: PE in a young woman 33-year-old woman Pulmonary Embolism (RVD+, probnp+) Pill (COC)

8 Case: PE in a young woman 33-year-old woman Pulmonary Embolism (RVD+, probnp+) Pill (COC) PT G20210A heterozygous

9 Case: PE in a young women 33-year-old woman Pulmonary Embolism (RVD+, probnp+) Pill (COC) PT G20210A heterozygous + strong familial history

10 Case: Recurrent VTE Your choice? 1. Stop Anticoagulation 2. VKA 3. ASA 100mg 4. LMWH 5. NOAC treatment dose 6. NOAC prophylactic dose

11 Case: PE in a young women 33-year-old woman Pulmonary Embolism (RVD+, probnp+) Pill (COC) Antiphospholipid syndrome (LA++, ACL++)

12 Case: Recurrent VTE Your choice? 1. Stop Anticoagulation 2. VKA 3. ASA 100mg 4. LMWH 5. NOAC treatment dose 6. NOAC prophylactic dose

13 Risk of recurrence after unprovoked VTE is high 0.20 Unprovoked Cumulative proportion Non-surgical triggers Surgery Baglin T et al, Lancet 2003;362: Time since event (months)

14 Duration of Anticoagulant Therapy for VTE Stop therapy 3 months Continue therapy Kearon C et al, Chest 2016;149:

15 Duration of Anticoagulant Therapy for VTE Stop therapy 3 months Continue therapy Continue anticoagulant therapy in based on the individualized assessment of risks & benefits Kearon C et al, Chest 2016;149:

16 Balancing the Risk of Recurrent VTE versus Bleeding is Critical for Deciding to Extend Treatment RECURRENCES WITHOUT ANTICOAGULATION BLEEDING UNDER ANTICOAGULATION PATIENT S and PHYSICIAN S PREFERENCE Haxaire C et al, PLoS One 2015;10:e

17 Balancing the Risk of Recurrent VTE versus Bleeding is Critical for Deciding to Extend Treatment RECURRENCES WITHOUT ANTICOAGULATION BLEEDING UNDER ANTICOAGULATION PATIENT S and PHYSICIAN S PREFERENCE EFFICACY/SAFETY/CONVENIENCE OAC Haxaire C et al, PLoS One 2015;10:e

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19 What to consider when deciding to extend anticoagulation therapy? Cumulative proportions of recurrent thrombosis after cessation of anticoagulant therapy 1 * (N=558) Cumulative proportion of recurrent events Time since event (months) Unprovoked Provoked by Nonsurgical risk factors Provoked by Surgery Extended anticoagulation therapy 2 3 months treatment duration 2 *Patients with malignant disease and antiphospholipid syndrome were excluded from the study. 1. Baglin T et al, Lancet 2003;362: Kearon C et al, Chest 2016;149:

20 Risk Factors for Recurrent VTE Recurrent VTE Unprovoked VTE VTE with Risk Factors: Major Transient Risk Factor Minor Transient Risk Factor Minor Persistent Risk Factor Major Persistent Risk Factor Kearon C et al, Chest 2016;149:

21 Assessing Recurrence Risk: Primary Estimators Primary estimator Surgical provoking risk factor: 1% in first year, 3% over 5 years Non-surgical provoking risk factor: 3% in first year, 15% over 5 years No provoking risk factor: 10% in first year, 30% over 5 years Persistent or progressive risk (e.g. cancer) Kearon C et al, Blood 2014;123:

22 Assessing Recurrence Risk: Secondary Estimators Secondary estimators Isolated distal DVT (50% lower than proximal DVT) Previous VTE (50% higher than first event) Secondary estimators after unprovoked event Male sex (1.5 2-fold increase) Positive D-Dimer 1 month after stopping ( fold higher) Kearon C et al, Blood 2014;123:

23 Risk Stratification in VTE Laboratory methods D-Dimer assay 5 Thrombin generation 6 Stratification methods Guidelines 4 1. Montagnana M et al, J Thromb Thrombolysis 2010;29:489-96; 2. Connolly GC et al, Best Pract Res Clin Haematol 2009;22:35-47; 3. Jimenez D et al, JAMA 2010;170: ; 4. Konstantinides et al. Eur Heart J 2014; pii: ehu283;4; 5. Eichinger S et al, JAMA 2003;290: ; 6. Lutsey PL et al, J Thromb Haemost 2009 ;7:

24 2016 ACCP Guidelines for VTE Antithrombotic Therapy Initial anticoagulation Acute DVT or haemodynamically stable PE and no cancer PE with hypotension ACCP recommendation NOAC preferred to VKA LMWH/VKA preferred to LMWH alone Thrombolytic therapy (systemic rather than catheter-directed unless bleeding risk is high) Grade of recommendation 2B 2C 2B (2C) DVT or PE with cancer LMWH suggested over NOAC or VKA 2C Duration of anticoagulant therapy Proximal DVT or PE 3 months recommended over shorter duration 1B First proximal DVT or PE provoked by surgery 3 months 1B Unprovoked DVT or PE Extended therapy if bleeding risk is low/moderate 2B 3 months if bleeding risk is high 1B DVT or PE associated with active cancer Extended therapy recommended over 3 months therapy 1B (2B if high bleeding risk) Kearon C et al, Chest 2016;149:

25 Risk Factors for Bleeding

26 Risk Factors for Bleeding Risk Factors Age >65 y Age >75 y Previous bleeding Cancer Metastatic cancer Renal failure Liver failure Thrombocytopenia Previous stroke Diabetes Anaemia Antiplatelet therapy Poor anticoagulant control Comorbidity and reduced functional capacity Recent surgery Frequent falls Alcohol abuse Nonsteroidal anti-inflammatory drug Anticoagulation 0-3 months Categorization of Risk of Bleeding Estimated Absolute Risk of Major Bleeding Low Risk (0 RF) Moderat e Risk (1 RF) Baseline risk (%) Increased risk (%) Total risk (%) Anticoagulation > 3 months Baseline risk (%/y) Increased risk (%/y) Total risk (%/y) High Risk (2 RF) Kearon C et al, Chest 2016;149:

27 Patient s and Physician s Preference

28 Patient s and Physician s Preference

29 EINSTEIN CHOICE Evaluated Rivaroxaban Versus ASA for Extended Treatment of VTE Multicentre, randomized, double-blind, active-comparator, event-driven, superiority study Population: Patients with confirmed symptomatic PE/DVT who completed 6 12 months anticoagulation* N=3396 Day 1 R Rivaroxaban 20 mg od n=1121 Rivaroxaban 10 mg od n=1136 ASA 100 mg od n= month planned treatment duration 30-day follow-up *Completed 6 12 months anticoagulation at randomization with no interruption of anticoagulation >1 week Patients randomized after the requisite number of primary efficacy outcomes was reached were treated for 6 months Weitz JI et al, Thromb Hemost 2015;114: ; Weitz JI et al, N Engl J Med 2017:doi: /NEJMoa

30 Both Rivaroxaban Doses Provided Superior Reduction in Recurrent VTE Rates Compared with ASA 5 ASA 100 mg od Cumulative incidence (%) Rivaroxaban 20 mg od Rivaroxaban 10 mg od Rivaroxaban 20 mg od vs ASA 1.5% vs 4.4% HR=0.34 (95% CI ), p<0.001 Rivaroxaban 10 mg od vs ASA 1.2% vs 4.4% HR=0.26 (95% CI ), p< Days Intention-to-treat analysis Weitz JI et al, N Engl J Med 2017:doi: /NEJMoa

31 Rates of Major Bleeding Were 0.5% and Similar to ASA 5 Cumulative incidence (%) Rivaroxaban 10 mg od Rivaroxaban 20 mg od vs ASA 6/1107 (0.5%) vs 3/1131 (0.3%) HR=2.01 (95% CI ), p=0.32 Rivaroxaban 10 mg od vs ASA 5/1127 (0.4%) vs 3/1131 (0.3%) HR=1.64 (95% CI ), p=0.50 Rivaroxaban 20 mg od Days ASA 100 mg od Safety analysis. No events after Day 360 up to Day 480 Weitz JI et al, N Engl J Med 2017:doi: /NEJMoa

32 Bleeding Outcome Analyses ASA 100 mg od (n=1131) Rivaroxaban 10 mg od (n=1127) Rivaroxaban 20 mg od (n=1107) 4 3,3 Incidence (%) ,3 0,4 0,5 2,0 2,4 1, ,7 1,1 1,1 1,5 0 Major bleeding Major or CRNM bleeding CRNM bleeding Non-major bleeding associated with study drug interruption for more than 14 days Similar rates of bleeding were observed in the rivaroxaban and ASA treatment groups Safety analysis. All treatment comparisons p>0.05 Weitz JI et al, N Engl J Med 2017:doi: /NEJMoa

33 Apixaban for Secondary Prevention of VTE Non-fatal and fatal VTE Placebo Apixaban 2.5 mg BD Apixaban 5 mg BD Cumulative event rate (%) Months Agnelli G et al. N Engl J Med 2013; 368:

34 Major or Clinically Relevant Nonmajor Bleeding Cumulative event rate (%) Placebo Apixaban 2.5 mg Apixaban 5 mg Months Agnelli G et al. N Engl J Med 2013; 368:

35 Case: Unprovoked PE 69-year-old man CAD, PCI LAD ASA 100mg, Statin, ACE-I Presents with unprovoked PE Familial history of VTE Treatment with NOAC initiated 1. with or without ASA 100mg? 2. without ASA 100mg?

36 Case: Unprovoked PE 69-year-old man CAD, PCI LAD ASA 100mg, Statin, ACE-I Presents with unprovoked PE Familial history of VTE Continued OAC after 3 months?

37 Case: Unprovoked PE 69-year-old man CAD, PCI LAD ASA 100mg, Statin, ACE Presents with unprovoked PE Familial history of VTE Continued OAC after 3 months? 1. with or without ASA 100mg? 2. without ASA 100mg?

38 Case: Recurrent VTE 29-year-old man Freak of Mountain bike and Snowboard Recurrent PE Continued OAC after 3 months?

39 Case: Recurrent VTE 29-year-old man Freak of Mountain biking and Snowboard Recurrent PE Continued OAC after 3 months 1. OD NOAC evening intake prophylactic dose? 2. OD NOAC evening intake therapeutic dose? 3. BD NOAC with antidote?

40 Thank you