1. Extended Anticoagulation in VTE Geoffrey Barnes, MD Cardiovascular and Vascular Medicine University of Michigan, USA 1 st Qatar Conference on Safe Anticoagulation Management February 27, 2015

2. Outline VTE Recurrence Risk Patient Selection for Extended Therapy Medication Selection for Extended Therapy My Approach

3. Definitions Venous Thromboembolism (VTE) – Deep Venous Thrombosis (DVT) – Pulmonary Embolism (PE) Treatment Phases – Acute/Initial – first few days – Intermediate/Long-term – up to 3-6 months – Chronic/Extended – beyond first 3-6 months Provoked – Transient surgical procedure – Immobilization – Pregnancy or Hormone-related (e.g estrogen contraceptives) Lancet. 2012; 379: 1835-1846

4. Clinical Case 65 year old man with CAD and a first unprovoked femoral-popliteal DVT Completed 3 months of warfarin therapy What is his recurrence risk? Does he need further therapy? If so, what is the best medication to use?

5. Outline VTE Recurrence Risk Patient Selection for Extended Therapy Medication Selection for Extended Therapy My Approach

6. Provoked vs Unprovoked BMJ. 2011; 342:d3036

7. Provoked vs Unprovoked Arch Int Med 2010;170:1710-1716 Blood 2002; 100:3484-8

8. VTE Location BMJ. 2011; 342:d3036 HR 0.49 (0.34-0.71)

9. Age and Obesity Arch Intern Med. 2000;160(6):761-8

10. Gender NEJM 2004;350:2558-2563

11. D-Dimer Positive D-Dimer  8.9%/year Negative D-Dimer  3.5%/year Positive D-Dimer  8.9%/year Negative D-Dimer  3.5%/year Ann Intern Med. 2008;149:481-490

12. D-Dimer Kearon Ann Int Med 2015;162:27 3%3% 97% 15%85%

13. D-Dimer Blood 2010; 115: 481–488 CMAJ 2008; 179: 417–426 On Anticoagulation Negative D-Dimer Positive D-Dimer 28% 4 weeks without Anticoagulation

14. Hypercoagulable States Factor V Leiden Protein C/S Deficiency Antithrombin Deficiency Elevated Homocysteine Dysfibrinogenemia Antiphospholipid Antibodies

15. Hypercoagulable States Considerations – How significant is the increased VTE recurrence risk? – How frequently is the hypercoagulable state found? – Can testing be done on anticoagulation? – Are there treatment implications? Blood 2013;122:817-824 Circulation 2014;130:283-287

16. Hypercoagulable States Factor V Leiden Protein C/S Deficiency Antithrombin Deficiency Elevated Homocysteine Dysfibrinogenemia Antiphospholipid Antibodies – VTE Recurrence Risk (RR ~2) – Favor use of Warfarin over DOACs currently Blood 2013;122:817-824 Circulation 2014;130:283-287

17. Outline VTE Recurrence Risk Patient Selection for Extended Therapy Medication Selection for Extended Therapy My Approach

18. VTE Recurrence Predictors Provoked vs Unprovoked PE and Proximal DVT vs Distal DVT Age Obesity Gender D-dimer Hypercoagulable States

19. Risk Prediction Models CMAJ 2008;179:417-426 Circulation 2010; 121:1630-1636 J Thromb Haemost 2012; 10: 1019–1025 Men and HERDOO Vienna Risk Model DASH GenderXXX D-DimerXXX Signs of Post-Thrombotic Syndrome X ObesityX AgeX Location of DVT/PEX Provoked?X

20. Men and HERDOO-2 High Risk: All Men Women with 2+ of Post-thrombotic Syndrome Elevated D-dimer Obesity 75% of patients are High Risk Freedom from Recurrent VTE CMAJ 2008;179:417-426

21. Outline VTE Recurrence Risk Patient Selection for Extended Therapy Medication Selection for Extended Therapy My Approach

22. Medication Options Warfarin Dabigatran Rivaroxaban Apixaban Aspirin

23. Warfarin NEJM 2003;348:1425-1434 and NEJM 2003;349:631-639

24. Dabigatran Recurrent VTEAny Bleeding NEJM 2013;368:709-718 Warfarin Placebo

25. Rivaroxaban NEJM 2010;363:2499-2510

26. Apixaban Recurrent VTEMajor and CRNM Bleeding NEJM 2012;368:699-708

27. Aspirin INSPIRE Collaborative (WARFASA & ASPIRE) Circulation 2014;130:1062-1071

28. VTE Recurrence Risk NEJM 2003;348:1425-1434. NEJM 2003;349:631-639. NEJM 2013;368:709-718. NEJM 2010;363:2499- 2510 NEJM 2012;368:699-708. NEJM 2012;368:699-708. Circulation 2014;130:1062-1071

29. Outline VTE Recurrence Risk Markers of Recurrence Risk Patient Selection for Extended Therapy Medication Selection for Extended Therapy My Approach

30. Barnes GD Vascular Medicine 2015 (in press) Predictive Factors: Provoked D-Dimer Gender

31. My Approach Drug Selection – Another indication? Example: Aspirin for CAD – Prefer to continue current medication? – Balance efficacy and risk Usually use apixaban or rivaroxaban

32. Clinical Case 65 year old man with CAD and a first unprovoked femoral-popliteal DVT Completed 3 months of warfarin therapy What is his recurrence risk? – High: >7-10% per year Does he need further therapy? – Yes If so, what is the best medication to use? – Apixaban or Rivaroxaban if CAD stable – Aspirin if recent PCI or MI requiring clopidogrel

33. Thank You

34. Louzada/Ottawa Score Risk FactorPointNumber of Points VTE Recurrence Risk (per year) Female1≤0≤5% Lung Cancer1113-16% Prior VTE1218% Breast Cancer325-50% TNM Stage = I-2 Cancer-associated VTE Circulation 2012;126:448-454