Supervisor: Vs 余垣斌 Presenter: CR 周益聖

1. Supervisor: Vs 余垣斌 Presenter: CR 周益聖

2. INTRODUCTION

3. VTE vs. Warfarin • 2-3 per 1000 in the general population • Recurrence after discontinuation of anticoagulant • 1% per year for transient risk factor • 10% per year for unprovoked VTE • Warfarin(INR 2.0-3.0) for the long-term treatment of VTE • Major bleeding 2% per year • VTE risk reduction > 90% • Low-intensity warfarin regimen (INR 1.5-2.0) for extended treatment • Major bleeding 0.9% per year • VTE risk reduction around 75-80% Ridker, N Engl J Med 2003 Linkins, Ann Intern Med. 2003 Becker, N Engl J Med 2012

4. The Duration of Anticoagulation I Trial Schulman et al., N Engl J Med 1995

5. Schulman et al., N Engl J Med 1995

6. Schulman et al., N Engl J Med 1995

7. Schulman et al., N Engl J Med 1995

8. The Duration of Anticoagulation II Trial 6mos vs. indefinitely Schulman et al., N Engl J Med 1997

9. Schulman et al., N Engl J Med 1997

10. Schulman et al., N Engl J Med 1997

11. Kearon et al., N Engl J Med 1999

12. Kearon et al., N Engl J Med 1999

13. Schulman et al., N Engl J Med 1997

14. ACCP guideline (9thedition)Antithrombotic Therapy for VTE • VKA for 3 months • Proximal or isolated distal VTE provoked by surgery or non surgical risk factor • First Unprovoked distal VTE • PE provoked by surgery or non surgical risk factor • Extended VKA except high bleeding risk • First Unprovoked proximal VTE • Second unprovoked VTE • First unprovoked DVT in cancer pt’ • First or second unprovoked PE • Extended VKA no matter low or high bleeding risk • PE in active cancer Kearon et al., CHEST 2012; 141:Suppl(2):e419S-e4194S

15. Pathogenesis of VTE Becker, N Engl J Med 2012

16. The Warfarin and Aspirin Study WARFASA Becattini et al., N Engl J Med 2012

17. Aim • Assess the clinical benefit of aspirin for the prevention of recurrence after a course of treatment with vitamin K antagonists in patients with unprovoked venous thromboembolism

18. WARFASA Design n=205 RANDO MIZ ATION Aspirin 100mg PO QD for 2 years Unprovoked VTE s/p Vitamin K antagonist 1:1 Placebo for 2 years n=403 n=197 • Assumption: 40% relative risk reduction with aspirin and expected event rate of 8.0% per year (Result:8.6%) • 70 events provide a power of 80% • Two sided α of 0.05

19. WARFASA Design • Multicenter, Investigator-initiated, Double-blind • Primary endpoint • recurrence of VTE • Secondary endpoint • nonfatal myocardial infarction • unstable angina • Stroke • transient ischemic attack • acute ischemia of the lower limbs • death from any cause • Principal safety outcome • major bleeding ( fatal, major organ, Hb↓ > 2g/dl, PRBC >2U)

20. Inclusion criteria • older than 18 years of age • treated for 6 to 18 months with vitamin K antagonists • unprovoked proximal deep-vein thrombosis (DVT), pulmonary embolism (PE), or both • in the absence of any known risk factor

21. Exclusion criteria • Known cancer • Known major thrombophilia • antiphospholipid antibodies • lupus anticoagulant • homozygous factor V Leiden • Prothrombin G21210A • deficiency of antithrombin, protein C or S • atrial fibrillation • prosthetic heart valve • Atherosclerosis requiring treatment with aspirin or other anti-platelet agents • Active bleeding or high risk for bleeding or a bleeding episode which occurred during the 6-18 months of anticoagulation • Pregnancy or breast-feeding • Women with venous thromboembolism associated with the use of estro-progestin therapy

23. Result

25. Recurrent VTE • Deep-vein thrombosis • 44 patients (ipsilateral in 51% of cases) • Pulmonary embolism • 27 patients (fatal in 2 patients) • Prior PE is at higher risk for recurrent PE compared to prior DVT • 12.7% vs. 3.2% • HR:5.52 • 95% confidence interval : 2.29 to 13.30 • P<0.001

26. Intention to treat analysis • 6.6% for aspirin vs. 11.2% for placebo per year • HR: 0.58 • 95%CI:0.36-0.93 • P=0.02

27. Post Hoc analysis • Prior PE • 6.7% for aspirin vs. 13.5% for placebo per year • HR: 0.38 • 95%CI:0.17-0.88 • P=0.02 • Prior DVT • 6.5% for aspirin vs. 10.2% for placebo per year • HR: 0.65 • 95%CI:0.65-1.20 • P=0.17

28. Risk factors for recurrent VTE • Age>65 years • HR: 2.26 • 95%CI:1.16-4.41 • P=0.02 • Male • HR: 2.02 • 95%CI:1.16-3.49 • P=0.01 • No association between anticoagulant > 6 months vs. longer

30. Hemorrhagic complications • Major bleeding • 1 bowel angiodysplasia in ASA vs. 1 gastric ulcer in placebo (0.3% per patient-year ) • Non major bleeding • 1 gingival bleeding and 2 cutaneous hematoma in ASA • 2 musculoskeletal bleeding and 1 hemorrhagic gastritis in placebo

31. Secondary outcome • Death • 6 in ASA (1.4% per year ) vs. 5 in placebo (1.3% per year ) • Sudden death • 1 in each due to PE • Arterial events • 8 in ASA (1.9 % per year ) vs. 5 in placebo (1.3% per year )

32. AE • Gastric pain • 1 in ASA and 2 in placebo • 1 cutaneous reaction in ASA • Renal failure in ASA • Antiplatelet • 5 in ASA and 3 in placebo • Anticoagulant • 3 in ASA and 2 in placebo

33. Discussion • Aspirin therapy, begun after 6 to 18 months of oral anticoagulant treatment, reduces the rate of recurrence by about 40% • no apparent increase in the risk of major bleeding • Aspirin is a potential alternative to extended oral anticoagulant treatment for the long-term secondary prevention of venous thromboembolism

34. Limitation • Patients excluded • clinically significant thrombophilia • a bleeding event during the period of anticoagulant treatment • Reduction in the risk of recurrence is lower with aspirin than with these new oral agents (80% for dabigatran and rivaroxaban) or low dose warfarin (60%) • Underpowered for showing effect of aspirin on the incidence of IHD or CVA • The results may not apply to whom require aspirin for the prevention of arterial events

35. Strengths • Randomized, placebo controlled, double blinded • Treatment for 2 years • ITT analysis = On treatment analysis

36. Conclusion • Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment • With no apparent increase in the risk of major bleeding

37. Thanks for your attention!