1) There is a considerable risk of recurrent venous thromboembolism (VTE) after stopping anticoagulation treatment, ranging from 3-15% per year depending on risk factors. 2) Cancer patients have a high risk of both recurrent VTE and bleeding during anticoagulation treatment. 3) Patients with a provoked VTE have a low recurrence risk of around 3% per year, while those with an unprovoked VTE have a risk up to 15% per year. 4) The risk of recurrence increases as soon as anticoagulation is stopped regardless of the previous duration of treatment.

1. Optimal duration of venous thrombosis treatment
Sabine Eichinger
Div. of Hematology and Hemostasis
Medical University of Vienna, Austria

2. Treatment of venous thromboembolism (VTE)
acute subacute chronic
2 weeks up to 3 - 6 months > 6 months
Heparin Vitamin K antagonists
acute subacute extendedRivaroxaban
2 weeks up to 3 - 6 months > 6 months2 weeks up to 3 - 6 months

3. Treatment of VTE
Months since randomization
Recurrencerisk(%)
Schulman, N Eng J Med 2013
Placebo
Anticoagulant
R
OAC ~ 6 mo
VTE

4. Take home!
• Considerable risk of recurrent VTE after stopping anticoagulation

5. Recurrence risk after VTE

6. Recurrence risk after VTE
Probabilityofrecurrence(%)
Years after anticoagulation
0 1 2 5 63 4
0
40
20
10
30
50

7. Baglin, J Thromb Haemost 2010
Recurrence risk after VTE
Location of VTE
PE (+DVT) Proximal DVT Distal DVT
Recurrence
(95% CI)
Year 1 7.4% (5.7-9.5) 8.4% (6.9-10.2) none
Year 5 22% (16.3-29.8) 26.4% (20.5-34.1) 7.6% (3.0-18.9)
Initial Diagnosis

8. Iorio, Arch Int Med 2010
Transient risk factor
Recurrence risk after VTE
3.3%/year

9. Prandoni, Blood 2002
Cancer patients
Recurrence during VKA
Anticoagulation after VTE
Major bleeding during VKA

10. Cancer patients
Anticoagulation after VTE
LMWH for 6 months
Complete remission +
no additional risk factors
Chemotherapy
Interventions
Stable disease
Patient‘s preference
Stop anticoagulation LMWH Oral anticoagulants
Active cancer ±
additional risk factors

11. Take home!
• Considerable risk of recurrent VTE after stopping anticoagulation
• Cancer patients are at high risk of recurrent VTE and bleeding
• Provoked VTE  low risk (~3%/yr)

12. Unprovoked VTE
Kyrle & Eichinger, Lancet 2010
Recurrence risk after VTE

13. Take home!
• Considerable risk of recurrent VTE after stopping anticoagulation
• Cancer patients are at high risk of recurrent VTE and bleeding
• Provoked VTE  low risk (~3%/yr)
• Unprovoked VTE  high risk (up to 15%/yr)

14. Treatment of VTE
Months since randomization
Recurrencerisk(%)
Schulman, N Eng J Med 2013
Placebo
Anticoagulant
R
OAC ~ 6 mo
VTE

15. Linkins, Ann Intern Med 2003
Time period of AC
Major bleeding
(%, 95% CI)
Intracranial bleeding
(%, 95% CI)
Initial 3 months 2.06 (2.04-2.08) 1.48 (1.40–1.56)
> 3 months 2.74 (2.71-2.77)/yr 0.65 (0.63–0.68)/yr
Bleeding during anticoagulation for VTE
Case fatality rate after 3 mo 9.1% (95% CI 2.5–21.7%)

16. Take home!
• Considerable risk of recurrent VTE after stopping anticoagulation
• Cancer patients are at high risk of recurrent VTE and bleeding
• Provoked VTE  low risk (~3%/yr)
• Unprovoked VTE  high risk (up to 15%/yr)
• Low recurrence risk during anticoagulation
• Risk of bleeding

17. Treatment of VTE
Months since randomization
Recurrencerisk(%)
Schulman, N Eng J Med 2013
Placebo
Anticoagulant
R
OAC ~ 6 mo
VTE

18. Duration of anticoagulation
Boutitie, BMJ 2011
Recurrence risk after VTE
6 12 18 months

19. Take home!
• Considerable risk of recurrent VTE after stopping anticoagulation
• Cancer patients are at high risk of recurrent VTE and bleeding
• Provoked VTE  low risk (~3%/yr)
• Unprovoked VTE  high risk (up to 15%/yr)
• Low recurrence risk during anticoagulation
• Risk of bleeding
• Recurrence risk increases as soon as anticoagulation is stopped
regardless of previous duration

20. Take home!
• Considerable risk of recurrent VTE after stopping anticoagulation
• Cancer patients are at high risk of recurrent VTE and bleeding
• Provoked VTE  low risk (~3%/yr)
• Unprovoked VTE  high risk (up to 15%/yr)
• Low recurrence risk during anticoagulation
• Risk of bleeding
• Recurrence risk increases as soon as anticoagulation is stopped
regardless of previous duration
• The case/fatality rate of recurrence is low (<5%)
• The case/fatality rate of severe bleeding while on anticoagulants is
high (~10%)

21. Management of patients with unprovoked VTE
• Identifying patients with low recurrence risk
– Thrombophilia screening

22. Risk factors of recurrence
HR 95% CI
Laboratory abnormality
Any vs. none
1.4 0.9 - 2.3
Men vs. women 2.7 1.8 - 4.2
Idiopathic vs. provoked 1.9 1.2 - 2.9
Christiansen, JAMA 2005

23. no RF
1 RF
2 RF
3 RF
4 RF
Risk factors (RF) in 158 pts with a second VTE
35%24%
40%
factor V Leiden, factor II G20210A, HHC, high factor VIII or IX
Kyrle & Eichinger, Lancet 2010

24. Management of patients with unprovoked VTE
• Identifying patients with low recurrence risk
– Thrombophilia screening
– Residual vein thrombosis

25. Management of patients with unprovoked VTE
• Identifying patients with low recurrence risk
– Thrombophilia screening
– Residual vein thrombosis
– D-Dimer
– Prediction models

26. Nomogram to predict recurrence:
Vienna Prediction ModelEichinger, Circulation 2010

27. Management of patients with unprovoked VTE
• Identifying patients with low recurrence risk
• Alternative antithrombotic concepts

28. Direct oral anticoagulants
EINSTEINext
Einstein Inv.
NEJM 2010
AMPLIFYext
Agnelli
NEJM 2012
RE-SONATE
Schulman
NEJM 2013
RE-MEDY
Schulman
NEJM 2013
Patients, n 1197 2486 1343 2856
Study drug
Rivaroxaban
1 x 20 mg
Apixaban
2 x 5 mg
2 x 2.5 mg
Dabigatran
2 x 150 mg
Dabigatran
2 x 150 mg
Control Placebo Placebo Placebo Warfarin

29. Recurrent VTE and related death
EINSTEINext - secondary prevention of VTE
EINSTEIN Investigators, N Engl J Med 2010

30. Agnelli, N Eng J Med 2013
Recurrent VTE and related death
AMPLIFYext - secondary prevention of VTE

31. RESONATE - secondary prevention of VTE
Recurrent VTE and related death
Schulman, N Eng J Med 2013

32. REMEDY - secondary prevention of VTE
Recurrent VTE and related death
Schulman, N Eng J Med 2013

33. Patients, n (%) Hazard Ratio (95% CI)
Rivaroxaban
Placebo
36 (6.0)
7 (1.2)
5.19 (2.3 – 11.7)
Apixaban
2.5 mg
5.0 mg
Placebo
27 (3.2)
35 (4.3)
22 (2.7)
1.20 (0.69 – 2.10)
1.62 (0.96 – 2.73)
Dabigatran
Placebo
36 (5.3)
12 (1.8)
2.92 (1.52 – 5.60)
Dabigatran
Warfarin
80 (5.6)
145 (10.2)
0.54 (0.41 – 0.71)
Major and clinically relevant non major bleeding

34. Aspirin for longterm prophylaxis of VTE
Brighton, N Engl J Med 2012

35. Anticoagulation after venous thrombosis
3 months long term
distal DVT
provoked* VTE unprovoked VTE
stop: bleeding risk
recurrence risk
alternative: rivaroxaban
aspirin
* Surgery, trauma, immobilisation, pregnancy/puerperium, female hormone intake, long haul travel
AWMF online, 6/20109th ACCP Consensus Conference on Antithrombotic Therapy; Kearon, Chest 2012