Review of anticoagulant use in VTE. As update as 2019 evidence available to me.

1. Update in VTE 2019
Focus on the current use of DOAC

2. Outline
Review the use of anticoagulant in VTE
Current use of DOAC in VTE
Prophylaxis
Treatment/secondary prevention
Clinical use in the future
Antidote of DOAC

3. The use of anticoagulant in VTE

4. The use of anticoagulant in VTE
Prophylaxis in high risk patients
Treatment/secondary prevention
Initial treatment
Duration of treatment
Investigation for the cause

5. Which patients need prophylaxis?
Risk of VTE in Asian population is actually high
In patients underwent TKA in PMK incidence of VTE was 61% on venogram1
In AIDA multinational study found 41% VTE on venogram2
In SMART multinational study found 1.2% symptomatic VTE3
This is comparable to 40-60% (1-14% symptomatic) in the western data
1. J Med Assoc Thai 2007;90(7):1342-7.
2. J Thromb Haemost 2005;3:2663-70. 3. J Thromb Haemost 2005;3:28–34.

6. Patient at risk of VTE
Surgical Non surgical

7. Model prediction in Sx
0 : very low : < 0.5%
1-2 : low : 1.5%
------------------------------------
3-4 : moderate : 3%
> 5 : high risk : 6%
Chest. 2012;141(2 Suppl):
e227S–e277S

8. 0 : very low : < 0.5%
1-2 : low : 1.5%
------------------------------------
3-4 : moderate : 3%
> 5 : high risk : 6%
Chest. 2012;141(2 Suppl):
e227S–e277S
Model prediction in Sx

9. Model prediction in non-Sx
High-risk patients
(score > 4)
---------------------------------------
DVT 6.7%
nonfatal PE 3.9%
fatal PE 0.4%
Chest. 2012;141(2 Suppl):
e195S–e226S

10. High-risk patients
(score > 4)
---------------------------------------
DVT 6.7%
nonfatal PE 3.9%
fatal PE 0.4%
Chest. 2012;141(2 Suppl):
e195S–e226S
Model prediction in non-Sx

11. Prevention in medical patients
Strong thrombotic risk
---------------------------------------
-
Active cancer
Previous VTE
Thrombophilia
Reduced mobility
Strong bleeding risk
---------------------------------------
-
Active UGIB
Recent bleeding < 3 mo
Plt < 50,000/mL

12. What modality?
Ambulation
Graduated compression stockinette
Intermittent pneumatic compression device
IVC filter
Medication

13. Medication prophylaxis
Low molecular weight heparin
Enoxaparin 40 mg SC OD
Enoxaparin 30 mg SC bid
Low dose unfractionated heparin bid or tid
Fondaparinux

14. Treatment of VTE
Initiate with LMWH or UFH
Follow by transition to VKA
Target INR 2-3 week
Duration of 3-6 months

15. Who deemed to need prolonged treatment?
No need for long term treatment if..
1 year recurrent risk < 5%
5 years recurrent risk < 15%
Provoked VTE risk is very low (<1%)
Unprovoked VTE risk is moderate (8%)
Recurrent/Thrombophilia/CA VTE risk is high (10%)
Hematology. 2018:426-31.

16. Who deemed to need prolonged treatment?
No need for long term treatment if..
1 year recurrent risk < 5%
5 years recurrent risk < 15%
Provoked VTE risk is very low (<1%)
Unprovoked VTE risk is moderate (8%)
Recurrent/Thrombophilia/CA VTE risk is high (10%)
Hematology. 2018:426-31.
Bleeding risk 1%/year with VKA
Bleeding risk 0.5-3.8%/year with
DOAC in real world practice
Bleeding complication have
mortality 3 time more!!

17. Direct oral anticoagulant

18. Available DOAC
Direct thrombin inhibitor
Dabigatran
Direct FXa inhibitor
Rivaroxaban, apixaban, edoxaban

19. Profiles of DOAC
Half life Elimination Prophylaxis Treatment Comment
Dabigatran 12-18 hr 80% renal Dabigatran 110 mg 1-4 hr
after Sx then 220 mg OD
150 mg bid Age > 80 y 110 mg bid;
LMWH 5 day then 110
mg bid
Rivaroxaban 5-13 hr 66% renal 10 mg OD 6-8 hr after Sx 15 mg bid x 3 wk
then 20 mg OD
Take with food to
increase absorption
Apixaban 12 hr 25% renal 2.5 mg bid 6-8 hr after Sx 10 mg bid x 7 day
then 5 mg bid
Edoxaban 10-14 hr 50% renal 30 mg OD 6-24 hr after Sx LMWH 5 day then
60 mg OD
Use 30 mg BW < 60kg,
CreClr < 50 mL/min,
strong p-GP inhibitor
use

20. Profiles of DOAC
Prophylaxis Treatment Comment
Dabigatran RE-NOVATE, RE-MODEL,
REMOBILIZE
RE-COVER
Rivaroxaban RECORD1/2/3/4 EINSTEIN PE/VTE
Apixaban ADVANCE1/3 AMPLIFY
Edoxaban STAR E-3/J-V Hokusai-VTE In Japan enoxaparin dose 20 mg q
12 hr for prophylaxis

21. Meta-analysis of DOAC vs VKA
Blood. 2014;124(12):1968-1975

22. Meta-analysis of DOAC vs VKA
RE-COVER
Dabigatran
EINSTEIN
Rivaroxaban
AMPLIFY
Apixaban
Hokusai VTE
Edoxaban
DOAC n = 13,512
vs
VKA n = 12,511
Recurrent VTE
Bleeding
Net clinical benefit
Blood. 2014;124(12):1968-1975

23. VTE and VTE-related death
Blood. 2014;124(12):1968-1975

24. Major bleeding
Blood. 2014;124(12):1968-1975

25. Bleeding by site
Blood. 2014;124(12):1968-1975

26. Net clinical benefit
Event in DOAC 3.2%
Event in VKA 4%
Relative risk 0.75 (95% CI 0.70-0.90)
Meta-analysis of DOAC vs VKA
Blood. 2014;124(12):1968-1975

27. Clinical use of DOAC in future

28. Extended use of DOAC
Can DOAC replace warfarin in Antiphospholipid syndrome?
Can DOAC replace LMWH in cancer associated VTE?

29. DOAC treatment in APS

30. RAPS trial design
APS patient
with VTE on
VKA at least
3 mo
Rivaroxaban 20 mg OD
N = 57
Warfarin INR 2.5
N = 59
ETP on
day 0
ETP on
day 42
210 days180 days
Recurrent
rate

31. RAPS trial
Baseline Day 42
VKA
Riva

32. RAPS trial
Rivaroxaban VKA
This trial did not design to detect clinical outcome
Relatively low risk population

33. DOAC treatment in high-risk APS
Blood 2018 132:1365-1371

34. TRAPS trial design
Triple positive
APS with VTE
Rivaroxaban 20 mg OD
N = 268
Warfarin INR 2.5
N = 268
4 years
Thrombotic and
bleeding event
Blood 2018 132:1365-1371

35. TRAPS trial was early terminate
Stroke 4
MI 3
Major bleeding 4
Major bleeding 2
Blood 2018 132:1365-1371

36. Conclusion of DOAC in APS
Warfarin is still the mainstay in APS
In high risk triple positive APS DOAC is clearly inferior to warfarin
In low risk APS there is insufficient evidence to recommend DOAC

37. DOAC in cancer associated VTE (CAT)
Currently there were two phase III trial
Hokusai-VTE in cancer : edoxaban vs dalteparin
SELECT-D : rivaroxaban vs dalteparin

38. Hokusai VTE cancer trial
N Engl J Med 2018;378:615-24

39. Hokusai VTE cancer trial
Pt with active cancer
Dx within 6 m
LMWH 5 days then
edoxaban 60 mg OD
N = 525
Dalteparin 200 U/kg OD x
30 days then 150 U/kg OD
N = 525
Treatment duration 6 -12
months
Primary outcome:
Recurrent + Major bleeding
N Engl J Med 2018;378:615-24

40. Hokusai VTE cancer trial
N Engl J Med 2018;378:615-24

41. Hokusai VTE cancer trial
Edoxaban was not inferior to dalteparin for the composite outcome
Edoxaban had lower recurrent but more bleeding events
GI tract cancer risk more bleeding with edoxaban
Duration of treatment was different (edoxaban 211 vs dalteparin 184 days)
N Engl J Med 2018;378:615-24

42. SELECT-D trial
J Clin Oncol 36:2017-2023.

43. SELECT-D trial
Pt with active cancer
Dx within 6 m
Rivaroxaban 15 mg bid x 3
wk then 20 mg OD
N = 203
Dalteparin 200 U/kg OD x
30 days then 150 U/kg OD
N = 203
Treatment duration 6 months
Primary outcome:
Recurrent VTE over 6 months
J Clin Oncol 36:2017-2023.

44. SELECT-D trial
HR 0.43
95% CI 0.19-0.99
J Clin Oncol 36:2017-2023.

45. SELECT-D trial
HR 3.76; 95% CI, 1.63 - 8.69
for CRNMB
HR 1.83
95% CI 0.68 - 4.96
J Clin Oncol 36:2017-2023.

46. Rivaroxaban can be used as an alternative to dalteparin in CAT
More bleeding with rivaroxaban especially in UGI cancer
SELECT-D trial
J Clin Oncol 36:2017-2023.

47. Conclusion of DOAC in CAT
There were two available evidence of DOAC in CAT: edoxaban, rivaroxaban
The efficacy were comparable to dalteparin (if not superior)
More bleeding risk especially in GI tract cancer
Class effect?
In selected patient with lower bleeding risk DOAC is good alternative

48. Reversal of DOAC

49. Idarucizumab
Monoclonal antibody
specifically bind
dabigatran

50. Idarucizumab
N Engl J Med 2015;373:511-20

51. Idarucizumab
Group A
life threatening
N = 51
Group B
Urgent procedure
N = 39
Idarucizumab
2.5 g
Idarucizumab
2.5 g
Reversal of
coagulogram within
4 hr
N Engl J Med 2015;373:511-20

52. Idarucizumab
Level of unbound
dabigatran
decrease after
the first infusion
N Engl J Med 2015;373:511-20

53. Idarucizumab
89% 88%
Time to
cessation of
bleeding 11.4 hr
N Engl J Med 2015;373:511-20

54. Andexanet
Modified recombinant human FXa
Lack of membrane binding site

55. Andexanet
N Engl J Med 2016; 375:1131-1141

56. Andexanet
Patient with bleeding
with 18 hr of anti FXa
N = 352
Intracranial 227
GIB 90
Efficacy in major bleeding +
anti Xa level > 75 ng/mL
- Reversal of anti-FXa
- Cessation of bleeding at 12 hr
Bolus dose
400 mg/15min
800 mg/30min
Infusion/2 hr
480 mg
960 mg
N Engl J Med 2016; 375:1131-1141

57. Andexanet effect on anti-FXa
Base line After infusion % reduction
Apixaban 149.7 ng/mL 11.1 ng/mL 92% (91-93)
Rivaroxaban 211.8 ng/mL 14.2 ng/mL 92% (88-94)
Enoxaparin 0.48 IU 0.15 IU 75% (66-79
N Engl J Med 2016; 375:1131-1141

58. Andexanet effect on anti-FXa
N Engl J Med 2016; 375:1131-1141

59. Andexanet
Good or better hemostatic efficacy at 12 hr was 82%
Death occurred in 14%
Thrombotic events 10%
The study was extended to recruit more patients with edoxaban treatment
N Engl J Med 2016; 375:1131-1141

60. Conclusion of antidote of DOAC
There are two antidote of DOAC available now
Idarucizumab for dabigatran
Andexanet for rivaroxaban, apixaban, (edoxaban)
The drugs have very fast onset and short half life
Anticoagulant should be restart as seen as possible

61. Conclusion

62. Conclusion
DOACs have comparable to standard of VTE treatment and prophylaxis
Not recommend in APS
May be acceptable in selected cancer associated VTE
Antidotes are currently available for dabigatran

63. Thank you for your attention
Q&A