1. Treatment of VTE Guidelines
2016 Update of ACCP
Treatment of VTE Guidelines
ACP 30th Congress, Anaheim
5 November 2016
Clive Kearon, McMaster University, Canada

2. Relevant Disclosures Research Support/P.I.
Canadian Institutes Health Research
“D-dimer Optimal Duration Study (DODS)”
Employee
No relevant
Consultant
Bayer Inc.
Major Stockholder
Speakers Bureau
Honoraria
Scientific Advisory Board

3. Overview Topics updated Grading of recommendations
Recommendations (for selected topics)

4. Update Topics: Which & Why

5. Update Topics: Which & Why
Old (in AT9)
New evidence
Controversial
New
Demand

6. Update Topics: Which & Why
Old (in AT9)
New evidence
Controversial
New
Demand
12 topics
26 statements
49 recommends
3 topics
4 statements
5 recommends

7. Topics Choice of anticoagulant Duration of anticoagulant
Aspirin for extended treatment
Isolated distal DVT & anticoagulation
Catheter Directed Thrombolysis for DVT
IVC filters additional to anticoagulation
Stockings to prevent PTS
Subsegmental PE & anticoagulation
Out of hospital PE treatment
PE: Lytics, Route & Catheter-based (3 topics)
Thromboendarterectomy for CTEPH
Upper DVT lytic therapy
Recurrent VTE treatment

8. Topics new new new Choice of anticoagulant Duration of anticoagulant
Aspirin for extended treatment
Isolated distal DVT & anticoagulation
Catheter Directed Thrombolysis for DVT
IVC filters additional to anticoagulation
Stockings to prevent PTS
Subsegmental PE & anticoagulation
Out of hospital PE treatment
PE: Lytics, Route & Catheter-based (3 topics)
Thromboendarterectomy for CTEPH
Upper DVT lytic therapy
Recurrent VTE treatment
new
new
new

9. Topics 7 I will review new new new Choice of anticoagulant
Duration of anticoagulant
Aspirin for extended treatment
Isolated distal DVT & anticoagulation
Catheter directed thrombolysis for DVT
IVC filters additional to anticoagulation
Stockings to prevent PTS
Subsegmental PE & anticoagulation
Out of hospital PE treatment
PE: Lytics, Route & Catheter-based (3)
Thromboendarterectomy for CTEPH
Upper DVT lytic therapy
Recurrent VTE treatment
new
new
new

10. Methods Systematic Review / Meta-Analysis
Predefined outcomes (VTE, Bleeding, Mortality)
Balance of benefits, harms/burden, costs
Quality of evidence
Recommendations

11. Grading of Recommendations

12. Grading of Recommendations
Strength (For or Against)
Grade 1: STRONG
(stated as: “We recommend…”)
clear benefit
applies to most
“just do it”
Grade 2: WEAK
(stated as: “We suggest…”)
not large benefit or
uncertain benefit
Decision strongly influenced by:
clinical differences
patient preference

13. Grading of Recommendations
Strength (For or Against)
Quality of Evidence A
Randomized Trials
Precise (narrow CIs) and
Bias very unlikely and
Consistent
Grade 1: STRONG
(stated as: “We recommend…”)
clear benefit
applies to most
“just do it” B
Randomized Trials
Less precise (wider CIs) or
Bias likely but not major or
Inconsistent
Grade 2: WEAK
(stated as: “We suggest…”)
not large benefit or
uncertain benefit
Decision strongly influenced by:
clinical differences
patient preference C
Randomized Trials
Major limitations
Observational Studies (only)
not very strong or exceptional

14. Choice of anticoagulant

15. Choice of anticoagulant
No Cancer
DOAC over VKA Grade 2B
VKA over LMWH Grade 2C
Cancer
LMWH over VKA Grade 2B
over DOAC Grade 2B

16. Choice of anticoagulant
No Cancer
DOAC over VKA Grade 2B
VKA over LMWH Grade 2C
similar efficacy
~2/3 major bleeding, ~1/2 ICB
easier for patients

17. Choice of anticoagulant
No Cancer
DOAC over VKA Grade 2B
VKA over LMWH Grade 2C
Cancer
LMWH over VKA Grade 2B
over DOAC Grade 2B

18. Choice of anticoagulant
Not Grade 1 for LMWH because:
VKA/DOAC often reasonable
(eg, no chemo, remission, non-metastatic, later)
No Cancer
DOAC over VKA Grade 2B
VKA over LMWH Grade 2C
Cancer
LMWH over VKA Grade 2B
over DOAC Grade 2B

19. for extended treatment VTE?
Aspirin
for extended treatment VTE?

20. Studies: 2 Participants: 1,224
ASA vs. Placebo for Extended Treatment Unprovoked VTE
Studies: 2 Participants: 1,224
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
VTE
Mod
0.65
(0.49, 0.86)
-60
(-24, -89)
Mj Bleeding
1.31
(0.48, 3.5) +4
(-6, +29)
Mortality
Low
0.82
(0.45, 1.5) -1
(-3, +3)
Simes Circ 2014

21. Studies: 2 Participants: 1,224
ASA vs. Placebo for Extended Treatment Unprovoked VTE
Studies: 2 Participants: 1,224
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
VTE
Mod
0.65
(0.49, 0.86)
-60
(-24, -89)
Mj Bleeding
1.31
(0.48, 3.5) +4
(-6, +29)
Mortality
Low
0.82
(0.45, 1.5) -1
(-3, +3)
Simes Circ 2014

22. Studies: 2 Participants: 1,224
ASA vs. Placebo for Extended Treatment Unprovoked VTE
Studies: 2 Participants: 1,224
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
VTE
Mod
0.65
(0.49, 0.86)
-60
(-24, -89)
Mj Bleeding
1.31
(0.48, 3.5) +4
(-6, +29)
Mortality
Low
0.82
(0.45, 1.5) -1
(-3, +3)
Simes Circ 2014

23. Studies: 2 Participants: 1,224
ASA vs. Placebo for Extended Treatment Unprovoked VTE
Studies: 2 Participants: 1,224
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
VTE
Mod
0.65
(0.49, 0.86)
-60
(-24, -89)
Mj Bleeding
1.31
(0.48, 3.5) +4
(-6, +29)
Mortality
Low
0.82
(0.45, 1.5) -1
(-3, +3)
Simes Circ 2014

24. Limitations Anticoagulants reduce VTE >80%
DOACS suggested if unprovoked & low/mod bleeding
Bleeding may be similar with ASA & DOACs
Both trials stopped early, and imprecision

25. Limitations Unprovoked proximal DVT or PE
Anticoagulants reduce VTE >80%
DOACS suggested if unprovoked & low risk bleeding
Bleeding may be similar with ASA & DOACs
Both trials stopped early, and imprecision
Unprovoked proximal DVT or PE
& stop anticoags & no contraindication
Aspirin over No aspirin Grade 2B

26. IVC Filters for DVT or PE

27. IVC Filters for DVT or PE (AT9)
Anticoagulated No Filter* Grade 1B
Not Anticoagulated Filter Grade 1B
(* may not apply to PE with hypotension)
Usual anticoagulation if becomes feasible# Grade 2B
(# permanent filter not a reason for indefinite anticoagulation)
Kearon et al CHEST 2012

28. IVCF vs. No IVCF if anticoagulated
PE + DVT + ≥1 severity factor (RVD in 2/3)
Studies: 1 Participants: F-U & Temp IVCF: 3 mo
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
PE-sympt*
Mod
2.0
(0.51, 7.9)
+15
(-7, +104)
Mj Bleeding
0.80
(0.32, 2.0)
-10
(-34, +49)
Mortality
1.25
(0.60, 2.6)
(-24, +96)
* Fatal PE: 6/6 vs 2/3
Mismetti, PREPIC 2, JAMA 2015

29. IVCF vs. No IVCF if anticoagulated
PE + DVT + ≥1 severity factor (RVD in 2/3)
Studies: 1 Participants: F-U & Temp IVCF: 3 mo
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
PE-sympt*
Mod
2.0
(0.51, 7.9)
+15
(-7, +104)
Mj Bleeding
0.80
(0.32, 2.0)
-10
(-34, +49)
Mortality
1.25
(0.60, 2.6)
(-24, +96)
* Fatal PE: 6/6 vs 2/3
Mismetti, PREPIC 2, JAMA 2015

30. IVCF vs. No IVCF if anticoagulated
PE + DVT + ≥1 severity factor (RVD in 2/3)
Studies: 1 Participants: F-U & Temp IVCF: 3 mo
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
PE-sympt*
Mod
2.0
(0.51, 7.9)
+15
(-7, +104)
Mj Bleeding
0.80
(0.32, 2.0)
-10
(-34, +49)
Mortality
1.25
(0.60, 2.6)
(-24, +96)
* Fatal PE: 6/6 vs 2/3
Mismetti, PREPIC 2, JAMA 2015

31. IVCF vs. No IVCF if anticoagulated
PE + DVT + ≥1 severity factor (RVD in 2/3)
Studies: 1 Participants: F-U & Temp IVCF: 3 mo
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
PE-sympt*
Mod
2.0
(0.51, 7.9)
+15
(-7, +104)
Mj Bleeding
0.80
(0.32, 2.0)
-10
(-34, +49)
Mortality
1.25
(0.60, 2.6)
(-24, +96)
* Fatal PE: 6/6 vs 2/3
Mismetti, PREPIC 2, JAMA 2015

32. IVC Filters for DVT or PE
Anticoagulated No Filter* Grade 1B
Not Anticoagulated Filter Grade 1B
(* may not apply to PE with hypotension)

33. Stockings to prevent PTS?

34. Stockings to prevent PTS?
AT9
Acute DVT GCS* Grade 2B
(*30-40 mmHg ankle, ≥ 2 yrs)

35. GCS vs. Placebo after DVT
Studies: 1 Participants: F-U: 2 years
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
PTS
Mod
1.01
(0.86, 1.18) +5
(-67, +86)
VTE
0.84
(0.54, 1.3)
-34
(-97, +65)
Pain & QoL
No difference
Kahn, SOX, Lancet 2014

36. GCS vs. Placebo after DVT
Studies: 1 Participants: F-U: 2 years
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
PTS
Mod
1.01
(0.86, 1.18) +5
(-67, +86)
VTE
0.84
(0.54, 1.3)
-34
(-97, +65)
Pain & QoL
No difference
Kahn, SOX, Lancet 2014

37. GCS vs. Placebo after DVT
Studies: 1 Participants: F-U: 2 years
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
PTS
Mod
1.01
(0.86, 1.18) +5
(-67, +86)
VTE
0.84
(0.54, 1.3)
-34
(-97, +65)
Pain & QoL
No difference
Kahn, SOX, Lancet 2014

38. GCS vs. Placebo after DVT
Studies: 1 Participants: F-U: 2 years
Qual Evid
(GRADE)
Hazard
Ratio
Difference
Per 1,000
PTS
Mod
1.01
(0.86, 1.18) +5
(-67, +86)
VTE
0.84
(0.54, 1.3)
-34
(-97, +65)
Pain & QoL
No difference
Kahn, SOX, Lancet 2014

39. Stockings to prevent PTS?
Acute DVT No GCS Grade 2B

40. Subsegmental PE (SSPE)

41. Subsegmental PE (SSPE) (must exclude proximal DVT if not anticoagulating)

42. SSPE & Recurrence Risk Convincing for SSPE good quality CTPA
surrounded by contrast
multiple
larger (≥1 image/projection)
Symptomatic, high CPTP
D-dimer elevated (marked, unexplained)

43. SSPE & Recurrence Risk Convincing for SSPE good quality CTPA
surrounded by contrast
multiple
larger (≥1 image/projection)
Symptomatic, high CPTP
Higher risk for progression
hospitalized/immobile
active cancer
no reversible RF
D-dimer elevated (marked, unexplained)

44. Others that favor no anticoagulation
SSPE & Recurrence Risk
Convincing for SSPE
good quality CTPA
surrounded by contrast
multiple
larger (≥1 image/projection)
Symptomatic, high CPTP
Higher risk for progression
hospitalized/immobile
active cancer
no reversible RF
D-dimer elevated (marked, unexplained)
Others that favor no anticoagulation
High bleeding risk; Good cardiopulmonary reserve
Patient preference

45. Others that favor no anticoagulation
SSPE & Recurrence Risk
Convincing for SSPE
good quality CTPA
surrounded by contrast
multiple
larger (≥1 image/projection)
Symptomatic, high CPTP
Higher risk for progression
hospitalized/immobile
active cancer
no reversible RF
D-dimer elevated (marked, unexplained)
Others that favor no anticoagulation
High bleeding risk; Good cardiopulmonary reserve
Patient preference

46. Subsegmental PE (SSPE) (must exclude proximal DVT if not anticoagulating)
Lower Risk Recurrence
Clinical surveillance over anticoagulation Grade 2C
Higher Risk Recurrence
Anticoagulation over clinical surveillance Grade 2C
(may repeat proximal US at 1 ± 2 wks)

47. PE and Systemic Thrombolysis
AT9
No hypotension (BP >90 mmHg) No Lysis Grade 1C
Hypotension & Not High Bleeding Risk Lysis Grade 2B

48. Fibrinolysis for Intermediate-Risk PE
RVD (echo or CTPA) Myocardial injury (troponin I or T)
1006 patients (tenecteplase ~0.5 mg or 100 U/kg)
7 days
Tenect.
Placebo
Diff.
Death 6 9 PE 1 7 -6
Bleeding 5 +5
Non-fatal Strokes +6
Major Bleeds 58 12
+46
Cardio Decomp. 8 25
-17
Meyer, PEITHO, NEJM 2014

49. Fibrinolysis for Intermediate-Risk PE
RVD (echo or CTPA) Myocardial injury (troponin I or T)
1006 patients (tenecteplase ~0.5 mg or 100 U/kg)
7 days
Tenect.
Placebo
Diff.
Death 6 9 PE 1 7 -6
Bleeding 5 +5
Non-fatal Strokes +6
Major Bleeds 58 12
+46
Cardio Decomp. 8 25
-17
Meyer, PEITHO, NEJM 2014

50. Fibrinolysis for Intermediate-Risk PE
RVD (echo or CTPA) Myocardial injury (troponin I or T)
1006 patients (tenecteplase ~0.5 mg or 100 U/kg)
7 days
Tenect.
Placebo
Diff.
Death 6 9 PE 1 7 -6
Bleeding 5 +5
Non-fatal Strokes +6
Major Bleeds 58 12
+46
Cardio Decomp. 8 25
-17
Meyer, PEITHO, NEJM 2014

51. PE and Systemic Thrombolysis
AT10
No hypotension (BP >90 mmHg) No Lysis Grade 1B
Hypotension & Not High Bleeding Risk Lysis Grade 2B

52. PE and Systemic Thrombolysis
AT10
No hypotension (BP >90 mmHg) No Lysis Grade 1B
Hypotension & Not High Bleeding Risk Lysis Grade 2B
Selected patients who deteriorate but not yet hypotensive
& low bleeding risk
(with qualifying remark)
No Lysis Grade 2C

53. Recurrent VTE on Anticoagulants

54. Recurrent VTE on Anticoagulants
Management will depend on circumstances

55. Recurrent VTE on Anticoagulants
Management will depend on circumstances
Treatment-related questions:
true recurrence?
started treatment recently?
adherent?
subtherapeutic INR?
drug-induced lowering of DOAC?
LMWH therapy?
stepped down dose?

56. Recurrent VTE on Anticoagulants
Management will depend on circumstances
Patient-related questions:
known cancer?
cancer needs to be excluded?
antiphospholipid antibody?
lupus anticoagulant increasing INR?
prothrombotic therapy (avoidable)?

57. Choice of anticoagulant
No Cancer
DOAC over VKA Grade 2B
VKA over LMWH Grade 2C
Cancer
LMWH over VKA Grade 2B
over DOAC Grade 2B

58. Recurrent VTE on Anticoagulants
On DOAC or VKA
(and no correctable cause)
Switch to LMWH (≥ 1 mo) Grade 2C
Already on LMWH
Increase dose ~25% (≥ 1 mo) Grade 2C

59. Take Home Messages DOACS over VKA
Aspirin after anticoags in unprovoked VTE if
Isolated SubSeg PE:YES: some; NO: others
Temporary IVCF & anticoagulated PE: NO
GCS to prevent PTS: NO
Lytics only if PE with hypotension
Recurrent VTE on anticoagulants
Correct cause, LMWH, higher dose LMWH