1. VTE Guidelines: 2016 update
Kelsey Van Gorkom, Pharm.D.
PGY-2 Geriatric Specialty Pharmacy Resident, CAVHS
AAHP Fall Seminar
September 29th, 2016

2. Disclosures
None

3. Objectives
Review the changes to the CHEST guidelines for VTE treatment.
Evaluate landmark trials leading to the approval of direct oral anticoagulants and use in VTE.
Construct a treatment plan to include selection of the appropriate anticoagulant and treatment duration.

4. Abbreviations DOAC: direct oral anticoagulant
VTE: venous thromboembolism
DVT: deep vein thrombosis
PE: pulmonary embolism
PTS: post-thrombotic syndrome
CDT: catheter directed thrombolysis
LMWH: low molecular weight heparin
UFH: unfractionated heparin

5. Proximal DVT
Distal DVT
Intro-VTE
3rd most common cause of cardiovascular morbidity and mortality
Proximal DVT accounts for ~80%
Typical treatment: anticoagulation therapy and compression stockings
Enden, T et al. Lancet. 2012;379:31-38.
Bashir R, et al. JAMA Intern Med ;174(9):
Image: S.Standring, ed. Overview of veins of the lower limb. In: Grays Anatomy, 39th ed, 2005, figure 110.5, page 1403, Elsevier Ltd.

6. Virchow’s Triad Hypercoagulability Stasis of blood flow
Factor V Leiden
Hyperhomocysteinemia
Protein C/S def
Antithrombin def
Malignancy
Estrogen therapy
Pregnancy
Atrial fibrillation
Left ventricular dysfunction
Bed rest
Paralysis
Venous obstruction
Endothelial injury
Atherosclerosis
Vascular injury/trauma
Abnormal or mechanical heart valve
Indwelling vascular catheter

7. Post-thrombotic syndrome (PTS)
Pain, swelling, heaviness, edema, ulcerations
20-50% of patients with proximal DVT
Occurs with anticoagulation and compression stockings therapy
Quality of life impairment
Bashir R, et al. JAMA Intern Med ;174(9):

8. Key changes in the 2016 VTE update
DOACs are suggested over warfarin for initial and long-term treatment of VTE in patients without cancer (Grade 2B)
Routine use of compression stockings is no longer recommended to prevent PTS (Grade 2B)
Subsegmental pulmonary embolism
Who should/should not receive therapy
Kearon et al. CHEST. 2016;149(2):

9. Key changes in level of evidence
Discouragement of IVC filter use in anticoagulated patients
Evaluation of indefinite anticoagulant therapy after a first unprovoked VTE based on risk vs benefit
Discouragement of thrombolytic therapy in PE patients who are not hypotensive and are not deteriorating on anticoagulation
Kearon et al. CHEST. 2016;149(2):

10. DOACs vs. warfarin In patient with VTE and no cancer:
Dabigatran, rivaroxaban, apixaban, or edoxaban over VKA (Grade 2B)
Lower risk of bleeding
Comparable recurrent VTE risk reduction
2010
Pradaxa
2011
Xarelto
2012 CHEST 9th ed
2012
Eliquis
2014
Edoxaban

11. Landmark trials Dabigatran Rivaroxaban Apixaban Edoxaban
RE-COVER (2009)
RE-COVER II (2014)
Rivaroxaban
EINSTEIN-DVT (2010)
EINSTEIN-PE (2012)
Apixaban
AMPLIFY (2013)
Edoxaban
HOKUSAI-VTE (2013)

12. RE-COVER Randomized, double-blind, double dummy, non-inferiority trial
Dabigatran 150mg BID or LMWH/warfarin with goal INR 2-3
Enrollment from , follow up ~6 months
Primary endpoint (efficacy): recurrent VTE or VTE related death
Secondary endpoints (safety): bleeding events, ACS
Result: dabigatran noninferior to warfarin in recurrent VTE and related deaths and major bleeding
Schulman S, et al. N Engl J Med. 2009;361(24):

13. RE-COVER: VTE or VTE- related death
2.4% in dabigatran group
2.1% in warfarin group
HR 1.10 (95% CI 0.65 to 1.84)
Schulman S, et al. N Engl J Med. 2009;361(24):

14. RE-COVER: Bleeding rates
Major bleeding:
1.6% in dabigatran group
1.9% in warfarin group
HR 0.82 (95% CI 0.45 to 1.48)
Non-major bleeding:
5.6% in dabigatran group
8.8% in warfarin group
HR 0.63 (95% CI )
Schulman S, et al. N Engl J Med. 2009;361(24):

15. RE-COVER 2 Randomized, double blind, double dummy trial
Dabigatran 150mg BID or LMWH/warfarin with goal INR 2-3
Enrollment from , ~6 month follow up
Primary outcome: recurrent VTE and VTE related death
Secondary outcomes (safety): major bleeding, clinically relevant nonmajor bleeding
Higher incidence of GI bleeds, ACS in dabigatran group
Results: dabigatran non-inferior to warfarin in VTE recurrence and related death and major bleeding
Schulman S, et al. Circulation. 2014;129:

16. RECOVER 2: VTE or VTE related death
2.3% in dabigatran group
2.2% in warfarin group
HR 1.08 (95% CI 0.64 to 1.80)
Schulman S et al. Circulation. 2014;129:

17. RECOVER 2: Bleeding rates
Major bleeding:
1.2% in dabigatran group
1.7% in warfarin group
HR 0.69 (95% CI 0.36 to 1.32)
Any bleeding:
15.6% in dabigatran group
22.1% in warfarin group
HR 0.67 (95% CI )
Schulman S, et al. Circulation. 2014;129:

18. Dabigatran Dosing (following 5-10 days parenteral anticoagulation)
150mg PO twice daily
CrCl ≤30mL/min: no recommendations available
CrCl <50mL with concomitant PGP inhibitors: avoid use
Drug interactions:
Dronedarone, ketoconazole, verapamil, amiodarone
Use with caution in patients with CAD
Dabigatran. Micromedex 2.0. Accessed August 20, 2016.

19. EINSTEIN-DVT
Randomized, open-label, event-driven, noninferiority trial
Rivaroxaban 15mg BID x 21 days, then 20mg daily vs LMWH/VKA
Randomized, double-blind, event-drive superiority trial
Rivaroxaban 20mg daily vs placebo for additional 6 or 12 months
Enrollment from:
Primary endpoint (efficacy): recurrent VTE
Secondary endpoint (safety): clinically relevant bleeding
Results: rivaroxaban noninferior to LMWH/VKA in VTE recurrence and major bleeding
Bauersachs R, et al. N Engl J Med. 2010;363(26):

20. EINSTEIN DVT: VTE or VTE related death
2.1% in rivaroxaban group
3% in LMWH/VKA group
HR 0.68 (95% CI )
Bauersachs R, et al. N Engl J Med. 2010;363(26):

21. EINSTEIN DVT: Bleeding rates
8.1% in rivaroxaban group
8.1% in LMWH/VKA group
HR 0.97 (95% CI )
Bauersachs R, et al. N Engl J Med. 2010;363(26):

22. EINSTEIN-PE Randomized, open-label, event-drive, non-inferiority trial
Rivaroxaban 15mg BID x21days vs LMWH/VKA
Enrollment from
Primary outcome (efficacy): recurrent VTE
Secondary outcome (safety): major or clinically relevant nonmajor bleeding
Results: rivaroxaban noninferior to warfarin in VTE recurrence and superior in major bleeding
Buller HR, et al. N Engl J Med. 2012;366(14):

23. EINSTEIN PE: VTE 2.1% in rivaroxaban group 1.8% in LMWH/VKA group
HR 1.12 (95% CI )
Buller HR, et al. N Engl J Med. 2012;366(14):

24. EINSTEIN PE: Bleeding rates
1.1% in rivaroxaban group
2.2% in LMWH/VKA group
HR 0.49 (95% CI )
Buller HR, et al. N Engl J Med. 2012;366(14):

25. Rivaroxaban Dosing CrCl < 30ml/min: avoid use Drug interactions:
15mg BID x 21days, then 20mg daily
Take with food to increase absorption
CrCl < 30ml/min: avoid use
Drug interactions:
Dronedarone, ketoconazole, verapamil, amiodarone
Rivaroxaban. Micromedex 2.0. Accessed August 20, 2016.

26. AMPLIFY Randomized, double-blind, noninferiority trial
Apixaban 10mg BID x 7 days, then 5mg BID compared to SQ enoxaparin followed by warfarin
Primary endpoint (efficacy): recurrent VTE or death related to VTE
Secondary endpoint (safety): major bleeding and major bleeding
Result: apixaban noninferior for VTE recurrence, superior in major bleeding
Agnelli G, et al. N Engl J Med. 2013;369(9):

27. AMPLIFY: VTE or VTE-related death
2.3% in apixaban group
2.7% in warfarin
RR 0.84 (95% CI 0.60 to 1.18)
Agnelli G, et al. N Engl J Med. 2013;369(9):

28. AMPLIFY: major bleeding
0.6% in apixaban group
1.8% in warfarin group
RR 0.31 (95% CI -1.7 to -0.6)
Agnelli G, et al. N Engl J Med. 2013;369(9):

29. Apixaban Dosing Dose adjustments Drug interactions:
10mg twice daily x 7 days, then 5mg twice daily
Dose adjustments
No dose adjustments recommended
SCr >2.5mg/dL or CrCl<25mL/min excluded from clinical trials
Drug interactions:
Clarithromycin, ketoconazole, ritonavir
Apixaban. Micromedex 2.0. Accessed August 20, 2016.

30. HOKUSAI-VTE Randomized, double-blind, noninferiority trial
Edoxaban 60mg daily vs edoxaban 30mg daily vs warfarin
Enrollment from , 3 to 12 month follow up
Primary outcome (efficacy): recurrent VTE
Secondary outcome (safety): major or clinically relevant nonmajor bleeding
Results: edoxaban noninferior to warfarin for VTE recurrence, superior to warfarin for major bleeding
Buller HR, et al. N Engl J Med. 2013;365(15):

31. HOKUSAI-VTE: VTE 3.2% in edoxaban group 3.5% in warfarin group
HR 0.89 (95% CI 0.7 to 1.13)
PE subgroup:
3.3% in edoxaban group
6.2% in warfarin group
HR 0.52, (95%CI )
Buller HR, et al. N Engl J Med. 2013;365(15):

32. HOKUSAI VTE: Bleeding rates
8.5% in edoxaban group
10.3% in warfarin group
HR 0.81 (95% CI 0.71 to 0.94)
Buller HR, et al. N Engl J Med. 2013;365(15):

33. Edoxaban Dosing Dose adjustments Drug interactions
60mg PO once daily following 5-10 days parenteral anticoagulation
<60kg: 30 mg once daily
Dose adjustments
< 60kg: 30mg once daily
CrCl mL/min: 30mg once daily
CrCl <15 mL/min: avoid use
Drug interactions
Use with specific PGP inhibitors: 30mg once daily
Verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, ketoconazole
Edoxaban. Micromedex 2.0. Accessed August 20, 2016.

34. Warfarin Place in therapy:
VKA recommended over LMWH (Grade 2C) in patients without cancer who do not take a DOAC
VKA recommended over LMWH (Grade 2C)
Kearon et al. CHEST. 2016;149(2):

35. LMWH Place in therapy: Patients with VTE and cancer
Recommend LMWH over VKA, DOACs (Grade 2C)
Kearon et al. CHEST. 2016;149(2):

36. Aspirin
Since AT9, 2 trials have compared ASA with placebo for prevention of recurrent VTE
Place in therapy
“In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B).”
Kearon et al. CHEST. 2016;149(2):

37. INSPIRE study
Aspirin for the prevention of recurrent venous thromboembolism
Randomized, double blind, placebo controlled trial
1224 patients
Aspirin EC 100mg: 616 patients
Placebo: 608 patients
Primary outcome: recurrent VTE
Secondary outcome: major bleeding
Simes J, et al. Circulation. 2014;130:

38. INSPIRE Results Primary outcome: recurrent VTE
Aspirin 5.1%
Placebo 7.5%
HR 0.58 (95% CI )
Secondary outcome: major bleeding
Aspirin 1.1%
Placebo 0.7%
HR 1.5 (95% CI )
Simes J, et al. Circulation. 2014;130:

39. Preferred anticoagulant Notes Cancer LMWH
Factor
Preferred anticoagulant
Notes
Cancer
LMWH
Want to avoid parenteral therapy
Rivaroxaban; apixaban
VKA, edoxaban, dabigatran require initial parenteral anticoagulation
Once daily therapy preferred
Rivaroxaban; edoxaban; VKA
Liver disease with coagulopathy
DOACs CI if INR raised due to liver disease
CrCl <30 mL/min
VKA
DOACs and LMWH CO with severe renal impairment
CAD
VKA; rivaroxaban; apixaban; edoxaban
ACS more often with dabigatran than with VKA
Hx GI bleeding; dyspepsia
VKA; apixaban
Dabigatran had high incidence of dyspepsia and GIB; rivaroxban and edoxaban may be associated with higher rate of GIB compared to VKA
Kearon et al. CHEST. 2016;149(2):

40. Recurrent VTE
VTE recurrence while on VKA, dabigatran, rivaroxaban, apixaban, or edoxaban
Recommend treating with LMWH for at least 1 month (Grade 2C)
Recurrent VTE on long-term LMWH
Increase dose of LMWH by 25-33% (Grade 2C)
Evaluate:
Compliance
Underlying malignancy
True recurrence
Kearon et al. CHEST. 2016;149(2):

41. 1st deep vein thrombosis (DVT) with transient risk factor
Indication
Duration of Therapy
1st deep vein thrombosis (DVT) with transient risk factor
3 months (Grade 1B)
1st unprovoked DVT proximal
Low to moderate bleed risk
High bleed risk
Chronic (2B)
3 months (1B)
1st unprovoked DVT distal
2nd unprovoked DVT
Chronic(1B)
3 months (2B)
Kearon C, et al. CHEST 2016; 149(2):
You J, et al. CHEST 2012; 133:531S-575S .

42. 1st pulmonary embolism (PE) with transient risk factor 3 months (1B)
Indication
Duration of Therapy
1st pulmonary embolism (PE) with transient risk factor
3 months (1B)
1st unprovoked PE
Low to moderate bleed risk
High bleed risk
Chronic (2B)
2nd unprovoked PE
Chronic (1B)
3 months (2B)
Kearon C, et al. CHEST 2016; 149(2):
You J, et al. CHEST 2012; 133:531S-575S .

43. Compression stockings
“…we suggest not using compression stockings routinely to prevent PTS (Grade 2b)”
2014 RCT found that routine use did not reduce PTS
May use for acute or chronic symptoms
Previously recommended to use for 2 years following
Kahn, et al. Lancet. 2014;383(9920):
Kearon et al. CHEST. 2016;149(2):

44. Compression stockings to prevent post-thrombotic syndrome
Multicenter, randomized, placebo-controlled trial
Enrollment 2004 to 2010
Compression stockings: 410 patients
Placebo: 396 patients
Primary outcome: diagnosis of PTS at 6 months or later
Compression stockings: 14.2% PTS
Placebo: 12.7% PTS
HR 1.13 (95% CI )
Results: routine use of graduated compression stockings did NOT reduce PTS or have other important benefits
Kahn SR, et al. Lancet. 2014;383(9920):880-8

45. Subsegmental PE
Subsegmental PE : no involvement of more proximal pulmonary arteries
Likely to have risen from a small DVT
US to exclude proximal DVT
“Whether the risk of progressive or recurrent VTE is high enough to justify anticoagulation in patients with subsegmental PE is uncertain.”
Kearon et al. CHEST. 2016;149(2):

46. Subsegmental PE Low risk for recurrent VTE High risk for recurrent VTE
Clincial surveillance over anticoagulation (Grade 2c)
High risk for recurrent VTE
Hospitalized/ reduced mobility
Active cancer
No reversible risk factor for VTE
Anticoagulation over clinical surveillance (Grade 2c)
Kearon et al. CHEST. 2016;149(2):

47. Acute PE
Treat at home or early discharge recommended over standard discharge (Grade 2B)
Low risk
Clinically stable
No recent bleeding
No renal/hepatic impairment
No severe thrombocytopenia
Expected to be compliant
Previously recommended early discharge over standard discharge
Kearon et al. CHEST. 2016;149(2):

48. Systemic thrombolytic therapy
“In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1B).”
“In selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C).”
Cardiac biomarkers
Vital signs
Tissue perfusion
Kearon et al. CHEST. 2016;149(2):

49. Fibrinolysis for patients with intermediate-risk PE
Randomized, double-blind, placebo-controlled
Tenecteplase and heparin or heparin alone
Primary outcome: death or hemodynamic decompensation
Secondary outcome: extracranial bleeding, ischemic or hemorrhagic stroke
Results:
Thrombolytic therapy prevented cardiovascular collapse but increased major bleeding
“no convincing net benefit from thrombolytic therapy”
Thrombolysis in patients who developed cardiovascular collapse after initially being treated with anticoagulant alone showed benefit
Kearon et al. CHEST. 2016;149(2):

50. Catheter directed thrombolysis
Localized delivery of thrombolytic agents directly into the thrombus
Possibly more effective in achieving local resolution of the thrombus
Reduces bleeding complications
Various types of catheters used
“For patients who require thrombolytic therapy and do not have a high risk of bleeding, the AT10 panel favored systemic thrombolytic therapy over CDT…higher quality of evidence to support systemic…”
Enden, T et al. Lancet. 2012;379:31-38.
Image:

51. CDT for PE
In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombolytic therapy using a peripheral vein over CDT (Grade 2C).”
“In patients with acute PE associated with hypotension and who have (i) high bleeding risk, (ii) failed systemic thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such intervention (Grade 2C).”
Kearon et al. CHEST. 2016;149(2):

52. CDT CAVENT trial 2012 Bashir, et al. 2014
Open-label, randomized controlled trial (189 patients)
CDT plus LMWH/VKA vs LMWH/ VKA
Assessed venous patency and bleeding following DVT
CDT reduced PTS, appears to be cost-effective
Bashir, et al. 2014
Retrospective review (3649 patients)
CDT associated with increase in transfusions, intracranial bleeds, PE, vena cava filter insertion
Long term outcomes and PTS not reported
Kearon et al. CHEST. 2016;149(2):
Enden, T et al. Lancet. 2012;379:31-38.
Bashir R, et al. JAMA Intern Med ;174(9):

53. Patients most likely to benefit from CDT
Iliofemoral DVT
Symptoms for <14 days
Good functional status
Life expectancy ≥1 year
Low risk of bleeding
Kearon et al. CHEST. 2016;149(2):

54. Pulmonary Thromboembolectomy
“In selected patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are identified by an experienced thromboendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C).”
Kearon et al. CHEST. 2016;149(2):

55. IVC filter
NOT recommended in combination with patients on anticoagulation (Grade 1B).
Based on results of PREPIC2 trial
IVC plus anticoagulation
No reduction in recurrent PE
Kearon C, et al. CHEST. 2016;149(2):
Mismetti P et al. JAMA. 2015;313(16):

56. Acknowledgements
David Dillinger, Pharm.D., BCACP

57. Question
Which of the following are not classified as an anticoagulant indicated in VTE?
Apixaban
Warfarin
Edoxaban
Clopidogrel

58. References
Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. NEJM ;361:
Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):
Bauersachs R, Berkowitz S, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. NEJM.2010;363(26): Doi: /NEJMoa
Buller H, Prins M, Lensing A, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. NEJM.2012;366(14): Doi: /NEJMoa
Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. NEJM. 2013;369:
Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:
Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE Collaboration. Circulation. 2014;130:
Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383(9920):
Enden T, Haig Y, Klow NE, et al. Long-term outcome after additionalcatheter-directed thrombolysis versus standard treatment for acuteiliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012;379(9810):31-38.
Bashir R, Zack CJ, Zhao H, Comerota AJ, Bove AA. Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med. 2014;174(9):

59. Image: http://www.pharmacy-tech-resources.com/images/Questions.jpg