This document discusses venous thromboembolism (VTE) and anticoagulation in cancer patients. It notes that cancer patients have a higher risk of VTE than non-cancer patients, and that VTE is a common cause of death in cancer patients. For initial treatment of VTE, low molecular weight heparin (LMWH) is the standard of care based on clinical trial evidence showing it reduces VTE recurrence compared to warfarin without increasing bleeding risk. For long-term treatment, LMWH is also preferred over warfarin due to warfarin's interactions with cancer and its treatments. Direct oral anticoagulants are an emerging option but more research is needed before recommending

1. Venous Thromboembolism (VTE)
and Anticoagulation
in Cancer
Anita Rajasekhar, MD, MS
FLASCO Spring Session
April 9, 2016

2. Overview
• Cancer and VTE risk
• Which anticoagulants to use in initial and
long-term treatment of VTE in cancer?
• Strategies for treatment of recurrent VTE
• When, if ever, to stop anticoagulant therapy?

3. Initial thoughts about cancer and VTE
• VTE causes death in 1/7 cancer patients
– 2nd leading cause of death behind cancer itself
• VTE relapse 6x higher in cancer patients than in
non-cancer patients
• Cancer patients bleed 4x more than non-cancer
patients on warfarin
• Thrombosis is associated with higher mortality
risk irrespective of cancer stage
Thodiyil et al. Cancer Treat Rev 2002; 28:151-155
Altinhas et al. JTH 2000; 2:1266-1271
Shen et al. South Med J 1980; 73:841-843
Bona et al. Am J Clin Oncol 2000; 23:71-73
Gitter et al. Mayo Clin Proc 1995; 70:725-733
Khorana et al JTH 2007 5;632-634

5. Options
Warfarin
Heparin LMWH
Dabigatran
Fondaparinux
1930 1954 1993 2001 2010 2011 2012 2015
Rivaroxaban
Apixaban
Edoxaban

6. VTE Treatment Phases and Anticoagulant Options
Induction: (<1 wk) Consolidation (1 wk- 3mos) Maintenance or Extended (> 3 mos)
ACTIVE TREATMENT SECONDARY PREVENTION

7. Consensus Guidelines for Initial Treatment VTE in Cancer
ACCP 2016 NCCN 2015 ASCO 2015
Not addressed LMWH (preferred)
• Dalteparin 200u/kg QD
• Enoxaparin 1mg/kg BID
• Tinzaparin 175u/kg QD
Fondaparinux (CI if CrCL <30)
• 5mg QD (<50kg)
• 7.5mg QD (50-100kg)
• 10mg QD (>100kg)
aPTT-adjusted UFH infusion*
LMWH if CrCL
>30mL/min
Kearon Chest 2016;149(2):293-294; http://www.nccn.org; Lyman JCO 2015;33(6):654-656; Akl Cochrane Database Sys Rev 2008
*Cochrane review showed 30% mortality reduction at 3 months in cancer patients
receiving initial LMWH vs. UFH.
• No difference in VTE recurrence. ? Antitumor properties of LMWH.

8. LONG TERM MANAGEMENT OF VTE
IN CANCER

9. VKA Disadvantages in the Cancer Patient
• Poor nutrition and low vitamin K state
• Frequent use of antibiotics
• Diarrheal disease
• Chemotherapy interactions
• Liver disease from cancer involvement
• Low grade disseminated intravascular
coagulation
• Malabsorption

10. VKAs in Cancer
• VKAs are less effective in patient with cancer with
rates of recurrent VTE 3x higher than in non-cancer
patients despite maintenance of therapeutic INR
– 21% annual risk recurrent VTE; 12% bleeding risk
• Qualitative studies reveal that patients are
acceptable to LMWH injections and most prefer
convenience and “empowerment” with LMWH
Prandoni Blood 100(10):3484–3488

11. CLOT TRIAL:
Warfarin vs. LMWH
• Multicenter, open-label, RCT study
• Groups balanced by age, gender,
ECOG, cancer stage/type
• 672 cancer patients with proximal
DVT, PE, or both
– Dalteparin x 6 months
– Dalteparin x 7dVKA
Death
Recurrent VTE
Lee AYY et al. N Engl J Med 2003; 349:146-153
62% reduction

12. CLOT Trial: Bleeding
LMWH
(n=336)
OAC
(n=336)
p value
Major bleed 6.0% 4.0% 0.27
Any bleed 14.0% 19.0% 0.09
Lee AYY et al. N Engl J Med 2003; 349:146-153

13. Lee et al Blood. 2013;122(14):2310-2317
Hull Am J Meyer 2006;119:1062-1072
Meyer Arch Int Med 2002; 162(15):1729-1735
Subsequent
LMWH Trials
LITE- Tinzaparin vs. VKA x 3 mo
CATHANOX- Enoxaparin vs. VKA x 3 mo
No difference
No difference
No difference

14. Favors LMWH
VTE Recurrence
RR 0.52 [CI 0.36-0.74]
Carrier Thromb Res 2014; 134(6):1214–1219
(LITE)
(CATHANOX)
(CLOT)

15. CATCH Trial
• Phase III RCT of 900 cancer patients
– Tinzaparin 175u/kg x 6 mos
– Tinzaparin 175u/kg x 5-10 days VKA x 6 mos
Lee JAMA 2015; 314(7):677–686
Recurrent VTE Major Bleeding

16. Consensus Guidelines on Long-term
VTE Management in Cancer
ACCP
2016
NCCN
2015
ASCO
2015
LMWH over VKA (2B)
If not treated with LMWH,
VKA over DOAC (2C)
If extended therapy,
continue same agent as
initial 3 months (2C)
LMWH over VKA for
first 6 months
(category 1)
LWMH preferred for 6
months
VKA acceptable if LMWH
not available
Use of direct OACs not
recommended
Kearon Chest 2016;149(2):293-294
http://www.nccn.org
Lyman JCO 2015;33(6):654-656

17. DIRECT ORAL ANTICOAGULANTS
(DOACS) AND CANCER

18. Leung The Hematologist 2011
Edoxaban

19. DOAC General Properties
Advantage Clinical Implication
Rapid onset of action No need for bridging
Predictable dose response Fixed dosing and no need for routine
coagulation monitoring
Low potential for food/drug
interactions
No dietary precautions and few drug
interactions
Oral dosing Convenient

20. Comparative Features of Old and New
Anticoagulants
Features Warfarin
LMWH
(Enox)
New Oral Anticoagulants
Dabigatran Rivaroxaban Apixaban Edoxaban
Target
Vit K epox
reduc
FXa>FIIa Thrombin
Factor
Xa
Factor
Xa
Factor
Xa
T (max) 72-96 h 3 h 2 h 2.5-4 h 3 h 1-2 h
Half-life 40 h 4-5 h 14-17 h 9-13 h 8-15 h 8-10 h
Monitoring INR-adjusted None None None None None
Dosing QD BID/QD BID BID/QD BID QD
Elimination
Cytochrome
P450 2C9
80% renal 80% renal 66% renal 25% renal ~50% renal
Assay PT/INR
Anti-factor Xa aPTT / TT /
dilute TT
? PT
Anti-factor Xa
Anti-factor Xa
? PT
Anti-factor Xa
Drug
Interactions
CYP 2C9
Potent P-gp
inhibitors/ inducers
Potent P-gp and CYP
3A4 inhib / inducers;
Optimal absorption if
taken with food
Potent P-gp and
CYP 3A4 inhib /
inducers
Potent P-gp
Inhibitors /
inducers
Wittkowsky AK. Pharmacotherapy 2011;31:1175.
Eliquis® (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; Dec 2012.
Pradaxa® (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; Nov 2012.
Xarelto® (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Nov 2012.

21. DOACs in Cancer
• Phase III VTE treatment trials
– Included few cancer patients (2.6-6%)
– Defn of “active cancer” varied
– Type & stage of cancer and concurrent chemotherapy
not specified
– Used warfarin as the control arm (not SOC LMWH)
• Phase II cancer DOAC study
– Prophylactic apixaban vs. placebo
– Advanced or metastatic ambulatory cancer patients
receiving chemotherapy
– Apixaban well-tolerated with minimal increase in
major bleeding
Levine et al. J Thromb Haemost 2012;10:807–814

22. VTE Recurrence
RR 0.66 [CI 0.39-1.11]
Carrier Thromb Res 2014; 134(6):1214–1219

23. Bleeding DOACs vs. VKA in VTE trials
Hull et al. J Thromb Haemost 2014; 12:1116–20.

24. ASH 2015
• Cancer-associated thrombosis and DOAC
– 1 prospective observational study
– 2 retrospective studies
– No difference in recurrent VTE rate and bleeding
between rivaroxaban and dalteparin.
Mantha et al. 2015 ASH Annual Meeting. Abstract 431.
Win et al. 2015 ASH Annual Meeting. Abstract 2319.
Chaudhury et al. 2015 ASH Annual Meeting. Abstract 432

25. Reasons to avoid DOACs in Cancer
• No antidote yet for FXa inhibitors (Idarucizumab for
dabigatran available)
• Virtually no experience in patients with thrombocytopenia
• Interactions with chemotherapy not tested
• ? Gastrointestinal absorption in vomiting cancer patients or
those with chemotherapy-induced intestinal mucosal
defects.
• Lessons from the RE-ALIGN study
• Proper RCT will be impossible to conduct if they “creep”
into standard of practice for cancer VTE
RCT of LMWH vs. DOACs in cancer patients needed!

26. DOACs and Chemotherapy Interactions
Lee et al Blood. 2013;122(14):2310-2317

27. Considerations before DOAC use in Cancer
Short et al. The Oncologist 2014; 19:82–93
Age <75yo
CrCL >30ml/min

28. Lee Blood 2013;122 (14):2310-2317
Recurrent VTE
in Cancer

29. Duration of Anticoagulation
• Guidelines recommend LMWH for at least 3-6 months
(CLOT, LITE, CATHANOX, CATCH)
• Limited data on anticoagulation beyond 6 months
• Duration should be based on ongoing risk factors
– Metastatic disease, active disease requiring systemic
chemotherapy continue beyond 3-6 mo
– Remission, cure, no ongoing therapy, catheter
removed stop after 3-6 mo
Revaluate yearly for risk/benefit of continued anticoagulation
Kearon Chest 2016;149(2):293-294
http://www.nccn.org
Lyman JCO 2013;31(17):2189-2204

30. Choice of Agent for Long-term Treatment
• Meta-analysis of 7 RCTs comparing extended
LMWH with VKA in cancer patients
Recurrent
VTE
Major
bleeding
Death
LMWH vs. VKA
(HR)
0.47 [0.32-
0.71]
1.07 [0.52-
2.19]
0.96 [0.81-
1.14]
Akl Cochrane Database of Systematic Reviews 2014, Issue 7.
Decision of long term drug should be based on
risks/benefits and patient values/preferences

31. ASH 2015
• Abstract 430: Switching to warfarin after 6
months of low–molecular-weight heparin for
cancer-associated thrombosis
– Not associated with an increased recurrence VTE,
major bleeding, or total bleeding when compared
with continuing therapy with a LMWH.
Chai-Adisaksopha et al. 2015 ASH Annual Meeting, Abstract 430

32. Summary
• Growing knowledge base of thrombosis in
morbidity and mortality in cancer patients
• LMWH remains standard of care for initial and
long-term treatment based on CLOT study.
• DOAC data emerging but routine use awaits RCT
• Treatment of recurrent VTE can be managed with
dose adjustment
• Need for indefinite anticoagulation and choice of
drug based on ongoing risk factors and case-by-
case assessment

33. Thank You

34. EXTRA SLIDES

35. Ongoing anticoagulation clinical trials in cancer
• Prospective observational study on treatment of incidental PE in
cancer (11/2016)
• RCT of Arixtra +/- IVCF in cancer patients with VTE (terminated)
• Prophylaxis in ambulatory high-risk cancer patients
– CASSINI: Rivaoxaban (recruiting)
– AVERT: Apixaban(recruiting)
• SELECT-D trial- RCT dalteparin vs. rivaroxaban in cancer patients at
high risk for recurrence
• RCT Edoxaban vs. Dalteparin after initial VTE in cancer patients
being treated long term (12/2017)
• HOKUSIA VTE-Cancer Study: RCT edoxaban vs. LMWH in acute VTE

36. Anticoagulation and Brain Tumors
Is the therapeutic management of venous thromboembolism
different in patients with primary central nervous system (CNS)
tumors or metastatic tumors in the brain?
• Emerging retrospective data suggest that patients with
primary CNS tumors or CNS metastases do relatively well on
anticoagulation
• Venous thromboembolism prophylaxis and treatment in these
patients have to be highly individualized and carefully
monitored.
• Majority have had treated brain lesions

37. ASH 2015
• Abstract 428: Outcomes of low–molecular-weight heparin
treatment of venous thromboembolism in patients with
primary and metastatic brain tumors
• Conclusion: No difference in recurrent VTE or major bleeding
in patients with cancer-associated thrombosis in the setting of
primary or metastatic brain tumor compared with controls.
– Subgroup analysis-incidence of CNS bleeding in primary
brain tumors was higher than metastatic brain tumors
(6.0% vs 3.5%, P = .008).
Chai-Adisaksopha et al ASH Annual Meeting 2015 Abstract 428.

38. Thrombolysis as Initial Treatment
• Thrombolysis trials excluded cancer patients
due to perceived higher risk of bleeding
• Data limited to single-center retrospective
series
– Outcomes: degree of clot lysis and short-term
complications
– Comparable results between cancer and non-
cancer patients
– Low level evidence, case-by-case basis with
particular attention to bleeding risk

39. Guideline Recommendations:
Primary Prophylaxis in Cancer
• ACCP 2012:
– If no additional risk factors, suggest against
routine prophylaxis (Grade 2B).
• previous VTE, immobilization, hormonal therapy,
angiogenesis inhibitors, thalidomide, lenalidomide.
– In patients with solid tumors and additional risk
factors at low risk of bleeding, suggest
prophylactic LMWH or LDUH (Grade 2B).

40. Guideline Recommendations:
Extended Prophylaxis
• ACCP 2012:
– For high VTE risk patients undergoing abdominal
or pelvic surgery for cancer, we recommend
extended duration pharmacologic prophylaxis (4
weeks) with LMWH (Grade 1B).

41. Dosing controversy of LMWH in obese
1. Dose based on total body weight
2. Dose based on ideal body weight
3. Cap at some maximum dose

42. Pharmacokinetic LMWH studies in Obese
Bazinet Thromb Res 2005;116:41-50
• Anti-Xa activity does not vary as a function of BMI
• Dose adjustments or capping not needed
• Do not need to routinely monitor anti-Xa activity
• Enoxaparin BID dosing preferred over QD dosing

43. Anti-Xa increases as a function of RI
Consider empiric dose
reduction or anti-Xa
monitoring in severe RI
Bazinet Thromb Res 2005;116:41-50

44. Summary of LMWH in RI
• Appropriate dose of LMWH in patients with
CrCl<30 mL/min is uncertain
Garcia Chest 2012; 141(2)(Suppl):e24S-e43S
Nutescu Ann Pharmacother 2009;43:1064-1083
Enoxaparin [package insert]. Sanofi-Aventis. Accessed November 24, 2014
• Clearance of the LMWH correlates with CrCl
- Exception: Tinzaparin
• Prefer UFH over LMWH with CrCl <30ml/min
• If LMWH used, monitor anti-Xa levels
• FDA dose adjusments in RI exist only for
enoxaparin (1mg/kg QD for CrCL<30 ml/min)
• Neither empiric dose reduction nor adjustment based
on anti-Xa activity has been prospectively evaluated
with an adequate control arm

45. Meta-analysis: DOACs in Elderly
Favors DOACs Favors conventional anticoagulation1.0
VTE or VTE-related death:
OR: 0.45 [0.27-0.77]
Major or
Clinically Relevant Bleeding:
OR: 1.02 [0.73-1.43]
Sardar J Am Geriatr Soc 2014;62:857-864
• DOACs more effective than standard therapy without
increasing risk of bleeding in elderly
• Older age by itself not a criterion to withhold or
dose reduce DOACs

46. Recommendations in Elderly
• Enoxaparin is the only LMWH with recommended
dose reduction for elderly
– Setting of acute STEMI (0.75mg/kg SQ BID)
• No empiric dose adjustments for other LMWH,
fondaparinux, or DOACs for elderly with normal
renal function
– In elderly with RI consider empiric dose reduction,
monitoring anti-Xa, or alternative anticoagulant
• Practice guidelines do not provide specific
recommendations.
Samama Drugs Aging 2011;28 (3):177-193
Enoxaparin [package insert]. Sanofi-Aventis. Accessed November 24, 2014

47. Pitfalls of Anti-Xa Monitoring
1. Anti-Xa targets have not been clinically validated
– Determined retrospectively; not used in RCTs
– Correlation with bleeding and thrombosis outcomes?
2. Anti-Xa activity may not fully represent antithrombotic
activity
3. Different target anti-Xa ranges
- Based on type, dose, and schedule of LMWH
4. Inter-laboratory variability
- Use chromogenic assay and a calibration
curve based on the specific anticoagulant
5. No consensus method for adjusting dose

48. General Recommendations:
Monitoring Anti-Xa Levels
• Measure peak activity 4hrs post LMWH dose, 3hrs post
fondaparinux
• Consider measuring trough to evaluate for accumulation in RI
Lim JTT 2001;29: 233-240
Garcia Chest 2012; 141(2)(Suppl):e24S-e43S
Michota Cleveland Clinic J Med 2005;72: S37-S42
Nutescu Ann of Pharm 2009;43: 1064-1083
Laposato Arch Pathol Lab Med 1998;122:799-807

49. Specific Monitoring Recommendations
in Vulnerable Populations
1. Obese
– Consider in morbidly obese (BMI>40) or on long-
term anticoagulation
2. Renal impairment
– Trough (goal <0.5 u/mL)
– If anti-Xa assay not available, use UFH
3. Elderly
– Consider in those with renal impairment
Shojania JTH 2004;2:2276-2277
Iorio JTH 2003;1:1906-1913
Lee NEJM 2003;349:146-153
Laposato Arch Pathol Lab Med 1998;122:799-807

50. Shelke et al. Drug Discovery Today. Disease Mechanisms 2011;8:e39-e45
How does cancer lead to blood clots?