1. VTE Management Issues In Malignancy
Jean M. Connors, MD
Brigham and Women’s Hospital
Dana Farber Cancer Institute
Harvard Medical School
Boston, MA

2. Disclosure:
Boehringer Ingelheim: Scientific Ad Boards

3. Agenda Frequently asked management questions: Incidental PE
IVC filter use
Central access catheter thrombosis

4. Incidental PE Question 1.
54 yo man with metastatic adenocarcinoma of the lung
Two cycles of chemotherapy, restaging CT: PE right lower lobe segmental artery.
Patient is fatigued with a cough, HR 85 bpm, bp128/72, RA O2 sat 96%. BNP normal.
CT demonstrates response, plans are to continue with the current treatment regimen.

5. Incidental PE
Should this patient be treated with anticoagulation?
a. Yes
b. No

6. Incidental PE
75% of cancer patients found to have unexpected PE in retrospect had symptoms that were attributed to cancer or treatment O’Connell JCO 2006
No difference in VTE recurrence rate, bleeding, or mortality in treated patients with symptomatic vs asymptomatic PE. den Exter JCO 2011
Incidental PE has similar worse outcomes as symptomatic PE when compared to cancer patients without VTE.

7. Incidental PE
Guidelines support treatment with anticoagulants for incidental PE despite lack of prospective RCTs.
The best biomarker for a hypercoaguable state is a clot.
Incidental clots in other locations should be considered for anticoagulation too:
Portal vein
Renal vein
Exception: Thrombosed vein at resected organ site

8. Incidental PE
Which of the following agents is preferred for initial treatment?
a. warfarin
b. IV unfractionated heparin (UFH)
c. dalteparin
d. dabigatran
e. rivaroxaban

9. Incidental PE No need for admission for IV UFH
Piran Thromb Res 2013
Font JNCCN 2014
Warfarin alone not upfront treatment for any VTE
New oral anticoagulants: not enough data
Dalteparin is the only FDA approved LMWH for treatment of cancer associated VTE, and is approved for once daily dosing
Fondaparinux
Enoxaparin

10. Background Hokusai-VTE study (edoxaban eligibility criteria)
Randomized, double blind, event driven, non-inferiority study (margin 1.5), patients with symptomatic DVT or PE
Patients with active cancer excluded if long-term therapy with LMWH anticipated
Patients with cancer were eligible if long-term therapy with LMWH not anticipated
“Active cancer” classified by investigator at time of study enrollment
Analysis of outcomes in cancer patients pre-specified

11. Background
Objectives
In RE-COVER™ and RE-COVER™ II, dabigatran was as effective as warfarin with a lower risk of bleeding1,2
The objective of this analysis was to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without active cancer* at any time during the study
A pre-specified subgroup analysis on pooled data from RE-COVER™ and RE-COVER™ II
*Active cancer defined as:
At baseline: a diagnosis of cancer (other than basal-cell or squamous-cell carcinoma of the skin) or any treatment for cancer within 5 years before enrolment, or recurrent or metastatic cancer
During the study: newly diagnosed cancer
1. Schulman S, et al. N Engl J Med 2009;361:2342– Schulman S, et al. Circulation In Press.

12. NOAC use in Cancer Patients
Active cancer patients excluded in many studies,
comprise only 5% of study patients
Life-expectancy, self-selection/self-exclusion
No data on types of cancers
“active” defined by enrolling MD
No data on use of concurrent chemotherapy
Drug-chemotherapy interactions:
CYP3A4 and P-GP
Short, Connors Oncologist 2014
Average age in VTE studies years old

13. NOAC use in Cancer Patients
Concerns about efficacy in strongly pro-thrombotic malignancies
RE-ALIGN results in mechanical valves: NEJM Sept 2013
Both recurrent VTE and bleeding found to be higher in cancer patients than non-cancer patients no matter which anticoagulant used.
In the patients included in the studies, no difference in efficacy or safety with NOAC vs warfarin.
Use after careful consideration in selected oncology patients.

14. IVC Filter
Question 2:
6 weeks later he is admitted to ICU with persistent hemoptysis. Anticoagulation is held.
Lower extremity Doppler US: no DVT.
Is an IVC filter indicated for secondary prophylaxis of pulmonary embolism?
a. Yes
b. No

15. IVC Filter Devices approved without study of efficacy, safety
No data to show decrease in mortality
Only 1 RCT. Patients were also anticoagulated. Decreased PE in first 2 weeks, increased DVT at 2 yrs and 8 yrs, no difference in mortality at 8 years Circulation 2005
Small retrospective case control studies in cancer patients
Increased complications
Increased lower extremity DVT rates
No survival benefit

16. ASH Choosing Wisely recommendation
IVC Filter
ASH Choosing Wisely recommendation
Overused in many clinical settings
In a recent retrospective study 47% of patients who received a filter did not have DVT.
JAMA Internal Medicine 2013
Up to 90% of “retrievable” filters never retrieved.
No evidence that prophylactic filter use improves outcomes.
Prophylactic filters are expensive, associated with vascular injury, and filter failure.
ASH Choosing Wisely Campaign

17. IVC Filters
Only use in patients with absolute contraindication to anticoagulation and acute lower extremity DVT
Immediate post-op neurosurgery
Recent life-threatening bleed
Patients with no pulmonary reserve
s/p sub-total pneumonectomy
Severe COPD
If the patient can be anticoagulated there is
no need for a filter.

18. ASH Choosing Wisely recommendation
Central Access Catheter Thrombosis
ASH Choosing Wisely recommendation
Question 3:
42 yo woman with squamous cell carcinoma of the head and neck requires treatment with combined radiation and chemotherapy.
A central access catheter is placed in the right IJ vein for venous access due to small peripheral veins.
One week later she presents with right arm swelling. There is no evidence of compartment syndrome. Ultrasound demonstrates an occlusive right axillary vein thrombus.

19. ASH Choosing Wisely recommendation
Central Access Catheter Thrombosis
ASH Choosing Wisely recommendation
  Which of the following is the most appropriate next step in management?
a. Start enoxaparin 1 mg/kg BID
b. Remove catheter immediately
c. Start enoxaparin 1 mg/kg BID; remove catheter in one week
d. Start therapeutic warfarin

20. ASH Choosing Wisely recommendation
Central Access Catheter Thrombosis
ASH Choosing Wisely recommendation
4.3% of patients with central access catheters will develop symptomatic line associated thrombosis.
Lee JCO 2006
Assess need for line:
Poor access
Ongoing IV treatments required
No evidence that early removal affects outcome
Kovacs JTH 2007
Try to leave catheter in place
Is it functioning?
Any contra-indications to anticoagulation?

21. ASH Choosing Wisely recommendation
Central Access Catheter Thrombosis
ASH Choosing Wisely recommendation
If symptoms do not resolve after 1-2 weeks of anticoagulation, consider removal
If line pulled and no other need for anticoagulation should treat for 3 months
If requires ongoing chemotherapy, has metastatic disease, and line remains in place, continue anticoagulation
Intensity of anticoagulation not clear after acute treatment
No data to support prophylaxis in all patients
Consider in those with significant other risk factors

22. The End