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

Disclosure: Boehringer Ingelheim: Scientific Ad Boards

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

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.

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

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.

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

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

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

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

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;361:2342–2352. 2. Schulman S, et al. Circulation 2013. In Press.

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 55-58 years old

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.

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

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

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

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.

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.  

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

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?

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

The End