Update on the Management of Cancer Associated VTE Jean M. Connors, MD 2018 Master Class Course Anticoagulation Management Services BWH/DFCI Hemostatic Antithrombotic Stewardship BWH Associate Professor of Medicine HMS r
Disclosure Disclosure I have nothing to disclose. Off Label/Investigational Discussion In accordance with Annenberg Center policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.
Question 1 A 48 year old woman a few weeks post resection of early stage breast cancer is undergoing radiation treatment. She presents to her local ER with dyspnea. A chest CT reveals PE. You are called by the ER for treatment advice. She is hemodynamically stable with no RV strain seen on CT, and RA 02 saturation of 94%. Weight is 83 kg and creatinine is 0.90 gm/dl.
Question 1 You recommend: A. Catheter directed thrombolysis B. Enoxaparin 1mg/kg once a day C. Start dabigatran 150 mg twice daily D. Enoxaparin 1 mg twice daily for 5 days then switch to edoxaban 60mg once daily E. Place an IVC filter
Question 2 A 67 yo man with squamous cell carcinoma of the base of the tongue develops left arm swelling 10 days after port-a-cath placement. He is being treated with concurrent chemo-radiation therapy and has a J-tube. Weight is 91 kg and creatinine is 1.3 mg/dl. You obtain a vascular US which reveals left subclavian and left IJ clot.
Question 2 You decide to treat with: A. Rivaroxaban 15 mg twice daily for 3 weeks then 20 mg once daily B. Apixaban 10 mg twice daily for one week followed by 5 mg bid C. Enoxaparin 1 mg/kg twice daily D. Edoxaban 60 mg once daily E. A, B, or D
Agenda Management of cancer associated VTE Review historic treatment approaches Discuss data on the use of DOAC for treatment Brief synopsis of DOAC reversal agents
Thromboembolism and Cancer VTE is a common complication in patients with cancer. Limited data are available to guide treatment and management. LMWH has been the gold standard for acute treatment of VTE since publication of the CLOT trial 2003. Recent follow up CATCH trial in 2015 suggests different conclusions. New data for DOAC use in cancer patients with VTE. Are DOAC poised to replace LMWH? And what about warfarin?
CLOT Trial Risk reduction 52%* 38% recurrent VTE in VKA occurred with INR<2.0 Most recurrences in 1 st month 672 patients Solid tumors Chemo-rx Lee NEJM 2003
CATCH: Recurrent VTE Probability of recurrent VTE (%) 14 12 10 8 6 4 2 0 warfarin, 10.5% (45 events); TTR 47% tinzaparin, 7.2% (31 events) 0 30 60 90 120 150 180 Days post-randomization Final analysis: no statistically significant difference between arms Lee JAMA 2015
LMWH vs Warfarin Patients in CLOT and CATCH failed warfarin management, not necessarily warfarin anticoagulation. Differences in the study populations affect outcomes less ill, less metastatic disease, fewer patients treated with chemotherapy in CATCH: outcomes with warfarin similar to LMWH Warfarin can be acceptable anticoagulant for many patients with cancer. It is best for patients on hormonal agents, biologics, or daily dose of chemotherapy.
Agenda Management of cancer associated VTE Review historic treatment approaches Discuss data on the use of DOAC for treatment Brief synopsis of DOAC reversal agents
Select-D Trial: rivaroxaban vs dalteparin for cancer VTE 406 patients randomized to rivaroxaban or dalteparin for 6 months, then planned 2 nd randomization to rivaroxaban or placebo for those with PE or residual leg vein thrombosis At 3 years closed the 2 nd randomization due to low accrual Excluded patients with esophageal or gastric cancer per DSMB for imbalance in bleeding events Fewer recurrent VTE (4% vs 11%) but increased major and CRNMB (5%/25% vs 3%/3%) with rivaroxaban Final results not yet published ASH oral presentation, Young 2017
Hokusai Cancer VTE 1,046 patients randomized to edoxaban or dalteparin for 12 months 98% defined as having active cancer, 53% with metastatic disease Patients on edoxoban had 10% greater duration of adherence to study drug (211 vs 184 days) Edoxaban non-inferior to dalteparin for composite endpoint of recurrent VTE or major bleeding (HR 0.97; 95% CI 0.70,1.36; p=0.006) Approximately 13% events each arm at 1 yr Fewer recurrent VTE with edoxaban (6.5% v. 10.3%) Increased major bleeding (6.3% v 3.2%) Increased upper GI bleeds primarily with GI malignancies Raskob ASH, NEJM 2017
Raskob, NEJM Dec 2017
Raskob, NEJM Dec 2017
Raskob, NEJM Dec 2017
DFCI Data: DOAC Use in Active Cancer Patients Retrospective review June 2015 through December 2016 241 patients getting active cancer treatment prescribed DOAC for VTE 4.7% major and CRNM bleeding 4.1% recurrent thrombotic events (10 patients) Characteristics of patients with recurrence: Advanced disease: ovarian, lung, breast, mesothelioma, neuroendocrine 6 had possible reasons for DOAC failure N/V/D, g-tube Reduced dose DOAC held for bleeding, procedures, non-compliance Drug-drug interactions O Neill THSNA 2018
VTE Management: DOAC use in cancer patients DOACs: Use in carefully selected patients Low thrombotic risk tumor type No drug-drug interactions Azole antifungals, anti-seizure meds, HIV meds Rifampin, other antibiotics Check chemotherapy, TKI, hormonal therapy interactions No expected fluctuation in renal status No weight extremes <50 kg or > 120-150 kg No concerns about GI tract Absorption: resected bowl, N/V/D Bleeding: anastomosis, lesions, history of GI bleed Esophageal or gastric cancer
Agenda Management of cancer associated VTE Review historic treatment approaches Discuss data on the use of DOAC for treatment Brief synopsis of DOAC reversal agents
*4F-PCC=KCentra Management of Bleeding in the Anticoagulated Patient Standard measures should be used to assess and treat the bleeding patient Reversing anticoagulation should reserved for patients with lifethreatening or major bleeding or require urgent/emergent surgery If you need to reverse anticoagulation use the following: LMWH: protamine Warfarin: 4 factor prothrombin complex concentrate (4F-PCC)* Dabigatran: 5 grams idarucizumab Apixaban, edoxaban, rivaroxaban: 4F-PCC* at 25-50 U/kg ~ 2000 U
Idarucizumab PRAXBIND = idarucizumab Humanized monoclonal antibody fragment that binds dabigatran 350 x higher affinity for dabigatran than dabigatran has for thrombin FDA approved Oct 16, 2015 RE-VERSE AD: real world study published in NEJM 2015 5 gram dose IV bolus immediate and sustained reversal of dabigatran activity over 24 hours
Andexanet alfa AndexXa = andexanet alfa decoy recombinant FXa molecule with mutation in catalytic site, lacks Gla domain universal Fxai antidote Interim analysis of real world study NEJM 2016: adjusted dose Waiting for FDA approval
VTE Management Summary LMWH remains the gold standard for VTE management in patients with cancer. Warfarin can be acceptable in many cases Data for DOAC suggest good efficacy based on one study Appear to be non-inferior to LMWH for low risk patients Use in carefully selected patients, avoid in those with GI bleed risk Reversal agents are available and may play a bigger role in cancer patients given their inherent increased risk of bleeding.
VTE Management Final Statement Data for optimal management for many situations are limited or non-existent, guidelines and expert consensus statements are available to aid in decision making ASCO, ITAC, ASH, NCCN, ISTH, ESMO
jconnors@bwh.harvard.edu
Aim: to assess whether oral apixaban is noninferior to subcutaneous dalteparin for the treatment of newly diagnosed proximal DVT and/or PE in patients with cancer. Investigator initiated, multinational, prospective, randomized, open-label with blind end-point evaluation (PROBE), non-inferiority clinical trial.