Management of Cancer Associated VTE

Transcription

1 Management of Cancer Associated VTE Jean M. Connors, MD 2017 Master Class Course Anticoagulation Management Services BWH/DFCI Hemostatic Antithrombotic Stewardship BWH Assistant Professor of Medicine HMS r

2 Agenda Why is LMWH the gold standard for treatment of cancer VTE? What about DOACs in cancer patients? Common difficult cancer VTE situations Failure of standard intensity anticoagulation Primary CNS tumor or CNS metastases and anticoagulation

3 Thromboembolism and Cancer LMWH accepted as gold standard of care for treatment of initial VTE in cancer patients since 2003 Data after 1 st 3-6 months of treatment are limited or nonexistent for both type of anticoagulant and duration General consensus is to continue anticoagulation in the setting of active/persistent cancer and treatment, which can be many years.

4 Studies leading up to CLOT Control Group LMWH Vitamin K antagonist (INR 2.0 to 3.0) CANTHANOX N=146 LITE N=200 Enoxaparin 1.5 mg/kg OD Tinzaparin 175 IU/kg OD CLOT N=672 Dalteparin 200 IU/kg OD then ~150 IU/kg OD 5 7 days 1 month 3 months 6 months

5 CLOT Trial Risk reduction 52%* 672 patients Solid tumors Chemo-rx

6 CLOT Trial Warfarin group: TTR 46%, mean INR 2.5 +/ Below therapeutic range 30% of time Above therapeutic range 24 % of time 20 of 53 recurrent thrombotic events occurred with INR < 2.0 Most recurrent events occurred within first month of OAC therapy Re-analysis using Fine/Grey instead of Kaplan Meier, only 30% risk reduction

7 CATCH Study: Study Design Prospective, randomized open-label, with blinded central adjudication Inclusion Criteria 18 yr or older proximal DVT PE active cancer ECOG 0, 1, 2 informed consent 72-hr screening R A N D O M I Z A T I O N Tinzaparin 175 IU/kg once daily Warfarin (target INR 2 3) + Initial tinzaparin 175 IU/kg x 5 10 days Clinic visits: Day Mo 1 T 2 T 3 T 4 T 5 T 6 telephone contacts at 2 weeks after every monthly visit ( T ) structured interviews to ascertain if outcome events occurred INR performed at least once every 2 weeks

8 Probability of recurrent VTE (%) Recurrent VTE warfarin, 10.5% (45 events); TTR 47% HR 0.65 (95% CI ) Wald s test p = 0.07 Risk reduction = 35% tinzaparin, 7.2% (31 events) Days post-randomization

9 Safety Outcome Analyses Event Tinzaparin n/n Warfarin n/n HR HR [95% CI] Major bleeding 13/449 12/ [0.40, 1.99] Clinically relevant non-major bleeding 50/449 73/ [0.49, 0.96] Overall mortality 150/ / [0.85, 1.36] Favors T Favors W HR, hazard ratio: tinzaparin /warfarin. Competing risk regression analyses adjusting for region, tumor stratum, and history of VTE

10 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.

11 RIETE Registry and Cancer VTE: Warfarin after 6 months of LMWH Retrospective review of cancer patients in REITE database. Treating MD decision to transition after initial 6 months of LMWH. No significant difference in recurrent VTE. Recurrent Free Survival LMWH-LMWH LMWH-warfarin Wald test P= Follow-up time (months)

12 DOAC use in Cancer Patients Commonly asked question, no dedicated RCT studies published:yet Limited data derived from sub-analysis of pivotal VTE studies, 4-6% of total populations. Active cancer patients excluded from major studies Life-expectancy, self-selection/self-exclusion, duration of anticoagulation, bleeding risk No data on types of cancers or stage No data on use or type of chemotherapy

13 Hokusai Edoxaban VTE Study 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

14 Objectives In RE-COVER and RE-COVER II, dabigatran was as effective as warfarin with a lower risk of bleeding 1,2 B A C K G R O U N D 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 squamouscell 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: Schulman S, et al. Circulation In Press.

15 DOAC Sub-studies: VTE Recurrence Meta-analysis of the DOAC VTE RCT sub-studies of cancer patients 4.3% of 26,000 patients described as having cancer Recurrent VTE and major bleeding rates similar in cancer patients Vedovati CHEST 2015

16 Factors affecting DOAC therapeutic window GI absorption N/V/D Resected segments of GI tract Concomitant drugs that change p-gp or CYP3A4 activity Hepatic insufficiency Factors Affecting Plasma Concentration Weight extremes <60 kg or > kg Renal insufficiency or fluctuating renal status Target levels not established and no ability to monitor

17 MSK Quality Assessment/Quality Improvement Initiative QA/QI Initiative at MSK A Clinical Pathway established at MSK, for rivaroxaban use in cancer patients. Standard VTE treatment dose rivaroxaban 200 patients enrolled and analyzed Efficacy and safety similar to RCT trial data Recurrent VTE: 4.4% Major Bleeding: 2.2% Mantha,J Thromb Thrombolysis 2017

18 MSK QAI Initiative: Clinical Pathway Relative contra-indications: Active bleeding or a high risk of bleeding (Has-Bled Score of 4). Untreated primary or metastatic CNS lesion. Body weight <50 kg or >150 kg. Clinically significant liver disease (Child-Pugh: B or C). Use of any antiplatelet agent other than aspirin 81 mg daily. Creatinine clearance <30 ml/min (Cockroft-Gault) Ongoing macroscopic hematuria or known untreated urinary tract lesion. Ongoing gastrointestinal bleeding or known untreated GI lesion. Expected poor GI absorption. Drug Interactions

19 DOAC use for Catheter Associated Thrombosis Pilot study of rivaroxaban use in 70 cancer patients with catheter associated thrombosis Prospective 3 centers 77% PICC, 23% tunneled lines 58% catheter survival at 12 weeks (28% no longer needed) 1 death from PE 10% major bleeds CLOT trial major bleeds 6% Kovacs, ASH 2016

20 Recurrent VTE on standard Intensity Anticoagulation Highly thrombogenic tumors can promote thrombus formation even in the setting of anticoagulation Two retrospective studies assess approach to management patients with recurrent VTE on anticoagulation 32% on full dose LMWH 30% patients sub-therapeutic INR Switched to full dose LMWH, or increased to % for 4 weeks 6 patients had a 2 nd recurrence 3 on standard intensity LMWH, 3 on 120% intensity 4.3% bleeding complications Carrier, JTH 2009

21 Recurrent VTE on standard Intensity Anticoagulation patients with recurrent VTE 33% on full dose LMWH LMWH dose increased to full dose or 120% dose for 4-12 weeks 4 patients on standard intensity LMWH had 2 nd recurrence 5.5% major bleeding when switched to full or escalated dose Ihaddadene, Thromb Research 2014

22 Recurrent VTE on standard Intensity Anticoagulation Based on limited data, consensus for care of cancer patietns with recurrent VTE on anticoagulation: If on warfarin switch to full dose parenteral agent If on DOAC switch to full dose LMWH/fondaparinux If on low or intermediate dose LWMH/fondaparinux, increase to full dose If on full dose LWMH/fondaparinux increase dose to % full dose If on 125% consider adding other agents

23 CNS Metastases and Anticoagulation Patients with moderate to high thrombosis risk cancers have risk of CNS metastases Limited date regarding use of anticoagulation in the setting of brain mets Anxiety for ICH 20-50% of patients with metastatic tumor have ICH

24 CNS Metastases and Anticoagulation Matched, retrospective cohort study of cancer patients with brain mets requiring anticoagulation. No difference in cumulative incidence of ICH at one year 4 x higher rate of ICH in melanoma and renal cell ca not influenced by LMWH Almost all had treatment for CNS disease Donato, Blood 2015

25 CNS Metastases and Anticoagulation Anticoagulation appears not to affect ICH in patients with brain metastases Treatment of brain metastases should ideally be started before start of anticoagulation but severity of VTE may necessitate cautious anticoagulation Type of primary tumor affects bleeding risk Meta-analysis reveals possible higher risk of ICH with primary CNS tumors (Zwicker, JTH 2016) Further study required

26 VTE Management Summary Anticoagulation management in cancer patients with VTE is truly personalized medicine Patient characteristics, tumor type, and cancer treatments all affect ability to tolerate anticoagulation Data for optimal management are limited or non-existent, guidelines and expert consensus statements are available to aid in decision making ASCO, ASH, NCCN, ISTH, ESMO

27 VTE Management Summary Acute VTE LMWH to start Continue if on chemotherapy with strong interactions with warfarin: taxol, gemcitabine, adriamycin Warfarin acceptable especially if no alternative Consider DOAC in carefully selected patients After 1-3 months Continue LMWH, but no need for bid injections, even if persistent cancer and active treatment Consider transition to warfarin Consider transition to DOAC in carefully selected patients

28 VTE Management Summary 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 concerns for GI absorption Patients understand that there are no RCT data

29

30 Question 1 A 63 year old man with an 8 year history of NHL is on voriconazole for fungal pneumonia following autologous transplant. He develops R lower leg swelling and is diagnosed with a right popliteal vein thrombus. You are called by the ER for advice regarding management.

31 Question 1 You decide to treat with: A. Admit for IV UFH B. Enoxaparin 1 mg/kg twice a day C. Warfarin alone D. Rivaroxaban 20 mg a day E. Dabigatran 150 mg twice a day.

32 Question 2 37 yo man presents with R MCA stroke and is ultimately found to have metastatic adenocarcinoma of the lung. He is placed on enoxaparin 1 mg/kg twice a day and is discharged with plans to follow up in oncology clinic in one week. He returns 3 days later with new stroke symptoms. His wife, an RN, states that he has not missed any injections.

33 Question 2 You decide to treat with: A. Continue enoxaprin 1 mg/kg twice daily B. Change enoxaparin dose to 1.5 mg/kg once a day C. Change enoxaparin dose to 1.25 mg/kg twice daily D. Switch to warfarin immediately E. Switch to apixaban 2.5 mg twice a day

34 Answers Question 1: B Question 2: C