Thromboembolism and cancer: New practices Marc Carrier
Marc Carrier Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Leo Pharma, BMS No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare Sanofi Aventis, Pfizer, Boehringer Ingelheim, Leo Pharma, Bayer. No relevant conflicts of interest to declare
Objectives Review the new evidence in the acute and long-term treatment of cancer-associated thrombosis Discuss the use of direct oral anticoagulant (DOACs) for the management of cancer-associated thrombosis
Incidence Annual incidence of VTE in the general population is 117 per 100,000 Cancer alone was associated with a 4.1-fold risk of thrombosis Chemotherapy increased the risk 6.5-fold Combining these estimates yields an approximate annual incidence of venous thromboembolism (VTE) of 1 per 200 in a population of cancer patients Heit JA et al. Arch Intern Med. 2000; 160: 809 815.
VTE as a cause of death Thromboembolism is the second leadingcause of death in cancer patients Annual death rate for VTE of 448 per 100,000 patients 47-fold increaseover the general population Figure from Khorana AA et al. Thromb Res 2010;e-pub. Khorana AA et al. J Thromb Haemost 2007;5:632-4.
ACCP 2016 In patients with DVT of the leg or PE and cancer ("cancer-associated thrombosis"), as long-term (first 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2B), dabigatran(grade 2C), rivaroxaban(grade 2C), apixaban(grade 2C) or edoxaban(grade 2C). Kearon C et al. Chest. 2016 Feb;149(2):315-52
Overall efficacy and safety of LMWH Recurrent VTE Major Bleeding Recurrent VTE: Major Bleeding: RR: 0.56 LMWH is associated with a significant reduction in the risk of recurrent VTE without a significant increase in major bleeding episodes 95% CI: 0.43-0.74 RR: 1.07 95% CI: 0.66-1.73
Overall efficacy and safety Recurrent VTE of DOAC Major Bleeding Recurrent VTE: Major bleeding: RR: 0.67 DOACs were associated with a non-significant lower risk of recurrent VTE and major bleeding episodes 95% CI: 0.38-1.18 RR: 0.69 95% CI: 0.34-1.41
Limitations Relatively small number of cancer patients included Tumor types and stages are not always reported Heterogeneity in active cancer definition DOAC vs. warfarin not vs. LMWH TTR not known? Selected cancer patients
Selected cancer patient population in DOAC trials? The higher annualized risk of recurrent VTE and major bleeding in LMWH trials suggests a higher-risk cancer population were enrolled in these studies Carrier M et al. Thromb Res. 2014 Dec;134(6):1214-9.
Drug to drug interactions Lee AY, Carrier M, Thromb Res. 2014 May;133 Suppl 2:S167-71.
Future directions Select-d trial Rivaroxaban vs. dalteparin Sample size: 530 ISRCTN86712308 Prospective cohort study Rivaroxaban Sample size: 137 NCT01989845 HOKUSAI- Cancer Edoxaban vs. dalteparin Sample size: 1000 NCT02073682
Extended anticoagulation therapy for cancer-associated thrombosis
Extended therapy Risks and consequences of major bleeding on anticoagulation Risks and consequences of recurrent VTE off anticoagulation
Risk factors for recurrent VTE after CAT Tumour type Higher Pancreas, lung, other GI, brain, ovary, myeloproliferative Lower Breast Stage of disease Stage III/IV, more extensive Stage I/II, less extensive Timing of VTE diagnosis < time from cancer diagnosis Type of VTE PE DVT DVT Residual vein thrombosis Age <65 65 Gender Female Male Cancer therapies Chemotherapy Tamoxifen > time from cancer diagnosis Aromatase inhibitors
ACCP 2016 In patients with DVT of the leg or PE and active cancer ("cancer-associated thrombosis") and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), and (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B) Kearon C et al. Chest. 2016 Feb;149(2):315-52
Who should probably continue anticoagulation? No contraindications to anticoagulation and: 1) Active advanced cancer or 2) Advanced cancer in complete remission for whom the short-term risk of cancer recurrence is high or in the presence of other ongoing major risk factors for thrombosis
Selection of therapy? Little data (only DALTECAN study) to guide selection of therapy Continuation of LMWH at the current dose is the preferred option for most situations Individualization of therapy (including warfarin and DOACs) may be reasonable in certain settings after considering patient preference and other clinical factors
DALTECAN study Design: Prospective multicenter cohort study with patients with cancerassociated VTE treated with dalteparin X 12 months (n=334) 185 (55.4%) completed 6 months of therapy 109 (33%) completed 12 months Median duration: 214 days Endpoints: 1. Primary endpoint: Major bleeding (months 1; 2-6; 7-12) 2. Recurrent VTE (months 1; 2-6; 7-12) Francis CW et al. J Thromb Haemost. 2015 Jun;13(6):1028-35.
Efficacy and safety of long-term LMWH % Rate per Month of VTE Occurrence 6.0 5.7 5.0 4.0 3.0 2.0 1.0 0.0 Month 1 Months 2-6 0.8 0.7 Months 7-12 % 3.5 2.5 1.5 1 0.5 Rate per Month of Major Bleeding 4 3 2 0 3.6 1.1 Month 1 Months 2-6 0.7 Months 7-12 Francis CW et al. J Thromb Haemost. 2015 Jun;13(6):1028-35.
Patient s perspective Most important attributes for anticoagulation choices: 1. Does not interfere with cancer treatment. 2. Efficacy and safety 3. Route of administration Noble SI et al. Haematologica. 2015;100:1486 1492.
Is a RCT feasible? ALICAT RCT is not feasible Patients have fixed views regarding their treatment wishes Clinicians have fixed opinions about anticoagulation Longheva Terminated early due to poor enrollment Noble SI et al. Health Technol Assess. 2015;19:vii 93. ClinicalTrials.gov/NCT01164046.
Who can stop anticoagulation? 1) the underlying cancer has been treated with curative intent and 2) any ongoing therapy is associated with a low risk of thrombosis.
May or may not benefit from anticoagulation? Complete remission with a low or moderate risk of recurrence of cancer and VTE Options: 1) Stop anticoagulation 2) LMWH therapy until the risk of cancer/vte recurrence is felt to be low 3) Substitution therapy with warfarin or DOACs.
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