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Thrombosis in Cancer An Update on Risk Assessment, Prevention and Treatment

Thrombosis in Cancer An Update on Risk Assessment, Prevention and Treatment. Agnes Lee, MD, MSc, FRCPC University of British Columbia, Vancouver, BC June 2011. Disclosure. Leo Pharma Sanofi aventis Pfizer Bayer Boehringer Ingelheim Daiichi Sankyo.

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Thrombosis in Cancer An Update on Risk Assessment, Prevention and Treatment

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  1. Thrombosis in CancerAn Update on Risk Assessment, Preventionand Treatment Agnes Lee, MD, MSc, FRCPC University of British Columbia, Vancouver, BC June 2011

  2. Disclosure • Leo Pharma • Sanofi aventis • Pfizer • Bayer • Boehringer Ingelheim • Daiichi Sankyo

  3. Common complication in patients with cancer Higher mortality among cancer patients with VTE than without 2nd leading cause of death in cancer patients Activation of coagulation is important for tumour progression and metastasis Effective prophylaxis and treatment will reduce morbidity and may decrease overall mortality Cancer-Associated Thrombosis Heit Arch Intern Med 2000. Heit Arch Intern Med 1999. Sorensen NEJM 2000. Pradoni N Engl J Med 1992. Sorensen N Engl J Med 1988. Chew Arch Intern Med 2006. Khorana J Thromb Haemost 2007.

  4. Objectives To review evidence and updates in: • Risk Assessment Models • Prevention of VTE • Treatment of Recurrent VTE

  5. Objectives To review evidence and updates in: • Risk Assessment Models • Prevention of VTE • Treatment of Recurrent VTE

  6. Risk Factors for VTE in Cancer • Risk varies from 1 – 30% depending on: Patient-related • Older age • Race • Prior VTE • Platelet count • Comorbid conditions • Cancer-related • Primary site • Histology • Metastatic disease • Time interval since diagnosis • Treatment-related • Surgery • Chemotherapy • Hormonal therapy • Antiangiogenic therapy • ESA • Hospitalization • Catheters Lyman et al. J Clin Oncol 2007.

  7. Risk Stratification Cancer-related Risk Factors Treatment-related Risk Factors Risk of VTE Patient-related Risk Factors 7

  8. Risk Stratification RAM? +/- Biomarkers? Cancer-related Risk Factors Treatment-related Risk Factors Patient-related Risk Factors 8

  9. Risk Assessment Models • Khorana Model • Ambulatory patients followed for febrile neutropenia and other complications on new chemo regimen • VTE not a predefined outcome • Ay Model • Ambulatory patients with new diagnosis of cancer or progression of cancer followed in the Vienna CATS • VTE is primary outcome and objectively verified • Khorana model + D-dimer + soluble P-selectin Khorana et al. Blood 2008. Ay et al Blood 2010.

  10. Khorana Model for Outpatients Khorana et al. Blood 2008.

  11. Prospective follow up of 819 patients Median observation time/follow-up: 656 days Khorana Model Validation Log-rank test P<0.001) Ay et al Blood 2010.

  12. Ay Model for Outpatients • Addition of D-dimer and soluble P-selectin to Khorana model: Ay et al Blood 2010.

  13. Objectives To review evidence and updates in: • Risk Assessment Models • Prevention of VTE • Treatment of Recurrent VTE

  14. ASCO Guidelines on Prophylaxis Surgical Patients Prophylaxis with LMWH or LDUH, with or without mechanical methods, for 7 – 10 days Up to 4 weeks in patients with high risk features Hospitalized Medical Patients Should be considered candidates for anticoagulant prophylaxis in the absence of contraindications Ambulatory Patients Routine prophylaxis NOT recommended LMWH or warfarin recommended for myeloma patients on IMiDs + chemo or dexamethasone Lyman et al. J Clin Oncol 2007.

  15. Extended Prophylaxis After Surgery P=0.02 P=0.01 P=0.06 NS NS NS VTE Maj Bleed VTE Maj Bleed VTE Maj Bleed ENOXACAN II FAME CANBESURE No. Cancer Pt 332 199 625 Bergqvist et al. N Engl J Med 2002. Rasmussen et al J Thromb Haemost 2006. Kakkar et al J Thromb Haemost 2010.

  16. 46% due to fatal PE Surgical Cancer Patients @RISTOS Prospective cohort N=2373 symptomatic VTE 2.1% overall mortality 1.7% Incidence of VTE, No. 1-5 5-10 11-15 16-20 21-25 25-30 >30 Days post surgery Agnelli et al. Ann Surg 2006.

  17. Surgical Cancer Patients @RISTOS Agnelli et al. Ann Surg 2006.

  18. Million Women Study • 947,454 middle aged women in UK 1996-2001 • Prospectively followed for PE, DVT or death from VTE using national hospital admission databases • In first 12 weeks after surgery, risk of VTE: • 1 in 45 for hip or knee replacement • 1 in 85 for cancer surgery • 1 in 115 for vascular surgery • 1 in 140 for any surgery Sweetland et al. BMJ 2009

  19. Million Women Study 91-fold peak incidence at 3 weeks 53-fold 34-fold risk of PE higher than DVT Sweetland et al. BMJ 2009

  20. ASCO Guidelines on Prophylaxis Surgical Patients Prophylaxis with LMWH or LDUH, with or without mechanical methods, for 7 – 10 days Up to 4 weeks in patients with high risk features Hospitalized Medical Patients Should be considered candidates for anticoagulant prophylaxis in the absence of contraindications Ambulatory Patients Routine prophylaxis NOT recommended LMWH or warfarin recommended for myeloma patients on IMiDs + chemo or dexamethasone Lyman et al. J Clin Oncol 2007.

  21. Prophylaxis of Oncology Inpatients Major guidelines recommend standard prophylaxis No studies focused on cancer patients for inpatient prophylaxis during medical admission A post hoc analysis (MEDENOX trial) reported non- significant reduction in VTE with enoxaparin (RR 0.50; 0.14 – 1.72) in cancer subgroup (N~35/group) Compliance is poor at ~25% Alikhan et al. Blood Coagul Fibrinolysis 2003. Amin et al J Clin Onco 2007 (abstract).

  22. Introduced VTE prophylaxis as a Required Organizational Practice Five tests of compliance Reviews started January 2011 Identified as a Clinical Care Management priority by MoH In hospital Prophylaxis http://www.accreditation.ca/uploadedFiles/CHAR-2009-EN.pdf

  23. ASCO Guidelines on Prophylaxis Surgical Patients Prophylaxis with LMWH or LDUH, with or without mechanical methods, for 7 – 10 days Up to 4 weeks in patients with high risk features Hospitalized MedicalPatients Should be considered candidates for anticoagulant prophylaxis in the absence of contraindications Ambulatory Patients Routine prophylaxis NOT recommended LMWH or warfarin recommended for myeloma patients on IMiDs + chemo or dexamethasone Lyman et al. J Clin Oncol 2007.

  24. Oncology Outpatient Prophylaxis RRR=85% P=0.03 Not significant Incidence of VTE Active: warfarin certoparin certoparin dalteparin drug Levine et al. Lancet 1994. Haas et al. JTH 2005. Perry et al. J Clin Oncol 2007.

  25. PROTECHT Study • Multicentre, double-blind, placebo-controlled 2:1 RCT • Advanced lung, breast, GI, pancreas, ovary, H+N • Nadroparin vs placebo for duration of chemo (up to 4m) *1-sided Agnelli et al. Lancet Oncol 2009.

  26. CONKO 004 Trial • 312 patients receiving chemotherapy for APC • Randomized to gemcitabine or gemcitabine + enoxaparin • Enoxaparin 1 mg/kg once daily x 12 weeks then 40 mg once daily • Primary outcome: symptomatic VTE and fatal PE at 12 weeks 9.9% P<0.01 P=0.6 3.8% 2.6% 1.3% VTE bleeding Riess et al. ASCO May 2009.

  27. FRAGEM Trial • 123 patients receiving chemotherapy for APC • Randomized to gemcitabine or gemcitabine + dalteparin • Dalteparin 200 U/kg once daily x 1 month then 150 U/kg x 2 months • Primary outcome: symptomatic VTE and fatal PE at 3 months 31% P=0.02 P=0.03 12% 9% 0% fatal PE or sudden death VTE Maraveyas et al. ESMO 2009.

  28. Prophylaxis in Oncol Outpatients Statistics for each study MH risk ratio and 95% CI MH risk Lower Upper ratio limit limit p-Value FAMOUS 0.77 0.21 2.84 0.70 TOPIC-1 1.01 0.36 2.81 0.99 TOPIC-2 0.53 0.25 1.11 0.09 PRODIGE 0.66 0.29 1.49 0.32 PROTECHT 0.50 0.22 1.13 0.10 SIDERAS 0.82 0.23 2.94 0.76 0.64 0.44 0.94 0.02 Other Cancers CONKO004 0.35 0.16 0.75 0.01 FRAGEM 0.37 0.17 0.81 0.01 Pancreas 0.36 0.20 0.62 <.001 0.1 0.2 0.5 1 2 5 10 LMWH Control Efficacy outcome: VTE Kuderer et al. ASH 2009.

  29. Objectives To review evidence and updates in: • Risk Assessment Models • Prevention of VTE • Treatment of Recurrent VTE

  30. Long Term Treatment RCTs of LMWH vs Vit K antagonists in cancer Lee et al N Engl J Med 2003. Meyer et al Arch Intern Med 2002. Deitcher et al Clin Appl Thromb Hemost 2006. Hull et al Am J Med 2006.

  31. risk reduction = 52% HR 0.48 (95% CI 0.30, 0.77) log-rank p = 0.002 25 20 VKA, 17% 15 Probability of Recurrent VTE, % 10 dalteparin, 9% 5 0 0 30 60 90 120 150 180 210 Days Post Randomization CLOT Recurrent VTE Lee et al. New Engl J Med 2003.

  32. Treatment of Recurrent VTE • LMWH dose escalation is effective in cancer patients with recurrent VTE on anticoagulation • 90% respond to 25-50% dose escalation • Fewer than 5% experience any bleeding • DO NOT INSERT IVC FILTER • Does not treat hypercoagulability or reduce symptoms • Can lead to more DVT, venous gangrene, limb loss • No data to show reduction in mortality or hospitalization • No evidence for other anticoagulants Carrier et al. J Thromb Haemost 2009. White et al. Arch Intern Med 2000.

  33. Symptomatic recurrent VTE Failure on Warfarin Failure on LMWH Increase LMWH by ~25% or back up to full dose* Switch to full dose LMWH* Reassess in 5-7 days† No improvement Symptomatic improvement Check peak anti-Xa level Continue same dose Increase LMWH dose accordingly to aim for: 1.6 – 2.0 U/mL for once daily dosing or 0.8 – 1.0 U/ml for twice daily dosing Resume usual follow-up *full dose refers to the recommended weight-adjusted dose of LMWH for the initial therapy of VTE. †Reassessment should consist of clinical evaluation of symptoms. Radiological imaging is not required except when deterioration is noted and further extension or new thrombosis is suspected. Approach to Recurrent VTE Lee. Hematology Education Program Book 2010.

  34. Treatment in Thrombocytopenia/Bleeding • LMWH dose reduction is effective in patients with thrombocytopenia (< 50 x 109/L) • consider platelet transfusion if VTE is acute • reduce dose to 50% if count 20 – 50 x 109/L • prophylactic or withhold dose if count <20 x 109/L • LMWH should be withheld if active bleeding • treat underlying bleeding source whenever possible • THERAPEUTIC ANTICOAGULATION DOES NOT CAUSE BLEEDING – LOOK FOR BLEEDING SOURCE Lee. J Clin Oncol 2009;27:4895-4901.

  35. PharmaCare Coverage • New Special Authority Criterion added March 17, 2011 • For treatment, dalteparin is approved for: “Associated with cancer, in patients who have either failure or are unable to tolerate oral therapy with warfarin (up to 6 months)” • Not available for other LMWH due to lack of data • For prophylaxis, all LMWHs are also approved for: “patients with thrombophilia (up to 3 months)” • Can be used for continuing prophylaxis after hospital discharge following surgery for cancer http://www.health.gov.bc.ca/pharmacare/sa/criteria/restricted/dalteparin.html

  36. Other Take Home Messages … • Patients tolerate long-term LMWH very well • Important to apply pressure to injection site for at least 2 minutes to reduce hematomas • LMWH should be stored at room temperature • refrigeration, freezing, heat will deactivate drug • PharmaCare coverage can be obtained immediately by phone at 1-877-657-1188, press #1 • Thrombosis Clinic referral fax: 604-875-5071

  37. Thrombosis in Cancer Summary • VTE is a very common complication that increase morbidity and mortality in cancer patients • Use a validated RAM to estimate risk of VTE in ambulatory patients with new or progressive disease • Selected cancer patients benefit from extended prophylaxis after surgery • Prophylaxis in hospitalized patients is a patient safety priority • LMWH is the “best” agent available for prevention and treatment

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