1. Thrombosis in Cancer An Update on Risk Assessment, Prevention and 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 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. Cancer-Associated Thrombosis

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

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

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

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. Patient CharacteristicScore Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) 2121 Pre-chemotherapy platelet count > 350,000/mm 3 1 Hb < 10g/dL or use of ESA1 Prechemotherapy leukocyte count > 11,000/mm 3 1 BMI > 35 kg/m 2 1 Khorana Model for Outpatients Khorana et al. Blood 2008.

11. Prospective follow up of 819 patients Median observation time/follow-up: 656 days 6-mo cumulative VTE rates: PatientsEvents n% Score ≥39317.7% Score 22219.6% Score 12293.8% Score 02761.5% Ay et al Blood 2010. Khorana Model Validation Log-rank test P<0.001)

12. 6-mo cumulative VTE rates: Patients, nEvents, % Score ≥53035% Score 45120.3% Score 313010.3% Score 22183.5% Score 11904.4% Score 02001.0% Addition of D-dimer and soluble P-selectin to Khorana model: Ay Model for Outpatients 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 Lyman et al. J Clin Oncol 2007. 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

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

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

17. @RISTOS Risk factors for VTEOdds Ratio (95% CI) previous history of VTE6.0 (2.1 – 16.8) anesthesia lasting > 2 hours4.5 (1.1 – 19.0) bed rest post-op > 4 days4.4 (2.5 – 7.8) advanced tumour2.7 (1.4 – 5.2) age > 602.6 (1.2 – 5.7) Agnelli et al. Ann Surg 2006. Surgical Cancer Patients

18. Million Women Study Sweetland et al. BMJ 2009 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

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

20. ASCO Guidelines on Prophylaxis Lyman et al. J Clin Oncol 2007. 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

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. In hospital Prophylaxis 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 http://www.accreditation.ca/uploadedFiles/CHAR-2009-EN.pdf

23. ASCO Guidelines on Prophylaxis Lyman et al. J Clin Oncol 2007. 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

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

25. 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) NadroparinPlaceboP-value No. Patients769381 1° endpoint: VTE + ATE2.0%3.9%0.02* Major bleeding0.7%00.18 1-yr mortality43%41% Agnelli et al. Lancet Oncol 2009. PROTECHT Study *1-sided

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 Riess et al. ASCO May 2009. VTE bleeding P<0.01 P=0.6 9.9% 1.3% 2.6% 3.8%

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 Maraveyas et al. ESMO 2009. VTE P=0.02 P=0.03 fatal PE or sudden death 31% 12% 9% 0%

28. Pancreas Statistics for each studyMH risk ratio and 95% CI MH riskLowerUpper ratiolimit p-Value FAMOUS0.770.212.840.70 TOPIC-11.010.362.810.99 TOPIC-20.530.251.110.09 PRODIGE0.660.291.490.32 PROTECHT0.500.221.130.10 SIDERAS0.820.232.940.76 0.640.440.940.02 CONKO0040.350.160.750.01 FRAGEM0.370.170.810.01 0.360.200.62<.001 0.10.20.512510 LMWHControl Other Cancers Kuderer et al. ASH 2009. Prophylaxis in Oncol Outpatients Efficacy outcome: VTE

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. Study Pt, No. Long-Term Treatment Rec VTE, % Major Bleed, % Death, %P-value Meyer 2002 71Warfarin21.122.7NS 67Enoxaparin 1.5 mg/kg10.511.3 Lee 2003 336Warfarin174410.002 336Dalteparin 200/150 IU/kg9639 Deitcher 2006 30Warfarin102.98.8NS 29Enoxaparin 1.0 mg/kg6.96.5 32Enoxaparin 1.5 mg/kg6.311.119.4 Hull 2006 100Warfarin10719NS 100Tinzaparin 175 IU/kg6720

31. CLOT Recurrent VTE Lee et al. New Engl J Med 2003. 0 5 10 15 20 25 Days Post Randomization 0306090120150180210 Probability of Recurrent VTE, % dalteparin, 9% VKA, 17% risk reduction = 52% HR 0.48 (95% CI 0.30, 0.77) log-rank p = 0.002

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. Approach to Recurrent VTE *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. Symptomatic recurrent VTE Failure on WarfarinFailure on LMWH Switch to full dose LMWH* Increase LMWH by ~25% or back up to full dose* Reassess in 5-7 days† No improvementSymptomatic improvement Check peak anti-Xa level 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 Continue same dose Resume usual follow- up Lee. Hematology Education Program Book 2010.

34. Treatment in Thrombocytopenia/Bleeding LMWH dose reduction is effective in patients with thrombocytopenia (< 50 x 10 9 /L) consider platelet transfusion if VTE is acute reduce dose to 50% if count 20 – 50 x 10 9 /L prophylactic or withhold dose if count <20 x 10 9 /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. 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 Thrombosis in Cancer Summary