A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer

1. Innovation ● Investigation ● Application A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Linking Science and Evidence to Clinical Practice— What Do Trials Teach? Program Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC

2. Of all cases of VTE: About 20% occur in cancer patients Annual incidence of VTE in cancer patients ≈ 1/250 Of all cancer patients: 15% will have symptomatic VTE As many as 50% have VTE at autopsy Compared to patients without cancer: Higher risk of first and recurrent VTE Higher risk of bleeding on anticoagulants Higher risk of dying VTE and Cancer: Epidemiology Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21

3. VTE is the second leading cause of death in hospitalized cancer patients1,2 The risk of VTE in cancer patients undergoing surgery is 3-to 5-fold higher than those without cancer2 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4 DVT and PE in CancerFacts, Findings, and Natural History Ambrus JL et al. J Med. 1975;6:61-64 Donati MB. Haemostasis. 1994;24:128-131 Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 Prandoni P et al. Ann Intern Med. 1996;125:1-7

4. VTE has significant negative impact on quality of life VTE may be the presenting sign of occult malignancy 10% with idiopathic VTE develop cancer within 2 years 20% have recurrent idiopathic VTE 25% have bilateral DVT Clinical Features of VTE in Cancer Buraet. al.,J ThrombHaemost 2004;2:445-51

5. 1.00 DVT/PE and Malignant Disease 0.80 0.60 Probability of Death Malignant Disease 0.40 DVT/PE Only 0.20 Nonmalignant Disease 0.00 0 20 40 60 80 100 120 140 160 180 Number of Days Thrombosis and SurvivalLikelihood of Death After Hospitalization Levitan N, et al. Medicine 1999;78:285

6. Incidence of VTE and Colon Cancer Stage 7% 6% 5% 4% 3% 2% 1% 0% Local Regional Remote Incidence of VTE (%) 0 50 100 150 200 250 300 350 400 Days after Cancer Diagnosis White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40

7. Symptomatic VTE in Cancer Reduces Survival Counterintuitively, Magnitude of Effect on Survival is Greatest with Local Stage Disease * p<0.05; †p<0.01); ‡ p<0.001) R.H. White et al. Thombosis Research 120 Suppl. 2 (2007) S29-S40

8. VTE Associated with Accelerated Death in Breast Cancer Does Symptomatic VTE Reflect Presence or Emergence of Metastatic, Aggressive Cancer? White, et al. Thromb Res,120 suppl. 2 (2007)

9. Recurrent Ovarian Cancer • 7% symptomatic VTE (2.8-6.1% in primary ovarian Cancer)• 78% of VTE in ROC occur within 2 months of second line chemo regimen: cisplatin-related• Ascites is the only independent risk factor for VTE (HR=2.2) Fotopoulou C et al. Thromb Res 2009

10. Hospital Mortality With or Without VTE Mortality (%) N=66,016 N=20,591 N=17,360 Khorana, JCO, 2006

11. Thrombosis Risk In Cancer Primary Prophylaxis • Medical Inpatients • Surgery • Radiotherapy • Central Venous Catheters

12. Cancer Type Men: prostate, colon, brain, lung Women: breast, ovary, lung Stage Treatments Surgery 10-20% proximal DVT 4-10% clinically evident PE 0.2-5% fatal PE Chemotherapy Central venous catheters (~4% generate clinically relevant VTE) Patient Prior VTE Comorbidities Genetic background Risk Factors for Cancer-Associated VTE

13. Cancer and Thrombosis Medical Inpatients

14. Antithrombotic Therapy: Choices Pharmacologic (Prophylaxis & Treatment) Nonpharmacologic (Prophylaxis) Low Molecular Weight Heparin (LMWH) Unfractionated Heparin (UH) Intermittent Pneumatic Compression Elastic Stockings Inferior Vena Cava Filter Oral Anticoagulants New Agents: e.g. Fondaparinux,Direct anti-Xa inhibitors,Direct anti-IIa, etc.?

15. Prophylaxis Studies in Medical Patients Relative risk reduction 47% Relative risk reduction 63% Rate of VTE (%) Relative risk reduction 44% Placebo Enoxaparin MEDENOX Trial Placebo Dalteparin PREVENT Placebo Fondaparinux ARTEMIS Francis, NEJM, 2007

16. 1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FOR VTE PROPHYLAXIS? Recommendation. Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation. ASCO Guidelines Lyman GH et al. J ClinOncol (25) 2007; 34: 5490-5505.

17. Cancer and Thrombosis Surgical Patients

18. Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Incidence of VTE in Surgical Patients Kakkar AK, et al. ThrombHaemost 2001; 86 (suppl 1): OC1732

19. Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Type of surgery • 52% General • 29% Urological • 19% Gynecologic 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings 2.1% incidence of clinically overt VTE (0.8% fatal) Most events occur after hospital discharge Most common cause of 30-day post-op death Natural History of VTE in Cancer Surgery: The @RISTOS Registry Agnelli, Ann Surg 2006; 243: 89-95

20. LMWH vs. UFH Abdominal or pelvic surgery for cancer (mostly colorectal) LMWH once daily vs. UFH tid for 7–10 days post-op DVT on venography at day 7–10 and symptomatic VTE Prophylaxis in Surgical Patients 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:438-444

21. Prophylaxis in Surgical Patients Canadian Colorectal DVT Prophylaxis Trial 16.9% P=0.052 13.9% N=234 Incidence of Outcome Event N=241 1.5% 2.7% VTE Major Bleeding (Cancer) (All) McLeod R, et al. Ann Surg 2001;233:438-444

22. Extended Prophylaxis inSurgical Patients 12.0% ENOXACAN II P=0.02 Incidence of Outcome Event N=167 5.1% 4.8% N=165 3.6% 1.8% NNT = 14 0% 0.4% 0.6% VTE Prox Any Major DVT Bleeding Bleeding Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980

23. A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment RESULTS: Cumulative incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15-76; P=0.012). CONCLUSIONS:4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis. Major Abdominal Surgery: FAME Investigators—Dalteparin Extended Rasmussen, J ThrombHaemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.

24. All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis. Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis. Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features. ASCO Guidelines: VTE Prophylaxis Lyman GH et al. J ClinOncol (25) 2007; 34: 5490-5505.

25. Thrombosis is a potential complication of central venous catheters, including these events: Fibrin sheath formation Superficial phlebitis Ball-valve clot Deep vein thrombosis (DVT) Central Venous Catheters Geerts W, et al. Chest Jun 2008: 381S–453S

26. Placebo-Controlled Trials Prophylaxis for Venous Catheters Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730

27. WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Young AM et al. Lancet 2009;373:567

28. WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Young AM et al. Lancet 2009;373:567

29. WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Young AM et al. Lancet 2009;373:567

30. Tolerability of Low-Dose Warfarin 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily INR measured at baseline and four time points 10% of all recorded INRs >1.5 Patients with elevated INR 2.0–2.9 6% 3.0–4.9 19% >5.0 7% Central Venous Catheters: Warfarin Masci et al. J ClinOncol. 2003;21:736-739

31. Influence of Thrombophilia on Thrombotic Complications of CVADs in Cancer In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls: The attributable risk of catheter associated thrombosis conferred by: CA + FVL OR=5.18 (95% confidence interval: 3.0-8.8) CA + G20210A OR=3.95 (95% confidence interval: 1.5-10.6) FVL 13.5% G20210A 3.6% Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564

32. 8th ACCP Consensus Guidelines No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Revised 2009 NCCN guidelines diverge from this philosophy Chest Jun 2008: 454S–545S

33. No recommendations from ACCP No data from randomized trials (RCTs) Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian) Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.) Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient

34. Tumor type Ovary, brain, pancreas, lung, colon Stage, grade, and extent of cancer Metastatic disease, venous stasis due to bulky disease Type of antineoplastic treatment Multiagent regimens, hormones,anti-VEGF, radiation Miscellaneous VTE risk factors Previous VTE, hospitalization, immobility, infection, thrombophilia Risk Factors for VTE inMedical Oncology Patients

35. Independent Risk Factors for DVT/PE Heit JA et al. ThrombHaemost. 2001;86:452-463

36. VTE Incidence In Various Tumors Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

37. Recommended for hospitalized cancer patients Not universally recommended for outpatients, but there are exceptions New data for certain agents Heterogeneous population Primary VTE Prophylaxis Need for risk stratification

38. VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in Myeloma Naluri SR et al. JAMA. 2008;300:2277

39. Bevacizumab Increases Risk of Symptomatic VTE by 33% vs Controls Naluri SR et al. JAMA. 2008;300:2277

40. Incidence of VTE: USA and Canada Greater than Israel, Australia, and Europe • rEPO used more in USA and Canada • L+Dex: 23% VTE with EPO vs 5% w/o EPO • Placebo + Dex: 7% VTE with EPO vs 1% without EPO Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma Treatment Odds Ratio P Value (95% CI) Lenalidomide plus 3.51 (1.77-6.97) <0.001 High-dose dexamethasone Concomitant erythropoietin 3.21 (1.72-6.01) <0.001 Knight: N Engl J Med.2006,354:2079

41. Warfarin therapy is complicated by: Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia and procedures Difficulty in venous access for monitoring Increased risk of both recurrence and bleeding Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why? Oral Anticoagulant Therapyin Cancer Patients: Problematic

42. CLOT: Landmark Cancer/VTE Trial Dalteparin Dalteparin CANCER PATIENTS WITH ACUTE DVT or PE Randomization Dalteparin Oral Anticoagulant [N = 677] • Primary Endpoints: Recurrent VTE and Bleeding • Secondary Endpoint: Survival Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

43. Risk reduction = 52% p-value = 0.0017 25 20 OAC Probability of Recurrent VTE, % 15 10 Dalteparin 5 0 0 30 60 90 120 150 180 210 Days Post Randomization Landmark CLOT Cancer Trial Reduction in Recurrent VTE Recurrent VTE • Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

44. Bleeding Events in CLOT * Fisher’s exact test Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

45. Treatment of Cancer-Associated VTE NS NS 0.002 0.09 0.09 0.03 NS 0.03 NS NR NS NS

46. New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendation—ACCP) NOTE: Dalteparin is only LMWH approved (May, 2007) for both the treatment and secondary prevention of VTE in cancer (NCCN preferred agent) Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—ACCP) Treatment and 2° Prevention of VTE in Cancer – Bottom Line New Development Chest Jun 2008: 454S–545S

47. CLOT 12-month Mortality All Patients 100 90 80 70 60 50 Dalteparin 40 OAC 30 Probability of Survival, % 20 10 0 HR 0.94 P-value = 0.40 0 30 60 90 120 180 240 300 360 Days Post Randomization Lee AY et al. J ClinOncol. 2005; 23:2123-9.

48. 100 90 80 70 60 50 40 30 20 10 0 Anti-Tumor Effects of LMWH CLOT 12-month Mortality Patients Without Metastases (N=150) Dalteparin OAC Probability of Survival, % HR = 0.50 P-value = 0.03 0 30 60 90 120 150 180 240 300 360 Days Post Randomization Lee AY et al. J ClinOncol. 2005; 23:2123-9.

49. LMWH Influences Survival of Patients with Advanced Solid Tumor Malignancies 6 wks LMWH immediately post diagnosis of CA-no initial chemo >6 mos anticipated survival <6 mos anticipated survival Klerk, C. P.W. et al. J ClinOncol; 23:2130-2135 2005

50. 84 patients randomized: Chemo +/- LMWH (18 weeks) Patients balanced for age, gender, stage, smoking history, ECOG performance status LMWH for Small Cell Lung CancerTurkish Study CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J ThrombHaemost 2004;2:1266.