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

2. VTE and Cancer VTE and Cancer: Epidemiology ► 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 Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21 Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21

3. VTE and Cancer 1.Ambrus JL et al. J Med. 1975;6:61-64 2.Donati MB. Haemostasis. 1994;24:128-131 3.Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 4.Prandoni P et al. Ann Intern Med. 1996;125:1-7 DVT and PE in Cancer Facts, Findings, and Natural History ► VTE is the second leading cause of death in hospitalized cancer patients 1,2 ► The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer 2 ► Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE 3 ► Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4

4. VTE and Cancer Clinical Features of VTE in Cancer ► 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 10% with idiopathic VTE develop cancer within 2 years 20% have recurrent idiopathic VTE 20% have recurrent idiopathic VTE 25% have bilateral DVT 25% have bilateral DVT Bura et. al., J Thromb Haemost 2004;2:445-51

5. VTE and Cancer Thrombosis and Survival Likelihood of Death After Hospitalization 0 20 40 60 80 100 120140 160 180 0 20 40 60 80 100 120140 160 180 0.00 0.20 0.401.000.80 0.60 DVT/PE and Malignant Disease Malignant Disease DVT/PE Only Nonmalignant Disease Number of Days Probability of Death Levitan N, et al. Medicine 1999;78:285

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

7. VTE and Cancer Symptomatic VTE in Cancer Reduces Survival Counterintuitively, Magnitude of Effect on Survival is Greatest with Local Stage Disease

8. VTE and Cancer 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. VTE and Cancer Recurrent Ovarian Cancer Fotopoulou C et al. Thromb Res 2009 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)

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

11. VTE and Cancer Thrombosis Risk In Cancer Primary Prophylaxis ► Medical Inpatients ► Surgery ► Radiotherapy ► Central Venous Catheters

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

13. VTE and Cancer Medical Inpatients Cancer and Thrombosis

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

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

16. VTE and Cancer ASCO Guidelines 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. Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

17. VTE and Cancer Surgical Patients Cancer and Thrombosis

18. VTE and Cancer ► Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732 Incidence of VTE in Surgical Patients No Cancer N=16,954CancerN=6124P-value Post-op VTE 0.61%1.26%<0.0001 Non-fatal PE 0.27%0.54%<0.0003 Autopsy PE 0.11%0.41%<0.0001 Death0.71%3.14%<0.0001

19. VTE and Cancer Natural History of VTE in Cancer Surgery: The @RISTOS Registry ► Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Tracked 30-day incidence of VTE in 2373 patients Type of surgery Type of surgery 52% General 52% General 29% Urological 29% Urological 19% Gynecologic 19% Gynecologic 82% received in-hospital thromboprophylaxis 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings 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 Agnelli, Ann Surg 2006; 243: 89-95

20. VTE and Cancer 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 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:438-444 Prophylaxis in Surgical Patients StudyNDesignRegimens ENOXACAN 1 631double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475double-blind enoxaparin vs. UFH

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

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

23. VTE and Cancer ► 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 Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.

24. VTE and Cancer ASCO Guidelines: VTE Prophylaxis ► 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. Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

25. VTE and Cancer 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. VTE and Cancer Placebo-Controlled Trials StudyRegimenN CRT (%) CRT (%) Reichardt* 2002 Dalteparin 5000 U daily placebo285140 11 (3.7) 11 (3.7) 5 (3.4) 5 (3.4) Couban*2002 Warfarin 1mg daily placebo130125 6 (4.6) 6 (4.6) 5 (4.0) 5 (4.0) ETHICS † 2004 Enoxaparin 40 mg daily placebo155155 22 (14.2) 28 (18.1) * symptomatic outcomes ; † routine venography at 6 weeks 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. VTE and Cancer Tolerability of Low-Dose Warfarin 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% 3.0–4.919% >5.0 7% Central Venous Catheters: Warfarin Masci et al. J Clin Oncol. 2003;21:736-739

28. VTE and Cancer 8 th ACCP Consensus Guidelines No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Chest Jun 2008: 454S–545S

29. VTE and Cancer Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient ► 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.)

30. VTE and Cancer Risk Factors for VTE in Medical Oncology Patients ► 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

31. VTE and Cancer Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery with institutionalization 21.72 Trauma12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease w/ extremity paresis 3.04 Serious liver disease 0.10 Heit JA et al. Thromb Haemost. 2001;86:452-463

32. VTE and Cancer VTE Incidence In Various Tumors Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Oncology Setting VTE Incidence Breast cancer (Stage I & II) w/o further treatment 0.2% Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage IV) w/ chemo 8% Non-Hodgkin’s lymphomas w/ chemo 3% Hodgkin’s disease w/ chemo 6% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma (thalidomide + chemo) 28% Renal cell carcinoma 43% Solid tumors (anti-VEGF + chemo) 47% Wilms tumor (cavoatrial extension) 4%

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

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

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

36. VTE and Cancer Knight: N Engl J Med.2006,354:2079 ► 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 Incidence of VTE: USA and Canada Greater than Israel, Australia, and Europe Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma TreatmentOdds RatioP Value (95% CI) Lenalidomide plus3.51 (1.77-6.97)<0.001 High-dose dexamethasone Concomitant erythropoietin 3.21 (1.72-6.01)<0.001 Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma TreatmentOdds RatioP Value (95% CI) Lenalidomide plus3.51 (1.77-6.97)<0.001 High-dose dexamethasone Concomitant erythropoietin 3.21 (1.72-6.01)<0.001

37. VTE and Cancer Oral Anticoagulant Therapy in Cancer Patients: Problematic ► 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?

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

39. VTE and Cancer Landmark CLOT Cancer Trial Reduction in Recurrent VTE 0 5 10 10 15 15 20 20 25 25 Days Post Randomization 0306090120150180210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = 0.0017 Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

40. VTE and CancerDalteparin N=338 N=338OACN=335 P-value* P-value* Major bleed 19 ( 5.6%) 19 ( 5.6%) 12 ( 3.6%) 12 ( 3.6%)0.27 Any bleed 46 (13.6%) 46 (13.6%) 62 (18.5%) 62 (18.5%)0.093 * Fisher’s exact test Bleeding Events in CLOT Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

41. VTE and Cancer Treatment of Cancer-Associated VTE StudyDesign Length of Therapy (Months)N Recurrent VTE (%) Major Bleeding (%)Death(%) CLOT Trial (Lee 2003) DalteparinOAC6336336917643941 CANTHENOX (Meyer 2002) EnoxaparinOAC3677111217161123 LITE (Hull ISTH 2003) TinzaparinOAC38087611682322 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC63236343.43.16.7 NS 0.03 NS 0.002 NS NR 0.09 0.03 0.09

42. VTE and Cancer Treatment and 2° Prevention of VTE in Cancer – Bottom Line ► 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 ► Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation— ACCP) Chest Jun 2008: 454S–545S New Development New Development

43. VTE and Cancer CLOT 12-month Mortality All Patients Lee AY et al. J Clin Oncol. 2005; 23:2123-9.

44. VTE and Cancer 0 10 20 30 40 50 60 70 80 90100 Days Post Randomization 0306090120150180240300360 Probability of Survival, % OAC Dalteparin HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWH CLOT 12-month Mortality Patients Without Metastases (N=150) Lee AY et al. J Clin Oncol. 2005; 23:2123-9.

45. VTE and Cancer ► 84 patients randomized: Chemo +/- LMWH (18 weeks) ► Patients balanced for age, gender, stage, smoking history, ECOG performance status LMWH for Small Cell Lung Cancer Turkish Study Altinbas et al. J Thromb Haemost 2004;2:1266. Chemotherapy plus Dalteparin Chemo alone P-value 1-y overall survival, % 51.329.50.01 2-y overall survival, % 17.2 0.0 0.00.01 Median survival, m 13.0 8.0 8.00.01 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily

46. VTE and Cancer VTE Prophylaxis Is Underused in Patients With Cancer 1.Kakkar AK et al. Oncologist. 2003;8:381-388 2.Stratton MA et al. Arch Intern Med. 2000;160:334-340 3.Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 Cancer: FRONTLINE Survey 1 — 3891 Clinician Respondents Rate of Appropriate Prophylaxis, % Major Surgery 2 Major Abdominothoracic Surgery (Elderly) 3 Medical Inpatients 4 Confirmed DVT (Inpatients) 5 Cancer: Surgical Cancer: Medical 4.Rahim SA et al. Thromb Res. 2003;111:215-219 5.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262

47. VTE and Cancer Conclusions and Summary ►Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopenia ►Long-term secondary prevention with LMWH has been shown to produce better outcomes than warfarin ►Guidelines and landmark trials support administration of LMWH in at risk patients ►Cancer patients are under-prophylaxed for VTE ►Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient population