1. The Art of Medical Prophylaxis, Impacting the Patient Early Anna Falanga, MD Hemostasis and Thrombosis Center Hematology-Oncology Dept Ospedali Riuniti Bergamo, Italy Satellite Symposium “Guidelines on Prevention and Treatment of Cancer-Associated Thrombosis” Stockholm, September 16, 2008

2. Adapted from: 1. ACCP 2004. 1.Geerts WH, et al. Chest. 2004;126:S338–S400, 2. Cohen A et al. Lancet 2008:371;387-394. Medical Conditions Although VTE is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic (TE) events and 70 to 80% of fatal pulmonary embolism (PE) occur in non-surgical patients 1 PE accounts for 5-10% of deaths in hospitalized patients, making VTE the most common preventable cause of in- hospital death 2

3. Venous Thromboembolism (VTE) Risk Hospitalized medical cancer patients are at increased risk for VTE Out of hospital cancer patients receiving therapy are at risk for VTE

4. VTE Prevention: We are Failing Our Patients Adapted from: 1.Kakkar AK et al. Oncologist. 2003;8:381-88. 2.Anderson FA et al. Ann Intern Med. 1991;115:591-95. 3. Rahim SA et al. Thromb Res. 2003;111:215-19 Cancer: 2001 FRONTLINE Survey 1 — 3891 Respondents Rate of Appropriate Prophylaxis, % 4. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-62. 5. Rashid J Royal Soc Med 2005. 6. Spencer FA et al. Arch Intern Med 2007;167:1471-75. 7. Tapson VF, et al. Chest 2007;132:936-45. 5 30 33 29 28 43 50 52 0 10 20 30 40 50 60 Surgical Onc Medical Onc US 91Canada 01US 02UK 03US 07World 07

5. Recommendations for VTE Prophylaxis in Patients with Cancer Released by International Medical Oncology Societies AIOM (Italian Medical Oncology Society) - 2006 ASCO (American Society of Clinical Oncology) - 2007 NCCN (National Comprehensive Cancer Network) - 2007, 2008 ESMO (European Society of Medical Oncology) - 2008

6. Recommendations for VTE Prophylaxis in Hospitalized Patients with Cancer Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation

7. Contraindications to Anticoagulation Active, uncontrollable bleeding Active cerebrovascular hemorrhage Dissecting or cerebral aneurysm Bacterial endocarditis Pericarditis, active peptic or other GI ulceration Severe, uncontrolled or malignant hypertension Severe head trauma Pregnancy (warfarin) Heparin-induced thrombocytopenia (heparin, LMWH) Epidural catheter placement.

8. Prophylaxis in Acutely I ll Medical Patients No randomized clinical trials designed a priori for hospitalized medical cancer patients Randomized, placebo-controlled trials in acutely ill hospitalized medical patients – MEDENOX 1 - enoxaparin 40 mg daily – PREVENT 2 - dalteparin 5000U daily – ARTEMIS 3 - fondaparinux 2.5 mg daily Adapted from: 1. Samama et al. N Engl J Med 1999;341:793-800; 2. Leizorovicz et al. Circulation 2004;110:874-79; 3. Cohen et al. Blood 2003; 102(11): 15.

9. MEDENOX 1 63%10Placebo Enoxaparin 40 mg PREVENT 2 49%45Placebo Dalteparin ARTEMIS 3 47%20Placebo Fondaparinux Study RRRNNTProphylaxis Patients with VTE, % Adapted from: 1 Samama et al. N Engl J Med 1999;341:793-800. 2 Leizorovicz et al. Circulation 2004;110:874-9. 3 Cohen et al. Br Med J 2006. P<0.001 P=0.0015 P=0.029 NNT = number needed to treat; RRR = relative risk reduction. RRR 63% 45% 47% 14.9 * (n=288) 5.5 (n=291) 5.0 (n=1,473) † 2.8 (n=1,518) 10.5 ‡ (n=323) 5.6 (n=321) *VTE at day 14; † VTE at day 21; ‡ VTE at day 15. Thromboprophylaxis of Medical Patients: Clear Benefits Over Placebo

10. MEDENOX PREVENT ARTEMIS Enox. 2.1 % Placebo 6.6 % Dalte. 2.6 % Placebo 5.0 % Fond. 1.5 % Placebo 3.4 % P = 0.002 P = 0.085P = 0.037 Proximal DVT + Symptomatic VTE at D14-21

11. R Enoxaparin 40 mg s.c. q.d. Enoxaparin 40 mg s.c. q.d. Placebo 10±4 38±4 Systematic Duplex ultrasound Days 6-month follow-up EXCLAIM: Study Design  Prospective, randomized, double-blind  5,090 patients: enrollment completed

12. Inclusion Criteria Adapted from Hull et al. J Thromb Thrombolysis. 2006; 22:31-38. Age > 75 years OR History of VTE OR Diagnosis of cancer + Age  40 years Recent immobilization (  3 days) Acute medical illness Heart failure, NYHA class III/IV Acute respiratory insufficiency Other acute medical conditions including: –post-acute ischemic stroke –acute infection without septic shock –active cancer Level 1 mobility (total bed rest or sedentary patients) Level 2 mobility (Level 1 with bathroom privileges) or Initial inclusion criteria Amended inclusion criteria

13. VTE eventsMajor bleeding P=0.0011 P=0.019 Symptomatic DVT P=0.0109 121 NNT NNT = number needed to treat NNH = number needed to harm 0 1 2 3 4 5 6 Incidence (%) 224 NNH 46 NNT Summary of Efficacy and Safety: End of the Double-blind Period Placebo (N=1681 efficacy pop; N=2027 safety pop) Enoxaparin (N=1666 efficacy pop; N=2013 safety pop)

14. Recommended Dose: Venous Thromboembolism Prophylaxis ManagementDrugRegimen Prophylaxis Patients with cancer receiving medical or surgical treatment while staying in hospital Unfractionated Heparin (UFH) 5000 U q 8 h Dalteparin5000 U daily Enoxaparin40 mg daily Fondaparinux2.5 mg daily

15. Prophylaxis in Medical Patients: Ambulatory Cancer Patients The role of thromboprophylaxis in ambulatory cancer patients during chemotherapy and hormone therapy is not established. One double-blind placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (INR 1.3-1.9) in patients receiving chemotherapy for metastatic breast cancer (Levine MN et al, Lancet 1994).

16. Patients *WarfarinPlacebop= n=152n=159 Thromboembolic events170.031 relative risk reduction = 85% * women receiving chemotherapy for metastatic breast cancer Adapted from Levine et al., Lancet 1994. Double Blind Randomized Trial of Very-low-dose Warfarin (INR 1.3- 1.9) for Prevention of Thromboembolism in Stage IV Breast Cancer

17. Warfarin Prophylaxis: Limitations Very difficult schedule Interaction with cytotoxics Tested only in breast cancer

18. Prophylaxis of VTE in Medical Cancer Patients LMWH benefits –Predictable anticoagulant effect –Single daily administration –Reduced toxicity (thrombocytopenia, osteoporosis) –Acceptable safety profile in oncological patient (long term use in recent studies: FAMOUS, CLOT)

19. Primary Prophylaxis During Chemotherapy: LMWH Recent Closed Studies StudyCancer TOPIC-1 1 Breast Cancer TOPIC-2 1 Non small cell lung cancer PRODIGE 2 Malignant glioma (grade III or IV) PROTECHTLung, Breast, Gastrointestinal, Ovarian, Head/Neck cancer Adapted from: 1 Haas J Tromb Haemost 2005, suppl. 1, Abs OR059; 2 Perry et al. Thromb Res 2007, suppl. 2, Abs PO40.

20. Primary Prophylaxis During Chemotherapy: LMWH Ongoing Studies AUTHORSTUDY Pancreatic cancer SCHEDULE MaraveyasProspective randomised Gemcitabine ± Dalteparin 200U/Kg o.d. PelzerProspective randomised Gemcitabine ± Enoxaparin 1 mg/Kg Adapted from ASCO 2007.

21. Recommendations for Primary VTE Prophylaxis in Ambulatory Patients with Cancer Current guidelines do not recommend: –Routine prophylaxis with an antithrombotic agent in ambulatory cancer patients

22. Special consideration: Prophylaxis in Multiple Myeloma patients Prophylaxis with LMWH or adjusted dose warfarin (INR~1.5) is recommended in multiple myeloma patients receiving thalidomide or lenalidomide + chemotherapy or dexamethasone (high VTE risk). However: –No RCTs available –Recommendation is based on extrapolation from non- randomized trials or randomized studies in other similar high- risk categories –Well-designed RCTs are urgently needed Adapted from ASCO Guidelines, JCO 2007.

23. Central Venous Catheter (CVC) – Related Thrombosis

24. Prophylaxis of CVC - Related Thrombosis The presence of CVC is a risk factor for VTE. Three recent clinical trials have assessed that the incidence of CVC-related symptomatic thrombosis is approximately 3% to 4%. These trials failed to show a significant effect of prophylaxis with 1 mg fixed dose warfarin, or LMWH dalteparin, or LMWH enoxaparin in reducing symptomatic and asymptomatic thrombosis in patients with cancer.

25. Randomised Controlled Clinical Trials of Prophylaxis of CVC - Related Thrombosis StudyDrugn.CRT (%) Karthaus M et al * Ann Onc 2006 Dalteparin, 5000 IU od Placebo 285 140 11 (3.7) 5 (3.4) Couban S et al * JCO 2005 Warfarin, 1 mg od Placebo 130 125 6 (4.6) 5 (4.0) Verso M et al ° JCO 2005 Enoxaparin, 40 mg od Placebo 155 22 (14.2) 28 (18.1) * Symptomatic events °Routine venography at 6 weeks

26. Current guidelines agree that extensive, routine prophylaxis to prevent CVC-related VTE is not recommended. To date prophylaxis might be tailored according to individual risk level. Recommendations for Prophylaxis for CVC – Related Thrombosis

27. Conclusion Evidence from epidemiological and clinical studies demonstrates that not only surgical patients but also medical patients with acute medical conditions and predisposing risk factors are at significant risk of VTE. Hospitalized cancer patients should be assessed for risk of VTE and given appropriate thromboprophylaxis. Early intervention with thromboprophylaxis (i.e. LMWH) will impact cancer patient outcome.