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The Art of Medical Prophylaxis, Impacting the Patient Early

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

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The Art of Medical Prophylaxis, Impacting the Patient Early

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

  2. 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 patients1 • PE accounts for 5-10% of deaths in hospitalized patients, making VTE the most common preventable cause of in-hospital death2 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.

  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 Cancer: 2001 FRONTLINE Survey1— 3891 Respondents 60 52 50 50 43 40 33 Rate of Appropriate Prophylaxis, % 30 29 28 30 20 10 5 0 Surgical Medical US 91 Canada 01 US 02 UK 03 US 07 World 07 Onc Onc 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 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. 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 Ill Medical Patients • No randomized clinical trials designed a priori for hospitalized medical cancer patients • Randomized, placebo-controlled trials in acutely ill hospitalized medical patients • MEDENOX1- enoxaparin 40 mg daily • PREVENT2 - dalteparin 5000U daily • ARTEMIS3 - 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. Thromboprophylaxis of Medical Patients: Clear Benefits Over Placebo RRR 63% 45% 47% Study RRR NNT Prophylaxis Patients with VTE, % MEDENOX1 63% 10 Placebo Enoxaparin 40 mg PREVENT2 49% 45 Placebo Dalteparin ARTEMIS3 47% 20 Placebo Fondaparinux 14.9* (n=288) P<0.001 5.5 (n=291) 5.0 (n=1,473)† P=0.0015 2.8 (n=1,518) 10.5‡(n=323) 5.6 (n=321) P=0.029 *VTE at day 14; †VTE at day 21; ‡VTE at day 15. NNT = number needed to treat; RRR = relative risk reduction. Adapted from: 1Samama et al. N Engl J Med 1999;341:793-800.2Leizorovicz et al. Circulation 2004;110:874-9. 3Cohen et al. Br Med J 2006.

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

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

  12. Age > 75 years OR • History of VTE OR • Diagnosis of cancer + Inclusion Criteria Initial inclusion criteria • 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 Amended inclusion criteria Level 1 mobility (total bed rest or sedentary patients) Level 2 mobility (Level 1 withbathroom privileges) or Adapted from Hull et al. J Thromb Thrombolysis. 2006; 22:31-38.

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

  14. Recommended Dose: Venous Thromboembolism Prophylaxis

  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. Double Blind Randomized Trial of Very-low-dose Warfarin (INR 1.3-1.9) for Prevention of Thromboembolism in Stage IV Breast Cancer Patients * Warfarin Placebo p= n=152 n=159 Thromboembolic events 1 7 0.031 relative risk reduction = 85% * women receiving chemotherapy for metastatic breast cancer Adapted from Levine et al., Lancet 1994.

  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 Adapted from: 1 Haas J TrombHaemost2005, suppl. 1, Abs OR059; 2 Perry et al. Thromb Res 2007, suppl. 2, Abs PO40.

  20. Primary Prophylaxis During Chemotherapy:LMWH Ongoing Studies 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 * Symptomatic events °Routine venography at 6 weeks

  26. Recommendations for Prophylaxis for CVC – Related Thrombosis • 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.

  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.

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