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An Oncologists Perspective on Cancer and Thrombosis

Oncology Grand Rounds University of North Carolina Lineberger Comprehensive Cancer Center April 21, 2009. An Oncologists Perspective on Cancer and Thrombosis. Gary H. Lyman, MD, MPH, FRCP(Edin) Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research

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An Oncologists Perspective on Cancer and Thrombosis

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  1. Oncology Grand Rounds University of North CarolinaLineberger Comprehensive Cancer CenterApril 21, 2009 An Oncologists Perspective on Cancer and Thrombosis Gary H. Lyman, MD, MPH, FRCP(Edin) Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Duke University School of Medicine and the Duke Comprehensive Cancer Center

  2. Cancer and Venous Thromboembolism (VTE) Association recognized since Trousseau’s observation more than 130 years ago1 Of all cases of VTE, approximately 20% occur in cancer patients.2 VTE affects 4-20% of cancer patients antemortem but has been reported in up to 50% on postmortem examination.3-4 Cancer-associated VTE has important clinical and economic consequences5-7 Armand Trousseau Patients with cancer: 20% All deep venous thrombosis and pulmonary embolism 4. Lyman GH et al: J Clin Oncol 2007; 25: 5490-5505. 5. Sorensen HT, et al. N Engl J Med. 2000;343:1846-1850. 6. Prandoni P, et al. Blood. 2002;100:3484-3488. 7. Khorana AA, et al. J Clin Oncol. 2006;24:484-490. 1. Trousseau, Armand. In Clinique Medicale de l'Hôtel-Dieu de Paris, 2nd ed. Paris: J.B. Bailliere et Fils; 1865 2. Lee AY. Br J. Haematol. 2005;128:291-302. 3. Gao S et al: Expert Rev Anticncer Ther 2004; 4: 303-320.

  3. Pathogenesis: Virchow’s Triad

  4. Growth Invasion Metastases Angiogenesis Hemostatic System Tumor Cells Procoagulant Activity Cytokines Growth Factors Fibrinolytic Activity Kuderer NM et al J Clin Oncol 2009 (in press)

  5. Risk of VTE Varies Over Natural History of Cancer 8 7 6 5 4 3 2 1 0 Hospitalization End of life Chemotherapy Metastasis Diagnosis Risk (Odds Ratio) Risk of VTE in the cancer population Remission Risk of VTE in the general population Time Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis;2007.

  6. VTE within Two years of Cancer Diagnosis Metastatic Disease Local-Regional Disease • The California Cancer Registry linked to the California Discharge Data, 1993 - 1995. • Among 235,149 cancer cases, 3775 (1.6%) were diagnosed with VTE within 2 years including 463 (12%) at the time cancer and 3312 (88%) subsequently. Chew, H. K. et al. Arch Intern Med 2006;166:458-464.

  7. Incidence of VTE in US Patients With and Without Cancer, 1979-1999 National Hospital Discharge Survey 4 Cancer 3 No cancer VTE Incidence (%) 2 1 0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 Years Stein PD, et al. Am J Med. 2006;119:60-68.

  8. Risk Factors for VTE in Patients with Cancer Patient-related factors Older age Gender Race (higher in African Americans, lower in Asians) Patient comorbidities History of VTE Treatment-related factors Major surgery Hospitalization Chemotherapy Hormonal therapy Antiangiogenic agents ESAs, ?Transfusions Cancer-related factors • Site of cancer • Advanced stage • Initial period after diagnosis Biomarkers • Platelet and leukocyte counts • Tissue factor • P-selectin • D-dimer Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis;2007.

  9. Risk Factors for VTE in Patients with Cancer Patient-related factors Older age Gender Race (higher in African Americans, lower in Asians) Patient comorbidities History of VTE Treatment-related factors Major surgery Hospitalization Chemotherapy Hormonal therapy Antiangiogenic agents ESAs, ?Transfusions Cancer-related factors • Site of cancer • Advanced stage • Initial period after diagnosis Biomarkers • Platelet and leukocyte counts • Tissue factor • P-selectin • D-dimer

  10. Important Consequences of VTE in Cancer Patients • Increased morbidity • Hospitalization • Anticoagulation • Postphlebitic syndrome • Increased mortality • Increased risk of recurrent VTE • Bleeding complications • Cancer treatment delays • Increased healthcare costs

  11. Important Consequences of VTE in Cancer Patients • Increased morbidity • Hospitalization • Anticoagulation • Postphlebitic syndrome • Increased mortality • Increased risk of recurrent VTE • Bleeding complications • Cancer treatment delays • Increased healthcare costs

  12. Effect of VTE on Risk of DeathStratified by Stage, Adjusted for Age and Race • CA Cancer Registry linked to Discharge Data • Overall Mortality • HR=3.7 [1.3-14.4] • Multivariate analysis • Stratified by stage • Adjusted for age, race • VTE is a significant predictor for 1 year mortality for each cancer type Chew, H. K. et al. Arch Intern Med 2006;166:458-464.

  13. VTE in Diffuse Large B-cell Lymphoma • Retrospective review of patients with DLBCL treated 1990-2001 • Symptomatic VTE at diagnosis or during initial treatment. • 27/211 patients (12.8%). • Median survival (years) • Controls: 5.20 [1.80 – 8.60] • VTE: 1.04 [0.75 – 1.33] • P = 0.038 • Multivariate Analysis for Mortality* * Adjusted for sex, race, and stage Komorokji RS et al. Leuk Lymph 2006; 47: 1029-1033

  14. Unsuspected PE On Routine Cancer StagingImpact on Survival • Retrospective review of 70 patients with unsuspected PE found on staging CT • 2003–2006 • VTE, anticoagulation or multiple cancers excluded • 2:1 matching based on • Cancer type • Age • Stage • Unsuspected PE: • Subsegmental: 24.3% • Proximal: 75.7% HR=1.79 [95% CI: 1.10-2.90; P=0.018] O’Connell CL et al: ASH 2008

  15. Unsuspected VTE in Cancer Patients Results from Autopsy Series University of Missouri Roswell Park Cancer Institute • Consecutive autopsies in 506 cancer patients • Causes of Death, n (%) • Major • Infection 184 (36%) • Hemorrhage 55 (11%) • VTE 35 (7%) • MI 35 (7%) • Contributing • Infection 68 (13%) • Hemorrhage (25%) • VTE 91 (18%) • MI 13 (3%) • 578 consecutive autopsies • 145 cancer patients, n (%) • PE 24 (17%) • Fatal PE 20 (14%) • 433 noncancer patients • PE 55 (13%) • Fatal PE 343 (8%) • Author’s conclusions: • 1 in 7 hospitalized cancer pts died of PE • 60% of fatal PEs occur in early or limited metastatic disease P<.05 Shen VS et al. South Med J 1980; 73: 841-843 Ambrus J et al J Med 1975; 6: 61-64

  16. Causes of Early Death in Ambulatory Cancer Patients Results from Prospective Study of Series • Patient Population • Prospective study of 4466 patients starting new chemotherapy • Consecutive patients accrued at 117 US practices • Median followup of 75 days, 141 (3.2%) died. • Causes of Death, n (%) • All 141 (100) • Progression of cancer 100 (70.9) • Thromboembolism 13 (9.2) • Arterial 8 (5.6) • Venous 5 (3.5) • Infection 15 (10.6) • Respiratory failure 5 (3.5) • Bleeding 2 (1.4) • Other 9 (6.4) • Unknown 5 (3.5) Distribution of Cancer Type Khorana AA et al. J Thromb Haemost 2007; 5: 632-634

  17. Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer ASCO Clinical Practice Guideline Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

  18. Clinical Questions Should patients with cancer receive anticoagulation for VTE prophylaxis while hospitalized? √ Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? √ Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis? What is the best method for treatment of patients with cancer with established VTE to prevent recurrence? √ Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?√ Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

  19. Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation. ASCO Recommendations for VTE Prophylaxis in Patients with CancerHospitalized Cancer Patients Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

  20. Risk of Inpatient VTE By Site of Cancer – Solid Tumor • Discharge database of the University HealthSystem Consortium • 115 U.S. academic medical centers • 66,106 adult neutropenic cancer patients hospitalized 1995 - 2002 12 10 8 Rate (%) 6 4 2 0 All Lung Ovary Brain Colon Uterine Other GI Stomach Pancreas Khorana et al, J Clin Oncol 2006; 24: 484-490

  21. Risk of Inpatient VTE by Type of Cancer – Hematologic Malignancies 7 6 5 Percent (%) 4 3 2 1 0 Hodgkin All Leukemia NHL Myeloma Account for one-third of all VTE NHL=Non-Hodgkin’s lymphoma Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

  22. VTE Inpatient Risk and Mortality PE-all patients • Discharge database of the University HealthSystemConsortium • 133 U.S. academic medical centers • 1,015,598 adult cancer patients hospitalized 1995 - 2003 7.0 VTE: 34,357 (3.4%) PE: 11,515 (1.1%) 6.5 20 6.0 18 5.5 16 5.0 4.5 14 4.0 12 Rate of VTE (%) 3.5 10 3.0 Inpatient Mortality (%) 8 2.5 2.0 6 1.5 4 P<0.0001 1.0 P<0.0001 2 0.5 0.0 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 1995 1996 1997 1998 1999 2000 2001 2002 2003 VTE No VTE VTE- patients on chemo VTE-all patients DVT-all patients Khorana AA et al. Cancer 2007; 110: 2339-2346

  23. Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients • 3 large, randomized, placebo-controlled, double-blind trials in medical patients at high risk including cancer • MEDENOX (enoxaparin)1 ~ 15% • PREVENT (dalteparin)2 ~5% • ARTEMIS (fondaparinux)3 ~15% • Screening for asymptomatic DVT with venography or ultrasound • Samama MM, et al. N Engl J Med. 1999;341:793-800. • Leizorovicz A, et al. Circulation. 2004;110:874-879. • Cohen AT, et al. BMJ. 2006;332:325-329.

  24. Anticoagulant Prophylaxis to Prevent Screen-Detected VTEHigh Risk Hospitalized Medical Patients: VTE RRR 63% 45% 47% Study RRR Thromboprophylaxis Patients with VTE (%) MEDENOX1 Placebo 14.9 P < 0.001 Enoxaparin 40 mg 5.5 Placebo PREVENT2 5.0 P = 0.0015 Dalteparin 5,000 units 2.8 10.5 Placebo ARTEMIS3 Fondaparinux 2.5 mg 5.6 1Samama MM, et al. N Engl J Med. 1999;341:793-800.2 Leizorovicz A, et al. Circulation. 2004;110:874-9. 3Cohen AT, et al. BMJ 2006; 332: 325-329.

  25. Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: Major Bleeding 1.7% 1.1% Incidence of Major Bleeding (%) 0.49% 0.2% 0.16% Study Samama MM, et al. N Engl J Med. 1999;341:793-800.Leizorovicz A, et al. Circulation. 2004;110:874-9. Cohen AT, et al. BMJ 2006; 332: 325-329..

  26. Routine prophylaxis with an antithrombotic agent is not recommended. Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. LMWH or adjusted dose warfarin (INR~1.5) is recommended. This recommendation is based on extrapolation from studies of post-operative prophylaxis in orthopedic surgery and a trial of adjusted dose warfarin in patients with breast cancer. Randomized clinical trials evaluating antithrombotic agents in pts with myeloma on thalidomide or lenalidomide are needed. Research is also urgently needed to identify better markers in ambulatory patients with cancer likely to develop VTE. ASCO Recommendations for VTE Prophylaxis in Patients with CancerAmbulatory Cancer Patients Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

  27. Prospective Study of Adult Cancer PatientsReceiving Systemic Chemotherapy • Prospective observational study conducted at 117 randomly selected US practice sites. • Data obtained on 4,458 consecutive adult patients initiating a new chemotherapy regimen between March 2003 and February 2006. • There were no exclusions for age, prior history or comorbid- ities with nearly 40% of patients age 65 and older. Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008).

  28. Reported Cause of Early Mortality Cancer Patients Starting New Chemotherapy [HR=5.48, 95%CI: 2.21-13.61; P<.0001] No VTE VTE Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008)

  29. RCTs of Thromboprophylaxis in Ambulatory Cancer PatientsWarfarin • 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 • 311 women with metastatic breast cancer on 1st- or 2nd-line chemotherapy • Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR 1.3-1.9 or placebo • 1 VTE in warfarin group vs 7 in placebo arm • 85% risk reduction, P = .03, with no increased bleeding INR=international normalized ratio Levine M, et al. Lancet. 1994;343:886-889.

  30. RCTs of Thromboprophylaxis in Ambulatory Cancer PatientsLow Molecular Weight Heparin 1. Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948. 2. Haas SK, et al. J Thromb Haemost. 2005(suppl 1):abstract OR059. 3. Perry JR et al. Proc ASCO 2007. 2011 4. Sideras K et al. Mayo Clin Proc 2006; 81:758-767. 5. Agnelli G et al. Am Soc Hemat Sunday December 7, 2008

  31. The PROTECHT StudyRCT of Thromboprophylaxis in Cancer Patients Receiving ChemotherapyDESIGN • Placebo-controlled, double blind, multicenter RCT • Nadroparin 3,800 anti Xa IU daily vs placebo: 2:1 • 1150 patients receiving chemotherapy for locally advanced or metastatic cancer. • Start with new CTX; continue for maximum of 4 m • Mean treatment duration: 90 days • Primary outcome: clinically detected thrombotic events, i.e., composite of venous and arterial TE* • Main safety outcome: Major bleeding * deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, unexplained death of possible thromboembolic origin Agnelli G et al: ASH 2009

  32. The PROTECHT StudyRCT of Thromboprophylaxis in Cancer Patients Receiving ChemotherapyRESULTS • Primary Efficacy Outcome: Any TE Event* • Nadroparin: 16 of 769 (2.1%) • Placebo: 15 of 381 (3.9%) • Relative risk reduction: 47.2%, (interim-adjusted p=0.033) • Absolute risk decrease: 1.8%; NNT = 53.8 • Venous thromboembolism (VTE): • Nadroparin: 11 of 769 (1.4%) • Placebo: 11 of 381 (2.9%) NS • Major Bleeding: • Nadroparin: 5 (0.7%) • Placebo: 0 (p= 0.177) • Absolute risk increase: 0.7%; NNH = 153.8 Agnelli G et al: ASH 2009

  33. 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 ASCO Recommendations for VTE Prophylaxis in Patients with CancerRelative contraindications for anticoagulation Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

  34. Risk of VTE in Cancer Patients Receiving ThalidomideMeta-analysis of RCTs [Estimates ± 95% CI] • Search identified 17 RCTs including 3,977 patients • Incidence of VTE • All Studies: 11.7% [8.1% - 16.5%] • Multiple Myeloma: 17.7% [10.9% - 22.1%] • Solid Tumors: 5.3% [2.1% - 12.8%] • Relative Risk for VTE • All Studies: 2.4 [1.9 – 3.0], P<.001 • Multiple Myeloma: 3.1 [2.1 – 4.4], P<.001 • Solid Tumors: 3.5 [1.1 – 10.6], P=.028 • Prophylaxis (all studies) • No prophylaxis: 3.5 [2.5 – 4.9], P<.001 • Prophylaxis: 1.9 [1.4 – 2.5], P<.001 Gray KN et al: ASH 2008

  35. Thromboembolism With BevacizumabArterial Thromboembolism Pooled analysis of 5 clinical trials of bevacizumab in metastatic colorectal, breast, or non-small cell lung cancer (N=1,745) Chemotherapy* plus bevacizumab (n=963) Chemotherapy* alone (n=782) HR=2.0 (95% CI, 1.05-3.75) P=.031 ATE/VTE Rate (%) *Irinotecan, capecitabine, fluorouracil and leucovorin, or carboplatin/paclitaxel Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:1232-1239.

  36. Thromboembolism With BevacizumabVenous Thromboembolism: Meta-Analysis of RCTs Relative Risk = 1.33 [95% CI: 1.13 – 1.56] Absolute Risk Increase: 2.2% [95% CI: 1.1% - 3.3%] Nalluri, S. R. et al. JAMA 2008;300:2277-2285.

  37. Thromboembolic Complications in Cancer Patients Receiving ESAs Comparative Effectiveness Review # 3 Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment RR TE = 1.67 [1.35 – 2.06] Bohlius, J. et al. JNCI 2006 98:708-714

  38. Predictors of Venous Thromboembolism Multivariate Logistic Regression Analysis • Retrospective cohort study of cancer pts at 60 US hospitals: 1995 – 2003. • Patients: N = 504,208 • RBC trans: 70,542 (14%) • Platelet trans: 15,237 (3%) • RBC transfusions • VTE: 7.2% • ATE: 5.2% • Mortality 1.34 [95% CI:1.29-1.38] Khorana, A. A. et al. Arch Intern Med 2008;168:2377-2381.

  39. LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the patient with cancer with established VTE. LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are acceptable for long-term therapy when LMWH is not available. After 6 months, indefinite anticoagulant therapy should be considered for patients with active cancer. The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long-term therapy with LMWH. ASCO Recommendations for VTE Prophylaxis in Patients with CancerPreventing Recurrence in Cancer Patients with Established VTE Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

  40. Recurrent VTE and bleeding during anticoagulant treatmentPatients with cancer and venous thrombosis 30 30 Hazard ratio 3.2 [1.9-5.4] Hazard ratio 2.2 [1.2-4.1] Cancer 21% 20 20 Cancer 12% Major Bleeding, % Recurrent VTE, % 10 10 No Cancer 7% No Cancer 5% 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) Time (months) Prandoni P et al. Blood 2002; 100: 3484-3488.

  41. RCTs of Long-term Treatment in Cancer Patients with VTE: RCTs of LMWH vs. Vitamin K Antagonists in Cancer * P < .05 1. Meyer G, et al. Arch Intern Med. 2002;162:1729-1735. 2. Lee AY, et al. N Engl J Med. 2003;349:146-153.3. Deitcher SR, et al. Clin Appl Thromb Hemost. 2006;12:389-396. 4. Hull RD, et al. Am J Med. 2006;119:1062-1072.

  42. The CLOT TrialStudy Schema Control Group Dalteparin 200 IU/kg OD Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo Randomization Experimental Group Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo 5 to 7 days 1 month 6 months Lee AY, et al. N Engl J Med. 2003;349:146-153.

  43. risk reduction = 52% HR 0.48 (95% CI 0.30, 0.77) log-rank p = 0.002 25 20 VKA, 17% 15 Probability of Recurrent VTE, % 10 dalteparin, 9% 5 0 0 30 60 90 120 150 180 210 Days Post Randomization CLOT Trial: Results: Symptomatic Recurrent VTE Lee AY, et al. N Engl J Med. 2003;349:146-153.

  44. CLOT Trial: Results: Bleeding Lee AY, et al. N Engl J Med. 2003;349:146-153.

  45. Anticoagulants are not recommended to improve survival in patients with cancer without VTE. People with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies. ASCO Recommendations for VTE Prophylaxis in Patients with CancerImproving survival in absence of established VTE Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

  46. Systematic Review of Anticoagulants as Cancer Treatment: Impact on Survival 1-Year Overall Mortality by Type of Anticoagulation RR [95% CI] Treatment Cancer Citation Rate 1 Rate 2 P Value 2 0.5 1 SCLC Altinbas .487 .700 .696 .476 1.018 .054 Mixed Kakkar .542 .592 .915 .766 1.093 .327 Mixed Klerk .608 .727 .836 .711 .983 .028 Mixed Sideras .603 .600 1.005 .766 1.319 .972 LMWH .88 .79 .98 .015 SCLC Lebeau .601 .698 .862 .724 1.026 .093 UFH .86 .72 .095 1.03 SCLC Chahinian .728 .802 .908 .775 1.063 .233 Breast Levine .382 .403 .948 .719 1.251 .705 SCLC Maurer .242 .278 .869 .608 1.240 .438 NSCLC Zacharski (1) .802 .796 1.008 .875 1.161 .915 SCLC Zacharski (2) .600 .840 .714 .497 1.027 .059 CRC Zacharski (3) .588 .529 1.111 .727 1.697 .625 Prostate Zacharski (4) .357 .300 1.190 .366 3.871 .770 HN Zacharski (5) .850 .667 1.275 .895 1.817 .172 NSCLC (early) Zacharski (6) .143 .300 .476 .137 1.651 .224 Warfarin .94 .85 1.04 .239 Combined .91 .85 .97 .003 Anticoagulation Control SCLC=small cell lung cancer; NSCLC=non-small cell lung cancer; HN=head and neck; CRC=colorectal cancer Kuderer NM, et al. Cancer. 2007;110:1149-1161

  47. Systematic Review of Anticoagulants as Cancer Treatment: Impact on Survival Major Bleeding Complications by Type of Anticoagulation Treatment Cancer Study Rate 1 Rate 2 0.1 0.2 0.5 1 2 5 10 RR [95% CI] P Value SCLC Altinbas .000 .000 1.025 .021 50.418 .990 NSCLC Haas (2) .037 .023 1.642 .605 4.453 .325 Mixed Sideras .029 .071 .412 .083 2.051 .261 Mixed Klerk .034 .006 5.203 .615 44.006 .089 Mixed Kakkar .005 .000 2.906 .119 70.874 .492 Breast Haas (1) .017 .000 7.120 .370 136.830 .127 LMWH 1.68 .86 3.27 .128 SCLC Lebeau .007 .007 1.007 .064 15.943 .996 UFH 1.01 .06 15.94 .996 SCLC Zacharski (2) .400 .080 5.000 1.217 20.549 .008 SCLC Maurer .067 .018 3.798 1.091 13.223 .023 SCLC Chahinian .068 .000 12.548 .727 216.606 .023 Prostate Zacharski (4) .571 .200 2.857 .763 10.695 .069 NSCLC (early) Zacharski (6) .524 .250 2.095 .885 4.960 .072 NSCLC Zacharski (1) .323 .071 4.521 2.092 9.768 .000 HN Zacharski (5) .500 .381 1.312 .652 2.642 .443 CRC Zacharski (3) .618 .206 3.000 1.473 6.109 .001 Breast Levine .007 .013 .523 .048 5.709 .588 Warfarin 2.98 2.13 4.16 <.001 Combined 2.59 1.94 3.49 <.001 Control Anticoagulation Kuderer NM, et al. Cancer. 2007;110:1149-1161

  48. Systematic Review of Anticoagulants as Cancer Treatment: Impact on Survival • Findings • Anticoagulation significantly decreased 1-year overall mortality with a relative risk of 0.905 [95% CI, 0.847-0.967]; P=.003 • Conclusions • Anticoagulants, particularly LMWH, significantly improved overall survival in cancer patients without VTE while increasing the risk for bleeding complications • Improved survival with anticoagulation may be dependent on tumor type • However: given the limitations of available data, the use of anticoagulants as antineoplastic therapy cannot be recommended until additional RCTs confirm these results Kuderer NM, et al. Cancer. 2007;110:1149-1161.

  49. Ongoing Randomized Clinical Trials Testing the Effect of LMWH on Survival in Cancer Patients INPACT=Improving with Nadroparin the Prognosis in Advanced Cancer Treatment; FOCUS=Fragmin® in Ovarian Cancer: Utility on Survival; FRAGMATIC=Fragmin® Added to Standard Therapy in Patients with Lung Cancer; ABEL=Adjuvant Bemiparin in Small Cell Lung Carcinoma; TILT=Tinzaparin in Lung Tumors. Courtesy Dr Anna Falanga

  50. Clinical Risk Model for Chemotherapy-associated VTEPatient Characteristics PS=performance status; BMI=body mass index; ESA=erythropoiesis-stimulating agents. Khorana AA et al. Blood. 2008; 111:4902-4907

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