2The Science and Medicine of Thrombosis in Cancer Mechanisms ● Mortality ● TherapeuticsThe Science and Medicine ofThrombosis in CancerThe Evolving and Foundation Role of LMWHs in Cancer and Thrombosis: Applying Science, Expert Analysis, and Landmark Trials to the Front Lines of Specialty PracticeProgram ChairmanCraig M. Kessler, MDProfessor of Medicine and PathologyGeorgetown University Medical CenterDirector of the Division of CoagulationDepartment of Laboratory MedicineLombardi Comprehensive Cancer CenterWashington, DC
3Welcome and Program Overview CME-accredited symposium jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program
4Program Educational Objectives As a result of this session, participants will:Learn about recent trials, research, and expert analysis of issues focused on thrombosis and cancer.Learn about mechanisms, morbidity, mortality, and therapeutic issues focused on thrombosis and cancer.Learn about relationships among the clotting cascade, agents affecting the coagulation system, and mortality outcomes in cancer patients.Learn about strategies for risk-directed prophylaxis against VTE in at risk patients with cancer.Learn how to assess and manage special needs of cancer patients at-risk for VTE, with a focus on protecting against recurrent DVT.
5Program FacultyCraig M. Kessler, MD—Program Chairman Professor of Medicine and Pathology Georgetown University Medical Center Lombardi Comprehensive Cancer Center Chief, Division of Coagulation Washington, DCFrederick R. Rickles, MD, FACPCenter for Health InnovationPublic Sector Healthcare, NoblisProfessor of Medicine, Pediatrics and Pharmacology and PhysiologyThe George Washington UniversityWashington, DCEdith Nutescu, Pharm.D., FCCPClinical Associate Professor, Pharmacy PracticeAffiliate Faculty, Center for Pharmacoeconomic ResearchDirector, Antithrombosis CenterThe University of Illinois at ChicagoCollege of Pharmacy & Medical CenterChicago, Illinois
7Clotting, Cancer, and Controversies Innovation ● Investigation ● ApplicationClotting, Cancer, and ControversiesWhat the Trials, Emerging Science, and Current Thinking Tell Us About The Evolving Science and Foundation Role of Anticoagulation in the Setting of CancerProgram ChairmanCraig Kessler, MD MACPDirector, Division of CoagulationLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DC
8VTE and Cancer—A Looming National Healthcare Crisis MISSION AND CHALLENGESRecognizing cancer patients at risk for DVT and identifying appropriate candidates for long-term prophylaxis and/or treatment with approved and indicated therapies are among the most important challenges encountered in contemporary pharmacy and clinical practice.
10Epidemiology of First-Time VTE VariableFindingSeasonal VariationPossibly more common in winter and less common in summerRisk Factors25% to 50% “idiopathic”15%-25% associated with cancer20% following surgery (3 months)Recurrent VTE6-month incidence, 7%;Higher rate in patients with cancerRecurrent PE more likely after PE than after DVTDeath After Treated VTE30-day incidence 6% after incident DVT30-day incidence 12% after PEDeath strongly associated with cancer, age, and cardiovascular diseaseWhite R. Circulation. 2003;107:I-4 –I-8.)
11Epidemiology of VTEOne major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders.Overall, about 25% to 50% of patient with first-time VTE have an idiopathic condition, without a readily identifiable risk factor.Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease.White R. Circulation. 2003;107:I-4–I-8.)
12Thrombophilia Enhances Risks of Thrombosis in Cancer Patients Risk of thrombosis in cancer patients within the previous five years according to the presence of factor V Leiden or G20210A prothrombin gene mutationMutationCancerPatients with first venous thrombosis (n=2706)Control without venous thrombosis (n=1757)Age- and sex-adjusted odds ratio (95% CI)Factor V LeidenNoYes212516351.00162265.1 ( )403953.3 ( )16112.1 ( )Prothombin 20210A24101693164274.5 ( )118362.3 ( )14Not determinedH. Decousus et al. Thrombosis Research 120 Suppl. 2 (2007) S51-S61
13Acute Medical Illness and VTE Multivariate Logistic Regression Modelfor Definite Venous Thromboembolism (VTE)Risk FactorOdds Ratio(95% CI)X2Age > 75 yearsCancerPrevious VTE1.03 ( )1.62 ( )2.06 ( )0.00010.080.02Acute infectious disease1.74 ( )Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:
14VTE Recurrence Hazard Ratio Baseline Characteristic Predictors of First VTE/ RecurrenceBaseline CharacteristicHazard Ratio(95% CI)Age1.17 ( )Body Mass Index1.24 ( )Neurologic diseasewith extremity paresis1.87 ( )Malignant neoplasmWith chemotherapyWithout chemotherapy4.24 ( )2.21 ( )Heit J, Mohr D, et al. Arch Intern Med. 2000;160:
15Progression of Chronic Venous Insufficiency From UpToDate 2006
16Rising VTE Incidence in Hospitalized Patients 21.510.5VTEDVT%PEYearStein PD et al. Am J Cardiol 2005; 95:
17DVT Registry (N=5,451) Top 5 Medical Comorbidities HypertensionImmobilityCancerObesity (BMI > 30)Cigarette SmokingAm J Cardiol 2004; 93:
18Implementation of Guidelines in Cancer PatientsImplementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines.
19Symposium Themes—Cancer/DVT Cancer rates are increasing as treatment for heart disease and cancer improveCancer increases VTE riskVTE is preventable (immunize!)VTE prophylaxis may slow cancerIncreased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATFFacilitate prophylaxis with alerts
20Cancer, Thrombosis, and the Biology of Malignancy Clotting, Cancer, and ControversiesCancer, Thrombosis, and the Biology of MalignancyScientific Foundations for the Role of Low-Molecular-Weight Heparin in Cancer PatientsFrederick R. Rickles, MDProfessor of Medicine, Pediatrics,Pharmacology and PhysiologyThe George Washington UniversityWashington, DC
21Cancer and Venous Thromboembolism The Legacy of Armand Trousseau (1801–1867)21
22Professor Armand Trousseau Lectures in Clinical Medicine “ I have always been struck with the frequency with which cancerous patients are affected with painful oedema of the superior or inferior extremities….”New Syndenham Society – 186522
23Professor Armand Trousseau More Observations About Cancer and Thrombosis “In other cases, in which the absence of appreciable tumour made me hesitate as to the nature of the disease of the stomach, my doubts were removed, and I knew the disease to be cancerous when phlegmasia alba dolens appeared in one of the limbs.”Lectures in Clinical Medicine, 186523
24Trousseau’s SyndromeIronically, Trousseau died of gastric carcinoma six months after writing to his student, Peter, on January 1st, 1867:“I am lost the phlebitis that has just appeared tonight leaves me no doubt as to the nature of my illness”24
25Trousseau’s SyndromeOccult cancer in patients with idiopathic venous thromboembolismThrombophlebitis in patients with cancer25
26Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 53.550Population-based MEGA studyN=3220 consecutive patients with 1st VTE vs. n=2131 control subjectsCA patients = OR 7x VTE risk vs. non-CA patients40283022.2Adjusted odds ratio20.319.82014.318.104.22.168.1LungBreastDistant> 15 yearsmetastases1 to 3 yearsHematological0 to 3 months5 to 10 yearsGastrointestinal3 to 12 monthsType of cancerTime since cancer diagnosisSilver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:71526
27Cancer, Mortality, and VTE Epidemiology and Risk Patients with cancer have a 4- to 6-fold increased risk for VTE vs. non-cancer patientsPatients with cancer have a 3-fold increased risk for recurrence of VTE vs. non-cancer patientsCancer patients undergoing surgery have a 2-fold increased risk for postoperative VTEDeath rate from cancer is four-fold higher if patient has concurrent VTEVTE 2nd most common cause of death in ambulatory cancer patients (tied with infection)Heit et al Arch Int Med 2000;160: and 2002;162: ; Prandoni et al Blood 2002;100: ; White et al Thromb Haemost 2003;90: ; Sorensen et al New Engl J Med 2000;343: ); Levitan et al Medicine 1999;78: ; Khorana et al J Thromb Haemost 2007;5:632-4
28Mechanisms of Cancer-Induced Thrombosis Critical Interfaces and Questions Pathogenesis?Biological significance?Potential importance for cancer therapy?
29Trousseau’s Observations (continued) “There appears in the cachexiae…aparticular condition of the blood thatpredisposes it to spontaneouscoagulation.”Lectures in Clinical Medicine, 1865
31Interface of Biology and Cancer Tumor CellsFibrinolytic activities:t-PA, u-PA, u-PAR,PAI-1, PAI-2Procoagulant ActivitiesFIBRINEndothelial cellsIL-1, TNF-a, VEGFMonocytePMN leukocyteActivation of coagulationPlateletsAngiogenesis,Basement matrix degradationFalanga and Rickles, New Oncology: Thrombosis, 2005; Hematology, 2007
32Pathogenesis of Thrombosis in Cancer – A Modification of Virchow’s Triad StasisProlonged bed restExtrinsic compression of blood vessels by tumorVascular InjuryDirect invasion by tumorProlonged use of central venous cathetersEndothelial damage by chemotherapy drugsEffect of tumor cytokines on vascular endotheliumHypercoagulabilityTumor-associated procoagulants and cytokines (tissue factor, CP, TNF, IL-1, VEGF, etc.)Impaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT, Protein C and S)Enhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets and host macrophages
33Mechanisms of Cancer-Induced Thrombosis Clot and Cancer Interfaces Pathogenesis?Biological significance?Potential importance for cancer therapy?
34Activation of Blood Coagulation in Cancer Biological Significance? Epiphenomenon?Is this a generic secondary event where thrombosis is an incidental findingor, is clotting activation . . .A Primary Event?Linked to malignant transformation
35Interface of Clotting Activation and Tumor BiologyFVII/FVIIaTFBlood CoagulationActivationTumor CellVEGFTHROMBINFIBRINAngiogenesisIL-8TFPAR-2Endothelial cellsAngiogenesisFalanga and Rickles, New Oncology:Thrombosis, 2005;1:9-16
36Coagulation Cascade and Tumor Biology Clotting-dependentClotting-dependentTFThrombinFibrinXaVIIaClotting-independentClotting-independentClotting-dependentPARsAngiogenesis, Tumor Growth and MetastasisFernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007;5:1584
37TF regulates VEGF expression in human cancer cell lines Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue FactorTF regulates VEGF expression in human cancer cell linesHuman cancer cells with increased TF are more angiogenic (and, therefore, more “metastatic’) in vivo due to high VEGF productionAbe et al Proc Nat Acad Sci 1999;96: ; Ruf et al Nature Med 2004;10:
38Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue FactorThe cytoplasmic tail of TF, which contains three serine residues, appears to play a role in regulating VEGF expression in human cancer cells, perhaps by mediating signal transduction4. Data consistent with new mechanism(s) by which TF signals VEGF synthesis in human cancer cells may provide insight into the relationship between clotting and cancerAbe et al Proc Nat Acad Sci 1999;96: ; Ruf et.al. Nature Med 2004;10:
39Activation of Blood Coagulation in Cancer and Malignant Transformation Epiphenomenon vs. Linked to Malignant Transformation?1. MET oncogene induction produces DIC in human liver carcinoma (Boccaccio lab)(Boccaccio et al Nature 2005;434: )2. Pten loss and EGFR amplification produce TF activation and pseudopalisading necrosis through JunD/Activator Protein-1 in human glioblastoma(Bratt lab)(Rong et al Ca Res 2005;65: ; Ca Res 2009;69:2540-9)3. K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma; TF and angiogenesis regulation in epithelial tumors by EGFR (ErbB1) – relationship to EMTs (Rak lab)(Yu et al Blood 2005;105: ; Milson et al Ca Res 2008;68: )
40Activation of Blood Coagulation in Cancer: Malignant Transformation “1. MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis”MET encodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) Drives physiological cellular program of “invasive growth” (tissue morphogenesis, angiogenesis and repair)Aberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastic transformation, invasion, and metastasisBoccaccio et al Nature 2005;434:
41Mouse model of Trousseau’s Syndrome “MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis”Mouse model of Trousseau’s SyndromeTargeted activated human MET to the mouse liver with lentiviral vector and liver-specific promoter slowly, progressive hepatocarcinogenesisPreceded and accompanied by a thrombo-hemorrhagic syndromeThrombosis in tail vein occurs early and is followed by fatal internal hemorrhageSyndrome characterized by d-dimer and PT and platelet count (DIC)
42Blood Coagulation Parameters in Mice Transduced with the MET Oncogene TransgeneParameterTime after Transduction (days)GFPMETPlatelets (x103)D-dimer (µg/ml)PT (s)< < <0.05<
43Mouse model of Trousseau’s Syndrome “MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis”Mouse model of Trousseau’s SyndromeGenome-wide expression profiling of hepatocytes expressing MET - upregulation of PAI-1 and COX-2 genes with 2-3x circulating protein levelsUsing either XR5118 (PAI-1 inhibitor) or rofecoxib (Vioxx; COX-2 inhibitor) resulted in inhibition of clinical and laboratory evidence for DIC in mice
44Activation of Blood Coagulation in Cancer: Malignant Transformation 2. “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”Pten = tumor suppressor with lipid and protein phosphatase activityLoss or inactivation of Pten (70-80% of glioblastomas) leads to Akt activation and upregulation of Ras/MEK/ERK signaling cascadeRong et al Ca Res 2005;65:
45“Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” Glioblastomas characterized histologically by “pseudopalisading necrosis”Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by thrombosisPseudopalisading cells produce VEGF and IL-8 and drive angiogenesis and rapid tumor growthTF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2)
46“Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” Results:Hypoxia and PTEN loss TF (mRNA, Ag and procoagulant activity); partially reversed with induction of PTENBoth Akt and Ras pathways modulated TF in sequentially transformed astrocytes3. Ex vivo data: TF (by IH-chemical staining) in pseudopalisades of # 7 human glioblastoma specimens
47Both Akt and Ras Pathways Modulate TF Expression By Transformed Astrocytes N = NormoxiaH = HypoxiaSimilar datafor EGFR –upregulationof TF via JunD/AP-1 transcription(CA Res 2009;69:2540-9)
48“Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”Pseudopalisading necrosisH&ETF IHCVascularEndothelium
49Activation of Blood Coagulation in Cancer: Malignant Transformation 3. “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”Activation of K-ras oncogene and inactivation of p53 tumor suppressor TF expression in human colorectal cancer cellsTransforming events dependent on MEK/MAPK and PI3KCell-associated and MP-associated TF activity linked to genetic status of cancer cellsTF siRNA reduced cell surface TF expression, tumor growth and angiogenesisTF may be required for K-ras-driven phenotypeYu et al Blood 2005;105:
50Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”TF expression in cancer cells parallels genetic tumor progressionwith an impact of K-ras and p53 statusMean Channel TF FlourescenceTF Activity (U/106 cells)del/+ mut/+ mut/++/+ +/+ del/del
51Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”Effect of TF si mRNA on tumor growth in vitro and in vivo
52Effect of TF si mRNA on new vessel formation in colon cancer “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells”Effect of TF si mRNA on new vessel formation in colon cancer%VWF-Positive Area
53Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistologySimilar amplification of TF with upregulated VEGF induced by mutated EGFR in glioblastoma and lung cancer cells, accompanied by epithelial-to-mesenchymal transition (EMT)Milsom et al CA Res 2008;68:
54Class Effect of siRNA for Angiogenesis Inhibition via Toll-Like Receptior 3 (TLR 3) (21 nucleotides)** Kleinman et al Nature2008;452:591Kalluri and Kansaki Nature 2008;452:543
55Mechanisms of Cancer-Induced Thrombosis Clinical Implications Pathogenesis?Biological significance?Potential importance for cancer therapy?
56Activation of Blood Coagulation in Cancer: Malignant Transformation Q: What do all of these experiments in mice have to do with real patients with cancer?A: They suggest two things:Tumor cell-derived, TF-rich microparticles (MPs) may be important as a predictive test for VTEAll patients with oncogene-driven cancer may need prophylactic anticoagulation
57Tissue Factor Expression, Angiogenesis, and Thrombosis in Human Pancreatic CancerRetrospective studyImmunohistologic (IH) and microarray data on expression of TF and VEGF, as well as microvascular density (MVD) in:Normal pancreas (10)Pre-malignant pancreatic lesions:Intraductal papillary mucinous neoplasms (IPMN; 70)Pancreatic intrepithelial neoplasia (PanIN; 40)Resected or metastatic pancreatic adenoca (130)SurvivalVTE RateKhorana et al Clin Cancer Res 2007;13:2870
58Immunohistologic Correlation of TF with the Expression of Other Angiogenesis Variables in Resected Pancreatic CancerHigh TF ExpressionLow TF ExpressionP ValueVEGF ExpressionNegative1341<0.0001Positive5315Microvessel DensityV6 per tissue core27330.047>6 per tissue core3923Median860.01Khorana et.al. Clin CA Res 2007:13:2870
59Symptomatic VTE in Pancreatic Cancer 5/19;26.3%1/22;4.5%Khorana et al Clin CA Res 2007;13:2872
60Median Survival of 122 Resected Pancreatic Cancer Patients 17.9P = 0.16(HR 2.06; )12.6MonthsKhorana et al Clin CA Res 2007;13:2872
61Year 2009 State-of-the-Science Update Cancer and ThrombosisYear 2009 State-of-the-Science UpdateKey Questions1. Does activation of blood coagulation affect the biology of cancer positively or negatively? 2. Can we treat tumors more effectively using coagulation protein targets? 3. Can anticoagulation alter the biology of cancer?
62Year 2009 State-of-the-Science Update Cancer and ThrombosisYear 2009 State-of-the-Science UpdateTentative Answers1. Epidemiologic evidence is suggestive that VTE is a bad prognostic sign in cancer2. Experimental evidence is supportive of the use of antithrombotic strategies for both prevention of thrombosis and inhibition of tumor growth3. Results of recent, randomized clinical trials of LMWHs in cancer patients indicate superiority to oral agents in preventing recurrent VTE, as well as increasing survival (not due to prevention of VTE)
63LMWH and Prolongation of Cancer Survival Mechanistic Explanations VTECoagulation ProteasesDirectHeparinOther
64Heparins and Tumour Biology Multiple Potential Modes of ActionAngiogenesisApoptosisHeparanaseAdhesion
65Embryonic Chick Aortic Rings Ex Vivo Angiogenesis:Embryonic Chick Aortic RingsControl Aortic Ring: Day 510U/ml Dalteparin-Treated Aortic Ring: Day 5Fernandez, Patierno and Rickles. Proc AACR 2003;44:698 (Abstr. #3055)
66Effects of Low-Molecular Weight Heparin on Lung Cancer Cell Apoptosis G1 arrestDecrease inS phase3-fold in p21WAF1and p27KIP1 (p <0.01)Reversed apoptosisand G1 arrest withp21 or p27 siRNAChen et al Cancer Invest 2008;26:718-24
67Heparins Inhibit Cytokine–Induced Capillary Tube Formation Tube Length (mm/cm2)500**400****300**Control*200100VEGFFGF-2TNF-Cytokine+UFH+enoxaparin+dalteparin§ = p<0.05 vs control, * = p<0.05 vs cytokineMarchetti et al. Thromb Res 2008;121:67
6840 mice with Lewis Lung Cancer (3LL) Rx qod x 15 with: LMWH and VEGF Antisense Oligonucleotides Inhibit Growth and Metastasis of 3LL Tumors in Mice40 mice with Lewis Lung Cancer (3LL)Rx qod x 15 with:Control (saline)VEGF antisense oligos (ASODN)VEGF mismatch sense oligo (MSODN)LMWH (dalteparin)LMWH + ASODNRESULTS: Growth Inhibit* Lung Mets*ASODN 47% 38%LMWH 27% 38%Combined 59% 25%* P < 0.05Zhang YH et al Chinese Med J 2006;86:749-52
69Inhibition of Binding of Selectins to Human Colon Carcinoma by Heparins Stevenson et al Clin Ca Res 2005;11:
70Heparin Inhibition of B16 Melanoma Lung Metastasis in Mice Stevenson et al Clin Ca Res 2005;11:
71Angiogenesis, Tumor Growth and Metastasis Coagulation Cascade and Tumor BiologyClotting-dependentClotting-dependentTFThrombinFibrinXaVIIaClotting-independentClotting-independentClotting-dependent?PARs?Angiogenesis, Tumor Growth and MetastasisLMWHs (e.g. dalteparin); Non-anticoagulant heparins or inhibitorsFernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584;Varki Blood 2007;110:
72A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Innovation ● Investigation ● ApplicationA Systematic Analysis of VTE Prophylaxis in the Setting of CancerLinking Science and Evidence to Clinical Practice—What Do Trials Teach?Program ChairmanCraig Kessler, MD MACPDirector, Division of CoagulationLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DC
73VTE and Cancer: Epidemiology Of all cases of VTE:About 20% occur in cancer patientsAnnual incidence of VTE in cancer patients ≈ 1/250Of all cancer patients:15% will have symptomatic VTEAs many as 50% have VTE at autopsyCompared to patients without cancer:Higher risk of first and recurrent VTEHigher risk of bleeding on anticoagulantsHigher risk of dyingLee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
74DVT and PE in Cancer Facts, Findings, and Natural History VTE is the second leading cause of death in hospitalized cancer patients1,2The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4Let’s continue examining the association between DVT/PE and cancer.Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE.As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer.Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer.Ambrus JL et al. J Med. 1975;6:61-64Donati MB. Haemostasis. 1994;24:Johnson MJ et al. Clin Lab Haem. 1999;21:51-54Prandoni P et al. Ann Intern Med. 1996;125:1-7
75Clinical Features of VTE in Cancer VTE has significant negative impact on quality of lifeVTE may be the presenting sign of occult malignancy10% with idiopathic VTE develop cancer within 2 years20% have recurrent idiopathic VTE25% have bilateral DVTBura et. al., J Thromb Haemost 2004;2:445-51
76Thrombosis and Survival Likelihood of Death After Hospitalization 0.000.200.401.000.800.60DVT/PE and Malignant DiseaseMalignant DiseaseDVT/PE OnlyNonmalignant DiseaseNumber of DaysProbability of DeathLevitan N, et al. Medicine 1999;78:285
77Incidence of VTE and Colon Cancer Stage Days after Cancer DiagnosisIncidence of VTE (%)7%6%5%4%3%2%1%0%Local Regional RemoteWhite RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40
78Symptomatic VTE in Cancer Reduces Survival Counterintuitively, Magnitude of Effect on Survival is Greatest with Local Stage DiseaseCancer typeHazard ratio (95% CI) for death within one year, cases with VTE diagnosed in year 1 vs. no VTE, by stageLocalRegionalRemoteProstate5.6 ( )‡4.7 ( ) ‡2.8 ( ) †Breast6.6 ( ) ‡2.4 ( ) ‡1.8 ( )*Lung3.1 ( ) ‡2.9 ( ) ‡2.5 ( ) ‡Colon/rectum3.2 ( ) ‡2.2 ( ) ‡2.0 ( ) ‡Melanoma14.4 ( ) ‡N/A2.8 ( ) †Non-Hodgkin’s lymphoma3.2 ( ) ‡2.0 ( ) †2.3 ( ) ‡Uterus7.0 ( ) ‡9.1 ( ) ‡1.7 ( )*Bladder3.2 ( ) ‡3.3 ( ) ‡3.3 ( ) ‡Pancreas2.3 ( )*3.8 ( ) ‡2.3 ( ) ‡Stomach2.4 ( )*1.5 ( )*1.8 ( ) ‡Ovary11.3 ( ) †4.8 ( )*2.3 ( ) ‡Kidney3.2 ( )*1.4 ( )1.3 ( )R.H. White et al. Thombosis Research 120 Suppl. 2 (2007) S29-S40* p<0.05; †p<0.01); ‡ p<0.001)
79VTE 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)
80Recurrent Ovarian Cancer • 7% symptomatic VTE ( % 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
81Hospital Mortality With or Without VTE N=66,016N=20,591N=17,360Khorana, JCO, 2006
82Thrombosis Risk In Cancer Primary ProphylaxisMedical InpatientsSurgeryRadiotherapyCentral Venous Catheters
85Antithrombotic Therapy: Choices Pharmacologic(Prophylaxis & Treatment)Nonpharmacologic(Prophylaxis)Low Molecular Weight Heparin (LMWH)IntermittentPneumaticCompressionElasticStockingsUnfractionatedHeparin (UH)InferiorVena CavaFilterSeveral classes of agents have been used for prophylaxis and treatment of VTENonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filterMost commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs)OralAnticoagulantsNew Agents: e.g.Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?
86Prophylaxis Studies in Medical Patients Relative risk reduction 47%Relative risk reduction 63%Rate of VTE (%)Relative risk reduction 44%Placebo EnoxaparinMEDENOX TrialPlacebo DalteparinPREVENTPlacebo FondaparinuxARTEMISFrancis, NEJM, 2007
87ASCO Guidelines 1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FORVTE 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:
89Incidence of VTE in Surgical Patients Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis:No CancerN=16,954CancerN=6124P-valuePost-op VTE0.61%1.26%<0.0001Non-fatal PE0.27%0.54%<0.0003Autopsy PE0.11%0.41%Death0.71%3.14%Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
90Natural History of VTE in Cancer Surgery: The @RISTOS Registry Web-Based Registry of Cancer SurgeryTracked 30-day incidence of VTE in 2373 patientsType of surgery• 52% General• 29% Urological• 19% Gynecologic82% received in-hospital thromboprophylaxis31% received post-discharge thromboprophylaxisFindings2.1% incidence of clinically overt VTE (0.8% fatal)Most events occur after hospital dischargeMost common cause of 30-day post-op deathAgnelli, Ann Surg 2006; 243: 89-95
91Prophylaxis in Surgical Patients LMWH vs. UFHAbdominal or pelvic surgery for cancer (mostly colorectal)LMWH once daily vs. UFH tid for 7–10 days post-opDVT on venography at day 7–10 and symptomatic VTEStudyNDesignRegimensENOXACAN 1631double-blindenoxaparin vs. UFHCanadian Colorectal DVT Prophylaxis 24751. ENOXACAN Study Group. Br J Surg 1997;84:1099–1032. McLeod R, et al. Ann Surg 2001;233:
92Prophylaxis in Surgical Patients Canadian Colorectal DVT Prophylaxis Trial16.9%P=0.05213.9%Incidence of Outcome EventN=234N=2411.5% 2.7%VTE Major Bleeding(Cancer) (All)McLeod R, et al. Ann Surg 2001;233:
93Extended Prophylaxis in Surgical Patients 12.0%ENOXACAN IIP=0.02Incidence of Outcome EventN=1674.8%5.1%N=1653.6%1.8%NNT = 140.6%0% 0.4%VTE Prox Any MajorDVT Bleeding BleedingBergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:
94Major Abdominal Surgery: FAME Investigators—Dalteparin Extended A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatmentRESULTS: 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.Rasmussen, J Thromb Haemost Nov;4(11): Epub 2006 Aug 1.
95ASCO 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:
96Central Venous Catheters Thrombosis is a potential complication of central venous catheters, including these events:Fibrin sheath formationSuperficial phlebitisBall-valve clotDeep vein thrombosis (DVT)Geerts W, et al. Chest Jun 2008: 381S–453S
97Prophylaxis for Venous Catheters Placebo-Controlled TrialsStudyRegimenNCRT (%)Reichardt* 2002Dalteparin 5000 U dailyplacebo28514011 (3.7)5 (3.4)Couban*2002Warfarin 1mg daily1301256 (4.6)5 (4.0)ETHICS†2004Enoxaparin 40 mg daily15522 (14.2)28 (18.1)*symptomatic outcomes; †routine venography at 6 weeksReichardt 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
98WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Thrombotic EventsWarfarin evaluationDose evaluationNo warfarin (n=404)Warfarin (n=408)Relative risk(95% CI, p value)Fixed-dose warfarin (n=471)Dose-adjusted warfarin (n=473)Relative risk (95% CI, p value)Catheter-related thrombotic events24(6%)0.99( , 0.98)34(7%)13(3%)0.38( ,0.002)No catheter-related event370(92%)372(91%)-433 (92%)448 (95%)Not known10(2%)124(<1%)All thrombotic events38(9%)300.78( ), 0.3037(8%)260.70( , 0.15)Young AM et al. Lancet 2009;373:567
99WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Bleeding and Raised INRWarfarin evaluationDose evaluationNo warfarin (n=404)Warfarin (n=408)Relative risk(95% CI, p value)Fixed-dose warfarin (n=471)Dose-adjusted warfarin (n=473)Relative risk (95% CI, p value)Major bleeding and no reported raised INR1 (<1%)3 (<1%)-5 (1%)7 (1%)Major bleeding and raised INR4 (<1%)2 (<1%)9 (2%)Total major bleeding7 (2%)6.93( , 0.07)16 (3%)2.28( , 0.09)Moderate and severe raised INR and no major bleeding12 (3%)Minor bleeding14 (3%)21 (4%)24 (5%)Young AM et al. Lancet 2009;373:567
100WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Combined thrombosis and major bleeding eventsWarfarin evaluationDose evaluationNo warfarin (n=404)Warfarin (n=408)Relative risk(95% CI, p value)Fixed-dose warfarin (n=471)Dose-adjusted warfarin (n=473)Relative risk (95% CI, p value)Total catheter-related thrombosis and major bleeding events25 (6%)31 (8%)1.23( , 0.51)41 (9%)29 (6%)0.84( , 0.17)All thrombotic and major bleeding events39 (10%)37 (9%)0.94( , 0.87)44 (9%)42 (9%)0.95( , 0.89)Young AM et al. Lancet 2009;373:567
101Central Venous Catheters: Warfarin Tolerability of Low-Dose Warfarin95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailyINR measured at baseline and four time points10% of all recorded INRs >1.5Patients with elevated INR2.0– %3.0– %> %Masci et al. J Clin Oncol. 2003;21:
102Influence 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: )CA + G20210A OR=3.95 (95% confidence interval: )FVL 13.5%G20210A 3.6%Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564
1038th 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 philosophyChest Jun 2008: 454S–545S
104Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient No recommendations from ACCPNo 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.)
105Risk Factors for VTE in Medical Oncology Patients Tumor typeOvary, brain, pancreas, lung, colonStage, grade, and extent of cancerMetastatic disease, venous stasis due to bulky diseaseType of antineoplastic treatmentMultiagent regimens, hormones, anti-VEGF, radiationMiscellaneous VTE risk factorsPrevious VTE, hospitalization, immobility, infection, thrombophilia
106Independent Risk Factors for DVT/PE Risk Factor/CharacteristicO.R.Recent surgery with institutionalization21.72Trauma12.69Institutionalization without recent surgery7.98Malignancy with chemotherapy6.53Prior CVAD or pacemaker5.55Prior superficial vein thrombosis4.32Malignancy without chemotherapy4.05Neurologic disease w/ extremity paresis3.04Serious liver disease0.10Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study.This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data.Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included.What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE.Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE.Heit JA et al. Thromb Haemost. 2001;86:
107VTE Incidence In Various Tumors Oncology SettingVTE IncidenceBreast cancer (Stage I & II) w/o further treatment0.2%Breast cancer (Stage I & II) w/ chemo2%Breast cancer (Stage IV) w/ chemo8%Non-Hodgkin’s lymphomas w/ chemo3%Hodgkin’s disease w/ chemo6%Advanced cancer (1-year survival=12%)9%High-grade glioma26%Multiple myeloma (thalidomide + chemo)28%Renal cell carcinoma43%Solid tumors (anti-VEGF + chemo)47%Wilms tumor (cavoatrial extension)4%Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
108Primary VTE Prophylaxis Recommended for hospitalized cancer patientsNot universally recommended for outpatients, but there are exceptionsNew data for certain agentsHeterogeneous populationNeed for risk stratification
109VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in MyelomaAll-Grade Venous Thromboembolism, No./Total No.Tumor TypeNo. of StudiesBevacizumabControlIncidence (95% CI), %RR (95% CI)Overall6155/1196107/108311.9( )1.29( )Colorectal cancer3108/56485/53219.1( )1.19( )NSCLC110/663/3214.9( )1.59( )Breast cancer17/22912/2157.3( )1.30( )Renal cell carcinoma20/3376/3043.0( )3.00( )Naluri SR et al. JAMA. 2008;300:2277
110Bevacizumab Increases Risk of Symptomatic VTE by 33% vs Controls Naluri SR et al. JAMA. 2008;300:2277
111Incidence of VTE: USA and Canada Greater than Israel, Australia, and Europe rEPO used more in USA and CanadaL+Dex: 23% VTE with EPO vs 5% w/o EPOPlacebo + Dex: 7% VTE with EPO vs 1% without EPOMultivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple MyelomaTreatment Odds Ratio P Value(95% CI)Lenalidomide plus 3.51 ( ) <0.001High-dose dexamethasoneConcomitant erythropoietin ( ) <0.001Knight: N Engl J Med.2006,354:2079111
112Oral 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 proceduresDifficulty in venous access for monitoringIncreased risk of both recurrence and bleedingIs it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?
113CLOT: Landmark Cancer/VTE Trial DalteparinDalteparinCANCER PATIENTS WITHACUTE DVT or PERandomizationDalteparinOral Anticoagulant[N = 677]Primary Endpoints: Recurrent VTE and BleedingSecondary Endpoint: SurvivalLee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
114Landmark CLOT Cancer Trial Reduction in Recurrent VTE510152025Days Post Randomization306090120150180210Probability of Recurrent VTE, %Risk reduction = 52%p-value =DalteparinOACRecurrent VTELee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
116Treatment of Cancer-Associated VTE StudyDesignLength of Therapy(Months)NRecurrent VTE(%)Major BleedingDeathCLOT Trial(Lee 2003)DalteparinOAC633691743941CANTHENOX(Meyer 2002)Enoxaparin36771112171623LITE(Hull ISTH 2003)Tinzaparin8087822ONCENOX(Deitcher ISTH 2003)Enox (Low)Enox (High)3236322.214.171.124NS0.002NS0.090.090.030.03NSNSNSNSNR
117Treatment and 2° Prevention of VTE in Cancer – Bottom Line New DevelopmentNew 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)Chest Jun 2008: 454S–545S
118CLOT 12-month Mortality All Patients Dalteparin 102030405060708090100120180240300360DalteparinOACHR 0.94 P-value = 0.40Days Post RandomizationProbability of Survival, %Lee AY et al. J Clin Oncol. 2005; 23:
119Anti-Tumor Effects of LMWH CLOT 12-month MortalityPatients Without Metastases (N=150)102030405060708090100DalteparinOACProbability of Survival, %HR = P-value = 0.03306090120150180240300360Lee AY et al. J Clin Oncol. 2005; 23:Days Post Randomization
120LMWH 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 survivalKlerk, C. P.W. et al. J Clin Oncol; 23:
121LMWH for Small Cell Lung Cancer Turkish Study 84 patients randomized: Chemo +/- LMWH (18 weeks)Patients balanced for age, gender, stage, smoking history, ECOG performance statusChemotherapyplus DalteparinChemo aloneP-value1-y overall survival, %51.329.50.012-y overall survival, %17.20.0Median survival, m13.08.0CEV = cyclophosphamide, epirubicin, vincristine;LMWH = Dalteparin, 5000 units dailyAltinbas et al. J Thromb Haemost 2004;2:1266.
122VTE Prophylaxis Is Underused in Patients With Cancer [1/Kakkar. Oncologist.2003/ p381/c1/line A1-A24; p383/c1/line 44-46, c2/line 1-3][2/Stratton. ArchInternMed. Feb.2000/ p336/c2/line 7-11][3/Bratzler. ArchInternMed. Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3][4/Rahim.ThrmbRes. 2003/p3/c2/line 1-5][5/Goldhaber. AmJCardiol.Jan.2004/ p261/c2/line 6-8]Cancer:FRONTLINE Survey1— 3891 Clinician RespondentsMajor Surgery2Cancer: SurgicalMajor Abdominothoracic Surgery (Elderly)3Confirmed DVT (Inpatients)5Rate of Appropriate Prophylaxis, %Medical Inpatients4Cancer: MedicalVTE prophylaxis is underused in patients with cancerThe Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey was a questionnaire distributed globally to clinicians involved in cancer care and accessible on a dedicated Web site1Data from 3891 completed questionnaires were available for analysis1The results indicated that 52% of respondents would routinely utilize thromboprophylaxis for surgical oncology patients, and that most respondents only considered thromboprophlyaxis in approximately 5% of their medical oncology patients1These results can be compared with prophylaxis rates in other patient groups as determined by other recent studiesA retrospective record review in 10 US teaching or community-based hospitals of patients undergoing major surgeries (major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement) showed VTE prophylaxis was used in 89% of patients2A retrospective record review of patients aged 65 and older in 20 Oklahoma hospitals undergoing major abdominothoracic surgery indicated that prophylaxis was used in 38% of patients3A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis5[1/Kakkar.Oncologist. 2003/p381/c1/ line A5-A22][1/Kakkar/p381/c1/ line A23-A24][1/Kakkar/p383/c1/ line 44-46, c2/line 1-3][2/Stratton.ArchIntern Med.Feb.2000/ p334/c1/line A14-A19, c2/line A1-A2; p336/c2/line 7-11][3/Bratzler.ArchIntern Med.Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3][4/Rahim.ThrmbRes. 2003/p1/line A1-A12; p3/c2/line 1-5][5/Goldhaber.AmJ Cardiol.Jan.2004/ p259/c1/line A1-A10; p261/c2/line 6-8]1. Kakkar AK et al. Oncologist. 2003;8:2. Stratton MA et al. Arch Intern Med. 2000;160:3. Bratzler DW et al. Arch Intern Med. 1998;158:4. Rahim SA et al. Thromb Res. 2003;111:5. Goldhaber SZ et al. Am J Cardiol. 2004;93:1. Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8:2. Stratton MA, Anderson FA, Bussey HI, et al. Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients. Arch Intern Med. 2000;160:3. Bratzler DW, Raskob GE, Murray CK, Bumpus LJ, Piatt DS. Underuse of venous thromboembolism prophylaxis for general surgery patients: physician practices in the community hospital setting. Arch Intern Med. 1998;158:4. Rahim SA, Panju A, Pai M, Ginsberg J. Venous thromboembolism prophylaxis in medical inpatients: a retrospective chart review. Thromb Res. 2003;111:5. Goldhaber SZ, Tapson VF, for the DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol. 2004;93:
123Conclusions and Summary Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopeniaLong-term secondary prevention with LMWH has been shown to produce better outcomes than warfarinGuidelines and landmark trials support administration of LMWH in at risk patientsCancer patients are under-prophylaxed for VTEHealth system pharmacists can play a pivotal role in improving clinical outcomes in this patient population
124Pharmacologic Prophylaxis of DVT in Special Populations Mechanisms ● Mortality ● TherapeuticsPharmacologic Prophylaxis of DVT in Special PopulationsEdith Nutescu, PharmD, FCCPClinical Associate ProfessorPharmacy PracticeAffiliate Faculty, Center forPharmacoeconomic ResearchDirector, Antithrombosis CenterThe University of Illinois at ChicagoCollege of Pharmacy & Medical CenterChicago, IL
125ObjectivesDifferentiate data with various LMWHs in special populationsReview appropriate dosing and monitoring of LMWHs in patients with obesity and renal failure
126Risk of Inadequate Therapy in High Risk Patients 524 VTE PatientsActive Cancer in 26%Only 1/3rd on LMWH monotherapyWeight > 100Kg in 15%Under-dosing of LMWH by > 10%36% of > pts 100Kg8% of pts < 100Kg (p < 0.001)CrCL < 30mL/min in 5%LMWH tx in 67%Cook LM, et.al. J Thromb Hemost 2007;5;
1278th ACCP Conference on Antithrombotic Therapy Obese Patients“In obese patients given LMWH prophylaxis or treatment, we suggest weight-based dosing (Grade 2C).”What is this weight-based dosing and how does it differ from typical dosing?At what weight do we move away from standard dosing and move to weight-based dosing?Hirsh J et al. Chest. 2008;133(suppl):141S-159S.
128Pharmacokinetic Characteristics of Low Molecular Weight Heparins Lipid solubility LOWPlasma protein binding HIGHTissue binding LOWVolume of distribution 5-7 LLogical conclusion:IBW may be a better predictor of LMWH dosing than TBW
129LMWH: Maximum Weights Studied Kinetic StudiesClinical TrialsDalteparin190 kg128 kg*Enoxaparin144 kg194 kgTinzaparin165 kg88 kgFondaparinux175.5 kg* max dose 18, ,000 IU/dayDuplaga BA et al. Pharmacotherapy 2001; 21:Synergy Trial: Data on FileDavidson, et al. J Thromb Haem 2007;5:1191-4
130LMWH Pharmacokinetics in Obesity N= 30 (< 100kg)35 ( kg)Tinzaparin 175 IU/kgSQ single doseActual body weight correlates best with anticoagulant response to LMWHs as measured by anti-factor Xa levelsClin Pharmacol Ther 2002;72: Thromb Haemost 2002;87:
132Dalteparin Pharmacokinetics In Obesity Correlation Coefficient Between Vd and:LBW 0.05ABW 0.52TBW 0.55Correlation Coefficient Between Cl and:LBW 0.01ABW 0.32TBW 0.39Conclusion:TBW may be a better predictor of LMWH dose than IBWYee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7.
133Dalteparin Pharmacokinetics In Obesity Dose: 200 U/kg qdDuration: 5 DaysMax TBW: 190kg<20% ofIBW20-40% of IBW> 40% ofN131410Mean Dose (U)14,03017,64623,565Ant-Xa Activity (u/ml)Day 3 Peak1.010.971.12 NSDay 3 Trough0.120.110.11 NSConclusion: Body mass does not appear to have an important effect on the response to LMWH up to a weight of 190kg in patients with normal renal function.Wilson SJ et al. Hemostasis 2001; 31:42-8.
134LMWH Safety and Effectiveness Using TBW Enoxaparin In ACS (ESSENCE/TIMI IIb) 16.1%14.3%P=0.131.6%0.4%Obese: BMI > 30mg/m2Enoxaparin max weight 158 kgSpinler SA et al. Am Heart J 2003; 146:33-41
135Safety Of TBW-based Dosing of Dalteparin for Treatment of Acute VTE in Obese Patients N = 193 patients 3 month outcomes: major bleeding = 1.0% (n=2)> 90 kg recurrent VTE = 1.6% (n=3)WEIGHT(kg)NMeanDoseFull dose +/- 5%QD DosingBIDDosing90-994019,3003924165220,8504925174121,47021261524,30022925,250810626,92054> 15028,280Failures defined as recurrent DVT.Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2.
136Fondaparinux In Obesity Results From the Matisse Trials < 50kg: 5mg qd50-100kg: 7.5mg qd> 100kg: 10mg qdEnoxaparin:(Matisse DVT)1mg/kg q12hHeparin:(Matisse PE)Adjusted per aPTTNo weight-dependentdifference inefficacy or safetyDavidson BL et al. J Thrombosis Haemost 2007; 5:
137Body Weight and Anti-Xa Activity for Prophylactic Doses of LMWH N = 17 patients and 2 volunteersEnoxaparin 40mg SQ x1 doseAntiXa levels hourly x10 hoursRegression line95% CI for line95% CI for data points20015010050Area under the curve for 10 hBody Weight (kg)Frederiksen SG et al. Br J Surgery 2003; 90:547-8
138Fixed Dosing For VTE Prevention DalteparinFixed Dosing For VTE PreventionSubgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill)BMI (kg/m2) Patients %Favors Dalteparin Favor Placebo<>Overall Prevent Trial0.010.10.551.010.0Relative RiskDalteparin 5,000 units daily was similarly effective in obese and non-obese patients (except patients with BMI>40) with no observed difference in mortality or major bleedingKucher N et al. Arch Int Med 2005;165:341-5.
139Enoxaparin VTE Prophylaxis in TKA/THA/Trauma 31.8%p<0.00116.7%N: Dose: 40 mg qd Obese : BMI>32kg/m2Samama MM et al. Thromb Haemost 1995; 73:977.
140Enoxaparin: VTE Prophylaxis in Bariatric Surgery 5.4%p<0.010.6%30mg bid: n=92BMI 51.7kg/m240mg bid: n=389BMI 50.3kg/m2Scholten Obes Surg 2002; 12:19-24.
141Dalteparin in Morbid Obesity: Bariatric Surgery 200180160140120P=0.031P=0.052N=135Bariatric SurgeryMean Weight: 148.8KgMean BMI: 53.7Dalteparin: 7,500 IU dailyP=0.444Body Weight (kg)Under target value<0.2 IU/mLn-=41Target value< IU/mLn-=81Over target value<>0.5 IU/mLn=13Anti-factor Xa levelNumber of patient (%)Body weight (kg)Below target value (<0.2 UI/ml)41 (30.4%)159.4 ± 35.8Target value (0.2–0.5 UI/ml)81 (60.0%)145.7 ± 28.4Above target value (>0.5 UI/ml)13 (9.6%)134.6 ± 24.2p value0.0152Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print]
142LMWH in Obesity: Summary Treatment: in controlled trials, LMWH dosing has been based on TBW (max kg)DalteparinDose based on TBWPI recommends dose cappingRecent clinical data supports TBW dosingQD or BID dosingEnoxaparinDose capping NOT recommendedBID dosing preferredTinzaparinDose based on TBW, NO dose adjustment or cappingAnti-Xa monitoring not necessary for TBW < 190kgProphylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients)Nutescu E, et.al. Ann Pharmacother; 2009; 43(6):
1438th ACCP Conference on Antithrombotic Therapy Renal Impairment For each of the antithrombotic agents, we recommend that clinicians follow manufacturer-suggested dosing guidelines (Grade 1C)We recommend that renal function be considered when making decisions about the use of and/or dose of LMWH or fondaparinux (Grade 1A)Options for patients with renal impairment (Grade 1B)Avoid agents that renal accumulateUse a lower doseMonitor the drug level or anticoagulant effectGeerts WH. Chest 2008;133(suppl):381S-453S.
144LMWH in Renal Dysfunction Manufacturer Recommendations Dalteparin“should be used with caution in patients with severe kidney insufficiency.”Monitor anti-Factor Xa for dose guiding with therapeutic dosesEnoxaparin“adjustment of dose is recommended for patients with severe renal impairment (CrCL < 30 mL/min).”Tinzaparin“patients with severe renal impairment should be dosed with caution.”Fondaparinux- Contraindicated in CrCL < 30mL/min
145Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n) Recent Meta-Analysis of LMWHs and Bleeding In Patients With Severe Renal DysfunctionStudy; yearPatients w/ renal insuff. (n/n)Patients w/ no renal insuff. (n/n)Peto OR (95%, CI)Weight (%)Collet, et al; 20010/281/832.010.26 (0.00 – 23.94)Paulas, et al; 20020/513/1496.020.26 (0.02 – 3.50)Siguret, et al; 20000/170/13Not estimableChow, et al; 20030/5Khazan, et al. (adj.); 20030/103/424.780.28 (0.01 – 5.16)(Prophylactic) 20033/363/4714.771.33 (0.25 – 7.05)(Therapeutic) 20032/173/618.623.09 (0.35 – 27.31)Spinler, et al; 20035/6974/3,43215.9310.05 (2.02 – 49.98)Green, et al; 20051/180/202.668.26 (0.16 – )Kruse & Lee; 20040/501/1202.220.24 (0.00 – 17.90)Macie, et al; 20042/76/2012.68(19.61 – 48,752.07)Peng, et al; 20040/70/43Thorevska, et al; 20047/6511/17135.561.85 (0.63 – 5.40)Bazinet, et al; 20051/362/1604.752.74 (0.15 – 51.73)Total (95%, CI)21/416107/4,555100.002.25 (1.19 – 4.27)Dosage adjustmentsfor renal dysfunctionFavors ↓’ed Favors ↑’edbleedingLim W, et al. Ann Intern Med. 2006;144:
146Enoxaparin PK and PD in Renal Impairment Result:Tmax: 3-4 hoursAmax: 10-35% higher in RI groupsCI/F linearly correlated with CrClDay 4CL/F(L/h)Half-life(h)AUC (0-24)(h●IU/mL)Normals0.986.87Mild RI0.879.9420% ↑Moderate RI0.7611.321% ↑Severe RI0.5815.965% ↑Sanderink GJCM. Thromb Res 2002;105:
147LMWH Renal Dosing in NSTE ACS Patients Dose may be to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl ml/minAnti-Xa monitoringDoses “appeared safe”Further prospective evaluation needed56 UA pts with CrCl <60 ml/minEnoxaparin dose empirically and anti-Xa level measured after 3rd doseCrCl(ml/min)<30(n = 28)>30 and <60(n =28)Age76+/-373+/-3Enoxaparin (mg/kg/12h)0.640.84Anti-Xa (IU/ml)0.95Collet JP et al. International J Cardiol 2001;80:81-2.
148Clinical Use Of Recommended Enoxaparin Dosage in Renal Impairment N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h126.96.36.199.188.8.131.52.184.108.40.2064321PEAK ANTI-Xa LEVELSTROUGH ANTI-Xa LEVELSAntifactor X1 Level (U/mL)Number of PatientsFirst doseSubsequent doses(second and third)Median % interquartile rangeTrough Antifactor Xa Level (U/mL)Trough Antifactor Xa Level (U/mL)Lachish T et al. Pharmacotherapy 2007; 27:
149Tinzaparin 175 U/kg Peak Anti-Xa Levels According to Renal Function No correlation between peak anti-Xa activity and ClcrNo accumulation of Anti-Xa activity after 10 days of therapySiguret V et al. Thromb Haemost 2000;84:800-4.
150Pharmacokinetics of Prophylactic Enoxaparin vs Tinzaparin Enoxaparin 40mg qdorTinazaparin 4500 IU qdN = 52 patientsMean age = 87.7 yrsMean wt = 52.3kgMean Clcr = 34.7ml/minMahe I et al. Thromb Haemost 2007; 97:581-6.
151Dalteparin 100 U/kg q12h Peak Anti-Xa Levels According to Renal Function No difference in peak anti-Xa activity between normal patients andpatients with renal impairment1.51.00.5Clcr > < 40Mean peakanti-Xa levelafter 5-6 dosesAntifactor Xa Level (U/mL)xxSubjects withoutRenal impairmentSubjects withRenal impairmentN=11N=11Shprecher AR et al. Pharmacotherapy 2005; 25:
152Pharmacokinetics of Prophylactic Doses of Dalteparin N = 115 elderly (age > 65) pts with acute medical illness and elevated SCrTx: dalteparin 5000 U or 2500 U SQ qd (risk-based) for VTE prophylaxisRenal FailureMild(n=12)Moderate(n=73)Severe(n=24)CrCL (ml/min)60-8930-59<30Day 6 peak anti-Xa0.0300.0330.048Minor Bleeding3Major BleedingP=0.72No evidence of accumulation of anti-Xa activityNo relationship between the degree of renal impairment and peak anti-Xa level on Day 6No association between creatinine clearance and anti-Xa levelsTincani E et al. Haematologica 2006; 91:976-9.
153Dalteparin Thromboprophylaxis in Critically Ill Patients with Severe Renal Insufficiency: The Direct StudyN=138 critically ill patientsCrCl < 30 ml/minMean CrCL 18.9ml/minDalteparin 5000 IU sc dailySerial anti Xa levels measured on days 3, 10, and 17Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mLResults:The median duration of dalteparin exposure was 7 (4-12) daysNo patient had a trough anti Xa level > 0.4 IU/mlBased on serial measurementspeak anti-Xa levels were 0.29 to 0.34 IU/mLtrough levels were lower than 0.06 IU/mLDouketis, et al. Arch Intern Med Sep 8;168(16):
154Dosing of LMWHs In Renal Impairment Recommendations FOR CrCL < 30 ml/minEnoxaparin:Prophylaxis doses: 30 mg sq QDTreatment doses: 1mg/Kg sq QDDalteparin and Tinzaparin:no specific dosing guidelinesNo or lower degree of accumulation expectedAnti-Factor Xa activity monitoringFOR CrCL mL/minNo specific recommendationsConcern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?)Monitoring anti-Xa ?Nutescu E, et.al. Ann Pharmacother; 2009; 43(6):
155Unresolved Issues in Renal Dosing of LMWHs CrCl (mL/min)Recommendations< 30Dose of enoxaparin should be adjusted; dalteparin and tinzaparin no short term accumulation expected.<LMWHs have not been adequately studied as repeated doses for prophylaxis and treatment indications; UFH is preferred in these patients.Issues with anti-factor Xa testing include:true therapeutic range, standardization, availability, recommendations for dose adjustment
156Anti-Xa Activity Level Monitoring Enoxaparin 1mg/kg SQ pharmacokinetic profilePeak (goal ~ U/ml) at 3-4 hrsTrough (goal < 0.5 U/ml) at hrsLaposata et al. Arch Pathol Lab Med. 1998;122:
157Fondaparinux Use in Patients with Impaired Renal Function Total clearance lower than in patients with normal renal functionMild impairment ~25%Moderate impairment ~40%Severe impairment ~55%Fondaparinux: PI
158Applying National Guidelines to Clinical Practice Mechanisms ● Mortality ● TherapeuticsApplying National Guidelines toClinical PracticeCurrent Status of ASCO and NCCN Guidelines forVTE Prophylaxis in Cancer PatientsProgram ChairmanCraig M. Kessler, MDProfessor of Medicine and PathologyGeorgetown University Medical CenterDirector of the Division of CoagulationDepartment of Laboratory MedicineLombardi Comprehensive Cancer CenterWashington, DC
159Hospitalized Patients with Cancer ASCO GuidelinesHospitalized Patients with CancerRole of VTE ProphylaxisEvidencePatients with cancer should be considered candidates for VTE prophylaxis with anticoagulants (UFH, LMWH, or fondaparinux) in the absence of bleeding or other contraindications to anticoagulationMultiple RCTs of hospitalized medical patients with subgroups of patients with cancer. The 8th ACCP guidelines strongly recommend (1A) prophylaxis with either low-dose heparin or LMWH for bedridden patients with active cancer.
160Role of VTE Prophylaxis Ambulatory Patients with Cancer Without VTE Receiving Systemic ChemotherapyRole of VTE ProphylaxisEvidenceRoutine prophylaxis with an antithrombotic agents is not recommended except as noted belowRoutine prophylaxis in ambulatory patients receiving chemotherapy is not recommended due to conflicting trials, potential bleeding, the need for laboratory monitoring and dose adjustment, and the relatively low incidence of VTE.LMWH or adjusted dose warfarin (INR ~ 1.5) is recommended in myeloma patients on thalidomide or lenalidomide plus chemotherapy or dexamethasoneThis recommendation is based on nonrandomized trial data and extrapolation from studies of postoperative prophylaxis in orthopedic surgery and a trial of adjusted-dose warfarin in breast cancer
161Patients with Cancer Undergoing Surgery Role of VTE ProphylaxisEvidenceAll patients undergoing major surgical intervention for malignant disease should be considered for thromboprophylaxis with low- dose UFH, LMWH, or fondaparinux starting as early as possible for at least 7-10 days unless contraindicated.RCTs of UFH and those comparing the effects of LMWH and UFH on DVT rates on patients with cancer indicate broadly similar prophylactic efficacies for these two agentsMechanical methods may be added to anticoagulation in very high risk patients but should not be used alone unless anticoagulation in contraindicated.A Cochrane review of 19 studies
162Undergoing Surgery (continued) Patients with CancerUndergoing Surgery (continued)Role of VTE ProphylaxisEvidenceLMWH for up to 4 weeks may be considered after major abdominal/pelvic surgery with residual malignant disease, obesity, and a previous history of VTERecent RCTs suggest that prolonging prophylaxis up to 4 weeks is more effective than short-course prophylaxis in reducing postoperative VTE.
163Treatment of Patients with Established VTE to Prevent Recurrence Role of VTE ProphylaxisEvidenceLMWH is the preferred approach for the initial 5-10 days in cancer patient with established VTE.LMWH for 3-6 months is more effective than vitamin K antagonists given for a similar duration for preventing recurrent VTE.LMWH for at least 6 months is preferred for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are acceptable when LMWH is not available. The CLOT study demonstrated a relative risk reduction of 49% with LMWH vs. a vitamin K antagonist. Dalteparin sodium approved by the FDA for extended treatment of symptomatic VTE to reduce the risk of recurrence of VTE in patients with cancer (FDA 2007)
164Role of VTE Prophylaxis Treatment of Patients with Established VTE to Prevent Recurrence (continued)Role of VTE ProphylaxisEvidenceAnticoagulation for an indefinite period should be considered for patients with active cancer (metastatic disease, continuing chemotherapy)In the absence of clinical trials, benefits and risks of continuing LMWH beyond 6 months is a clinical judgment in the individual patient. Caution is urged in elderly patients and those with intracranial malignancy.Inferior vena cava filters are reserved for those with contraindications to anticoagulation or PE despite adequate long-term LMWH.Consensus recommendations due to lack of date in cancer-specific populations
165Anticoagulants in the Absence of Established VTE to Improve Survival Role of VTE ProphylaxisEvidenceAnticoagulants are not currently recommended to improve survival in patients with cancer without VTE.RCTs and meta-analysis of warfarin, UFH and LMWH have reported encouraging but variable results generally showing clinical benefit only in subgroup analyses.
166Summary of NCCN Guidelines Updates Summary of Major Changes in the Version of the NCCN Venous Thromboembolic Disease Guidelines
167Changes in 2009 NCCN Guidelines Stage 1 Immediate:“Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk assessment (heparin phase)” changed to “Stage 1 Immediate: At diagnosis or during diagnostic evaluation”Low –molecular-weight-heparin: New footnote “6” was added that states, “Although each of the low molecular weight heparins (LMWH), have been studies in randomized control trials in cancer patients, dalteparin’s efficacy in this population is supported by the highest quality evidence and it is the only LMWH approved by the FDA for this indication.”Unfractionated heparin (IV): target aPTT range changed from “ x control) to “ x control…” (Also for VTE-H) in these patients.
168Changes in 2009 NCCN Guidelines Stage 3 Chronic:“Third bullet: “Consider indefinite anticoagulation….” changed to “Recommend indefinite anticoagulation….”Fourth bullet: “For catheter associated thrombosis, anticoagulate as long as catheter is in place and for at least 3 months after catheter removal”.
169Changes in 2009 NCCN Guidelines 6Although each of the low molecular weight heparins (LMWH) have been studied in randomized controlled trials in cancer patients, dalteparin’s efficacy in this population is supported by the highest quality evidence and is the only LMWH approved by the FDA for this indication.Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism on patients with cancer. New Eng J Med 2003;349(2):
170(VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such therapy, and the panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Following hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post-operation. Careful evaluation and follow-up of cancer patients in whom VTE is suspected and prompt treatment and follow-up for patients diagnosed with VTE is recommended after the cancer status of the patient is assessed and the risks and benefits of treatment are considered.
171(VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism Stage 1 Immediate: At diagnosis or during diagnostic evaluation:Low-molecular-weight heparin (LMWH)Dalteparin (200 units/kg subcutaneous daily)Enoxaparin (1 mg/kg subcutaneous every 12 hours)Tinzaparin (175 units/kg subcutaneous daily)Fondaparinux (5 mg [<50 kg]; 7.5 mg [ kg]; 10 mg [> 100 kg] subcutaneous dailyUnfractionated heparin (IV) (80 units/kg load, then 18 units/kg per hour, target aPTT of x control or per hospital SOP)
172(VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism Additional VTE risk factors for surgical oncology patients with a previous episode of VTE include anesthesia times longer than 2 hours, advanced stage disease, bed rest, > 4 days and patients age 60 years or older. Extended prophylaxis out to 4 weeks post-surgery was associated with a greater than 50% reduction in venographic VTE
173(VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism Stage 2 Acute: Short term, during transition to chronic phase:LMWH (category 1) is preferred as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancerIf UFH or factor Xa antagonist, transition to LMWH or warfarinWarfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR )
174Therapeutic Anticoagulation Failure INRSwitch to heparin (LMWH preferred)or fondaparinuxIncrease warfarin dose and treat with parenteral agent until INR target achieved or consider switching to heparin (LMWH preferred) or fondaparinuxPatientonwarfarinCheckSub-therapeutic
175Therapeutic Anticoagulation Failure aPTTIncrease dose of heparinor Switch to LMWHor Switch to fondaparinuxand Consider placementof IVC filterand Consider HITIncrease dose of heparin to reach therapeutic levelPatientonheparinCheckaPTT levelsSub-therapeutic