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The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer

A Year 2009 Update for The Health System Pharmacist. The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer. Program Co-Chairs. Samuel Z. Goldhaber, MD Professor of Medicine Harvard Medical School Cardiovascular Division Director, Venous Thromboembolism

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The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer

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  1. A Year 2009 Update for The Health System Pharmacist The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Program Co-Chairs Samuel Z. Goldhaber, MD Professor of Medicine Harvard Medical School Cardiovascular Division Director, Venous Thromboembolism Research Group Brigham and Women’s Hospital Boston, MA Edith Nutescu, PharmD, FCCP Clinical Associate Professor Pharmacy Practice Affiliate Faculty, Center for Pharmacoeconomic Research Director, Antithrombosis Center The University of Illinois at Chicago College of Pharmacy & Medical Center Chicago, IL

  2. Welcome and Program Overview Jointly sponsored by the University of Florida College of Pharmacy and CMEducation Resources, LLC.Jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLCCommercial Support: Sponsored by an independent educational grant from Eisai, Inc.Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based managementProcesses: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studiesCOI: Full faculty disclosures provided in syllabus and at the beginning of the program

  3. CEU Credit Designation Statement The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The University of Florida College of Pharmacy will mail the Statements of Continuing Pharmacy Education Credit within 4 weeks after the course.To receive credit you must attend the sessions for which you want credit and complete an evaluation form. The College of Pharmacy will award 2 (two) continuing pharmacy education credits (2.0 CEU’s) upon completion of this program.

  4. Program Educational Objectives As a result of this session, attendees will be able to: • List the recent trials, research, and expert analysis of issues focused on thrombosis and cancer. • Outline specific strategies for risk-directed prophylaxis against DVT in at-risk patients with cancer. • Describe dose anticoagulation therapy for patients requiring prophylaxis in special patient populations. • Outline steps for avoiding medication errors using anticoagulation in cancer patients at risk for DVT. • List the guidelines for DVT prophylaxis in cancer issued by the National Comprehensive Cancer Network (NCCN), the American College of Chest Physicians (ACCP), and the Surgeon General’s Report.

  5. Program Faculty Program Co-Chairs Edith Nutescu, PharmD, FCCP Clinical Associate Professor, Pharmacy Practice Affiliate Faculty, Center for Pharmacoeconomic Research Director, Antithrombosis Center The University of Illinois at Chicago College of Pharmacy & Medical Center Chicago, IL Samuel Z. Goldhaber, MD Professor of Medicine Harvard Medical School Cardiovascular Division Director, Venous Thromboembolism Research Group Brigham and Women’s Hospital Boston, MA Distinguished Experts and Presenters John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Karen Fiumara, PharmD Medication Safety Officer Brigham and Women’s Hospital Adjunct Assistant Professor of Pharmacy Practice Massachusetts College of Pharmacy and Allied Health Sciences Adjunct Assistant Professor of Pharmacy Practice Bouve’ College of Health Sciences Northeastern University Boston, MA

  6. Faculty COI Financial Disclosures Samuel Z. Goldhaber, MD Grant/Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; sanofi-aventis; Consultant: Boehringer-Ingelheim; BMS; Eisai; Merck; Pfizer; sanofi-aventis Edith Nutescu, PharmD Speakers Bureau: Eisai Inc., GlaxoSmithKline, sanofi-aventis U.S. Advisory Committees or Review Panels, Board Membership, etc.: BoehringerIngelheim Pharmaceuticals, Inc., Scios Inc. Karen Fiumara, PharmD Nothing to disclose John Fanikos, RPh, MBA Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines Company

  7. A Year 2009 Update for The Health System Pharmacist Cancer and Prevention of VTE Landmark Advances and New Paradigms of Care for the Health System Pharmacist Program Co-Chair Samuel Z. Goldhaber, MD Professor of Medicine Harvard Medical School Cardiovascular Division Director, Venous Thromboembolism Research Group Brigham and Women’s Hospital Boston, MA

  8. VTE and Cancer—A Looming National Healthcare Crisis MISSION AND CHALLENGES Recognizing 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.

  9. Comorbidity Connection COMORBIDITY CONNECTION CAP UTI Cancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder Thrombophilia Surgery History of DVT Other SUBSPECIALIST STAKEHOLDERS Infectious diseases Oncology PHARMACISTS Cardiology Pulmonary medicine Hematology Oncology/hematology Interventional Radiology Hospitalist Surgeons EM PCP

  10. Epidemiology of First-Time VTE White R. Circulation. 2003;107:I-4 –I-8.)

  11. Epidemiology of VTE • One 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.)

  12. Overview Comorbidity Connection Comorbidity Connection

  13. Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968

  14. Comorbid Condition and DVT Risk • Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%. • The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively. • Together, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med.  2002 Jun 10;162(11):1245-8.  Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

  15. VTE Recurrence Predictors of First Overall VTE Recurrence Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768

  16. 25 20 15 10 5 0 ICOPER Cumulative Mortality 17.5% Mortality (%) 7 14 30 60 90 Days From Diagnosis Lancet 1999;353:1386-1389

  17. Stages of Chronic Venous Insufficiency • Varicose veins • Ankle/ leg edema • Stasis dermatitis • Lipodermatosclerosis • Venous stasis ulcer

  18. Progression of Chronic Venous Insufficiency From UpToDate 2006

  19. Rising VTE Incidence in Hospitalized Patients Stein PD et al. Am J Cardiol 2005; 95: 1525-1526

  20. DVT Registry (N=5,451):Top 5 Medical Comorbidities 1. Hypertension 2. Immobility 3. Cancer 4. Obesity (BMI > 30) 5. Cigarette Smoking Am J Cardiol 2004; 93: 259-262

  21. Implementation Implementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines.

  22. SURGEON GENERAL:CALL TO ACTION TO PREVENT DVT AND PESeptember 15, 2008

  23. Surgeon General’s Call to Action 42-Page Document • Issued September 15, 2008 • Endorsed by Secretary, HHS • Endorsed by Director, NHLBI • Foreword by Acting Surgeon General, Steven K. Galson, MD, MPH (RADM, U.S. Public Health Service)

  24. Call to Action for VTE Foreword • Dr. Galson’s 1st Call To Action • > 350,000-600,000 Americans suffer VTE annually • > 100,000 U.S. deaths per year • Negative impact on QOL of survivors • “Must disseminate info widely” to “address gap” because we’re not applying knowledge systematically

  25. Call to Action for VTE I. Major Public Health ProblemII. Reducing VTE RiskIII. Gaps in Application, Awareness of EvidenceIV. Public Health ResponseV. Catalyst for Action

  26. Symposium Themes • Cancer rates are increasing as heart disease Rx improves and as cancer Rx improves. • Cancer increases VTE risk. • VTE is preventable (immunize!) • VTE prophylaxis may slow cancer • Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATF • Facilitate prophylaxis with alerts.

  27. A Year 2009 Update for The Health System Pharmacist Cancer and Prevention of VTE Landmark Advances and New Paradigms of Care for the Health System Pharmacist Edith Nutescu, PharmD, FCCP Clinical Associate Professor Pharmacy Practice Affiliate Faculty, Center for Pharmacoeconomic Research Director, Antithrombosis Center The University of Illinois at Chicago College of Pharmacy & Medical Center Chicago, IL

  28. Peculiar Relationship Between Cancer and Thrombosis may indicate Hypercoagulation/ thrombosis Occult Cancer may cause Hypercoagulation/ thrombosis Cancer

  29. Thromboembolism in Malignancy • 15% of cancer patients develop venous or arterial thrombosis1 • Annual incidence of VTE in all patients: 117 in 100,0002 • Cancer increases risk of thrombosis 4.1-fold3 • Chemotherapy increases risk of thrombosis 6.5-fold3 • Annual incidence of VTE in patients with cancer: 1 in 2004 1. Green KB, Silverstein RL. HematolOncolClin North Am. 1996;10:499-530. 2. Silverstein MD et al. Arch Intern Med. 1998;158:585-593 3. Heit JA et al. Arch Intern Med. 2000;160:809-815 4. Lee AYY, Levine MN. Circulation. 2003;107(23 Suppl 1):I17-21.

  30. Patient-related factors Older age Comorbidities Treatment-related factors Recent surgery Hospitalization Chemotherapy Hormonal therapy Antiangiogenic agents Erythropoiesis-stimulating agents Factors That May Affect Risk for Cancer-Associated VTE Cancer-related factors • Site of cancer • Advanced stage • Initial period after diagnosis Biological factors (biomarkers) • Elevated pre-chemotherapy platelet count • D-dimer • Tissue factor expression by tumor cells Rao MV, et al., In Khorana AA, Francis CW, eds.2007

  31. Risk of Inpatient VTE by Type of Cancer n=3550 n=68 n=326 n=43 n=51 n=53 n=55 n=127 n=95 14 12.10 12 9.50 10 8.96 7.64 7.41 Rate of VTE, % 8 7.00 6.75 6.50 5.37 6 4 2 0 All Brain Lung Colon Other Abdominal Ovarian Stomach Pancreatic Endometrial/ Cervical In hospitalized neutropenic cancer patients Khorana AA et al. J ClinOncol. 2006;24:484-490.

  32. Risk of Inpatient VTE by Type of Cancer N=3550 n=641 n=650 n=79 n=262 n=204 7 5.79 6 5.37 5.01 5 4.39 3.87 3.93 4 Rate of VTE, % 3 2 1 0 Leukemia NHL Myeloma Hodgkin’s All Breast In hospitalized neutropenic cancer patients Khorana AA et al. J ClinOncol. 2006;24:484-490.

  33. Patients With Cancer Represent About 20% of All DVT and PE Patients with cancer: approximately 19.8% All DVT and PE Heit JA. et al. Arch Intern Med 2002;162:1245-1248.

  34. 1.00 DVT/PE and Malignant Disease 0.80 0.60 Probability of Death Malignant Disease 0.40 DVT/PE Only 0.20 Nonmalignant Disease 0.00 0 20 40 60 80 100 120 140 160 180 Number of Days VTE, Cancer, and Survival N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer Levitan N, et al. Medicine 1999;78:285

  35. VTE and Inpatient Mortality No Venous Thromboembolism Venous Thromboembolism 20 18 16 16.13 16.41 14 14.85 12 Mortality, % 10 10.59 8 8.67 7.98 6 4 2 0 All (n=66,016) NonmetastaticCancer (n=20,591) MetastaticCancer (n=17,360) Khorana AA et al. J ClinOncol. 2006;24:484-490.

  36. Prophylaxis Rates in Hospitalized Patients Amin A et al. J ThrombHaemost. 2007; 5:1610-6.

  37. Thromboprophylaxis Is Underutilizedin Non-surgical Patients With Cancer Premiere Perspective™ database: 72,391 discharges from 225 hospitals between January 2002 and September 2005 Patients Receiving Appropriate DVT Prophylaxis, % Amin AN et al. J ClinOncol. 2007;25 (suppl):Abstract 9047.

  38. Clots and Cancer—A Looming National Healthcare Crisis MISSION AND CHALLENGES Recognizing cancer patients at risk for DVT and identifying patients who are appropriate candidates for long-term prophylaxis and/or treatment with approved and indicated therapies are among the most important and difficult challenges encountered in contemporary pharmacy and clinical practice.

  39. Clotting, Cancer, and Controversies A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Linking Science and Evidence to Clinical Practice—What Do Trials Teach the Health System Pharmacist? Program Co-Chairman Samuel Z. Goldhaber, MD Professor of Medicine Harvard Medical School Cardiovascular Division Director, Venous Thromboembolism Research Group Brigham and Women’s Hospital Boston, MA

  40. VTE and Cancer: Epidemiology • Of all cases of VTE: • About 20% occur in cancer patients • Annual incidence of VTE in cancer patients ≈ 1/250 • Of all cancer patients: • 15% will have symptomatic VTE • As many as 50% have VTE at autopsy • Compared to patients without cancer: • Higher risk of first and recurrent VTE • Higher risk of bleeding on anticoagulants • Higher risk of dying Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21

  41. DVT and PE in CancerFacts, Findings, and Natural History • VTE is the second leading cause of death in hospitalized cancer patients1,2 • The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2 • Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3 • Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4 Ambrus JL et al. J Med. 1975;6:61-64 Donati MB. Haemostasis. 1994;24:128-131 Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 Prandoni P et al. Ann Intern Med. 1996;125:1-7

  42. Clinical Features of VTE in Cancer • VTE has significant negative impact on quality of life • VTE may be the presenting sign of occult malignancy • 10% with idiopathic VTE develop cancer within 2 years • 20% have recurrent idiopathic VTE • 25% have bilateral DVT Buraet. al.,J ThrombHaemost 2004;2:445-51

  43. 1.00 DVT/PE and Malignant Disease 0.80 0.60 Probability of Death Malignant Disease 0.40 DVT/PE Only 0.20 Nonmalignant Disease 0.00 0 20 40 60 80 100 120 140 160 180 Number of Days Thrombosis and SurvivalLikelihood of Death After Hospitalization Levitan N, et al. Medicine 1999;78:285

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

  45. Trends in VTE in Hospitalized Cancer Patients 7.0 6.5 6.0 5.5 5.0 4.5 4.0 Rate of VTE (%) 3.5 3.0 2.5 2.0 1.5 1.0 P<0.0001 0.5 0.0 1995 1996 1997 1998 1999 2000 2001 2002 2003 VTE- patients on chemotherapy VTE-all patients DVT-all patients PE-all patients Khorana AA et al. Cancer. 2007.

  46. Thrombosis Risk In Cancer Primary Prophylaxis • Medical Inpatients • Surgery • Radiotherapy • Central Venous Catheters

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

  48. VTE Risk And Cancer Type“Solid And Liquid Malignancies” Relative Risk of VTE Ranged From 1.02 to 4.34 4.5 4 3.5 3 2.5 2 1.5 1 0.5 Pancreas Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney Colon Ovary Liver Leukemia Breast Cervix Bladder Relative Risk of VTE in Cancer Patients Stein PD, et al. Am J Med 2006; 119: 60-68

  49. Cancer and Thrombosis Medical Inpatients

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