A Year 2009 Update for The Health System Pharmacist The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Program Co-Chairs Edith.

A Year 2009 Update for The Health System Pharmacist The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer 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

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, LLC Commercial 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 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

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.

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.

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 Adjunct Assistant Professor of Pharmacy Practice Massachusetts College of Pharmacy and Allied Health Sciences Bouve’ College of Health Sciences Northeastern University

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.: Boehringer Ingelheim 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

Cancer and Prevention of VTE
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

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.

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

Epidemiology of First-Time VTE
Variable Finding Seasonal Variation Possibly more common in winter and less common in summer Risk Factors 25% to 50% “idiopathic” 15%-25% associated with cancer 20% following surgery (3 months) Recurrent VTE 6-month incidence, 7%; Higher rate in patients with cancer Recurrent PE more likely after PE than after DVT Death After Treated VTE 30-day incidence 6% after incident DVT 30-day incidence 12% after PE Death strongly associated with cancer, age, and cardiovascular disease White R. Circulation. 2003;107:I-4 –I-8.)

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.)

Comorbidity Connection
Overview Comorbidity Connection

Acute Medical Illness and VTE
Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Risk Factor Odds Ratio (95% CI) X2 Age > 75 years Cancer Previous VTE 1.03 ( ) 1.62 ( ) 2.06 ( ) 0.0001 0.08 0.02 Acute infectious disease 1.74 ( ) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:

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): Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

VTE Recurrence Hazard Ratio Baseline Characteristic
Predictors of First Overall VTE Recurrence Baseline Characteristic Hazard Ratio (95% CI) Age 1.17 ( ) Body Mass Index 1.24 ( ) Neurologic disease with extremity paresis 1.87 ( ) Malignant neoplasm With chemotherapy Without chemotherapy 4.24 ( ) 2.21 ( ) Heit J, Mohr D, et al. Arch Intern Med. 2000;160:

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

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

Progression of Chronic Venous Insufficiency
From UpToDate 2006

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

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:

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

SURGEON GENERAL: CALL TO ACTION TO PREVENT DVT AND PE September 15, 2008

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)

Call to Action for VTE Foreword Dr. Galson’s 1st Call To Action
> 350, ,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

Call to Action for VTE I. Major Public Health Problem II. Reducing VTE Risk III. Gaps in Application, Awareness of Evidence IV. Public Health Response V. Catalyst for Action

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.

Cancer and Prevention of VTE
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

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

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. Hematol Oncol Clin North Am. 1996;10: 2. Silverstein MD et al. Arch Intern Med. 1998;158: 3. Heit JA et al. Arch Intern Med. 2000;160: 4. Lee AYY, Levine MN. Circulation. 2003;107(23 Suppl 1):I17-21.

Factors That May Affect Risk for Cancer-Associated VTE
Patient-related factors Older age Comorbidities Treatment-related factors Recent surgery Hospitalization Chemotherapy Hormonal therapy Antiangiogenic agents Erythropoiesis-stimulating agents 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 A wide range of factors may influence risk for cancer-associated VTE1 Rao MV, et al., In Khorana AA, Francis CW, eds. 2007

Risk of Inpatient VTE by Type of Cancer
n= 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 7.41 7.64 Rate of VTE, % 8 7.00 6.75 6.50 5.37 6 4 2 In a study of 3550 patients hospitalized for neutropenic cancer, venous thromboembolism (VTE) occurred in 5.37%1 The differing rates of VTE among types of cancer suggest that factors intrinsic to each kind of tumor may contribute to hypercoagulability1 All Brain Lung Stomach Colon Pancreatic Other Abdominal Ovarian Endometrial/ Cervical In hospitalized neutropenic cancer patients Khorana AA et al. J Clin Oncol. 2006;24: _______________________________________________________________________________________ Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:

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 In this figure, a continuation of data from the same study of 3550 hospitalized cancer patients shown in the preceding slide, the rates of venous thromboembolism (VTE) are relatively lower, and the Y axis maximum is 5.79%, compared with 12.1% in the previous figure1 All Leukemia NHL Hodgkin’s Myeloma Breast In hospitalized neutropenic cancer patients Khorana AA et al. J Clin Oncol. 2006;24: _______________________________________________________________________________________ Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:

Patients With Cancer Represent About 20% of All DVT and PE
Patients with cancer: approximately 19.8% Patients with cancer represent about 20% of all DVT and PE All DVT and PE Heit JA. et al. Arch Intern Med 2002;162: _______________________________________________________________________________________ Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: see MRL. Arch Intern Med. 2002;162:

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

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 A recent study showed that the mortality rate was significantly lower in hospitalized neutropenic cancer patients with no diagnosed venous thromboembolism (VTE) than in those with identified VTE (7.98% vs 14.85%, respectively; P<0.0001)1 All (n=66,016) Nonmetastatic Cancer (n=20,591) Metastatic Cancer (n=17,360) Khorana AA et al. J Clin Oncol. 2006;24: _______________________________________________________________________________________ Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:

Prophylaxis Rates in Hospitalized Patients
Amin A et al. J Thromb Haemost. 2007; 5: 37

Patients Receiving Appropriate DVT Prophylaxis, %
Thromboprophylaxis Is Underutilized in 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, % Data from the Premiere Perspective™ database of over 72,000 discharges from 225 US hospitals between January 2002 and September 2005 show that thromboprophylaxis is widely underused among cancer patients1 The study analyzes medical records and determines if patients should have received DVT prophylaxis according to the 2004 ACCP guidelines1 Only about 30% of all patients with cancer received appropriated DVT prophylaxis1 27.7% of nonsurgical patients with cancer received appropriate prophylaxis1 Amin AN et al. J Clin Oncol. 2007;25 (suppl):Abstract 9047. _______________________________________________________________________________________ Amin AN, Stemkowski SA, Lin J, Yang G. Assessing adherence to the American College of Chest Physicians’ (ACCP) recommendations for thromboprophylaxis in hospitalized cancer patients ASCO Annual Meeting Proceedings Part I. J Clin Oncol. 2007;25(18S)(suppl): Abstract 9047.

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.

A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer
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

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

DVT and PE in Cancer Facts, 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 Let’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;6:61-64 Donati MB. Haemostasis. 1994;24: Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 Prandoni P et al. Ann Intern Med. 1996;125:1-7

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 Bura et. al., J Thromb Haemost 2004;2:445-51

Thrombosis and Survival Likelihood of Death After Hospitalization
0.00 0.20 0.40 1.00 0.80 0.60 DVT/PE and Malignant Disease Malignant Disease DVT/PE Only Nonmalignant Disease Number of Days Probability of Death Levitan N, et al. Medicine 1999;78:285

Hospital Mortality With or Without VTE
N=66,016 N=20,591 N=17,360 Khorana, JCO, 2006

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

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

Risk Factors for Cancer-Associated VTE
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

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

Cancer and Thrombosis Medical Inpatients

Thromboembolism in Hospitalized Neutropenic Cancer Patients
Retrospective cohort study of discharges using the University Health System Consortium 66,106 adult neutropenic cancer patients between 1995 and 2002 at 115 centers Khorana, JCO, 2006

Neutropenic Patients: Results
8% had thrombosis 5.4% venous and 1.5% arterial in 1st hospitalization Predictors of thrombosis Age over 55 Site (lung, GI, gynecologic, brain) Comorbidities (infection, pulmonary and renal disease, obesity) Khorana, JCO, 2006

Predictors of VTE in Hospitalized Cancer Patients
Characteristic OR P Value Site of Cancer Lung Stomach Pancreas Endometrium/cervix Brain 1.3 1.6 2.8 2 2.2 <0.001 0.0035 Age 65 y 1.1 0.005 Arterial thromboembolism 1.4 0.008 Comorbidities (lung/renal disease, infection, obesity) [Khorana.JClinOncol. Jan.2006/p489/Table 4] Khorana AA et al. J Clin Oncol. 2006;24:

Antithrombotic Therapy: Choices
Pharmacologic (Prophylaxis & Treatment) Nonpharmacologic (Prophylaxis) Low Molecular Weight Heparin (LMWH) Intermittent Pneumatic Compression Elastic Stockings Unfractionated Heparin (UH) Inferior Vena Cava Filter Several classes of agents have been used for prophylaxis and treatment of VTE Nonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filter Most 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) Oral Anticoagulants New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?

Prophylaxis Studies in Medical Patients
Relative risk reduction 47% Relative risk reduction 63% Rate of VTE (%) Relative risk reduction 44% Placebo Enoxaparin MEDENOX Trial Placebo Dalteparin PREVENT Placebo Fondaparinux ARTEMIS Francis, NEJM, 2007

ASCO Guidelines 1. SHOULD HOSPITALIZED PATIENTS WITH
CANCER RECEIVE ANTICOAGULATION FOR VTE 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:

Cancer and Thrombosis Surgical Patients

Incidence 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 Cancer N=16,954 Cancer N=6124 P-value Post-op VTE 0.61% 1.26% <0.0001 Non-fatal PE 0.27% 0.54% <0.0003 Autopsy PE 0.11% 0.41% Death 0.71% 3.14% Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732

Natural History of VTE in Cancer Surgery: The @RISTOS Registry
Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Type of surgery • 52% General • 29% Urological • 19% Gynecologic 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings 2.1% incidence of clinically overt VTE (0.8% fatal) Most events occur after hospital discharge Most common cause of 30-day post-op death Agnelli, Ann Surg 2006; 243: 89-95

Prophylaxis in Surgical Patients
LMWH vs. UFH Abdominal or pelvic surgery for cancer (mostly colorectal) LMWH once daily vs. UFH tid for 7–10 days post-op DVT on venography at day 7–10 and symptomatic VTE Study N Design Regimens ENOXACAN 1 631 double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:

Prophylaxis in Surgical Patients
Canadian Colorectal DVT Prophylaxis Trial 16.9% P=0.052 13.9% Incidence of Outcome Event N=234 N=241 1.5% 2.7% VTE Major Bleeding (Cancer) (All) McLeod R, et al. Ann Surg 2001;233:

Extended Prophylaxis in Surgical Patients
12.0% ENOXACAN II P=0.02 Incidence of Outcome Event N=167 4.8% 5.1% N=165 3.6% 1.8% NNT = 14 0.6% 0% 0.4% VTE Prox Any Major DVT Bleeding Bleeding Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:

Major 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 treatment RESULTS: 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.

ASCO 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:

Central Venous Catheters
Thrombosis is a potential complication of central venous catheters, including these events: Fibrin sheath formation Superficial phlebitis Ball-valve clot Deep vein thrombosis (DVT) Geerts W, et al. Chest Jun 2008: 381S–453S

Prophylaxis for Venous Catheters
Placebo-Controlled Trials Study Regimen N CRT (%) Reichardt* 2002 Dalteparin 5000 U daily placebo 285 140 11 (3.7) 5 (3.4) Couban* 2002 Warfarin 1mg daily 130 125 6 (4.6) 5 (4.0) ETHICS† 2004 Enoxaparin 40 mg daily 155 22 (14.2) 28 (18.1) *symptomatic outcomes; †routine venography at 6 weeks Reichardt 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

Central Venous Catheters: Warfarin
Tolerability of Low-Dose Warfarin 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily INR measured at baseline and four time points 10% of all recorded INRs >1.5 Patients with elevated INR 2.0– % 3.0– % > % Masci et al. J Clin Oncol. 2003;21:

Prophylaxis for Central Venous Access Devices
Summary Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) Routine prophylaxis is not warranted to prevent catheter-related thrombosis, but catheter patency rates/infections have not been studied Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis

8th ACCP Consensus Guidelines
No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Chest Jun 2008: 454S–545S

Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient
No recommendations from ACCP No 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.)

Ambulatory Chemotherapy Patients
Cancer and Thrombosis Ambulatory Chemotherapy Patients

Risk Factors for VTE in Medical Oncology Patients
Tumor type Ovary, brain, pancreas, lung, colon Stage, grade, and extent of cancer Metastatic disease, venous stasis due to bulky disease Type of antineoplastic treatment Multiagent regimens, hormones, anti-VEGF, radiation Miscellaneous VTE risk factors Previous VTE, hospitalization, immobility, infection, thrombophilia

Independent Risk Factors for DVT/PE
Risk Factor/Characteristic O.R. Recent surgery with institutionalization 21.72 Trauma 12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease w/ extremity paresis 3.04 Serious liver disease 0.10 Dr. 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:

VTE Incidence In Various Tumors
Oncology Setting VTE Incidence Breast cancer (Stage I & II) w/o further treatment 0.2% Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage IV) w/ chemo 8% Non-Hodgkin’s lymphomas w/ chemo 3% Hodgkin’s disease w/ chemo 6% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma (thalidomide + chemo) 28% Renal cell carcinoma 43% Solid tumors (anti-VEGF + chemo) 47% Wilms tumor (cavoatrial extension) 4% Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

Primary VTE Prophylaxis
Recommended for hospitalized cancer patients Not recommended or generally used for outpatients Very little data Heterogeneous Need for risk stratification

Ambulatory Cancer plus Chemotherapy
Study Methods Prospective observational study of ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a maximum of 4 cycles 115 U.S. centers participated Patients enrolled between March, 2002 and August, who had completed at least one cycle of chemotherapy were included in this analysis METHODS: We analyzed data from a prospective observational study conducted by the Awareness of Neutropenia in Chemotherapy Study Group, funded by Amgen, Inc. Patients were enrolled on study at the start of a new chemotherapy regimen, and followed prospectively for a maximum of 4 cycles, at 115 participating US centers. Patients enrolled between March, 2002 and August, who had completed at least one cycle of chemotherapy were included in this analysis. Khorana, Cancer, 2005

Ambulatory Cancer plus Chemotherapy
Study Methods VTE events were recorded during mid-cycle or new-cycle visits Symptomatic VTE was a clinical diagnosis made by the treating clinician Statistical analysis Odds ratios to estimate relative risk Multivariate logistic regression to adjust for other risk factors VTE events were recorded during mid-cycle or new-cycle visits. Since this was an observational study, VTE was diagnosed by the treating physician by usual tests based on clinical suspicion. Statistical analysis included generation of odds ratios to estimate relative risk, and a logistic regression analysis to adjust for other risk factors. The predictive model was constructed based on the multivariate analysis. The risk score estimates for each variable were derived using beta-coefficients from the multivariate model. First order interactions were incorporated into the final score. Khorana, Cancer, 2005

Incidence of VTE 0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% Baseline Cycle 1
Rate of VTE (%) A total of 58 patients (1.93%) developed VTE during a median follow-up period of 2.4 months (0.8%/month). One patient developed VTE prior to starting chemotherapy. The rate of VTE did not differ significantly among chemotherapy cycles, occurring in 0.77% during cycle 1, 0.74% during cycle 2, and 0.7% during cycle 3. As shown in this figure, the cumulative rate of VTE was 2.2% (95% CI, ) during cycles 1 through 3. VTE / 2.4 months VTE/month VTE /cycle Cumulative rate (95% CI) 1.93% 0.8% 0.7% 2.2% ( ) Khorana, Cancer, 2005

Risk Factors: Site of Cancer
12 10 8 6 VTE (%) / 2.4 months 4 2 The primary site of cancer affected the risk of VTE (p=0.01), with the highest rates observed in patients with upper gastrointestinal cancers (particularly gastric and pancreatic) (2.3%/month), and lung cancer (1.2%/month). Among patients with hematologic malignancies, those with a diagnosis of Hodgkin’s or non-Hodgkin’s lymphoma had the highest rates of VTE (1.1%/month). Lung NHL Colon Breast Upper GI Others Hodgkin’s All patients Site of Cancer Khorana, Cancer, 2005

Incidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet Count
p for trend=0.005 0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5% 4.0% 4.5% 5.0% <217 >337 Incidence Of VTE Over 2.4 Months(%) This figure depicts the incidence of venous thromboembolism by quartiles of pre-chemotherapy platelet count. As can be seen, elevated platelet counts were associated with an increased risk of venous thromboembolism. Patients in the highest quartile of pre-chemotherapy platelet count with a count of > 337,000/ cu mm, had a 3.6% risk of VTE, and this was significantly greater than the 1.1 % risk observed with patients in the lowest quartile, with a pre-chemotherapy platelet count of < 217,000/ cu mm. The p value for trend was highly significant at 0.005, and the difference between the highest and lowest quartile was also significant at 3 Pre-chemotherapy Platelet Count/mm (x1000) Khorana, Cancer, 2005

Risk Factors: Multivariate Analysis
Characteristic OR P value Site of Cancer Upper GI Lung Lymphoma 3.88 1.86 1.5 0.03 0.0076 0.05 0.32 Pre-chemotherapy platelet count > 350,000/mm3 2.81 0.0002 Hgb < 10g/dL or use of red cell growth factor 1.83 Use of white cell growth factor in high-risk sites 2.09 0.008 We included clinically and statistically significant variables in a multivariate logistic regression analysis. This slide demonstrates variables found to be significant in this analysis. Risk factors independently associated with VTE included primary site of cancer (upper gastrointestinal or lung), an elevated pre-chemotherapy platelet count, hemoglobin < 10g/dL or use of erythropoietin (a combined variable), and use of white cell growth factors. We found a significant first-order interaction between site of cancer and use of white cell growth factors (p=0.02). Patients with sites of cancer associated with higher risk of VTE (upper gastrointestinal, lung or lymphoma) had a significantly increased risk of VTE associated with white cell growth factor use (VTE rate of 5.9% versus 1.52% without growth factor use, p =0.0001; odds ratio 4.0, [95% CI, ]). In contrast, patients with other sites of cancer did not appear to have an increased risk of VTE with the use of white cell growth factors (VTE rate of 1.31% versus 1.42% without growth factor use, p =0.84). Khorana, Cancer, 2005

Patient Characteristic
Predictive Model Patient Characteristic Score Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) 2 1 Platelet count > 350,000/mm3 Hgb < 10g/dL or use of ESA Leukocyte count > 11,000/mm3 BMI > 35 Khorana AA et al. JTH Suppl Abs O-T-002

Predictive Model Risk Score 1 2 3 4 N 1,352 974 476 160 33
0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 1 2 3 4 Actual Incidence Estimated Incidence 95 % Confidence Limits Incidence of VTE Over 2.4 Months The performance of the predictive risk assessment model is illustrated in this figure, which shows the rate of VTE by risk score. As you can see, the predicted incidence of VTE, shown as a yellow line, correlates closely with the actual incidence of VTE, shown as red triangles. The goodness of the model fit was confirmed by Hosmer and Lemeshow test. The proposed predictive model discriminates well between subgroups of patients at low and high risk of VTE during chemotherapy. Patients with a risk score of 0 had a VTE rate of 0.8% over the median 2.4 month follow-up. In contrast, patients with a risk score of 2 had a 3-fold higher rate at 2.7%, and those with a risk score of 3 had a 6.3% rate of VTE. Risk Score 1 2 3 4 N 1,352 974 476 160 33 VTE(%) /2.4 mos. 0.8 1.8 2.7 6.3 13.2

Predictive Model Validation
8% n=734 n=1627 n=340 0.8% 1.8% 7.1% Development cohort 7% 0.3% 2.0% 6.7% Validation cohort n=374 n=842 n=149 6% 5% Rate of VTE over 2.5 mos (%) 4% 3% 2% 1% 0% Risk Low (0) Intermediate(1-2) High(>3) Khorana AA et al. JTH Suppl Abs O-T-002

Oral 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 procedures Difficulty in venous access for monitoring Increased risk of both recurrence and bleeding Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?

CLOT: Landmark Cancer/VTE Trial
Dalteparin Dalteparin CANCER PATIENTS WITH ACUTE DVT or PE Randomization Dalteparin Oral Anticoagulant [N = 677] Primary Endpoints: Recurrent VTE and Bleeding Secondary Endpoint: Survival Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Landmark CLOT Cancer Trial
Reduction in Recurrent VTE 5 10 15 20 25 Days Post Randomization 30 60 90 120 150 180 210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Bleeding Events in CLOT
Dalteparin N=338 OAC N=335 P-value* Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27 Any bleed 46 (13.6%) 62 (18.5%) 0.093 * Fisher’s exact test Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Treatment of Cancer-Associated VTE
Study Design Length of Therapy (Months) N Recurrent VTE (%) Major Bleeding Death CLOT Trial (Lee 2003) Dalteparin OAC 6 336 9 17 4 39 41 CANTHENOX (Meyer 2002) Enoxaparin 3 67 71 11 21 7 16 23 LITE (Hull ISTH 2003) Tinzaparin 80 87 8 22 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) 32 36 34 3.4 3.1 6.7 NS 0.002 NS 0.09 0.09 0.03 0.03 NS NS NS NS NR

Treatment and 2° Prevention of VTE in Cancer – Bottom Line
New Development New 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 Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—ACCP) Chest Jun 2008: 454S–545S

CLOT 12-month Mortality All Patients Dalteparin OAC
10 20 30 40 50 60 70 80 90 100 120 180 240 300 360 Dalteparin OAC HR 0.94 P-value = 0.40 Days Post Randomization Probability of Survival, % Lee AY et al. J Clin Oncol. 2005; 23:

Anti-Tumor Effects of LMWH
CLOT 12-month Mortality Patients Without Metastases (N=150) 10 20 30 40 50 60 70 80 90 100 Dalteparin OAC Probability of Survival, % HR = P-value = 0.03 30 60 90 120 150 180 240 300 360 Lee AY et al. J Clin Oncol. 2005; 23: Days Post Randomization

LMWH for Small Cell Lung Cancer Turkish Study
84 patients randomized: Chemo +/- LMWH (18 weeks) Patients balanced for age, gender, stage, smoking history, ECOG performance status Chemotherapyplus Dalteparin Chemo alone P-value 1-y overall survival, % 51.3 29.5 0.01 2-y overall survival, % 17.2 0.0 Median survival, m 13.0 8.0 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J Thromb Haemost 2004;2:1266.

VTE 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 Respondents Major Surgery2 Cancer: Surgical Major Abdominothoracic Surgery (Elderly)3 Confirmed DVT (Inpatients)5 Rate of Appropriate Prophylaxis, % Medical Inpatients4 Cancer: Medical VTE prophylaxis is underused in patients with cancer The 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 site1 Data from 3891 completed questionnaires were available for analysis1 The 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 patients1 These results can be compared with prophylaxis rates in other patient groups as determined by other recent studies A 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 patients2 A 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 patients3 A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4 In 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:

Conclusions and Summary
Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopenia Long-term secondary prevention with LMWH has been shown to produce better outcomes than warfarin Guidelines and landmark trials support administration of LMWH in at risk patients Cancer patients are under-prophylaxed for VTE Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient population

Venous Thromboembolism (VTE) Prophylaxis in the
Clotting, Cancer, and Clinical Strategies Venous Thromboembolism (VTE) Prophylaxis in the Cancer Patient and Beyond Guidelines and Implications for Clinical Practice 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

Outline of Presentation
Guidelines for VTE prevention Performance to date Opportunities for improvement Guidelines for VTE Treatment

Prophylaxis Rates in Hospitalized Patients
Amin A et al. J Thromb Haemost. 2007; 5: 98 98

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

Time Distribution of VTE Events Following Cancer Surgery
@RISTOS Registry: prospective cohort N=2373 12 10 VTE Events 8 6 4 2 1-5 d 6-10 d 11-15 d 16-20 d 21-25 d 26-30 d > 30 d Agnelli G et al. Ann Surg 2006; 243:89-95. 100

NCCN Clinical Practice Guidelines in Oncology™ “…The panel of experts includes medical and surgical oncologists, hematologists, cardiologists, internists, radiologists. And a pharmacist.” Recommendations for VTE Prophylaxis & Treatment in Patients with Cancer

1A is the highest possible grade
2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A) General, Gynecologic, Urologic Surgery Low Dose Unfractionated Heparin 5,000 units TID LMWH > 3,400 units Daily Dalteparin 5,000 units Enoxaparin 40 mg Tinzaparin 4,500 units GCS and/or IPC Cancer patients with an acute medical illness receive prophylaxis that is appropriate for their current risk state (Grade 1A) Low Dose Unfractionated Heparin LMWH Contraindication to anticoagulant prophylaxis (Grade 1C+) GCS or IPC [Geerts. Chest.Sept.2004/ p371S/c1/line 1-8] [Geerts/ p338S/c1/Abstract/ line 4-8] In the 2004 guidelines on venous thromboembolism prophylaxis endorsed by the ACCP, Geerts and coworkers reviewed evidence from 11 studies on the use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in patients with general medical conditions1 ACCP Grade 1A treatment options for deep vein thrombosis (DVT) prophylaxis in general medical patients with clinical risk factors for DVT/PE (including active cancer, bed rest, heart failure, severe lung disease, prior DVT/PE, sepsis, acute neurologic disease, or IBD)1 LMWH Low-dose UFH The investigators assigned a Grade of 1A to 2 for treatment options, defined as follows:1 Grade 1: Benefits of a given intervention are certain to outweigh the risks, burdens, and costs of the intervention Grade 2: Less certainty that the benefits outweigh the risks, burdens, and costs Methodological quality of evidence subcategorized by letters A-C A: Randomized clinical trials (RCTs) with consistent results B: RCTs with inconsistent results C: Observational studies, generalizations from single patient group in an RCT compared to a similar patient group not in the RCT. More compelling evidence in this category is graded C+ [1/Geerts. Chest.Sept.2004/ p371S/c1/line 1-8] [1/Geerts/ p338S/c1/Abstract/ line 4-8] 1A is the highest possible grade Indicates that benefits outweigh risks, burdens, and costs, with consistent RCT level of evidence Geerts WH et al. Chest. 2004;126(suppl):338S-400S ___________________________________________________________________________________ Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl):338S-400S.

NCCN Practice Guidelines in VTE Disease
At Risk Population Initial Prophylaxis Continue Prophylaxis After Discharge ? Prophylactic anticoagulation therapy (category 1) + sequential compression device (SCD) Adult patient Diagnosis or clinical suspicion of cancer Inpatient NO Relative contra-indication to anticoagulation treatment Mechanical prophylaxis (options) - SCD - Graduated compression stockings YES Modifiable risk factors: Lifestyle, smoking, tobacco, obesity, activity level/exercise RISK FACTOR ASSESSMENT Age Prior VTE Familial thrombophilia Active cancer Trauma Major surgical procedures Acute or chronic medical illness requiring hospitalization or prolonged bed rest Central venous catheter/IV catheter Congestive heart failure Pregnancy Regional bulky lymphadenopathy with extrinsic vascular compression AGENTS ASSOCIATED WITH INCREASED RISK Chemotherapy Exogenous estrogen compounds - HRT - Oral contraceptives - Tamoxifen/Raloxifene - Diethystilbestrol Thalidomide/lenalidomide

Inpatient Prophylactic Anticoagulation Therapy LMWH - Dalteparin 5,000 units subcutaneous daily - Enoxaparin 40 mg subcutaneous daily - Tinzaparin 4,500 units (fixed dose) subcutaneous daily or units/kg subcutaneous daily Pentasaccharide - Fondaparinux 2.5 mg subcutaneous daily Unfractionated heparin 5,000 units subcutaneous 3 times daily

Relative Contraindications to Prophylactic or Therapeutic Anticoagulation Recent CNS bleed, intracranial or spinal lesion at high risk for bleeding Active bleeding (major): more than 2 units transfused in 24 hours Chronic, clinically significant measurable bleeding > 48 hours Thrombocytopenia (platelets < 50,000/mcL) Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis) Recent major operation at high risk for bleeding Underlying coagulopathy Clotting factor abnormalities - Elevated PT or aPTT (excluding lupus inhibitors) - Spinal anesthesia/lumbar puncture High risk for falls

Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ?
“Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation” Lyman GH et al. J Clin Oncol (25) 2007; 34:

Incidence and Relative Risk of High-Grade VTE with Bevacizumab
Tumor Type No. Studies Bevacizumab Control Incidence RR Overall 13 235/3795 134/3167 6.3 1.38 Colo-rectal 4 96/1315 50/1128 7.3 1.56 NSCLC 78/1228 41/862 6.6 1.24 Breast Cancer 2 20/594 13/561 3.9 1.47 Renal Cell 1 7/337 2/304 2.0 2.86 Mesothelioma 9/53 5/55 17.0 1.89 Pancreatic Cancer 24/268 23/257 9.0 1.00 SR Nalluri et al. JAMA 2008;300(19):

Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? “Routine prophylaxis is not recommended.” “Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis.” Lyman GH et al. J Clin Oncol (25) 2007; 34:

Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ?
All patients should be considered for thromboprophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Mechanical methods should not be used as monotherapy. Prophylaxis should continue for at least 7-10 days post-op. Prolonged prophylaxis may be considered for cancer with high risk features. Lyman GH et al. J Clin Oncol (25) 2007; 34:

Compliance With ACCP VTE Prophylaxis Guidelines Is Poor
Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group 9.9% 6.7% 35,124 62,012 5,000 10,000 70,000 Number of patients At risk for DVT/PE Received compliant care 15.3% 12.7% 52.4% 2324 9175 1388 Orthopedic Surgery At-risk Medical Conditions General Surgery Urologic Surgery Gynecologic Surgery [Yu.AHA.May [poster]p1/Fig 1, Fig 2] [1/Yu.AHA.May [poster]p1/Fig 1, Fig 2] A study by Yu and colleagues showed that even when risk is recognized, the thromboprophylactic strategy chosen may be inadequate The study assessed compliance with the 2001 ACCP guidelines for prophylaxis for DVT and PE. The authors looked at records from more than 120,000 adult hospital admissions between January 2001 and March 20051 Orthopedic surgery patients (n=2324) had the highest rate of compliance, 52.4%1 The rate of compliance for patients with at-risk medical conditions (n=62,012) was 15.3%. For general surgery patients (n=35,124), the rate of compliance was 12.7%1 For urologic (n=1338) and gynecologic (n=9175) surgery patients, the rates of compliance were 9.9% and 6.7%, respectively1 Overall, only 23.4% of patients received some form of prophylaxis and only 13.3% of patients received guideline-recommended prophylaxis1 Thus, only about a quarter of patients received prophylaxis at all, and of those only about half received the prophylaxis recommended by ACCP guidelines for patients with their condition1 Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based on the 6th American College of Chest Physicians (ACCP) guidelines. HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 _______________________________________________________________________________ Yu H-T, Dylan ML, Lin J, Dubois RW. Prophylaxis of venous thromboembolism: do providers follow guidelines [poster]? Presented at the American Heart Association 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, May 7-9, 2006; Washington, DC.

Reasons for Inadequate Duration of VTE Prophylaxis
Started Late Started late & Ended Early Ended Early At-Risk Medical (n=5,994) 1,347 (22.5) 2,961 (49.4) 1,686 (28.1) Abdominal Surgery (n=3,240) 824 (25.4) 1,764 (54.4) 652 (20.1) Urologic surgery (n=158) 18 (11.4) 73 (46.2) 67 (42.4) Gynecologic surgery (n=163) 13 (8.0) 43 (26.4) 107 (65.6) Neurosurgery (n=250) 66 (26.4) 125 (50.0) 59 (23.6) HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76

Use of Thromboprophylaxis
Predictors of the Use of Thromboprophylaxis Effect Odds Ratio (95% CI) Malignancy 0.40 Others Infection Bleeding Risk Gender Hospital Size Age LOS Cardiovascular Disease Internal Medicine Respiratory AMC Duration of Immobility VTE Risk Factors Kahn SR et Al. Thromb Res 2007; 119: Odds Ratio

Unfractionated Heparin Prophylaxis: BID vs TID—What Works, What Doesn’t?
Meta-analysis: 12 RCTs DVT, PE, all VTE events, Bleeding Proximal DVT plus PE BID VTE event rate: 2.34 events per 1,000 patient days TID event rate: 0.86 events per 1,000 patient days P=0.05 NNT 676 hospital prophylaxis days with UFH TID to prevent 1 major bleed with 1,649 hospital prophylaxis days of TID dosing King CS et al. CHEST 2007;131:

Heparin, Low Molecular Weight Heparin Prophylaxis
Meta-analysis 36 randomized controlled trials 23,000 hospitalized medical patients UFH 5,000 units TID is more effective in preventing DVT than UFH BID Low molecular weight heparin is 33% more effective than unfractionated heparin in preventing DVT RR for DVT 0.68 (p=0.004) LMWH vs UFH DVT Risk Study Reduction (95% CI) Weight % Harenberg et al, ( ) Turpie et al, ( ) Dumas et al, ( ) Bergmann & Neuhart ( ) et al, 1996 Harenberg et al, ( ) Lechler et al, ( ) Hillbom et al, ( ) Kleber, et al ( ) Diener et al, ( ) Overall (95% CI) ( ) Risk Ratio LMWH Better LMWH Worse Wein L et al. Arch Intern Med. 2007;167:

BWH/DFCI Partners Cancer Care Experience
Consecutive patients, < 60 days 2 Nursing units LOS ranged from 3 days to 31 days Number of days where doses were omitted ranged from to 6 days

VTE Incidence: More Common in the Outpatient Setting
Medical records of residents (n=477,800) 587 VTE events (104 per 100,000 population) 30 Day recurrence 4.8 % Patients receiving prophylaxis during high risk periods VTE Event Location Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):

Thrombosis in Malignancy 7TH ACCP Consensus Conference Recommendations
Initial Phase 5-7 days Dalteparin 200/kg q24h (GRADE 1A) Chronic Phase Continue anticoagulation (warfarin or LMWH) long-term or until malignancy resolves (GRADE 1C) days 3 - 6 mos 6 mos - indefinite Subacute Phase 3 - 6 months Dalteparin* 150 units/kg q24h (GRADE 1A) * Dalteparin Approved for Extended Treatment to Reduce the Recurrence of Blood Clots in Patients with Cancer Buller HR, et al. Chest 2004; 126 (suppl 3): 401s-428s

Warfarin vs. Dalteparin for VTE Treatment in Malignancy
Recurrent Thrombosis Dalteparin: 9.0% of 336 Warfarin: % of 336 Dalteparin: 200 units/kg/day x 1 mo, then 150 units/kg/day Warfarin dosed to INR 2-3 Duration: 6 months 25 20 15 10 5 P=0.002 Oral anticoagulant Probability of Recurrent Venous Thromboembolism (%) Dalteparin Days after Randomization No. at Risk Dalteparin Oral anticoagulant Lee AY et al. New Engl J Med 2003; 349: 118

Subgroup Analysis Dalteparin Warfarin P Value
12-month Cumulative Mortality Rate Dalteparin Warfarin P Value Metastatic Disease (n=452) 72% 69% P = 0.46 Non-metastatic Disease (n=150) 20% 36% P=0.03 Failures defined as recurrent DVT. Lee AY et al. J Clin Oncol. 2005; 23: 119

Dalteparin Cost Effectiveness in Recurrent VTE
Cost Parameter Dalteparin (n=338) Warfarin (n=338) Drug 2852 269 Laboratory 303 437 Diagnostic Tests 253 267 Unscheduled Visits 286 300 Transfusions 143 208 Major bleeding 97.5 92.3 VTE Recurrence 228 429 Mean Cost Per Patient 4162 2003 Dranitsaris G. Pharmacoeconomics 2006; 24(6):

NCCN Practice Guidelines—Venous Thromboembolic Disease
Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis Immediate LMWH - Dalteparin (200 units/kg subcutaneous daily) - Enoxaparin (1 mg/kg subcutaneous every 12 hrs) - Tinzaparin (175 units/kg subcutaneous daily) Pentasaccharide - Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [ lg]; 10 mg [>100 kg] subcutaneous daily Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to x control)

NCCN Practice Guidelines—Venous Thromboembolic Disease
Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis Long Term LMWH is preferred as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR ) Duration of Long Term Therapy Minimum time of 3-6 mo for DVT and 6-12 mo for PE Consider indefinite anticoaugulation if active cancer or persistent risk factors For catheter associated thrombosis, anticoagulate as long as catheter is in place and for 1-3 mo after catheter removal

What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE ?
LMWH is the preferred approach for the initial 5-10 days. LMWH, given for at least 6 months, is the preferred for long-term anticoagulant therapy. After 6 months, anticoagulation therapy should be considered for select patients. For CNS malignancies, elderly patients anticoagulation is recommended with careful monitoring and dose adjustment. Lyman GH et al. J Clin Oncol (25) 2007; 34:

Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? “Anticoagulants are not recommended to improve survival in patients with cancer without VTE.” Lyman GH et al. J Clin Oncol (25) 2007; 34:

Antithrombotic Therapy Practices in U.S. Hospitals
Survey of 38 U.S. Hospitals n=939 DVT or PE 50% patients reached INR >2 for 2 consecutive days Therapy n (%) LMWH 527 (56.1%) UFH 562 (59.8%) UFH SC 78 (8.3%) DTI 6 (0.6%) Tapson V et al. Arch Intern Med 2005

Self-Managed Long Term LMWH Therapy
2212 patients with proximal vein thrombosis assessed for eligibility 1475 excluded for anticoagulant violations or inability to give written consent 737 Randomized 369 assigned to LMWH 369 assigned to usual care with heparin and warfarin 3 lost to follow-up 1 withdrew consent 3 lost to follow-up 5 withdrew consent 369 included in analysis 369 included in analysis Hull R. Am Jour Med 2007; 120:72-82

Self-Managed Long Term LMWH Therapy
Outcomes Tinzaparin (n=369) Usual Care (n=368) Absolute Difference (95% CI) p-value New VTE at 3 Mos 18 (4.9) 21 (5.7) -0.8 ( ) NS New VTE at 12 Mos 33 (8.9) 36 (9.8) -0.8 ( ) All Bleeding 48 (13.0) 73 (19.8) -6.8 ( ) p=.011 Major Bleeding 12 (3.3) 17 (4.6) -1.4 ( ) Minor Bleeding 56 (15.2) -5.5 ( ) p=.022 Stratified Bleeding-High Risk 31/144 (21.5) 39/146 (26.7) -5.2 (-15%-4.6%) Stratified Bleeding-Low Risk 17/225 (7.6) 34/222 (15.3) -7.8 ( %) p=.01 Thrombocytopenia (<150) 9 (2.4) 1.6 ( ) Bone Fracture 4 (1.1) 7 (1.9) -0.8 ( ) Hull R. Am Jour Med 2007; 120:72-82

LMWHs and Bleeding in Patients with Renal Dysfunction
Dosage adjustments for renal dysfunction Lim W et al. Ann Intern Med 2006; 144:673-84

Barriers to Long-term Use of LMWH for
Treatment of Cancer-associated VTE Initial treatment LMWH for 3-6 months % UFH/LMWH for 5-7 days % followed by warfarin Reasons LMWH not used long-term Not covered by medical insurance % Physician preference % Patient refused long-term injections % History of HIT % Severe renal insufficiency % Wittkowsky AK. J Thromb Haemost. 2006; 4:

Examine your current practices of VTE prophylaxis and treatment
Conclusions Examine your current practices of VTE prophylaxis and treatment Review available guidelines as a benchmark Consider the use of a pharmacologic or mechanical intervention Evaluate use of Reminder or Risk Scoring Systems Utilize the regimen providing the best efficacy in reducing events and offering best compliance Follow-up with patients to monitor and avoid adverse events and to ensure optimal outcomes

Pharmacologic Prophylaxis of DVT in Special Populations
A Year 2009 Update for The Health System Pharmacist Pharmacologic Prophylaxis of DVT in Special Populations 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

Objectives Differentiate data with various LMWHs in special populations Review appropriate dosing and monitoring of LMWHs in patients with obesity and renal failure Discuss cautions of using emerging agents in special populations

Risk of Inadequate Therapy in High Risk Patients
524 VTE Patients Active Cancer in 26% Only 1/3rd on LMWH monotherapy Weight > 100Kg in 15% Under-dosing of LMWH by > 10% 36% of > pts 100Kg 8% of pts < 100Kg (p < 0.001) CrCL < 30mL/min in 5% LMWH tx in 67% Cook LM, et.al. J Thromb Hemost 2007;5;

8th 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.

Pharmacokinetic Characteristics of Low Molecular Weight Heparins
Lipid solubility LOW Plasma protein binding HIGH Tissue binding LOW Volume of Distribution 5-7 L Logical conclusion: IBW may be a better predictor of LMWH dosing than TBW

LMWH: Maximum Weights Studied
Kinetic Studies Clinical Trials Dalteparin 190 kg 128 kg* Enoxaparin 144 kg 194 kg Tinzaparin 165 kg 88 kg Fondaparinux 175.5 kg * max dose 18, ,000 IU/day Duplaga BA et al. Pharmacotherapy 2001; 21: Synergy Trial: Data on File Davidson, et al. J Thromb Haem 2007;5:1191-4

LMWH Pharmacokinetics in Obesity
N= 30 (< 100kg) 35 ( kg) Tinzaparin 175 IU/kg SQ single dose Actual body weight correlates best with anticoagulant response to LMWHs as measured by anti-factor Xa levels Clin Pharmacol Ther 2002;72: Thromb Haemost 2002;87:

Dalteparin Pharmacokinetics in Obesity
Dose: 200 U/kg qd Duration: routine Obese (BMI > 30) Normal (BMI < 30) N 10 TBW (mean +/- SD) /- 22.1 69.7 +/- 9.3 LBW (mean +/- SD) 64.1 +/- 12.3 66.1 +/- 8.7 Mean Vd (l) 12.39 8.36 Mean CI (l/hr) 1.30 1.11 Yee JYV, Duffull SB. Eur J Clin Pharmacol 2000; 56:293-7.

Dalteparin Pharmacokinetics In Obesity
Correlation Coefficient Between Vd and: LBW 0.05 ABW 0.52 TBW 0.55 Correlation Coefficient Between Cl and: LBW 0.01 ABW 0.32 TBW 0.39 Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7. Conclusion: TBW may be a better predictor of LMWH dose than IBW

Dalteparin Pharmacokinetics In Obesity
Dose: 200 U/kg qd Duration: 5 Days Max TBW: 190kg <20% of IBW 20-40% of IBW > 40% of IBW N 13 14 10 Mean Dose (U) 14,030 17,646 23,565 Ant-Xa Activity (u/ml) Day 3 Peak 1.01 0.97 1.12 NS Day 3 Trough 0.12 0.11 0.11 NS Conclusion: 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.

LMWH Safety and Effectiveness Using TBW Enoxaparin In ACS (ESSENCE/TIMI IIb)
16.1% 14.3% P=0.13 1.6% 0.4% Obese: BMI > 30mg/m2 Enox max weight 158 kg Spinler SA et al. Am Heart J 2003; 146:33-41

Safety 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) N Mean Dose Full dose +/- 5% QD Dosing BID Dosing 90-99 40 19,300 39 24 16 52 20,850 49 25 17 41 21,470 21 26 15 24,300 22 9 25,250 8 10 6 26,920 5 4 > 150 28,280 Failures defined as recurrent DVT. Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2.

Fondaparinux In Obesity Results From the Matisse Trials
< 50kg: 5mg qd 50-100kg: 7.5mg qd > 100kg: 10mg qd Enoxaparin: (Matisse DVT) 1mg/kg q12h Heparin: (Matisse PE) Adjusted per aPTT No weight-dependent difference in efficacy or safety Davidson BL et al. J Thrombosis Haemost 2007; 5:

Body Weight and Anti-Xa Activity for Prophylactic Doses of LMWH
N = 17 patients and 2 volunteers Enoxaparin 40mg SQ x1 dose AntiXa levels hourly x10 hours Regression line 95% CI for line 95% CI for data points 200 150 100 50 Area under the curve for 10 h Body Weight (kg) Frederiksen SG et al. Br J Surgery 2003; 90:547-8

Fixed Dosing For VTE Prevention
Dalteparin: Fixed Dosing For VTE Prevention Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill) BMI (kg/m2) Patients % Favors Dalteparin Favor Placebo < > Overall Prevent Trial 0.01 0.1 0.55 1.0 10.0 Relative Risk Dalteparin 5,000 units daily was similarly effective in obese and non-obese patients (except pts with BMI>40) with no observed difference in mortality or major bleeding Kucher N et al. Arch Int Med 2005;165:341-5.

Enoxaparin VTE Prophylaxis in TKA/THA/Trauma
31.8% p<0.001 16.7% N: Dose: 40 mg qd Obese : BMI>32kg/m2 Samama MM et al. Thromb Haemost 1995; 73:977.

Enoxaparin: VTE Prophylaxis in Bariatric Surgery
5.4% p<0.01 0.6% 30mg bid: n=92 BMI 51.7kg/m2 40mg bid: n=389 BMI 50.3kg/m2 Scholten Obes Surg 2002; 12:19-24.

Dalteparin in Morbid Obesity: Bariatric Surgery
200 180 160 140 120 P=0.031 P=0.052 N=135 Bariatric Surgery Mean Weight: 148.8Kg Mean BMI: 53.7 Dalteparin: 7,500 IU daily P=0.444 Body Weight (kg) Under target value <0.2 IU/mL n-=41 Target value < IU/mL n-=81 Over target value <>0.5 IU/mL n=13 Anti-factor Xa level Number of patient (%) Body weight (kg) Below target value (<0.2 UI/ml) 41 (30.4%) 159.4 ± 35.8 Target value (0.2–0.5 UI/ml) 81 (60.0%) 145.7 ± 28.4 Above target value (>0.5 UI/ml) 13 (9.6%) 134.6 ± 24.2 p value 0.0152 Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print]

LMWH in Obesity: Summary
Treatment: in controlled trials, LMWH dosing has been based on TBW (max kg) Dalteparin Dose based on TBW PI recommends dose capping Recent clinical data supports TBW dosing QD or BID dosing Enoxaparin Dose capping NOT recommended BID dosing preferred Tinzaparin Dose based on TBW, NO dose adjustment or capping Anti-Xa monitoring not necessary for TBW < 190kg Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients) Nutescu E, et.al. Ann Pharmacother; 2009; in press.

8th 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 accumulate Use a lower dose Monitor the drug level or anticoagulant effect Geerts WH. Chest 2008;133(suppl):381S-453S.

LMWH 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 doses Enoxaparin “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

Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n)
Recent Meta-Analysis of LMWHs and Bleeding In Patients With Severe Renal Dysfunction Study; year Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n) Peto OR (95%, CI) Weight (%) Collet, et al; 2001 0/28 1/83 2.01 0.26 (0.00 – 23.94) Paulas, et al; 2002 0/51 3/149 6.02 0.26 (0.02 – 3.50) Siguret, et al; 2000 0/17 0/13 Not estimable Chow, et al; 2003 0/5 Khazan, et al. (adj.); 2003 0/10 3/42 4.78 0.28 (0.01 – 5.16) (Prophylactic) 2003 3/36 3/47 14.77 1.33 (0.25 – 7.05) (Therapeutic) 2003 2/17 3/61 8.62 3.09 (0.35 – 27.31) Spinler, et al; 2003 5/69 74/3,432 15.93 10.05 (2.02 – 49.98) Green, et al; 2005 1/18 0/20 2.66 8.26 (0.16 – ) Kruse & Lee; 2004 0/50 1/120 2.22 0.24 (0.00 – 17.90) Macie, et al; 2004 2/7 6/201 2.68 (19.61 – 48,752.07) Peng, et al; 2004 0/7 0/43 Thorevska, et al; 2004 7/65 11/171 35.56 1.85 (0.63 – 5.40) Bazinet, et al; 2005 1/36 2/160 4.75 2.74 (0.15 – 51.73) Total (95%, CI) 21/416 107/4,555 100.00 2.25 (1.19 – 4.27) Dosage adjustments for renal dysfunction Favors ↓’ed Favors ↑’ed bleeding Lim W, et al. Ann Intern Med. 2006;144:

Sanderink GJCM. Thromb Res 2002;105:225-31.
Enoxaparin PK and PD in Renal Impairment Result: Tmax: 3-4 hours Amax: 10-35% higher in RI groups CI/F”linearly correlated with CrCl Day 4 CL/F (L/h) Half-life (h) AUC (0-24) (h●IU/mL) Normals 0.98 6.87 Mild RI 0.87 9.94 20% ↑ Moderate RI 0.76 11.3 21% ↑ Severe RI 0.58 15.9 65% ↑ Sanderink GJCM. Thromb Res 2002;105:

LMWH 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/min Anti-Xa monitoring Doses “appeared safe” Further prospective evaluation needed 56 UA pts with CrCl <60 ml/min Enoxaparin dose empirically  and anti-Xa level measured after 3rd dose CrCl (ml/min) <30 (n = 28) >30 and <60 (n =28) Age 76+/-3 73+/-3 Enoxaparin (mg/kg/12h) 0.64 0.84 Anti-Xa (IU/ml) 0.95 Collet JP et al. International J Cardiol 2001;80:81-2.

Clinical Use Of Recommended Enoxaparin Dosage in Renal Impairment
N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h 1.0. 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 6 5 4 3 2 1 PEAK ANTI-Xa LEVELS TROUGH ANTI-Xa LEVELS Antifactor X1 Level (U/mL) Number of Patients First dose Subsequent doses (second and third) Median % interquartile range Trough Antifactor Xa Level (U/mL) Trough Antifactor Xa Level (U/mL) Lachish T et al. Pharmacotherapy 2007; 27:

Tinzaparin 175 U/kg Peak Anti-Xa Levels According to Renal Function
No correlation between peak anti-Xa activity and Clcr No accumulation of Anti-Xa activity after 10 days of therapy Siguret V et al. Thromb Haemost 2000;84:800-4.

Pharmacokinetics of Prophylactic Enoxaparin vs Tinzaparin
Enoxaparin 40mg qd or Tinazaparin 4500 IU qd N = 52 patients Mean age = 87.7 yrs Mean wt = 52.3kg Mean Clcr = 34.7ml/min Mahe I et al. Thromb Haemost 2007; 97:581-6.

Dalteparin 100 U/kg q12h Peak Anti-Xa Levels According to Renal Function
No difference in peak anti-Xa activity between normal patients and patients with renal impairement 1.5 1.0 0.5 Clcr > < 40 Mean peak anti-Xa level after 5-6 doses Antifactor Xa Level (U/mL) x x Subjects without Renal impairment Subjects with Renal impairment N=11 N=11 Shprecher AR et al. Pharmacotherapy 2005; 25:

Pharmacokinetics of Prophylactic Doses of Dalteparin
N = 115 elderly (age > 65) pts with acute medical illness and elevated SCr Tx: dalteparin 5000 U or 2500 U SQ qd (risk-based) for VTE prophylaxis Renal Failure Mild (n=12) Moderate (n=73) Severe (n=24) CrCL (ml/min) 60-89 30-59 <30 Day 6 peak anti-Xa 0.030 0.033 0.048 Minor Bleeding 3 Major Bleeding P=0.72 No evidence of accumulation of anti-Xa activity No relationship between the degree of renal impairment and peak anti-Xa level on Day 6 No association between creatinine clearance and anti-Xa levels Tincani E et al. Haematologica 2006; 91:976-9.

Douketis, et al. Arch Intern Med. 2008 Sep 8;168(16):1805-12.
Dalteparin Thromboprophylaxis in Critically Ill Patients with Severe Renal Insufficiency: The Direct Study N=138 critically ill patients CrCl < 30 ml/min Mean CrCL 18.9ml/min Dalteparin 5000 IU sc daily Serial anti Xa levels measured on days 3, 10, and 17 Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mL Results: The median duration of dalteparin exposure was 7 (4-12) days No patient had a trough anti Xa level > 0.4 IU/ml Based on serial measurements peak anti-Xa levels were 0.29 to 0.34 IU/mL trough levels were lower than 0.06 IU/mL Douketis, et al. Arch Intern Med Sep 8;168(16):

Dosing of LMWHs In Renal Impairment Recommendations
FOR CrCL < 30 ml/min Enoxaparin: Prophylaxis doses: 30 mg sq QD Treatment doses: 1mg/Kg sq QD Dalteparin and Tinzaparin: no specific dosing guidelines No or lower degree of accumulation expected Anti-Factor Xa activity monitoring FOR CrCL mL/min No specific recommendations Concern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?) Monitoring anti-Xa ? Nutescu E, et.al. Ann Pharmacother; 2009; in press.

Unresolved Issues in Renal Dosing of LMWHs
CrCl (mL/min) Recommendations < 30 Dose 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

Anti-Xa Activity Level Monitoring
Enoxaparin 1mg/kg SQ pharmacokinetic profile Peak (goal ~ U/ml) at 3-4 hrs Trough (goal < 0.5 U/ml) at hrs Laposata et al. Arch Pathol Lab Med. 1998;122:

ANTI-Xa MONITORING: Recommendations
Level 3 Evidence: (isolated anecdotal studies or the consensus of experts) Laboratory monitoring using an anti-Xa assay MAY be of value in certain clinical settings Use peak levels 4 hrs after SQ dose Through levels in renal impairment maybe preferred Use chromogenic, not clot-based assays Peak: for BID dosing: U/ml for QD dosing: U/ml Through: < 0.4 U/ml Laposata et al. Arch Pathol Lab Med. 1998;122: Nutescu E, et.al. Ann Pharmacother; 2009; in press.

Fondaparinux Pharmacokinetics
100% bioavailable Cmax = 0.34 µg/mL (SD: 0.04) Tmax = 1.7 h (SD: 0.4) T1/2 = 17.2 h (SD: 3.2) Elimination = RENAL 0.35 0.3 0.25 concentration (µg/mL) Pentasaccharide* 0.2 0.15 0.1 0.05 Plasma levels of Pentasaccharide* rise rapidly following subcutaneous administration.1 Peak plasma level (Cmax) are reached within two hours of dosing (Tmax) and significant levels (Cmax/2) within 25 minutes; this ensures a rapid onset of antithrombotic activity following dosing of Pentasaccharide*.1 The rapid rise in plasma level of Pentasaccharide* through the 24 hours following dosing allows once-daily dosing.1 The low inter and intravariability of Pentasaccharide’s pharmacokinetics allowed a single regimen to be used for all patients included in Phase III trials for VTE prophylaxis.1,2,3,4,5 *fondaparinux Donat F, Duret JP, Santoni A, Cariou R, Neciari J, Magnani H et al. Pharmacokinetis of Org31540/SR90107A in young and elderly healthy subjects: a highly favourable pharmacokinetic profile. Thromb Haemost. July Abstract P3094 Lassen M. The Ephesus Study: Comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) after elective hip replacement surgery Blood J Am Soc Hem. 2000; 96(11): Abstract 2109 Eriksson BI.The Penthifra Study: Comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) after hip fracture surgery Blood J Am Soc Hem ; 96(11): Abstract 2110 Turpie G. The Pentathlon 2000 Study: Comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) after elective hip replacement Blood J Am Soc Hem. 2000; 96(11): Abstract 2112 Bauer K. The Pentamaks Study: Comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) after elective major knee surgery Blood J Am Soc Hem. 2000; 96(11): Abstract 2111 4 8 12 16 20 24 28 32 36 Time (h) Donat F, et al. Clin Pharmacokinetics 2002; 41 (suppl 2):1-9.

Fondaparinux Use in Patients with Impaired Renal Function
Total clearance lower than in patients with normal renal function Mild impairment ~25% Moderate impairment ~40% Severe impairment ~55% Fondaparinux: PI

Full-dose Fondaparinux Risk Of Major Bleeding
4.8% 3.8% Incidence (%) 2.4% n=504 1.6% n=1288 n=1565 Clcr 80 mL/min Clcr 50–80 mL/min Clcr 30–50 mL/min Clcr < 30 ml/min Data on file, GlaxoSmithKline

Influence of Renal Function Fondaparinux vs Enoxaparin in ACS
OASIS-5: Fondaparinux 2.5mg qd vs enoxaparin 1mg/kg q12h for 2-8 days Fox KAA et al. Ann Intern Med 2007; 147:

Electronic Alerts: Future Horizons
A Year 2009 Update for The Health System Pharmacist Electronic Alerts: Future Horizons 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 Bouve’ College of Health Sciences Northeastern University Boston, MA

Background Past 10 years the prevention of medication errors has become a primary focus in healthcare In 1995 Bates et al. published landmark study indicating 28% of hospital admissions are attributed to preventable medication errors The IOM report “To Err is Human” have led to increased research and development of both medical informatics and computerized alerting systems Bates DW et al. JAMA 1995;274:

CPOE : Friend or Foe? Recently, institutions are beginning to critically assess electronic systems, such as CPOE VA Medical Center in Salt Lake City: 74% of medication errors occur during prescribing 11% during administration 0% during transcription Bates et al. study: 56% of medication errors - prescribing 24% of medication errors – administration 6% of medication errors – transcription Nebeker JR et al. Arch of Intern Med 2005;165:

CPOE : Friend or Foe? VA Medical Center attributed low error rates during the transcription and administration to information system upgrades such as: Bar code technology during administration, EMAR and computerized drug-drug interaction and allergy screening Concluded that their systems are working as designed but lack decision support within CPOE leading to high error rates during prescribing Nebeker JR et al. Arch of Intern Med 2005;165:

CPOE Alerts Institutions that utilize decision support and computerized alerts during prescribing have reported high rates of physician override A study conducted at BIDMC reported that 94.2% of computerized alerts were overridden Reviewers concluded of the 189 rules studied, 36.5% of the rules were invalid and agreed with the physician’s decision 97.9% of the time Weingart SN et al. Arch of Intern Med 2003;163:

Saving CPOE from Extinction
CPOE must evolve to keep up with the growing demand for effective medical informatics and technology solutions Next generation of CPOE will utilize algorithms that take into account patient specific factors and generate prescribing recommendations to providers One area in which CPOE has proven beneficial is VTE prophylaxis

Medical Error Rates Two errors per day = 99% proficiency level
If 99% was good enough: How do we transform health care into a high reliability industry? Airline industry = 2 unsafe landings per day Mail industry = 16,000 pieces of mail lost every hour Banking industry = 32,000 checks deducted from the wrong account per hour Leape LL. JAMA. 1994;272:

Background At Brigham and Women’s Hospital, we have initiated a series of trials aimed at increasing prophylaxis by: Changing MD behavior and Improving the implementation of prophylaxis strategies

Types of Interventions
Electronic computer generated alerting systems Efficacy of these alerting systems have been studied in: RCT trial of a 1-screen alert Cohort study of a 3-screen alert

First Generation Electronic Alerts
BWH utilizes BICS (Brigham Integrated Computing System) for all order entry functions Admitting records, demographic information, lab results, medication orders, etc. VTE group utilized computer system to screen all patients admitted to the hospital for High Risk VTE status

First Generation Alert: Development
Aim: to increase rate of prophylaxis in patients at risk for DVT and PE Developed computer program to detect and identify which patients were at risk Alert the responsible physician of high risk patient (via e alert) and offer opportunity to order appropriate prophylaxis

Study Schema All Adult Patients DVT Risk Score > 4 YES Presence of
Prophylaxis NO Generate Alert

Definition of “High Risk”
VTE risk score ≥ 4 points: Cancer 3 (ICD codes) Prior VTE 3 (ICD codes) Hypercoagulability 3 (Leiden, ACLA) Major surgery 2 (> 60 minutes) Bed rest 1 (“bed rest” order) Advanced age 1 (> 70 years) Obesity 1 (BMI > 29 kg/m2) HRT/OC 1 (order entry)

Randomization VTE Risk Score > 4 No Prophylaxis N = 2506 Control
Intervention Single Alert n = 1255 Control No Alert n = 1251 Kucher N, et al. NEJM 2005;352:

Physician Notification of Alerts
For patients randomized to the intervention arm, their responsible physician received an electronic alert at the moment they logged into the CPOE system. Once the physician clicks on the alert they are presented with multiple options.

First Generation Computerized Alerts for VTE Prevention
Utilization of computer generated alerts to house staff reduced the incidence of VTE by 41% VTE prophylaxis was prescribed in 33.5% of patients in the intervention group Following study conclusion a follow up cohort study was conducted Kucher N, et al. NEJM. 2005;352:

Second Generation: Electronic Computer Generated Alerts

BWH VTE Alerts: The Future
Goals: Engage the house officer with an interactive alert to increase acceptance and gain feedback Update the DVT prophylaxis template to meet current practice guidelines Provide real-time knowledge links

Interactive Techniques
Provide objective data to the house officer that this alert positively impacts patient outcome Create opportunity to capture rationale for declining alert Hypothesized that many physicians fear a risk of bleeding with anticoagulation Provide a final opportunity to order mechanical prophylaxis Alert attending physician if alert is not acknowledged after 24 hours

DVT Alert Screen This alert screen is identical to the NEJM trial except of the inclusion of educational information about the NEJM article. A MD may also choose to review alert details, which

Rule Logic – Alert Details
Which displays the patient specific criteria and rule logic, that qualify the patient as high risk.

Option A After reviewing the alert details The MD can then proceed to order DVT prophylaxis via an order set template

The template allows the MD to select mechanical, pharmacological or combination prophylaxis.

Option C or “Done” If at any point the user selects “exit”, “done” or “escape” they are presented with a screen that prompts for a reason for declining the alert

The reasons provided are Patient is already receiving anticoagulants, risk of bleed outweighs benefits of anticoagulant therapyk, pt is CMO, Schedule of surgery or other. If med enters other, they must enter a reason that is at least 15 characters long. Once a reason has been selected….

The user has a final opportunity to order mechanical prophylaxis via a second order entry template. The user is also provided with additional point of care information that mechanical prophylaxis does not increase risk of bleeding,

Escalation and Timing of Alerts
Alerts should be set up to generate each day at 8:30 AM If an alert was not acknowledged after 24 hours the attending physician on record should be text paged. These enhanced VTE alerts are set to fire at 8:30am every day which corresponds to peak prescribing times and morning rounds and should the MD ignore the alert for >24 hours, the attending MD is then notified via text page.

Quality Assurance Weekly reports are reviewed
Allows core team to review all aspects of the alerts including: Type of action taken Rate of overrides Rational for declining the alerts Results coming soon

Pharmacy/Physician Collaboration
Alerts Pharmacy/Physician Collaboration Human Alerts

VTE Prophylaxis: hALERT
Multicentered RCT of human alerts (hALERT). Objective: to recruit hospitals that differ from BWH re: IT, community vs. academic, urban vs. suburban/rural, location within USA. Can a human alert be more effective than an electronic alert?

Methodology Patients admitted to the hospital are screen by human for increased VTE risk High risk patients are randomized to alert or no alert Physicians of patients in alert group receive page alerting them of high risk status Records are checked for prophylaxis order 48 hours after alert 90 day follow up for clinically significant VTE and clinically importing bleeding

hALERT: Capturing New Prophylaxis Orders
Enrolled patients must be reexamined in hours to determine whether prophylaxis orders were written. Capturing prophylaxis orders after enrollment applies to both the Intervention Group and to the Control Group.

Human Alert Trial Human (often RN or pharmacist) issues the Alert, not a computer The attending physician, not the intern, receives the Alert Diversity of centers: community, suburban, throughout the USA Will attendings pay more attention than house staff?

Conclusions Changing behavior is challenging
Multi-disciplinary team involvement is critical to successful implementation Need to engage providers and obtain feedback Designing “smart alerts” that include decision support functionality or “human alerts” that require face to face contact may be effective

Electronic Alerts to Prevent Infusion Errors

Patient Case—Infusion Pump Error
Error Description 57 YOM endstage CMP EF = 10% Heart transplant candidate with BIVAD Receiving UFH 900 units per hour (9 mls/hr) New order to reduce Heparin 800 units per 10:22 PM Infusion pump set for 800 mls per hour 8:45 PM aPTT = 75.1 1:13 AM Protamine 25mg 1:28 AM aPTT = >150 3:13 AM aPTT = >150 3:32 AM Protamine 26mg 2 Units PRBC 4:08 AM aPTT = >150 8:21 AM aPTT = 44.4 The following patient case is a classic example of heparin errors that we often see. Patient is a 57 y/o male with endstage cardiomyopathy with biventricular assist device. Patient was receiving UFH at 900 units per hour. A new order was written to reduce the heparin to 800 units per hour. RN programmed infusion pump was set for 800 mls per hour. The RN programs the pump, leaves the room, goes back into the room approximately 1 hour later and the patient had received the entire bag 250 ml bag over less than ½ an hour. So the patient receives an entire 24 hours supply of heparin in ½ hour. These types of errors are usually reported as a “device error”. Our patient did have significant sequale in that he received protamine and PRBC, however did not experience a major bleeding episode.

Medications Causing Harm
Background National Data Heparin has been identified both nationally and internally at BWH as a medication frequently associated with ADE Removed access to different formulations Standardized UFH Concentration Calculate infusion rates in OE Rank Medications Causing Harm 1. Insulin 2. Morphine 3. Heparin 4. Warfarin 5. Potassium 6. Furosemide 7. Vancomycin 8. Hydromorphone 9. Meperidine 10. Diltiazem Unfortunately, cases like this are not a rare exception. Both nationally as defined by MEDMARx and internally here at BWH heparin has been identified as a medication that is frequently associated with causing “harm”. At BWH heparin is routinely associated with medication errors and for quite some time heparin has been the second most likely medication to be associated with an adverse event. In light of these events we in pharmacy tried to decrease events by: Removing access to different formuations Standardized UFH concentrations (25,000/250ml) Even programmed order entry to calculate the rate in an attempt to ellimiate some of the confusion surrounding med calculations which anyone who cares about patient safety will tell you is a real problem. MEDMARXSM The United States Pharmacopoeia (USP)Convention Inc.

UFH Error Analysis: BWH
1 event per 1,000 patients 52% - Administration related 31% - Equipment failure, rate or dosing error 23% - Infusion Pump 6% - Prolonged LOS or significant harm ***Patient Safety Initiative: Hospital invested 3 million dollars in state of the art infusion pumps*** John Fanikos from the pharmacy department in conjuction with Dr. Goldhaber published a paper evaluating medication errors associated with anticoagulation therpay in the hospital. We found that the majority 52.5% of errors are administration related. These errors where often described at “equipment failure, rate or dosing errors”. These resulted in approximately 1 event per patients, which correlates to approximately one error per week. However, only a small % of these ADE were found to result in prolonged LOS or significant patient harm. We know that heparin is not the only IV medication that is associate with significant potential to cause ADE, and hospital admistration invested 3 million dollars in state of the art infusion pump technology in an attempt to increase pt safety. Realizing the Fanikos J et al. Medication Errors associated with anticoagulation therapy in the hospital. Am J Cardiol 2004;94:

Objectives Evaluate impact of “smart” infusion technology on anticoagulation administration To determine if infusion technology equipped with drug libraries may reduce medication errors

Features of the “Smart” Pumps
“Smart” pumps share safety features of older pumps including dose calculation functions, free-flow protection and occlusion alerts “Smart” pumps also equipped with a drug library Provide dose and rate limits on commonly used medications Provide users with overdose and underdose alerts based on predetermined limits defined by the drug library

Methods We programmed the drug library to alert for overdoses or underdoses Alerts where subsequently recorded in the device’s electronic memory, along with the user’s next action We retrospectively reviewed all anticoagulant alerts and the user’s next action for all devices from 10/2003 through 1/2005 Medication Underdose Alert Overdose Alert UFH <300 units/hour >2,800 units/hour Argatroban <0.5 mcg/kg/min >10 mcg/kg/min Lepirudin <5 mg/hour >16.5 mg/hour Bivalirudin <0.2 mg/kg/hour >1.8 mg/kg/hour

Dosing Errors and their Magnitude

Data Entry Errors Frequently Repeated with UFH
27.2 % entry errors User repeated the error Although RN’s Don’t recognize they make mistake.

Alerts by Time of Day

Conclusions The drug library and its alerting system intercept programming errors Despite alerts, data entry errors are frequently repeated by the user The highest alert incidence occurs on weekdays between 2 PM and 4 PM, corresponding to Nursing Shift change

A Year 2009 Update for The Health System Pharmacist The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Program Co-Chairs Edith.

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A Year 2009 Update for The Health System Pharmacist The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Program Co-Chairs Edith.

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Presentation on theme: "A Year 2009 Update for The Health System Pharmacist The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Program Co-Chairs Edith."— Presentation transcript:

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