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The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith.

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Presentation on theme: "The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith."— Presentation transcript:

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

3 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 Welcome and Program Overview

4 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 CEUs) upon completion of this program. 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 CEUs) upon completion of this program. CEU Credit Designation Statement

5 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.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.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.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.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 Generals Report.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 Generals Report.

6 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 Womens Hospital Boston, MA 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 Womens Hospital Boston, MA Distinguished Experts and Presenters John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Womens Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Karen Fiumara, PharmD Medication Safety Officer Brigham and Womens Hospital Adjunct Assistant Professor of Pharmacy Practice Massachusetts College of Pharmacy and Allied Health Sciences Adjunct Assistant Professor of Pharmacy Practice Bouve College of Health Sciences Northeastern University Boston, MA Distinguished Experts and Presenters John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Womens Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Karen Fiumara, PharmD Medication Safety Officer Brigham and Womens Hospital Adjunct Assistant Professor of Pharmacy Practice Massachusetts College of Pharmacy and Allied Health Sciences Adjunct Assistant Professor of Pharmacy Practice Bouve College of Health Sciences Northeastern University Boston, MA

7 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 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

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

9 VTE and CancerA Looming National Healthcare Crisis MISSION AND CHALLENGES 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. MISSION AND CHALLENGES 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.

10 COMORBIDITYCONNECTIONCAPUTICancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder ThrombophiliaSurgery History of DVT OtherCOMORBIDITYCONNECTIONCAPUTICancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder ThrombophiliaSurgery History of DVT OtherSUBSPECIALISTSTAKEHOLDERS Infectious diseases OncologyPHARMACISTSCardiology Pulmonary medicine HematologyOncology/hematology Interventional Radiology HospitalistSurgeonsEMPCPSUBSPECIALISTSTAKEHOLDERS Infectious diseases OncologyPHARMACISTSCardiology Pulmonary medicine HematologyOncology/hematology Interventional Radiology HospitalistSurgeonsEMPCP Comorbidity Connection

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

12 Epidemiology of VTE White R. Circulation. 2003;107:I-4 –I-8.) 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. 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. 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. Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease.

13 Comorbidity Connection ComorbidityConnection Overview Overview

14 Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968 Risk Factor Odds Ratio (95% CI) X2X2X2X2 Age > 75 years Cancer Previous VTE 1.03 (1.00-1.06) 1.62 (0.93-2.75) 2.06 (1.10-3.69) 0.00010.080.02 Acute infectious disease 1.74 (1.12-2.75) 0.02

15 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%. 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. 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 Together, the 8 risk factors accounted for 74% of disease occurrence Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%. 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. 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 Together, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

16 VTE Recurrence Predictors of First Overall VTE Recurrence Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768 Baseline Characteristic Hazard Ratio (95% CI) Age 1.17 (1.11-1.24) Body Mass Index 1.24 (1.04-1.7) Neurologic disease with extremity paresis 1.87 (1.28-2.73) Malignant neoplasm With chemotherapy Without chemotherapy 4.24 (2.58-6.95) 2.21 (1.60-3.06)

17 ICOPER Cumulative Mortality Mortality (%) Days From Diagnosis 17.5% 0 5 10 15 20 25 Lancet 1999;353:1386-1389 714306090

18 Stages of Chronic Venous Insufficiency 1.Varicose veins 2.Ankle/ leg edema 3.Stasis dermatitis 4.Lipodermatosclerosis 5.Venous stasis ulcer 1.Varicose veins 2.Ankle/ leg edema 3.Stasis dermatitis 4.Lipodermatosclerosis 5.Venous stasis ulcer

19 Progression of Chronic Venous Insufficiency From UpToDate 2006

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

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

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

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

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

25 Call to Action for VTE Dr. Galsons 1 st Call To Action Dr. Galsons 1 st Call To Action > 350,000-600,000 Americans suffer VTE annually > 350,000-600,000 Americans suffer VTE annually > 100,000 U.S. deaths per year > 100,000 U.S. deaths per year Negative impact on QOL of survivors Negative impact on QOL of survivors Must disseminate info widely to address gap because were not applying knowledge systematically Must disseminate info widely to address gap because were not applying knowledge systematically Dr. Galsons 1 st Call To Action Dr. Galsons 1 st Call To Action > 350,000-600,000 Americans suffer VTE annually > 350,000-600,000 Americans suffer VTE annually > 100,000 U.S. deaths per year > 100,000 U.S. deaths per year Negative impact on QOL of survivors Negative impact on QOL of survivors Must disseminate info widely to address gap because were not applying knowledge systematically Must disseminate info widely to address gap because were not applying knowledge systematically Foreword

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

27 Symposium Themes 1.Cancer rates are increasing as heart disease Rx improves and as cancer Rx improves. 2.Cancer increases VTE risk. 3.VTE is preventable (immunize!) 4.VTE prophylaxis may slow cancer 5.Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATF 6.Facilitate prophylaxis with alerts. 1.Cancer rates are increasing as heart disease Rx improves and as cancer Rx improves. 2.Cancer increases VTE risk. 3.VTE is preventable (immunize!) 4.VTE prophylaxis may slow cancer 5.Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATF 6.Facilitate prophylaxis with alerts.

28 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 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 Cancer and Prevention of VTE Landmark Advances and New Paradigms of Care for the Health System Pharmacist Cancer and Prevention of VTE Landmark Advances and New Paradigms of Care for the Health System Pharmacist A Year 2009 Update for The Health System Pharmacist

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

30 Thromboembolism in Malignancy 15% of cancer patients develop venous or arterial thrombosis 1 15% of cancer patients develop venous or arterial thrombosis 1 Annual incidence of VTE in all patients: 117 in 100,000 2 Annual incidence of VTE in all patients: 117 in 100,000 2 Cancer increases risk of thrombosis 4.1-fold 3 Cancer increases risk of thrombosis 4.1-fold 3 Chemotherapy increases risk of thrombosis 6.5-fold 3 Chemotherapy increases risk of thrombosis 6.5-fold 3 Annual incidence of VTE in patients with cancer: 1 in 200 4 Annual incidence of VTE in patients with cancer: 1 in 200 4 15% of cancer patients develop venous or arterial thrombosis 1 15% of cancer patients develop venous or arterial thrombosis 1 Annual incidence of VTE in all patients: 117 in 100,000 2 Annual incidence of VTE in all patients: 117 in 100,000 2 Cancer increases risk of thrombosis 4.1-fold 3 Cancer increases risk of thrombosis 4.1-fold 3 Chemotherapy increases risk of thrombosis 6.5-fold 3 Chemotherapy increases risk of thrombosis 6.5-fold 3 Annual incidence of VTE in patients with cancer: 1 in 200 4 Annual incidence of VTE in patients with cancer: 1 in 200 4 1. Green KB, Silverstein RL. Hematol Oncol Clin North Am. 1996;10:499-530. 2. Silverstein MD et al. Arch Intern Med. 1998;158:585-593 3. Heit JA et al. Arch Intern Med. 2000;160:809-815 4. Lee AYY, Levine MN. Circulation. 2003;107(23 Suppl 1):I17-21.

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

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

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

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

35 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180 0.00 0.20 0.401.000.80 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, Cancer, and Survival N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer

36 VTE and Inpatient Mortality Khorana AA et al. J Clin Oncol. 2006;24:484-490. All (n=66,016) Nonmetastatic Cancer (n=20,591) Metastatic Cancer (n=17,360) Metastatic Cancer (n=17,360) Mortality, % No Venous Thromboembolism Venous Thromboembolism 7.98 10.59 8.67 14.85 16.1316.41 0 2 4 6 8 10 12 14 16 18 20

37 Amin A et al. J Thromb Haemost. 2007; 5:1610-6. Prophylaxis Rates in Hospitalized Patients Prophylaxis Rates in Hospitalized Patients

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

39 Clots and CancerA 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. 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.

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

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

42 1.Ambrus JL et al. J Med. 1975;6:61-64 2.Donati MB. Haemostasis. 1994;24:128-131 3.Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 4.Prandoni P et al. Ann Intern Med. 1996;125:1-7 DVT and PE in Cancer Facts, Findings, and Natural History VTE is the second leading cause of death in hospitalized cancer patients 1,2 VTE is the second leading cause of death in hospitalized cancer patients 1,2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer 2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer 2 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE 3 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE 3 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4 VTE is the second leading cause of death in hospitalized cancer patients 1,2 VTE is the second leading cause of death in hospitalized cancer patients 1,2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer 2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer 2 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE 3 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE 3 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4

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

44 Thrombosis and Survival Likelihood of Death After Hospitalization 0 20 40 60 80 100 120140 160 180 0 20 40 60 80 100 120140 160 180 0.00 0.20 0.401.000.80 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

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

46 Trends in VTE in Hospitalized Cancer Patients VTE- patients on chemotherapy VTE-all patients DVT-all patients PE-all patients 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 199519961997199819992000200120022003 Rate of VTE (%) P<0.0001 Khorana AA et al. Cancer. 2007.

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

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

49 VTE Risk And Cancer Type Solid And Liquid Malignancies Stein PD, et al. Am J Med 2006; 119: 60-68 Relative Risk of VTE in Cancer Patients PancreasBrainMyeloprolStomachLymphomaUterusLungEsophagusProstateRectalKidneyColonOvaryLiverLeukemiaBreastCervixBladder 4.543.532.521.510.5 Relative Risk of VTE Ranged From 1.02 to 4.34

50 Medical Inpatients Cancer and Thrombosis

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

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

53 Predictors of VTE in Hospitalized Cancer Patients CharacteristicOR P Value Site of Cancer LungStomachPancreasEndometrium/cervixBrain1.31.62.822.2<0.0010.0035<0.001<0.001<0.001 Age 65 y 1.10.005 Arterial thromboembolism 1.40.008 Comorbidities (lung/renal disease, infection, obesity) 1.3-1.6<0.001 Khorana AA et al. J Clin Oncol. 2006;24:484-490.

54 Pharmacologic (Prophylaxis & Treatment) Nonpharmacologic(Prophylaxis) Antithrombotic Therapy: Choices Intermittent Pneumatic Compression Elastic Stockings Inferior Vena Cava Filter Oral Anticoagulants Unfractionated Heparin (UH) Low Molecular Weight Heparin (LMWH) New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?

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

56 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. 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: 5490-5505.

57 Surgical Patients Cancer and Thrombosis

58 Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732 Incidence of VTE in Surgical Patients No Cancer N=16,954CancerN=6124P-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%<0.0001 Death0.71%3.14%<0.0001

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

60 LMWH vs. UFH Abdominal or pelvic surgery for cancer (mostly colorectal) Abdominal or pelvic surgery for cancer (mostly colorectal) LMWH once daily vs. UFH tid for 7–10 days post-op LMWH once daily vs. UFH tid for 7–10 days post-op DVT on venography at day 7–10 and symptomatic VTE DVT on venography at day 7–10 and symptomatic VTE LMWH vs. UFH Abdominal or pelvic surgery for cancer (mostly colorectal) Abdominal or pelvic surgery for cancer (mostly colorectal) LMWH once daily vs. UFH tid for 7–10 days post-op LMWH once daily vs. UFH tid for 7–10 days post-op DVT on venography at day 7–10 and symptomatic VTE DVT on venography at day 7–10 and symptomatic VTE 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:438-444 Prophylaxis in Surgical Patients StudyNDesignRegimens ENOXACAN 1 631double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475double-blind enoxaparin vs. UFH

61 Canadian Colorectal DVT Prophylaxis Trial 13.9% 1.5% 2.7% 16.9% N=234 N=241 McLeod R, et al. Ann Surg 2001;233:438-444 P=0.052 Incidence of Outcome Event Incidence of Outcome Event VTEMajor Bleeding VTEMajor Bleeding (Cancer) (All) Prophylaxis in Surgical Patients

62 VTE Prox Any Major VTE Prox Any Major DVT Bleeding Bleeding DVT Bleeding Bleeding P=0.02 5.1% 1.8% Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980 ENOXACAN II Incidence of Outcome Event Incidence of Outcome Event N=167 N=165 0% 0.4% 12.0% 4.8% NNT = 14 0.6% 3.6% Extended Prophylaxis in Surgical Patients

63 A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment 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). 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. 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. A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment 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). 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. 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. Major Abdominal Surgery: FAME InvestigatorsDalteparin Extended Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.

64 ASCO Guidelines: VTE Prophylaxis All patients undergoing major surgical intervention for malignant disease should be considered for 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. 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. 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. All patients undergoing major surgical intervention for malignant disease should be considered for 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. 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. 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: 5490-5505.

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

66 Placebo-Controlled Trials StudyRegimenN CRT (%) CRT (%) Reichardt* 2002 Dalteparin 5000 U daily placebo285140 11 (3.7) 11 (3.7) 5 (3.4) 5 (3.4) Couban*2002 Warfarin 1mg daily placebo130125 6 (4.6) 6 (4.6) 5 (4.0) 5 (4.0) ETHICS ETHICS 2004 Enoxaparin 40 mg daily placebo155155 22 (14.2) 28 (18.1) * symptomatic outcomes ; routine venography at 6 weeks Prophylaxis for Venous Catheters 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

67 Tolerability of Low-Dose Warfarin Tolerability of Low-Dose Warfarin 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily INR measured at baseline and four time points INR measured at baseline and four time points 10% of all recorded INRs >1.5 10% of all recorded INRs >1.5 Patients with elevated INR Patients with elevated INR 2.0–2.9 6% 3.0–4.919% >5.0 7% Tolerability of Low-Dose Warfarin Tolerability of Low-Dose Warfarin 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily INR measured at baseline and four time points INR measured at baseline and four time points 10% of all recorded INRs >1.5 10% of all recorded INRs >1.5 Patients with elevated INR Patients with elevated INR 2.0–2.9 6% 3.0–4.919% >5.0 7% Central Venous Catheters: Warfarin Masci et al. J Clin Oncol. 2003;21:736-739

68 Summary Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) 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 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 Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosisSummary Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) 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 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 Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis Prophylaxis for Central Venous Access Devices

69 8 th 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

70 Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient No recommendations from ACCP No recommendations from ACCP No data from randomized trials (RCTs) 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) 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.) Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.) No recommendations from ACCP No recommendations from ACCP No data from randomized trials (RCTs) 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) 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.) Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.)

71 Ambulatory Chemotherapy Patients Cancer and Thrombosis

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

73 Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery with institutionalization 21.72 Trauma12.69 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 Heit JA et al. Thromb Haemost. 2001;86:452-463

74 VTE Incidence In Various Tumors Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 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-Hodgkins lymphomas w/ chemo 3% Hodgkins 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%

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

76 Ambulatory Cancer plus Chemotherapy Study Methods Study Methods Prospective observational study of ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a maximum of 4 cycles 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 115 U.S. centers participated Patients enrolled between March, 2002 and August, 2004 who had completed at least one cycle of chemotherapy were included in this analysis Patients enrolled between March, 2002 and August, 2004 who had completed at least one cycle of chemotherapy were included in this analysis Study Methods Study Methods Prospective observational study of ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a maximum of 4 cycles 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 115 U.S. centers participated Patients enrolled between March, 2002 and August, 2004 who had completed at least one cycle of chemotherapy were included in this analysis Patients enrolled between March, 2002 and August, 2004 who had completed at least one cycle of chemotherapy were included in this analysis Khorana, Cancer, 2005

77 Ambulatory Cancer plus Chemotherapy VTE events were recorded during mid-cycle or new-cycle visits VTE events were recorded during mid-cycle or new-cycle visits Symptomatic VTE was a clinical diagnosis made by the treating clinician Symptomatic VTE was a clinical diagnosis made by the treating clinician Statistical analysis Statistical analysis Odds ratios to estimate relative risk Odds ratios to estimate relative risk Multivariate logistic regression to adjust for other risk factors Multivariate logistic regression to adjust for other risk factors VTE events were recorded during mid-cycle or new-cycle visits VTE events were recorded during mid-cycle or new-cycle visits Symptomatic VTE was a clinical diagnosis made by the treating clinician Symptomatic VTE was a clinical diagnosis made by the treating clinician Statistical analysis Statistical analysis Odds ratios to estimate relative risk Odds ratios to estimate relative risk Multivariate logistic regression to adjust for other risk factors Multivariate logistic regression to adjust for other risk factors Khorana, Cancer, 2005 Study Methods Study Methods

78 Incidence of VTE VTE / 2.4 months VTE/month VTE /cycle Cumulative rate (95% CI) 1.93%0.8%0.7% 2.2% (1.7-2.8) 0.0% 0.5% 1.0% 1.5% 2.0% 2.5%3.0%Baseline Cycle 1 Cycle 2 Cycle 3 Rate of VTE (%) Khorana, Cancer, 2005

79 Risk Factors: Site of Cancer 0 2 4 6 8 10 12 All patients Breast Colon Lung Upper GI Hodgkins NHL Others Site of Cancer VTE (%) / 2.4 months Khorana, Cancer, 2005

80 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 <217 217-270 217-270 270-337 270-337 >337 Pre-chemotherapy Platelet Count/mm 3 (x1000) (x1000) Incidence Of VTE Over 2.4 Months(%) Khorana, Cancer, 2005

81 Risk Factors: Multivariate Analysis CharacteristicOR P value Site of Cancer Upper GI LungLymphoma3.881.861.50.030.00760.050.32 Pre-chemotherapy platelet count > 350,000/mm 3 2.810.0002 Hgb < 10g/dL or use of red cell growth factor 1.830.03 Use of white cell growth factor in high- risk sites 2.090.008 Khorana, Cancer, 2005

82 Predictive Model Patient Characteristic Score Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) 21 Platelet count > 350,000/mm 3 1 Hgb < 10g/dL or use of ESA 1 Leukocyte count > 11,000/mm 3 1 BMI > 35 1 Khorana AA et al. JTH Suppl Abs O-T-002

83 Risk Score 01234 N1,35297447616033 VTE(%) /2.4 mos. 0.81.82.76.313.2 Incidence of VTE Over 2.4 Months Predictive Model

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

85 Oral Anticoagulant Therapy in Cancer Patients: Problematic Warfarin therapy is complicated by: Warfarin therapy is complicated by: Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia and procedures Frequent interruptions for thrombocytopenia and procedures Difficulty in venous access for monitoring Difficulty in venous access for monitoring Increased risk of both recurrence and bleeding Increased risk of both recurrence and bleeding Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why? Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why? Warfarin therapy is complicated by: Warfarin therapy is complicated by: Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia and procedures Frequent interruptions for thrombocytopenia and procedures Difficulty in venous access for monitoring Difficulty in venous access for monitoring Increased risk of both recurrence and bleeding Increased risk of both recurrence and bleeding Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why? Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?

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

87 Landmark CLOT Cancer Trial Reduction in Recurrent VTE 0 5 10 10 15 15 20 20 25 25 Days Post Randomization 0306090120150180210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = 0.0017 Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

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

89 Treatment of Cancer-Associated VTE StudyDesign Length of Therapy (Months)N Recurrent VTE (%) Major Bleeding (%)Death(%) CLOT Trial (Lee 2003) DalteparinOAC 6336336917643941 CANTHENOX (Meyer 2002) EnoxaparinOAC 3677111217161123 LITE (Hull ISTH 2003) TinzaparinOAC 38087611682322 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC 63236343.43.16.7 NS 0.03 NS 0.002 NS NR 0.09 0.03 0.09

90 Treatment and 2° Prevention of VTE in Cancer – Bottom Line New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendationACCP) New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendationACCP) NOTE: Dalteparin is only LMWH approved (May, 2007) for both the treatment and secondary prevention of VTE in cancer 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 recommendationACCP) Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendationACCP) New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendationACCP) New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendationACCP) NOTE: Dalteparin is only LMWH approved (May, 2007) for both the treatment and secondary prevention of VTE in cancer 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 recommendationACCP) Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendationACCP) Chest Jun 2008: 454S–545S New Development New Development

91 CLOT 12-month Mortality All Patients Lee AY et al. J Clin Oncol. 2005; 23:2123-9.

92 0 10 20 30 40 50 60 70 80 90100 Days Post Randomization 0306090120150180240300360 Probability of Survival, % OAC Dalteparin HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWH CLOT 12-month Mortality CLOT 12-month Mortality Patients Without Metastases (N=150) Lee AY et al. J Clin Oncol. 2005; 23:2123-9.

93 84 patients randomized: Chemo +/- LMWH (18 weeks) 84 patients randomized: Chemo +/- LMWH (18 weeks) Patients balanced for age, gender, stage, smoking history, ECOG performance status Patients balanced for age, gender, stage, smoking history, ECOG performance status 84 patients randomized: Chemo +/- LMWH (18 weeks) 84 patients randomized: Chemo +/- LMWH (18 weeks) Patients balanced for age, gender, stage, smoking history, ECOG performance status Patients balanced for age, gender, stage, smoking history, ECOG performance status LMWH for Small Cell Lung Cancer Turkish Study Altinbas et al. J Thromb Haemost 2004;2:1266. Chemotherapy plus Dalteparin Chemo alone P-value 1-y overall survival, % 51.329.50.01 2-y overall survival, % 17.2 0.0 0.00.01 Median survival, m 13.0 8.0 8.00.01 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily

94 VTE Prophylaxis Is Underused in Patients With Cancer 1.Kakkar AK et al. Oncologist. 2003;8:381-388 2.Stratton MA et al. Arch Intern Med. 2000;160:334-340 3.Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 Cancer: FRONTLINE Survey 1 3891 Clinician Respondents Rate of Appropriate Prophylaxis, % Major Surgery 2 Major Abdominothoracic Surgery (Elderly) 3 Medical Inpatients 4 Confirmed DVT (Inpatients) 5 Cancer: Surgical Cancer: Medical 4.Rahim SA et al. Thromb Res. 2003;111:215-219 5.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262

95 Conclusions and Summary Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopeniaRisk 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 warfarinLong-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 patientsGuidelines and landmark trials support administration of LMWH in at risk patients Cancer patients are under-prophylaxed for VTECancer patients are under-prophylaxed for VTE Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient populationHealth system pharmacists can play a pivotal role in improving clinical outcomes in this patient population

96 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 Womens Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Clotting, Cancer, and Clinical Strategies

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

98 Amin A et al. J Thromb Haemost. 2007; 5:1610-6. Prophylaxis Rates in Hospitalized Patients Prophylaxis Rates in Hospitalized Patients

99 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180 0.00 0.20 0.401.000.80 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, Cancer, and Survival N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer

100 Time Distribution of VTE Events Following Cancer Surgery Agnelli G et al. Ann Surg 2006; 243:89-95. @RISTOS Registry: prospective cohort N=2373 VTE Events 0 2 4 6 8 10 12 1-5 d6-10 d11-15 d16-20 d21-25 d26-30 d> 30 d

101 www.nccn.org www.nccn.org NCCN Clinical Practice Guidelines in Oncology NCCN Clinical Practice Guidelines in Oncology …The panel of experts includes medical and surgical oncologists, hematologists, cardiologists, internists, radiologists. And a pharmacist. …The panel of experts includes medical and surgical oncologists, hematologists, cardiologists, internists, radiologists. And a pharmacist. www.asco.org www.asco.org Recommendations for VTE Prophylaxis & Treatment in Patients with CancerRecommendations for VTE Prophylaxis & Treatment in Patients with Cancer

102 2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A) General, Gynecologic, Urologic Surgery General, Gynecologic, Urologic Surgery Low Dose Unfractionated Heparin 5,000 units TID Low Dose Unfractionated Heparin 5,000 units TID LMWH > 3,400 units Daily LMWH > 3,400 units Daily –Dalteparin 5,000 units –Enoxaparin 40 mg –Tinzaparin 4,500 units GCS and/or IPC 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 Low Dose Unfractionated Heparin LMWH LMWH Contraindication to anticoagulant prophylaxis (Grade 1C+) GCS or IPC GCS or IPC Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A) General, Gynecologic, Urologic Surgery General, Gynecologic, Urologic Surgery Low Dose Unfractionated Heparin 5,000 units TID Low Dose Unfractionated Heparin 5,000 units TID LMWH > 3,400 units Daily LMWH > 3,400 units Daily –Dalteparin 5,000 units –Enoxaparin 40 mg –Tinzaparin 4,500 units GCS and/or IPC 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 Low Dose Unfractionated Heparin LMWH LMWH Contraindication to anticoagulant prophylaxis (Grade 1C+) GCS or IPC GCS or IPC Geerts WH et al. Chest. 2004;126(suppl):338S-400S 1A is the highest possible grade Indicates that benefits outweigh risks, burdens, and costs, with consistent RCT level of evidence

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

104 http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice Guidelines in VTE Disease Inpatient Prophylactic Anticoagulation Therapy LMWH LMWH - Dalteparin 5,000 units subcutaneous daily - Enoxaparin 40 mg subcutaneous daily - Tinzaparin 4,500 units (fixed dose) subcutaneous daily or 75 units/kg subcutaneous daily Pentasaccharide Pentasaccharide - Fondaparinux 2.5 mg subcutaneous daily Unfractionated heparin 5,000 units subcutaneous 3 times daily Unfractionated heparin 5,000 units subcutaneous 3 times daily

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

106 Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ? 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 Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ? 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 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: 5490-5505.

107 Incidence and Relative Risk of High-Grade VTE with Bevacizumab Tumor Type No. Studies BevacizumabControlIncidenceRR Overall13235/3795134/31676.31.38 Colo-rectal496/131550/11287.31.56 NSCLC478/122841/8626.61.24 Breast Cancer 220/59413/5613.91.47 Renal Cell 17/3372/3042.02.86 Mesothelioma19/535/5517.01.89 Pancreatic Cancer 124/26823/2579.01.00 SR Nalluri et al. JAMA 2008;300(19):2277-2285

108 Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? Routine prophylaxis is not recommended. Routine prophylaxis is not recommended. Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? Routine prophylaxis is not recommended. Routine prophylaxis is not recommended. Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. 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: 5490-5505.

109 Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ? Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ? All patients should be considered for thromboprophylaxis. All patients should be considered for thromboprophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Mechanical methods should not be used as monotherapy. 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. Prophylaxis should continue for at least 7-10 days post-op. Prolonged prophylaxis may be considered for cancer with high risk features. Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ? Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ? All patients should be considered for thromboprophylaxis. All patients should be considered for thromboprophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Mechanical methods should not be used as monotherapy. 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. 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: 5490-5505.

110 Compliance With ACCP VTE Prophylaxis Guidelines Is Poor 9.9% 6.7% 35,124 62,012 0 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 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 Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group

111 HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 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) Reasons for Inadequate Duration of VTE Prophylaxis

112 Odds Ratio Malignancy0.40 Others 0.58 Infection 0.83 Bleeding Risk 0.91 Gender 0.92 Hospital Size 0.93 Age 1.00 LOS 1.05 Cardiovascular Disease 1.06 Internal Medicine 1.33 Respiratory 1.35 AMC 1.46 Duration of Immobility 1.60 VTE Risk Factors 1.78 Malignancy0.40 Others 0.58 Infection 0.83 Bleeding Risk 0.91 Gender 0.92 Hospital Size 0.93 Age 1.00 LOS 1.05 Cardiovascular Disease 1.06 Internal Medicine 1.33 Respiratory 1.35 AMC 1.46 Duration of Immobility 1.60 VTE Risk Factors 1.78 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Effect Odds Ratio (95% CI) Predictors of the Use of Thromboprophylaxis Kahn SR et Al. Thromb Res 2007; 119:145-155

113 Unfractionated Heparin Prophylaxis: BID vs TIDWhat Works, What Doesnt? Meta-analysis: 12 RCTs DVT, PE, all VTE events, Bleeding DVT, PE, all VTE events, Bleeding Proximal DVT plus PE Proximal DVT plus PE BID VTE event rate: BID VTE event rate: 2.34 events per 1,000 patient days TID event rate: TID event rate: 0.86 events per 1,000 patient days P=0.05 P=0.05 NNT NNT 676 hospital prophylaxis days with UFH TID to prevent 676 hospital prophylaxis days with UFH TID to prevent 1 major bleed with 1,649 hospital prophylaxis days of TID dosing 1 major bleed with 1,649 hospital prophylaxis days of TID dosingMeta-analysis: 12 RCTs DVT, PE, all VTE events, Bleeding DVT, PE, all VTE events, Bleeding Proximal DVT plus PE Proximal DVT plus PE BID VTE event rate: BID VTE event rate: 2.34 events per 1,000 patient days TID event rate: TID event rate: 0.86 events per 1,000 patient days P=0.05 P=0.05 NNT NNT 676 hospital prophylaxis days with UFH TID to prevent 676 hospital prophylaxis days with UFH TID to prevent 1 major bleed with 1,649 hospital prophylaxis days of TID dosing 1 major bleed with 1,649 hospital prophylaxis days of TID dosing King CS et al. CHEST 2007;131:507-516

114 Heparin, Low Molecular Weight Heparin Prophylaxis Wein L et al. Arch Intern Med. 2007;167:1476-86. LMWH vs UFH DVT Risk Study Reduction (95% CI) Weight % Harenberg et al, 1990 0.70 (0.16-3.03) 3.4 Turpie et al, 1992 0.29 (0.10-0.81) 11.4 Dumas et al, 1994 0.74 (0.38-1.43) 14.4 Bergmann & Neuhart 0.94 (0.39-2.26) 8.1 et al, 1996 Harenberg et al, 1996 2.89 (0.30-27.71) 0.8 Lechler et al, 1996 0.25 (0.03-2.23) 3.3 Hillbom et al, 2002 0.55 (0.31-0.98) 20.5 Kleber, et al 2003 0.77 (0.43-1.38) 19.4 Diener et al, 2006 0.76 (0.42-1.38) 18.9 Overall (95% CI) 0.68 (0.52-0.88) LMWH Better LMWH Worse 0.1 1.0 10 Risk Ratio Meta-analysis Meta-analysis 36 randomized controlled trials 36 randomized controlled trials 23,000 hospitalized medical patients 23,000 hospitalized medical patients UFH 5,000 units TID is more effective in preventing DVT than UFH BID 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 Low molecular weight heparin is 33% more effective than unfractionated heparin in preventing DVT RR for DVT 0.68 (p=0.004 ) RR for DVT 0.68 (p=0.004 )

115 BWH/DFCI Partners Cancer Care Experience Consecutive patients, < 60 days Consecutive patients, < 60 days 2 Nursing units 2 Nursing units LOS ranged from 3 days to 31 days LOS ranged from 3 days to 31 days Number of days where doses were omitted ranged from 1 to 6 days Number of days where doses were omitted ranged from 1 to 6 days

116 VTE Incidence: More Common in the Outpatient Setting Medical records of residents (n=477,800) Medical records of residents (n=477,800) 587 VTE events (104 per 100,000 population) 587 VTE events (104 per 100,000 population) 30 Day recurrence 4.8 % 30 Day recurrence 4.8 % VTE Event Location Patients receiving prophylaxis during high risk periods Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777

117 Thrombosis in Malignancy 7 TH ACCP Consensus Conference Recommendations Initial Phase 5-7 days Dalteparin 200/kg q24h (GRADE 1A) Subacute Phase 3 - 6 months Dalteparin* 150 units/kg q24h (GRADE 1A) Chronic Phase Continue anticoagulation (warfarin or LMWH) long-term or until malignancy resolves (GRADE 1C) 5 - 7 days3 - 6 mos6 mos - indefinite Buller HR, et al. Chest 2004; 126 (suppl 3): 401s-428s * Dalteparin Approved for Extended Treatment to Reduce the Recurrence of Blood Clots in Patients with Cancer

118 Recurrent Thrombosis Dalteparin: 9.0% of 336 Warfarin: 17% of 336 Dalteparin: 200 units/kg/day x 1 mo, then 150 units/kg/day Warfarin dosed to INR 2-3 Duration: 6 months Warfarin vs. Dalteparin for VTE Treatment in Malignancy Lee AY et al. New Engl J Med 2003; 349:146-53. 25201510 5 0 0 30 60 90 120 150 180 210 Dalteparin Oral anticoagulant P=0.002 Probability of Recurrent Venous Thromboembolism (%) Days after Randomization No. at Risk Dalteparin 336 301 264 235 227 210 164 Oral anticoagulant 336 280 242 221 200 194 154

119 Subgroup Analysis Lee AY et al. J Clin Oncol. 2005; 23:2123-9. 12-month Cumulative Mortality Rate 12-month Cumulative Mortality Rate DalteparinWarfarin P Value Metastatic Disease (n=452) 72%69% P = 0.46 Non-metastatic Disease (n=150) 20%36%P=0.03

120 Dalteparin Cost Effectiveness in Recurrent VTE Cost Parameter Dalteparin (n=338) Warfarin (n=338) Drug 2852269 Laboratory 303437 Diagnostic Tests 253267 Unscheduled Visits 286300 Transfusions 143208 Major bleeding 97.592.3 VTE Recurrence 228429 Mean Cost Per Patient 41622003 Dranitsaris G. Pharmacoeconomics 2006; 24(6):5093-607

121 http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice GuidelinesVenous Thromboembolic Disease Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated Thrombosis Immediate LMWH LMWH - Dalteparin (200 units/kg subcutaneous daily) - Enoxaparin (1 mg/kg subcutaneous every 12 hrs) - Tinzaparin (175 units/kg subcutaneous daily) Pentasaccharide Pentasaccharide - Fondaparinux (5.0 mg [ 100 kg] subcutaneous daily - Fondaparinux (5.0 mg [ 100 kg] subcutaneous daily Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to 2.0-2.9 x control) Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to 2.0-2.9 x control)

122 http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice GuidelinesVenous 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 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 2.0-3.0) Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR 2.0-3.0) Duration of Long Term Therapy Minimum time of 3-6 mo for DVT and 6-12 mo for PE Minimum time of 3-6 mo for DVT and 6-12 mo for PE Consider indefinite anticoaugulation if active cancer or persistent risk factors 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 For catheter associated thrombosis, anticoagulate as long as catheter is in place and for 1-3 mo after catheter removal

123 What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE ? 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 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. 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. 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. For CNS malignancies, elderly patients anticoagulation is recommended with careful monitoring and dose adjustment. What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE ? 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 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. 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. 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. For CNS malignancies, elderly patients anticoagulation is recommended with careful monitoring and dose adjustment. Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

124 Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? 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. Anticoagulants are not recommended to improve survival in patients with cancer without VTE. Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? 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. Anticoagulants are not recommended to improve survival in patients with cancer without VTE. Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

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

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

127 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 (-4.2-2.4) NS New VTE at 12 Mos 33 (8.9) 36 (9.8) -0.8 (-5.5-3.5) NS All Bleeding 48 (13.0) 73 (19.8) -6.8 (-12.4- - 1.5) p=.011 Major Bleeding 12 (3.3) 17 (4.6) -1.4 (-4.3-1.4) NS Minor Bleeding 36 (9.8) 56 (15.2) -5.5 (-10.4- - 0.6) p=.022 Stratified Bleeding- High Risk 31/144 (21.5) 39/146 (26.7) -5.2 (-15%-4.6%) NS Stratified Bleeding-Low Risk 17/225 (7.6) 34/222 (15.3) -7.8 (-13.6- - 1.9%) p=.01 Thrombocytopenia (<150) 21 (5.7) 9 (2.4) 1.6 (-3.6-0.3) NS Bone Fracture 4 (1.1) 7 (1.9) -0.8 (-0.9-2.6) NS Hull R. Am Jour Med 2007; 120:72-82

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

129 Barriers to Long-term Use of LMWH for Treatment of Cancer-associated VTE Wittkowsky AK. J Thromb Haemost. 2006; 4:2090-1. Initial treatment LMWH for 3-6 months 19% UFH/LMWH for 5-7 days 81% followed by warfarin followed by warfarin Reasons LMWH not used long-term Not covered by medical insurance 49.4% Physician preference 32.0% Patient refused long-term injections 13.6% History of HIT 2.5% Severe renal insufficiency 2.5%

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

131 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 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 A Year 2009 Update for The Health System Pharmacist

132 Objectives 1.Differentiate data with various LMWHs in special populations 2.Review appropriate dosing and monitoring of LMWHs in patients with obesity and renal failure 3.Discuss cautions of using emerging agents in special populations

133 Risk of Inadequate Therapy in High Risk Patients 524 VTE Patients 524 VTE Patients Active Cancer in 26% Active Cancer in 26% Only 1/3 rd on LMWH monotherapy Only 1/3 rd on LMWH monotherapy Weight > 100Kg in 15% Weight > 100Kg in 15% Under-dosing of LMWH by > 10% Under-dosing of LMWH by > 10% –36% of > pts 100Kg –8% of pts < 100Kg (p < 0.001) CrCL < 30mL/min in 5% CrCL < 30mL/min in 5% LMWH tx in 67% LMWH tx in 67% 524 VTE Patients 524 VTE Patients Active Cancer in 26% Active Cancer in 26% Only 1/3 rd on LMWH monotherapy Only 1/3 rd on LMWH monotherapy Weight > 100Kg in 15% Weight > 100Kg in 15% Under-dosing of LMWH by > 10% Under-dosing of LMWH by > 10% –36% of > pts 100Kg –8% of pts < 100Kg (p < 0.001) CrCL < 30mL/min in 5% CrCL < 30mL/min in 5% LMWH tx in 67% LMWH tx in 67% Cook LM, et.al. J Thromb Hemost 2007;5;937-41.

134 8 th ACCP Conference on Antithrombotic Therapy 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? 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? At what weight do we move away from standard dosing and move to weight-based dosing? What is this weight-based dosing and how does it differ from typical dosing? 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? 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. Obese Patients

135 Pharmacokinetic Characteristics of Low Molecular Weight Heparins Lipid solubilityLOW Plasma protein bindingHIGH Tissue bindingLOW Volume of Distribution5-7 L Lipid solubilityLOW Plasma protein bindingHIGH Tissue bindingLOW Volume of Distribution5-7 L Logical conclusion: IBW may be a better predictor of LMWH dosing than TBW

136 LMWH: Maximum Weights Studied * max dose 18,000 - 20,000 IU/day Duplaga BA et al. Pharmacotherapy 2001; 21:218-34. Synergy Trial: Data on File Davidson, et al. J Thromb Haem 2007;5:1191-4 Kinetic Studies Clinical Trials Dalteparin 190 kg 128 kg* Enoxaparin 144 kg 194 kg Tinzaparin 165 kg 88 kg Fondaparinux 175.5 kg

137 LMWH Pharmacokinetics in Obesity Actual body weight correlates best with anticoagulant response to LMWHs as measured by anti-factor Xa levels Pharmacol Clin Pharmacol Ther 2002;72:308-18. Thromb Haemost 2002;87:817-23.

138 Dalteparin Pharmacokinetics in Obesity Yee JYV, Duffull SB. Eur J Clin Pharmacol 2000; 56:293-7. Dose: 200 U/kg qd Duration: routine Obese (BMI > 30) Normal (BMI < 30) N1010 TBW (mean +/- SD) 106.4 +/- 22.1 69.7 +/- 9.3 LBW (mean +/- SD) 64.1 +/- 12.3 66.1 +/- 8.7 Mean Vd (l) 12.398.36 Mean CI (l/hr) 1.301.11

139 Dalteparin Pharmacokinetics In Obesity Correlation Coefficient Between Vd and: LBW0.05 ABW0.52 TBW0.55 Correlation Coefficient Between Cl and: LBW0.01 ABW0.32 TBW0.39 Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7. Correlation Coefficient Between Vd and: LBW0.05 ABW0.52 TBW0.55 Correlation Coefficient Between Cl and: LBW0.01 ABW0.32 TBW0.39 Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7. Conclusion: TBW may be a better predictor of LMWH dose than IBW

140 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. 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. 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 N131410 Mean Dose (U) 14,03017,64623,565 Ant-Xa Activity (u/ml) Day 3 Peak 1.010.97 1.12 NS Day 3 Trough 0.120.11 0.11 NS

141 LMWH Safety and Effectiveness Using TBW Enoxaparin In ACS (ESSENCE/TIMI IIb) 14.3% 16.1% P=0.39 P=0.13 Obese: BMI > 30mg/m2 Enox max weight 158 kg Spinler SA et al. Am Heart J 2003; 146:33-41 0.4% 1.6%

142 Safety Of TBW-based Dosing of Dalteparin for Treatment of Acute VTE in Obese Patients Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2. N = 193 patients 3 month outcomes: major bleeding = 1.0% (n=2) > 90 kg recurrent VTE = 1.6% (n=3) > 90 kg recurrent VTE = 1.6% (n=3) WEIGHT(kg)NMeanDose Full dose +/- 5% QD Dosing BIDDosing 90-994019,300392416 100-1095220,850492517 110-1194121,470212615 120-1292524,30022169 130-1391625,2508106 140-149926,920654 > 150 1028,280664

143 Fondaparinux In Obesity Results From the Matisse Trials Davidson BL et al. J Thrombosis Haemost 2007; 5:1191-4. Fondaparinux: < 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

144 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 Frederiksen SG et al. Br J Surgery 2003; 90:547-8 40 60 80 100 120 140 160 Body Weight (kg) Area under the curve for 10 h 200 150 100 50 0 200 150 100 50 0 Regression line 95% CI for line 95% CI for data points Regression line 95% CI for line 95% CI for data points

145 Kucher N et al. Arch Int Med 2005;165:341-5. 0.010.10.551.010.0 Favors Dalteparin Favor Placebo Relative Risk < 25 37.5 25-29.9 33.1 30-34.9 18.9 35-39.9 7.1 > 40 3.3 Overall Prevent Trial Dalteparin: Fixed Dosing For VTE Prevention Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill) BMI (kg/m2) Patients % 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

146 Enoxaparin VTE Prophylaxis in TKA/THA/Trauma Samama MM et al. Thromb Haemost 1995; 73:977. N: 807 Dose: 40 mg qd Obese : BMI>32kg/m 2 31.8% 16.7% p<0.001

147 Enoxaparin: VTE Prophylaxis in Bariatric Surgery Scholten Obes Surg 2002; 12:19-24. 30mg bid: n=92 BMI 51.7kg/m 2 5.4% 0.6% p<0.01 40mg bid: n=389 BMI 50.3kg/m 2 BMI 50.3kg/m 2

148 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 N=135 Bariatric Surgery Mean Weight: 148.8Kg Mean BMI: 53.7 Dalteparin: 7,500 IU daily Dalteparin in Morbid Obesity: Bariatric Surgery Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print] P=0.031 P=0.052 P=0.444 Under target value <0.2 IU/mL n-=41 Under target value <0.2 IU/mL n-=41 Target value <0.2-0.5 IU/mL n-=81 Target value <0.2-0.5 IU/mL n-=81 Over target value <>0.5 IU/mL n=13 Over target value <>0.5 IU/mL n=13 200 180 160 140 120 0 200 180 160 140 120 0 Body Weight (kg)

149 LMWH in Obesity: Summary Treatment: in controlled trials, LMWH dosing has been based on TBW (max 160-190 kg) Treatment: in controlled trials, LMWH dosing has been based on TBW (max 160-190 kg) Dalteparin Dalteparin Dose based on TBW Dose based on TBW PI recommends dose capping PI recommends dose capping Recent clinical data supports TBW dosing Recent clinical data supports TBW dosing –QD or BID dosing Enoxaparin Enoxaparin Dose based on TBW Dose based on TBW Dose capping NOT recommended Dose capping NOT recommended BID dosing preferred BID dosing preferred Tinzaparin Tinzaparin Dose based on TBW, NO dose adjustment or capping Dose based on TBW, NO dose adjustment or capping Anti-Xa monitoring not necessary for TBW < 190kg Anti-Xa monitoring not necessary for TBW < 190kg Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients) Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients) Treatment: in controlled trials, LMWH dosing has been based on TBW (max 160-190 kg) Treatment: in controlled trials, LMWH dosing has been based on TBW (max 160-190 kg) Dalteparin Dalteparin Dose based on TBW Dose based on TBW PI recommends dose capping PI recommends dose capping Recent clinical data supports TBW dosing Recent clinical data supports TBW dosing –QD or BID dosing Enoxaparin Enoxaparin Dose based on TBW Dose based on TBW Dose capping NOT recommended Dose capping NOT recommended BID dosing preferred BID dosing preferred Tinzaparin Tinzaparin Dose based on TBW, NO dose adjustment or capping Dose based on TBW, NO dose adjustment or capping Anti-Xa monitoring not necessary for TBW < 190kg Anti-Xa monitoring not necessary for TBW < 190kg Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients) Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients) Nutescu E, et.al. Ann Pharmacother; 2009; in press.

150 8 th ACCP Conference on Antithrombotic Therapy Renal Impairment For each of the antithrombotic agents, we recommend that clinicians follow manufacturer-suggested dosing guidelines (Grade 1C) 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) 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) Options for patients with renal impairment (Grade 1B) Avoid agents that renal accumulate Avoid agents that renal accumulate Use a lower dose Use a lower dose Monitor the drug level or anticoagulant effect Monitor the drug level or anticoagulant effect For each of the antithrombotic agents, we recommend that clinicians follow manufacturer-suggested dosing guidelines (Grade 1C) 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) 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) Options for patients with renal impairment (Grade 1B) Avoid agents that renal accumulate Avoid agents that renal accumulate Use a lower dose Use a lower dose Monitor the drug level or anticoagulant effect Monitor the drug level or anticoagulant effect Geerts WH. Chest 2008;133(suppl):381S-453S.

151 LMWH in Renal Dysfunction Manufacturer Recommendations Dalteparin should be used with caution in patients with severe kidney insufficiency. should be used with caution in patients with severe kidney insufficiency. Monitor anti-Factor Xa for dose guiding with therapeutic doses Monitor anti-Factor Xa for dose guiding with therapeutic dosesEnoxaparin adjustment of dose is recommended for patients with severe renal impairment (CrCL < 30 mL/min). 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. patients with severe renal impairment should be dosed with caution.Fondaparinux - Contraindicated in CrCL < 30mL/min Dalteparin should be used with caution in patients with severe kidney insufficiency. should be used with caution in patients with severe kidney insufficiency. Monitor anti-Factor Xa for dose guiding with therapeutic doses Monitor anti-Factor Xa for dose guiding with therapeutic dosesEnoxaparin adjustment of dose is recommended for patients with severe renal impairment (CrCL < 30 mL/min). 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. patients with severe renal impairment should be dosed with caution.Fondaparinux - Contraindicated in CrCL < 30mL/min

152 Study; year Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n) Peto OR (95%, CI) Weight (%) Peto OR (95%, CI) Collet, et al; 2001 0/281/832.01 0.26 (0.00 – 23.94) Paulas, et al; 2002 0/513/1496.02 0.26 (0.02 – 3.50) Siguret, et al; 2000 0/170/13 Not estimable Chow, et al; 2003 0/50/13 Not estimable Khazan, et al. (adj.); 2003 0/103/424.78 0.28 (0.01 – 5.16) (Prophylactic) 2003 3/363/4714.77 1.33 (0.25 – 7.05) (Therapeutic) 2003 2/173/618.62 3.09 (0.35 – 27.31) Spinler, et al; 2003 5/6974/3,43215.93 10.05 (2.02 – 49.98) Green, et al; 2005 1/180/202.66 8.26 (0.16 – 418.42) Kruse & Lee; 2004 0/501/1202.22 0.24 (0.00 – 17.90) Macie, et al; 2004 2/76/2012.68 977.78 (19.61 – 48,752.07) Peng, et al; 2004 0/70/43 Not estimable Thorevska, et al; 2004 7/6511/17135.56 1.85 (0.63 – 5.40) Bazinet, et al; 2005 1/362/1604.75 2.74 (0.15 – 51.73) Total (95%, CI) 21/416107/4,555100.00 2.25 (1.19 – 4.27) Recent Meta-Analysis of LMWHs and Bleeding In Patients With Severe Renal Dysfunction Lim W, et al. Ann Intern Med. 2006;144:673-684. Dosage adjustments for renal dysfunction 0.01 0.1110100 Favors edFavors ed bleeding

153 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/Flinearly correlated with CrCl Result: Tmax: 3-4 hours Amax: 10-35% higher in RI groups CI/Flinearly correlated with CrCl Day 4 CL/F(L/h)Half-life(h) AUC (0-24) (hIU/mL) Normals0.986.87 Mild RI 0.879.94 20% 20% Moderate RI 0.7611.3 21% 21% Severe RI 0.5815.9 65% 65%

154 LMWH Renal Dosing in NSTE ACS Patients 56 UA pts with CrCl <60 ml/min 56 UA pts with CrCl <60 ml/min Enoxaparin dose empirically and anti-Xa level measured after 3 rd dose Enoxaparin dose empirically and anti-Xa level measured after 3 rd dose 56 UA pts with CrCl <60 ml/min 56 UA pts with CrCl <60 ml/min Enoxaparin dose empirically and anti-Xa level measured after 3 rd dose Enoxaparin dose empirically and anti-Xa level measured after 3 rd dose CrCl (ml/min) (ml/min)<30 (n = 28) (n = 28) >30 and 30 and <60 (n =28) (n =28) Age76+/-373+/-3 Enoxaparin (mg/kg/12h) 0.640.84 Anti-Xa (IU/ml) 0.950.95 Collet JP et al. International J Cardiol 2001;80:81-2. Dose may be to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl 30-60 ml/minDose may be to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl 30-60 ml/min Anti-Xa monitoringAnti-Xa monitoring Doses appeared safeDoses appeared safe Further prospective evaluation neededFurther prospective evaluation needed

155 Clinical Use Of Recommended Enoxaparin Dosage in Renal Impairment Lachish T et al. Pharmacotherapy 2007; 27:1347-52. PEAK ANTI-Xa LEVELS TROUGH ANTI-Xa LEVELS N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h First dose Subsequent doses (second and third) Subsequent doses (second and third) 1.0. 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 1.0. 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Median 25-75% interquartile range Antifactor X1 Level (U/mL) 65432106543210 65432106543210 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 Trough Antifactor Xa Level (U/mL) Number of Patients

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

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

158 Shprecher AR et al. Pharmacotherapy 2005; 25:817-22. No difference in peak anti-Xa activity between normal patients and patients with renal impairement Clcr > 80 80 < 40 Mean peak 0.47 0.55 anti-Xa level after 5-6 doses N=11N=11 Dalteparin 100 U/kg q12h Peak Anti-Xa Levels According to Renal Function 1.5 1.0 0.5 0 1.5 1.0 0.5 0 Subjects without Renal impairment Subjects with Renal impairment Antifactor Xa Level (U/mL) x x x x

159 Pharmacokinetics of Prophylactic Doses of Dalteparin Tincani E et al. Haematologica 2006; 91:976-9. 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) 60-8930-59<30 Day 6 peak anti-Xa 0.0300.0330.048 Minor Bleeding 030 Major Bleeding 000 P=0.72P=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

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

161 Dosing of LMWHs In Renal Impairment Recommendations FOR CrCL < 30 ml/min Enoxaparin: Enoxaparin: Prophylaxis doses: 30 mg sq QD Prophylaxis doses: 30 mg sq QD Treatment doses: 1mg/Kg sq QD Treatment doses: 1mg/Kg sq QD Dalteparin and Tinzaparin: Dalteparin and Tinzaparin: no specific dosing guidelines no specific dosing guidelines No or lower degree of accumulation expected No or lower degree of accumulation expected Anti-Factor Xa activity monitoring Anti-Factor Xa activity monitoring FOR CrCL 30-50 mL/min No specific recommendations No specific recommendations Concern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?) Concern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?) Monitoring anti-Xa ? Monitoring anti-Xa ? FOR CrCL < 30 ml/min Enoxaparin: Enoxaparin: Prophylaxis doses: 30 mg sq QD Prophylaxis doses: 30 mg sq QD Treatment doses: 1mg/Kg sq QD Treatment doses: 1mg/Kg sq QD Dalteparin and Tinzaparin: Dalteparin and Tinzaparin: no specific dosing guidelines no specific dosing guidelines No or lower degree of accumulation expected No or lower degree of accumulation expected Anti-Factor Xa activity monitoring Anti-Factor Xa activity monitoring FOR CrCL 30-50 mL/min No specific recommendations No specific recommendations Concern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?) Concern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?) Monitoring anti-Xa ? Monitoring anti-Xa ? Nutescu E, et.al. Ann Pharmacother; 2009; in press.

162 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. < 20-15 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

163 Anti-Xa Activity Level Monitoring Enoxaparin 1mg/kg SQ pharmacokinetic profile Peak (goal ~ 0.5-1 U/ml) at 3-4 hrs Trough (goal < 0.5 U/ml) at 11-12 hrs Laposata et al. Arch Pathol Lab Med. 1998;122:799-807.

164 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 settingsLaboratory monitoring using an anti-Xa assay MAY be of value in certain clinical settings Use peak levels 4 hrs after SQ doseUse peak levels 4 hrs after SQ dose Through levels in renal impairment maybe preferredThrough levels in renal impairment maybe preferred Use chromogenic, not clot-based assaysUse chromogenic, not clot-based assays Peak:Peak: for BID dosing: 0.5-1.1U/mlfor BID dosing: 0.5-1.1U/ml for QD dosing: 1.0-2.0 U/mlfor QD dosing: 1.0-2.0 U/ml Through: < 0.4 U/mlThrough: < 0.4 U/ml 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 settingsLaboratory monitoring using an anti-Xa assay MAY be of value in certain clinical settings Use peak levels 4 hrs after SQ doseUse peak levels 4 hrs after SQ dose Through levels in renal impairment maybe preferredThrough levels in renal impairment maybe preferred Use chromogenic, not clot-based assaysUse chromogenic, not clot-based assays Peak:Peak: for BID dosing: 0.5-1.1U/mlfor BID dosing: 0.5-1.1U/ml for QD dosing: 1.0-2.0 U/mlfor QD dosing: 1.0-2.0 U/ml Through: < 0.4 U/mlThrough: < 0.4 U/ml Laposata et al. Arch Pathol Lab Med. 1998;122:799-807. Nutescu E, et.al. Ann Pharmacother; 2009; in press.

165 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 Pentasaccharide* concentration (µg/mL) 04 8 12162024283236 Donat F, et al. Clin Pharmacokinetics 2002; 41 (suppl 2):1-9. Time (h) Fondaparinux Pharmacokinetics 100% bioavailable C max = 0.34 µg/mL (SD: 0.04) T max = 1.7 h (SD: 0.4) T 1/2 = 17.2 h (SD: 3.2) Elimination = RENAL

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

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

168 Influence of Renal Function Fondaparinux vs Enoxaparin in ACS Fox KAA et al. Ann Intern Med 2007; 147:304-10. OASIS-5: Fondaparinux 2.5mg qd vs enoxaparin 1mg/kg q12h for 2-8 days

169 Electronic Alerts: Future Horizons Karen Fiumara, PharmD Medication Safety Officer Brigham and Womens Hospital Adjunct Assistant Professor of Pharmacy Practice Massachusetts College of Pharmacy and Allied Health Sciences Adjunct Assistant Professor of Pharmacy Practice Bouve College of Health Sciences Northeastern University Boston, MA Karen Fiumara, PharmD Medication Safety Officer Brigham and Womens Hospital Adjunct Assistant Professor of Pharmacy Practice Massachusetts College of Pharmacy and Allied Health Sciences Adjunct Assistant Professor of Pharmacy Practice Bouve College of Health Sciences Northeastern University Boston, MA A Year 2009 Update for The Health System Pharmacist

170 Past 10 years the prevention of medication errors has become a primary focus in healthcare 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 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 The IOM report To Err is Human have led to increased research and development of both medical informatics and computerized alerting systems Past 10 years the prevention of medication errors has become a primary focus in healthcare 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 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 The IOM report To Err is Human have led to increased research and development of both medical informatics and computerized alerting systems Background Bates DW et al. JAMA 1995;274:1311-16

171 CPOE : Friend or Foe? Recently, institutions are beginning to critically assess electronic systems, such as CPOE Recently, institutions are beginning to critically assess electronic systems, such as CPOE VA Medical Center in Salt Lake City: VA Medical Center in Salt Lake City: 74% of medication errors occur during prescribing 74% of medication errors occur during prescribing 11% during administration 11% during administration 0% during transcription 0% during transcription Bates et al. study: Bates et al. study: 56% of medication errors - prescribing 56% of medication errors - prescribing 24% of medication errors – administration 24% of medication errors – administration 6% of medication errors – transcription 6% of medication errors – transcription Recently, institutions are beginning to critically assess electronic systems, such as CPOE Recently, institutions are beginning to critically assess electronic systems, such as CPOE VA Medical Center in Salt Lake City: VA Medical Center in Salt Lake City: 74% of medication errors occur during prescribing 74% of medication errors occur during prescribing 11% during administration 11% during administration 0% during transcription 0% during transcription Bates et al. study: Bates et al. study: 56% of medication errors - prescribing 56% of medication errors - prescribing 24% of medication errors – administration 24% of medication errors – administration 6% of medication errors – transcription 6% of medication errors – transcription Nebeker JR et al. Arch of Intern Med 2005;165:1111-16.

172 VA Medical Center attributed low error rates during the transcription and administration to information system upgrades such as: 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 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 Concluded that their systems are working as designed but lack decision support within CPOE leading to high error rates during prescribing VA Medical Center attributed low error rates during the transcription and administration to information system upgrades such as: 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 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 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;165:1111-16. CPOE : Friend or Foe?

173 Institutions that utilize decision support and computerized alerts during prescribing have reported high rates of physician override 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 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 physicians decision 97.9% of the time Reviewers concluded of the 189 rules studied, 36.5% of the rules were invalid and agreed with the physicians decision 97.9% of the time Institutions that utilize decision support and computerized alerts during prescribing have reported high rates of physician override 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 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 physicians decision 97.9% of the time Reviewers concluded of the 189 rules studied, 36.5% of the rules were invalid and agreed with the physicians decision 97.9% of the time Weingart SN et al. Arch of Intern Med 2003;163:2625-31. CPOE Alerts

174 Saving CPOE from Extinction CPOE must evolve to keep up with the growing demand for effective medical informatics and technology solutionsCPOE 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 providersNext 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 prophylaxisOne area in which CPOE has proven beneficial is VTE prophylaxis CPOE must evolve to keep up with the growing demand for effective medical informatics and technology solutionsCPOE 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 providersNext 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 prophylaxisOne area in which CPOE has proven beneficial is VTE prophylaxis

175 Medical Error Rates Two errors per day = 99% proficiency level Two errors per day = 99% proficiency level If 99% was good enough: If 99% was good enough: How do we transform health care into a high reliability industry? How do we transform health care into a high reliability industry? Two errors per day = 99% proficiency level Two errors per day = 99% proficiency level If 99% was good enough: If 99% was good enough: How do we transform health care into a high reliability industry? How do we transform health care into a high reliability industry? Leape LL. JAMA. 1994;272:1851-7. –Airline industry = 2 unsafe landings per day –Banking industry = 32,000 checks deducted from the wrong account per hour –Mail industry = 16,000 pieces of mail lost every hour

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

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

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

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

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

181 Definition of High Risk VTE risk score 4 points: Cancer3(ICD codes) Cancer3(ICD codes) Prior VTE3(ICD codes) Prior VTE3(ICD codes) Hypercoagulability3(Leiden, ACLA) Hypercoagulability3(Leiden, ACLA) Major surgery2(> 60 minutes) Major surgery2(> 60 minutes) Bed rest1(bed rest order) Bed rest1(bed rest order) Advanced age1(> 70 years) Advanced age1(> 70 years) Obesity1(BMI > 29 kg/m 2 ) Obesity1(BMI > 29 kg/m 2 ) HRT/OC1(order entry) HRT/OC1(order entry) VTE risk score 4 points: Cancer3(ICD codes) Cancer3(ICD codes) Prior VTE3(ICD codes) Prior VTE3(ICD codes) Hypercoagulability3(Leiden, ACLA) Hypercoagulability3(Leiden, ACLA) Major surgery2(> 60 minutes) Major surgery2(> 60 minutes) Bed rest1(bed rest order) Bed rest1(bed rest order) Advanced age1(> 70 years) Advanced age1(> 70 years) Obesity1(BMI > 29 kg/m 2 ) Obesity1(BMI > 29 kg/m 2 ) HRT/OC1(order entry) HRT/OC1(order entry)

182 Randomization Kucher N, et al. NEJM 2005;352:969-977 VTE Risk Score > 4 No Prophylaxis N = 2506 Intervention Single Alert n = 1255 Control No Alert n = 1251

183 Physician Notification of Alerts

184

185 First Generation Computerized Alerts for VTE Prevention Utilization of computer generated alerts to house staff reduced the incidence of VTE by 41% 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 VTE prophylaxis was prescribed in 33.5% of patients in the intervention group Following study conclusion a follow up cohort study was conducted Following study conclusion a follow up cohort study was conducted Utilization of computer generated alerts to house staff reduced the incidence of VTE by 41% 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 VTE prophylaxis was prescribed in 33.5% of patients in the intervention group Following study conclusion a follow up cohort study was conducted Following study conclusion a follow up cohort study was conducted Kucher N, et al. NEJM. 2005;352:969-977.

186 Second Generation: Electronic Computer Generated Alerts Alerts

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

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

189 DVT Alert Screen

190 Rule Logic – Alert Details

191 Option A

192

193 Option C or Done

194

195

196 Escalation and Timing of Alerts Alerts should be set up to generate each day at 8:30 AM 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. If an alert was not acknowledged after 24 hours the attending physician on record should be text paged. Alerts should be set up to generate each day at 8:30 AM 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. If an alert was not acknowledged after 24 hours the attending physician on record should be text paged.

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

198 Human Alerts Pharmacy/Physician Collaboration Alerts

199 VTE Prophylaxis: hALERT Multicentered RCT of human alerts (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. 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? Can a human alert be more effective than an electronic alert? Multicentered RCT of human alerts (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. 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? Can a human alert be more effective than an electronic alert?

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

201 hALERT: Capturing New Prophylaxis Orders Enrolled patients must be reexamined in 24-48 hours to determine whether prophylaxis orders were written. Enrolled patients must be reexamined in 24-48 hours to determine whether prophylaxis orders were written. Capturing prophylaxis orders after enrollment applies to both the Intervention Group and to the Control Group. Capturing prophylaxis orders after enrollment applies to both the Intervention Group and to the Control Group. Enrolled patients must be reexamined in 24-48 hours to determine whether prophylaxis orders were written. Enrolled patients must be reexamined in 24-48 hours to determine whether prophylaxis orders were written. Capturing prophylaxis orders after enrollment applies to both the Intervention Group and to the Control Group. Capturing prophylaxis orders after enrollment applies to both the Intervention Group and to the Control Group.

202 Human Alert Trial 1.Human (often RN or pharmacist) issues the Alert, not a computer 2.The attending physician, not the intern, receives the Alert 3.Diversity of centers: community, suburban, throughout the USA 4.Will attendings pay more attention than house staff? 1.Human (often RN or pharmacist) issues the Alert, not a computer 2.The attending physician, not the intern, receives the Alert 3.Diversity of centers: community, suburban, throughout the USA 4.Will attendings pay more attention than house staff?

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

204 Electronic Alerts to Prevent Infusion Errors Alerts

205 Patient CaseInfusion Pump Error Error Description 57 YOM endstage CMP 57 YOM endstage CMP EF = 10% EF = 10% Heart transplant candidate with BIVAD Heart transplant candidate with BIVAD Receiving UFH 900 units per hour (9 mls/hr) Receiving UFH 900 units per hour (9 mls/hr) New order to reduce Heparin 800 units per hour @ 10:22 PM New order to reduce Heparin 800 units per hour @ 10:22 PM Infusion pump set for 800 mls per hour Infusion pump set for 800 mls per hour Error Description 57 YOM endstage CMP 57 YOM endstage CMP EF = 10% EF = 10% Heart transplant candidate with BIVAD Heart transplant candidate with BIVAD Receiving UFH 900 units per hour (9 mls/hr) Receiving UFH 900 units per hour (9 mls/hr) New order to reduce Heparin 800 units per hour @ 10:22 PM New order to reduce Heparin 800 units per hour @ 10:22 PM Infusion pump set for 800 mls per hour Infusion pump set for 800 mls per hour 8:45 PM aPTT = 75.1 8:45 PM aPTT = 75.1 1:13 AM Protamine 25mg 1:13 AM Protamine 25mg 1:28 AM aPTT = >150 1:28 AM aPTT = >150 3:13 AM aPTT = >150 3:13 AM aPTT = >150 3:32 AM Protamine 26mg 3:32 AM Protamine 26mg 2 Units PRBC 2 Units PRBC 4:08 AM aPTT = >150 4:08 AM aPTT = >150 8:21 AM aPTT = 44.4 8:21 AM aPTT = 44.4

206 Background Rank Medications Causing Harm 1.Insulin 2.Morphine 3.Heparin 4.Warfarin 5.Potassium 6.Furosemide 7.Vancomycin 8.Hydromorphone 9.Meperidine 10.Diltiazem MEDMARXSM 2001. The United States Pharmacopoeia (USP)Convention Inc. Heparin has been identified both nationally and internally at BWH as a medication frequently associated with ADEHeparin has been identified both nationally and internally at BWH as a medication frequently associated with ADE Removed access to different formulationsRemoved access to different formulations Standardized UFH ConcentrationStandardized UFH Concentration Calculate infusion rates in OECalculate infusion rates in OE National Data

207 UFH Error Analysis: BWH 1 event per 1,000 patients 1 event per 1,000 patients 52% - Administration related 52% - Administration related 31% - Equipment failure, rate or dosing error 31% - Equipment failure, rate or dosing error 23% - Infusion Pump 23% - Infusion Pump 6% - Prolonged LOS or significant harm 6% - Prolonged LOS or significant harm 1 event per 1,000 patients 1 event per 1,000 patients 52% - Administration related 52% - Administration related 31% - Equipment failure, rate or dosing error 31% - Equipment failure, rate or dosing error 23% - Infusion Pump 23% - Infusion Pump 6% - Prolonged LOS or significant harm 6% - Prolonged LOS or significant harm Fanikos J et al. Medication Errors associated with anticoagulation therapy in the hospital. Am J Cardiol 2004;94:532-535 ***Patient Safety Initiative: Hospital invested 3 million dollars in state of the art infusion pumps***

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

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

210

211

212

213

214 Methods We programmed the drug library to alert for overdoses or underdoses We programmed the drug library to alert for overdoses or underdoses Alerts where subsequently recorded in the devices electronic memory, along with the users next action Alerts where subsequently recorded in the devices electronic memory, along with the users next action We retrospectively reviewed all anticoagulant alerts and the users next action for all devices from 10/2003 through 1/2005 We retrospectively reviewed all anticoagulant alerts and the users next action for all devices from 10/2003 through 1/2005 We programmed the drug library to alert for overdoses or underdoses We programmed the drug library to alert for overdoses or underdoses Alerts where subsequently recorded in the devices electronic memory, along with the users next action Alerts where subsequently recorded in the devices electronic memory, along with the users next action We retrospectively reviewed all anticoagulant alerts and the users next action for all devices from 10/2003 through 1/2005 We retrospectively reviewed all anticoagulant alerts and the users 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

215 Dosing Errors and their Magnitude

216 Data Entry Errors Frequently Repeated with UFH 27.2 % entry errors User repeated the error

217 Alerts by Time of Day

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


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