Presentation on theme: "A Year 2009 Update for The Health System Pharmacist The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Program Co-Chairs Edith."— Presentation transcript:
2A Year 2009 Update forThe Health System PharmacistThe Pharmacologic Foundations of DVT Prophylaxis in the Setting of CancerProgram Co-ChairsEdith Nutescu, PharmD, FCCPClinical Associate ProfessorPharmacy PracticeAffiliate Faculty, Center forPharmacoeconomic ResearchDirector, Antithrombosis CenterThe University of Illinois at ChicagoCollege of Pharmacy & Medical CenterChicago, ILSamuel Z. Goldhaber, MDProfessor of MedicineHarvard Medical SchoolCardiovascular DivisionDirector, Venous ThromboembolismResearch GroupBrigham and Women’s HospitalBoston, MA
3Welcome and Program Overview Jointly sponsored by the University of Florida College of Pharmacy and CMEducation Resources, LLC. Jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Eisai, Inc. Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program
4CEU Credit Designation Statement The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The University of Florida College of Pharmacy will mail the Statements of Continuing Pharmacy Education Credit within 4 weeks after the course. To receive credit you must attend the sessions for which you want credit and complete an evaluation form. The College of Pharmacy will award 2 (two) continuing pharmacy education credits (2.0 CEU’s) upon completion of this program.
5Program Educational Objectives As a result of this session, attendees will be able to:List the recent trials, research, and expert analysis of issues focused on thrombosis and cancer.Outline specific strategies for risk-directed prophylaxis against DVT in at-risk patients with cancer.Describe dose anticoagulation therapy for patients requiring prophylaxis in special patient populations.Outline steps for avoiding medication errors using anticoagulation in cancer patients at risk for DVT.List the guidelines for DVT prophylaxis in cancer issued by the National Comprehensive Cancer Network (NCCN), the American College of Chest Physicians (ACCP), and the Surgeon General’s Report.
6Program Faculty Program Co-Chairs Edith Nutescu, PharmD, FCCP Clinical Associate Professor, Pharmacy PracticeAffiliate Faculty, Center for PharmacoeconomicResearchDirector, Antithrombosis CenterThe University of Illinois at ChicagoCollege of Pharmacy & Medical CenterChicago, ILSamuel Z. Goldhaber, MDProfessor of MedicineHarvard Medical SchoolCardiovascular DivisionDirector, Venous Thromboembolism ResearchGroupBrigham and Women’s HospitalBoston, MADistinguished Experts and PresentersJohn Fanikos, RPh, MBAAssistant Director of PharmacyBrigham and Women’s HospitalAssistant Clinical Professor of PharmacyNortheastern UniversityMassachusetts College of PharmacyBoston, MAKaren Fiumara, PharmDMedication Safety OfficerAdjunct Assistant Professor of Pharmacy PracticeMassachusetts College of Pharmacy and AlliedHealth SciencesBouve’ College of Health Sciences NortheasternUniversity
7Faculty COI Financial Disclosures Samuel Z. Goldhaber, MDGrant/Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; sanofi-aventis;Consultant: Boehringer-Ingelheim; BMS; Eisai; Merck; Pfizer; sanofi-aventisEdith Nutescu, PharmDSpeakers Bureau: Eisai Inc., GlaxoSmithKline, sanofi-aventis U.S.Advisory Committees or Review Panels, Board Membership, etc.: Boehringer Ingelheim Pharmaceuticals, Inc., Scios Inc.Karen Fiumara, PharmDNothing to discloseJohn Fanikos, RPh, MBASpeakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines Company
8Cancer and Prevention of VTE A Year 2009 Update forThe Health System PharmacistCancer and Prevention of VTELandmark Advances and New Paradigms of Care for the Health System PharmacistProgram Co-ChairSamuel Z. Goldhaber, MDProfessor of MedicineHarvard Medical SchoolCardiovascular DivisionDirector, Venous Thromboembolism Research GroupBrigham and Women’s HospitalBoston, MA
9VTE and Cancer—A Looming National Healthcare Crisis MISSION AND CHALLENGESRecognizing cancer patients at risk for DVT and identifying appropriate candidates for long-term prophylaxis and/or treatment with approved and indicated therapies are among the most important challenges encountered in contemporary pharmacy and clinical practice.
11Epidemiology of First-Time VTE VariableFindingSeasonal VariationPossibly more common in winter and less common in summerRisk Factors25% to 50% “idiopathic”15%-25% associated with cancer20% following surgery (3 months)Recurrent VTE6-month incidence, 7%;Higher rate in patients with cancerRecurrent PE more likely after PE than after DVTDeath After Treated VTE30-day incidence 6% after incident DVT30-day incidence 12% after PEDeath strongly associated with cancer, age, and cardiovascular diseaseWhite R. Circulation. 2003;107:I-4 –I-8.)
12Epidemiology of VTEOne major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders.Overall, about 25% to 50% of patient with first-time VTE have an idiopathic condition, without a readily identifiable risk factor.Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease.White R. Circulation. 2003;107:I-4 –I-8.)
14Acute Medical Illness and VTE Multivariate Logistic Regression Modelfor Definite Venous Thromboembolism (VTE)Risk FactorOdds Ratio(95% CI)X2Age > 75 yearsCancerPrevious VTE1.03 ( )1.62 ( )2.06 ( )0.00010.080.02Acute infectious disease1.74 ( )Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:
15Comorbid Condition and DVT Risk Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%.The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively.Together, the 8 risk factors accounted for 74% of disease occurrenceHeit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med. 2002 Jun 10;162(11): Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study
16VTE Recurrence Hazard Ratio Baseline Characteristic Predictors of First Overall VTE RecurrenceBaseline CharacteristicHazard Ratio(95% CI)Age1.17 ( )Body Mass Index1.24 ( )Neurologic disease with extremity paresis1.87 ( )Malignant neoplasmWith chemotherapyWithout chemotherapy4.24 ( )2.21 ( )Heit J, Mohr D, et al. Arch Intern Med. 2000;160:
17ICOPER Cumulative Mortality 51015202517.5%Mortality (%)714306090Days From DiagnosisLancet 1999;353:
18Stages of Chronic Venous Insufficiency Varicose veinsAnkle/ leg edemaStasis dermatitisLipodermatosclerosisVenous stasis ulcer
19Progression of Chronic Venous Insufficiency From UpToDate 2006
20Rising VTE Incidence in Hospitalized Patients Stein PD et al. Am J Cardiol 2005; 95:
22ImplementationImplementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines.
23SURGEON GENERAL: CALL TO ACTION TO PREVENT DVT AND PE September 15, 2008
24Surgeon General’s Call to Action 42-Page Document Issued September 15, 2008Endorsed by Secretary, HHSEndorsed by Director, NHLBIForeword by Acting Surgeon General, Steven K. Galson, MD, MPH (RADM, U.S. Public Health Service)
25Call to Action for VTE Foreword Dr. Galson’s 1st Call To Action > 350, ,000 Americans suffer VTE annually> 100,000 U.S. deaths per yearNegative impact on QOL of survivors“Must disseminate info widely” to “address gap” because we’re not applying knowledge systematically
26Call to Action for VTEI. Major Public Health Problem II. Reducing VTE Risk III. Gaps in Application, Awareness of Evidence IV. Public Health Response V. Catalyst for Action
27Symposium ThemesCancer rates are increasing as heart disease Rx improves and as cancer Rx improves.Cancer increases VTE risk.VTE is preventable (immunize!)VTE prophylaxis may slow cancerIncreased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATFFacilitate prophylaxis with alerts.
28Cancer and Prevention of VTE A Year 2009 Update forThe Health System PharmacistCancer and Prevention of VTELandmark Advances and New Paradigms of Care for the Health System PharmacistEdith Nutescu, PharmD, FCCPClinical Associate ProfessorPharmacy PracticeAffiliate Faculty, Center forPharmacoeconomic ResearchDirector, Antithrombosis CenterThe University of Illinois at ChicagoCollege of Pharmacy & Medical CenterChicago, IL
29Peculiar Relationship Between Cancer and Thrombosis may indicateHypercoagulation/thrombosisOccult Cancermay causeHypercoagulation/thrombosisCancer
30Thromboembolism in Malignancy 15% of cancer patients develop venous or arterial thrombosis1Annual incidence of VTE in all patients: 117 in 100,0002Cancer increases risk of thrombosis 4.1-fold3Chemotherapy increases risk of thrombosis 6.5-fold3Annual incidence of VTE in patients with cancer: 1 in 20041. Green KB, Silverstein RL. Hematol Oncol Clin North Am. 1996;10:2. Silverstein MD et al. Arch Intern Med. 1998;158:3. Heit JA et al. Arch Intern Med. 2000;160:4. Lee AYY, Levine MN. Circulation. 2003;107(23 Suppl 1):I17-21.
31Factors That May Affect Risk for Cancer-Associated VTE Patient-related factorsOlder ageComorbiditiesTreatment-related factorsRecent surgeryHospitalizationChemotherapyHormonal therapyAntiangiogenic agentsErythropoiesis-stimulating agentsCancer-related factorsSite of cancerAdvanced stageInitial period after diagnosisBiological factors (biomarkers)Elevated pre-chemotherapy platelet countD-dimerTissue factor expression by tumor cellsA wide range of factors may influence risk for cancer-associated VTE1Rao MV, et al., In Khorana AA, Francis CW, eds. 2007
32Risk of Inpatient VTE by Type of Cancer n= n=68 n=326 n=43 n=51 n=53 n=55 n=127 n=951412.10129.50108.967.417.64Rate of VTE, %87.006.756.505.37642In a study of 3550 patients hospitalized for neutropenic cancer, venous thromboembolism (VTE) occurred in 5.37%1The differing rates of VTE among types of cancer suggest that factors intrinsic to each kind of tumor may contribute to hypercoagulability1AllBrainLungStomachColonPancreaticOther AbdominalOvarianEndometrial/ CervicalIn hospitalized neutropenic cancer patientsKhorana AA et al. J Clin Oncol. 2006;24:_______________________________________________________________________________________Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:
33Risk of Inpatient VTE by Type of Cancer N=3550 n=641 n=650 n=79 n=262 n=20475.7965.375.0154.393.873.934Rate of VTE, %321In this figure, a continuation of data from the same study of 3550 hospitalized cancer patients shown in the preceding slide, the rates of venous thromboembolism (VTE) are relatively lower, and the Y axis maximum is 5.79%, compared with 12.1% in the previous figure1AllLeukemiaNHLHodgkin’sMyelomaBreastIn hospitalized neutropenic cancer patientsKhorana AA et al. J Clin Oncol. 2006;24:_______________________________________________________________________________________Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:
34Patients With Cancer Represent About 20% of All DVT and PE Patients with cancer: approximately 19.8%Patients with cancer represent about 20% of all DVT and PEAll DVT and PEHeit JA. et al. Arch Intern Med 2002;162:_______________________________________________________________________________________Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: see MRL. Arch Intern Med. 2002;162:
35VTE, Cancer, and Survival N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer0.000.200.401.000.800.60DVT/PE and Malignant DiseaseMalignant DiseaseDVT/PE OnlyNonmalignant DiseaseNumber of DaysProbability of DeathLevitan N, et al. Medicine 1999;78:285
36VTE and Inpatient Mortality No Venous ThromboembolismVenous Thromboembolism20181616.1316.411414.8512Mortality, %1010.5988.677.98642A recent study showed that the mortality rate was significantly lower in hospitalized neutropenic cancer patients with no diagnosed venous thromboembolism (VTE) than in those with identified VTE (7.98% vs 14.85%, respectively; P<0.0001)1All (n=66,016)Nonmetastatic Cancer (n=20,591)Metastatic Cancer (n=17,360)Khorana AA et al. J Clin Oncol. 2006;24:_______________________________________________________________________________________Khorana AA, Francis CW, Culakova E, et al. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:
37Prophylaxis Rates in Hospitalized Patients Amin A et al. J Thromb Haemost. 2007; 5:37
38Patients Receiving Appropriate DVT Prophylaxis, % Thromboprophylaxis Is Underutilized in Non-surgical Patients With CancerPremiere Perspective™ database: 72,391 discharges from 225 hospitals between January 2002 and September 2005Patients Receiving Appropriate DVT Prophylaxis, %Data from the Premiere Perspective™ database of over 72,000 discharges from 225 US hospitals between January 2002 and September 2005 show that thromboprophylaxis is widely underused among cancer patients1The study analyzes medical records and determines if patients should have received DVT prophylaxis according to the 2004 ACCP guidelines1Only about 30% of all patients with cancer received appropriated DVT prophylaxis127.7% of nonsurgical patients with cancer received appropriate prophylaxis1Amin AN et al. J Clin Oncol. 2007;25 (suppl):Abstract 9047._______________________________________________________________________________________Amin AN, Stemkowski SA, Lin J, Yang G. Assessing adherence to the American College of Chest Physicians’ (ACCP) recommendations for thromboprophylaxis in hospitalized cancer patients ASCO Annual Meeting Proceedings Part I. J Clin Oncol. 2007;25(18S)(suppl): Abstract 9047.
39Clots and Cancer—A Looming National Healthcare Crisis MISSION AND CHALLENGESRecognizing 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.
40A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Clotting, Cancer, and ControversiesA Systematic Analysis of VTE Prophylaxisin the Setting of CancerLinking Science and Evidence to Clinical Practice—What Do Trials Teach the Health System Pharmacist?Program Co-ChairmanSamuel Z. Goldhaber, MDProfessor of MedicineHarvard Medical SchoolCardiovascular DivisionDirector, Venous Thromboembolism Research GroupBrigham and Women’s HospitalBoston, MA
41VTE and Cancer: Epidemiology Of all cases of VTE:About 20% occur in cancer patientsAnnual incidence of VTE in cancer patients ≈ 1/250Of all cancer patients:15% will have symptomatic VTEAs many as 50% have VTE at autopsyCompared to patients without cancer:Higher risk of first and recurrent VTEHigher risk of bleeding on anticoagulantsHigher risk of dyingLee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
42DVT and PE in Cancer Facts, Findings, and Natural History VTE is the second leading cause of death in hospitalized cancer patients1,2The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4Let’s continue examining the association between DVT/PE and cancer.Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE.As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer.Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer.Ambrus JL et al. J Med. 1975;6:61-64Donati MB. Haemostasis. 1994;24:Johnson MJ et al. Clin Lab Haem. 1999;21:51-54Prandoni P et al. Ann Intern Med. 1996;125:1-7
43Clinical Features of VTE in Cancer VTE has significant negative impact on quality of lifeVTE may be the presenting sign of occult malignancy10% with idiopathic VTE develop cancer within 2 years20% have recurrent idiopathic VTE25% have bilateral DVTBura et. al., J Thromb Haemost 2004;2:445-51
44Thrombosis and Survival Likelihood of Death After Hospitalization 0.000.200.401.000.800.60DVT/PE and Malignant DiseaseMalignant DiseaseDVT/PE OnlyNonmalignant DiseaseNumber of DaysProbability of DeathLevitan N, et al. Medicine 1999;78:285
45Hospital Mortality With or Without VTE N=66,016N=20,591N=17,360Khorana, JCO, 2006
46Trends in VTE in Hospitalized Cancer Patients 7.06.56.05.55.04.54.0Rate of VTE (%)3.53.02.52.01.51.0P<0.00010.50.0199519961997199819992000200120022003VTE- patients on chemotherapyVTE-all patientsDVT-all patientsPE-all patientsKhorana AA et al. Cancer
47Thrombosis Risk In Cancer Primary ProphylaxisMedical InpatientsSurgeryRadiotherapyCentral Venous Catheters
49VTE Risk And Cancer Type “Solid And Liquid Malignancies” Relative Risk of VTE Ranged From 1.02 to 4.344.543.532.521.510.5PancreasBrainMyeloprolStomachLymphomaUterusLungEsophagusProstateRectalKidneyColonOvaryLiverLeukemiaBreastCervixBladderRelative Risk of VTE inCancer PatientsStein PD, et al. Am J Med 2006; 119: 60-68
51Thromboembolism in Hospitalized Neutropenic Cancer Patients Retrospective cohort study of discharges using the University Health System Consortium66,106 adult neutropenic cancer patients between 1995 and 2002 at 115 centersKhorana, JCO, 2006
52Neutropenic Patients: Results 8% had thrombosis5.4% venous and 1.5% arterial in 1st hospitalizationPredictors of thrombosisAge over 55Site (lung, GI, gynecologic, brain)Comorbidities (infection, pulmonary and renal disease, obesity)Khorana, JCO, 2006
53Predictors of VTE in Hospitalized Cancer Patients CharacteristicORP ValueSite of CancerLungStomachPancreasEndometrium/cervixBrain220.127.116.112.2<0.0010.0035Age 65 y1.10.005Arterial thromboembolism1.40.008Comorbidities (lung/renal disease, infection, obesity)[Khorana.JClinOncol. Jan.2006/p489/Table 4]Khorana AA et al. J Clin Oncol. 2006;24:
54Antithrombotic Therapy: Choices Pharmacologic(Prophylaxis & Treatment)Nonpharmacologic(Prophylaxis)Low Molecular Weight Heparin (LMWH)IntermittentPneumaticCompressionElasticStockingsUnfractionatedHeparin (UH)InferiorVena CavaFilterSeveral classes of agents have been used for prophylaxis and treatment of VTENonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filterMost commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs)OralAnticoagulantsNew Agents: e.g.Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?
55Prophylaxis Studies in Medical Patients Relative risk reduction 47%Relative risk reduction 63%Rate of VTE (%)Relative risk reduction 44%Placebo EnoxaparinMEDENOX TrialPlacebo DalteparinPREVENTPlacebo FondaparinuxARTEMISFrancis, NEJM, 2007
56ASCO Guidelines 1. SHOULD HOSPITALIZED PATIENTS WITH CANCER RECEIVE ANTICOAGULATION FORVTE PROPHYLAXIS?Recommendation. Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation.Lyman GH et al. J Clin Oncol (25) 2007; 34:
58Incidence of VTE in Surgical Patients Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis:No CancerN=16,954CancerN=6124P-valuePost-op VTE0.61%1.26%<0.0001Non-fatal PE0.27%0.54%<0.0003Autopsy PE0.11%0.41%Death0.71%3.14%Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
59Natural History of VTE in Cancer Surgery: The @RISTOS Registry Web-Based Registry of Cancer SurgeryTracked 30-day incidence of VTE in 2373 patientsType of surgery• 52% General• 29% Urological• 19% Gynecologic82% received in-hospital thromboprophylaxis31% received post-discharge thromboprophylaxisFindings2.1% incidence of clinically overt VTE (0.8% fatal)Most events occur after hospital dischargeMost common cause of 30-day post-op deathAgnelli, Ann Surg 2006; 243: 89-95
60Prophylaxis in Surgical Patients LMWH vs. UFHAbdominal or pelvic surgery for cancer (mostly colorectal)LMWH once daily vs. UFH tid for 7–10 days post-opDVT on venography at day 7–10 and symptomatic VTEStudyNDesignRegimensENOXACAN 1631double-blindenoxaparin vs. UFHCanadian Colorectal DVT Prophylaxis 24751. ENOXACAN Study Group. Br J Surg 1997;84:1099–1032. McLeod R, et al. Ann Surg 2001;233:
61Prophylaxis in Surgical Patients Canadian Colorectal DVT Prophylaxis Trial16.9%P=0.05213.9%Incidence of Outcome EventN=234N=2411.5% 2.7%VTE Major Bleeding(Cancer) (All)McLeod R, et al. Ann Surg 2001;233:
62Extended Prophylaxis in Surgical Patients 12.0%ENOXACAN IIP=0.02Incidence of Outcome EventN=1674.8%5.1%N=1653.6%1.8%NNT = 140.6%0% 0.4%VTE Prox Any MajorDVT Bleeding BleedingBergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:
63Major Abdominal Surgery: FAME Investigators—Dalteparin Extended A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatmentRESULTS: Cumulative incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15-76; P=0.012).CONCLUSIONS: 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis.Rasmussen, J Thromb Haemost Nov;4(11): Epub 2006 Aug 1.
64ASCO Guidelines: VTE Prophylaxis All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis.Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis.Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features.Lyman GH et al. J Clin Oncol (25) 2007; 34:
65Central Venous Catheters Thrombosis is a potential complication of central venous catheters, including these events:Fibrin sheath formationSuperficial phlebitisBall-valve clotDeep vein thrombosis (DVT)Geerts W, et al. Chest Jun 2008: 381S–453S
66Prophylaxis for Venous Catheters Placebo-Controlled TrialsStudyRegimenNCRT (%)Reichardt* 2002Dalteparin 5000 U dailyplacebo28514011 (3.7)5 (3.4)Couban*2002Warfarin 1mg daily1301256 (4.6)5 (4.0)ETHICS†2004Enoxaparin 40 mg daily15522 (14.2)28 (18.1)*symptomatic outcomes; †routine venography at 6 weeksReichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730
67Central Venous Catheters: Warfarin Tolerability of Low-Dose Warfarin95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailyINR measured at baseline and four time points10% of all recorded INRs >1.5Patients with elevated INR2.0– %3.0– %> %Masci et al. J Clin Oncol. 2003;21:
68Prophylaxis for Central Venous Access Devices SummaryRecent 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 studiedLow-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis
698th 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
70Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient No recommendations from ACCPNo data from randomized trials (RCTs)Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian)Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.)
71Ambulatory Chemotherapy Patients Cancer and ThrombosisAmbulatory Chemotherapy Patients
72Risk Factors for VTE in Medical Oncology Patients Tumor typeOvary, brain, pancreas, lung, colonStage, grade, and extent of cancerMetastatic disease, venous stasis due to bulky diseaseType of antineoplastic treatmentMultiagent regimens, hormones, anti-VEGF, radiationMiscellaneous VTE risk factorsPrevious VTE, hospitalization, immobility, infection, thrombophilia
73Independent Risk Factors for DVT/PE Risk Factor/CharacteristicO.R.Recent surgery with institutionalization21.72Trauma12.69Institutionalization without recent surgery7.98Malignancy with chemotherapy6.53Prior CVAD or pacemaker5.55Prior superficial vein thrombosis4.32Malignancy without chemotherapy4.05Neurologic disease w/ extremity paresis3.04Serious liver disease0.10Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study.This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data.Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included.What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE.Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE.Heit JA et al. Thromb Haemost. 2001;86:
74VTE Incidence In Various Tumors Oncology SettingVTE IncidenceBreast cancer (Stage I & II) w/o further treatment0.2%Breast cancer (Stage I & II) w/ chemo2%Breast cancer (Stage IV) w/ chemo8%Non-Hodgkin’s lymphomas w/ chemo3%Hodgkin’s disease w/ chemo6%Advanced cancer (1-year survival=12%)9%High-grade glioma26%Multiple myeloma (thalidomide + chemo)28%Renal cell carcinoma43%Solid tumors (anti-VEGF + chemo)47%Wilms tumor (cavoatrial extension)4%Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
75Primary VTE Prophylaxis Recommended for hospitalized cancer patientsNot recommended or generally used for outpatientsVery little dataHeterogeneousNeed for risk stratification
76Ambulatory Cancer plus Chemotherapy Study MethodsProspective observational study of ambulatory cancer patients initiating a new chemotherapy regimen, and followed for a maximum of 4 cycles115 U.S. centers participatedPatients enrolled between March, 2002 and August, who had completed at least one cycle of chemotherapy were included in this analysisMETHODS: We analyzed data from a prospective observational study conducted by the Awareness of Neutropenia in Chemotherapy Study Group, funded by Amgen, Inc. Patients were enrolled on study at the start of a new chemotherapy regimen, and followed prospectively for a maximum of 4 cycles, at 115 participating US centers. Patients enrolled between March, 2002 and August, who had completed at least one cycle of chemotherapy were included in this analysis.Khorana, Cancer, 2005
77Ambulatory Cancer plus Chemotherapy Study MethodsVTE events were recorded during mid-cycle or new-cycle visitsSymptomatic VTE was a clinical diagnosis made by the treating clinicianStatistical analysisOdds ratios to estimate relative riskMultivariate logistic regression to adjust for other risk factorsVTE events were recorded during mid-cycle or new-cycle visits. Since this was an observational study, VTE was diagnosed by the treating physician by usual tests based on clinical suspicion. Statistical analysis included generation of odds ratios to estimate relative risk, and a logistic regression analysis to adjust for other risk factors. The predictive model was constructed based on the multivariate analysis. The risk score estimates for each variable were derived using beta-coefficients from the multivariate model. First order interactions were incorporated into the final score.Khorana, Cancer, 2005
78Incidence of VTE 0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% Baseline Cycle 1 Rate of VTE (%)A total of 58 patients (1.93%) developed VTE during a median follow-up period of 2.4 months (0.8%/month). One patient developed VTE prior to starting chemotherapy. The rate of VTE did not differ significantly among chemotherapy cycles, occurring in 0.77% during cycle 1, 0.74% during cycle 2, and 0.7% during cycle 3. As shown in this figure, the cumulative rate of VTE was 2.2% (95% CI, ) during cycles 1 through 3.VTE / 2.4 monthsVTE/monthVTE /cycleCumulative rate (95% CI)1.93%0.8%0.7%2.2% ( )Khorana, Cancer, 2005
79Risk Factors: Site of Cancer 121086VTE (%) / 2.4 months42The primary site of cancer affected the risk of VTE (p=0.01), with the highest rates observed in patients with upper gastrointestinal cancers (particularly gastric and pancreatic) (2.3%/month), and lung cancer (1.2%/month). Among patients with hematologic malignancies, those with a diagnosis of Hodgkin’s or non-Hodgkin’s lymphoma had the highest rates of VTE (1.1%/month).LungNHLColonBreastUpper GIOthersHodgkin’sAll patientsSite of CancerKhorana, Cancer, 2005
80Incidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet Count p for trend=0.0050.0%0.5%1.0%1.5%2.0%2.5%3.0%3.5%4.0%4.5%5.0%<217>337Incidence Of VTE Over 2.4Months(%)This figure depicts the incidence of venous thromboembolism by quartiles of pre-chemotherapy platelet count. As can be seen, elevated platelet counts were associated with an increased risk of venous thromboembolism. Patients in the highest quartile of pre-chemotherapy platelet count with a count of > 337,000/ cu mm, had a 3.6% risk of VTE, and this was significantly greater than the 1.1 % risk observed with patients in the lowest quartile, with a pre-chemotherapy platelet count of < 217,000/ cu mm. The p value for trend was highly significant at 0.005, and the difference between the highest and lowest quartile was also significant at3Pre-chemotherapy Platelet Count/mm(x1000)Khorana, Cancer, 2005
81Risk Factors: Multivariate Analysis CharacteristicORP valueSite of CancerUpper GILungLymphoma3.881.861.50.030.00760.050.32Pre-chemotherapy platelet count > 350,000/mm32.810.0002Hgb < 10g/dL or use of red cell growth factor1.83Use of white cell growth factor in high-risk sites2.090.008We included clinically and statistically significant variables in a multivariate logistic regression analysis. This slide demonstrates variables found to be significant in this analysis. Risk factors independently associated with VTE included primary site of cancer (upper gastrointestinal or lung), an elevated pre-chemotherapy platelet count, hemoglobin < 10g/dL or use of erythropoietin (a combined variable), and use of white cell growth factors. We found a significant first-order interaction between site of cancer and use of white cell growth factors (p=0.02). Patients with sites of cancer associated with higher risk of VTE (upper gastrointestinal, lung or lymphoma) had a significantly increased risk of VTE associated with white cell growth factor use (VTE rate of 5.9% versus 1.52% without growth factor use, p =0.0001; odds ratio 4.0, [95% CI, ]). In contrast, patients with other sites of cancer did not appear to have an increased risk of VTE with the use of white cell growth factors (VTE rate of 1.31% versus 1.42% without growth factor use, p =0.84).Khorana, Cancer, 2005
82Patient Characteristic Predictive ModelPatient CharacteristicScoreSite of CancerVery high risk (stomach, pancreas)High risk (lung, lymphoma, gynecologic, GU excluding prostate)21Platelet count > 350,000/mm3Hgb < 10g/dL or use of ESALeukocyte count > 11,000/mm3BMI > 35Khorana AA et al. JTH Suppl Abs O-T-002
83Predictive Model Risk Score 1 2 3 4 N 1,352 974 476 160 33 0%2%4%6%8%10%12%14%16%18%1234Actual IncidenceEstimated Incidence95 % Confidence LimitsIncidence of VTE Over 2.4 MonthsThe performance of the predictive risk assessment model is illustrated in this figure, which shows the rate of VTE by risk score. As you can see, the predicted incidence of VTE, shown as a yellow line, correlates closely with the actual incidence of VTE, shown as red triangles. The goodness of the model fit was confirmed by Hosmer and Lemeshow test.The proposed predictive model discriminates well between subgroups of patients at low and high risk of VTE during chemotherapy. Patients with a risk score of 0 had a VTE rate of 0.8% over the median 2.4 month follow-up. In contrast, patients with a risk score of 2 had a 3-fold higher rate at 2.7%, and those with a risk score of 3 had a 6.3% rate of VTE.Risk Score1234N1,35297447616033VTE(%) /2.4 mos.0.81.82.76.313.2
84Predictive Model Validation 8%n=734n=1627n=3400.8%1.8%7.1%Development cohort7%0.3%2.0%6.7%Validation cohortn=374n=842n=1496%5%Rate of VTE over 2.5 mos (%)4%3%2%1%0%Risk Low (0) Intermediate(1-2) High(>3)Khorana AA et al. JTH Suppl Abs O-T-002
85Oral Anticoagulant Therapy in Cancer Patients: Problematic Warfarin therapy is complicated by:Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc.Frequent interruptions for thrombocytopenia and proceduresDifficulty in venous access for monitoringIncreased risk of both recurrence and bleedingIs it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?
86CLOT: Landmark Cancer/VTE Trial DalteparinDalteparinCANCER PATIENTS WITH ACUTE DVT or PERandomizationDalteparinOral Anticoagulant[N = 677]Primary Endpoints: Recurrent VTE and BleedingSecondary Endpoint: SurvivalLee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
87Landmark CLOT Cancer Trial Reduction in Recurrent VTE510152025Days Post Randomization306090120150180210Probability of Recurrent VTE, %Risk reduction = 52%p-value =DalteparinOACRecurrent VTELee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
89Treatment of Cancer-Associated VTE StudyDesignLength of Therapy(Months)NRecurrent VTE(%)Major BleedingDeathCLOT Trial(Lee 2003)DalteparinOAC633691743941CANTHENOX(Meyer 2002)Enoxaparin36771112171623LITE(Hull ISTH 2003)Tinzaparin8087822ONCENOX(Deitcher ISTH 2003)Enox (Low)Enox (High)3236318.104.22.168NS0.002NS0.090.090.030.03NSNSNSNSNR
90Treatment and 2° Prevention of VTE in Cancer – Bottom Line New DevelopmentNew standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendation—ACCP)NOTE: Dalteparin is only LMWH approved (May, 2007) for both the treatment and secondary prevention of VTE in cancerOral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—ACCP)Chest Jun 2008: 454S–545S
91CLOT 12-month Mortality All Patients Dalteparin OAC 102030405060708090100120180240300360DalteparinOACHR 0.94 P-value = 0.40Days Post RandomizationProbability of Survival, %Lee AY et al. J Clin Oncol. 2005; 23:
92Anti-Tumor Effects of LMWH CLOT 12-month MortalityPatients Without Metastases (N=150)102030405060708090100DalteparinOACProbability of Survival, %HR = P-value = 0.03306090120150180240300360Lee AY et al. J Clin Oncol. 2005; 23:Days Post Randomization
93LMWH for Small Cell Lung Cancer Turkish Study 84 patients randomized: Chemo +/- LMWH (18 weeks)Patients balanced for age, gender, stage, smoking history, ECOG performance statusChemotherapyplus DalteparinChemo aloneP-value1-y overall survival, %51.329.50.012-y overall survival, %17.20.0Median survival, m13.08.0CEV = cyclophosphamide, epirubicin, vincristine;LMWH = Dalteparin, 5000 units dailyAltinbas et al. J Thromb Haemost 2004;2:1266.
94VTE Prophylaxis Is Underused in Patients With Cancer [1/Kakkar. Oncologist.2003/ p381/c1/line A1-A24; p383/c1/line 44-46, c2/line 1-3][2/Stratton. ArchInternMed. Feb.2000/ p336/c2/line 7-11][3/Bratzler. ArchInternMed. Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3][4/Rahim.ThrmbRes. 2003/p3/c2/line 1-5][5/Goldhaber. AmJCardiol.Jan.2004/ p261/c2/line 6-8]Cancer:FRONTLINE Survey1— 3891 Clinician RespondentsMajor Surgery2Cancer: SurgicalMajor Abdominothoracic Surgery (Elderly)3Confirmed DVT (Inpatients)5Rate of Appropriate Prophylaxis, %Medical Inpatients4Cancer: MedicalVTE prophylaxis is underused in patients with cancerThe Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey was a questionnaire distributed globally to clinicians involved in cancer care and accessible on a dedicated Web site1Data from 3891 completed questionnaires were available for analysis1The results indicated that 52% of respondents would routinely utilize thromboprophylaxis for surgical oncology patients, and that most respondents only considered thromboprophlyaxis in approximately 5% of their medical oncology patients1These results can be compared with prophylaxis rates in other patient groups as determined by other recent studiesA retrospective record review in 10 US teaching or community-based hospitals of patients undergoing major surgeries (major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement) showed VTE prophylaxis was used in 89% of patients2A retrospective record review of patients aged 65 and older in 20 Oklahoma hospitals undergoing major abdominothoracic surgery indicated that prophylaxis was used in 38% of patients3A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis5[1/Kakkar.Oncologist. 2003/p381/c1/ line A5-A22][1/Kakkar/p381/c1/ line A23-A24][1/Kakkar/p383/c1/ line 44-46, c2/line 1-3][2/Stratton.ArchIntern Med.Feb.2000/ p334/c1/line A14-A19, c2/line A1-A2; p336/c2/line 7-11][3/Bratzler.ArchIntern Med.Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3][4/Rahim.ThrmbRes. 2003/p1/line A1-A12; p3/c2/line 1-5][5/Goldhaber.AmJ Cardiol.Jan.2004/ p259/c1/line A1-A10; p261/c2/line 6-8]1. Kakkar AK et al. Oncologist. 2003;8:2. Stratton MA et al. Arch Intern Med. 2000;160:3. Bratzler DW et al. Arch Intern Med. 1998;158:4. Rahim SA et al. Thromb Res. 2003;111:5. Goldhaber SZ et al. Am J Cardiol. 2004;93:1. Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8:2. Stratton MA, Anderson FA, Bussey HI, et al. Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients. Arch Intern Med. 2000;160:3. Bratzler DW, Raskob GE, Murray CK, Bumpus LJ, Piatt DS. Underuse of venous thromboembolism prophylaxis for general surgery patients: physician practices in the community hospital setting. Arch Intern Med. 1998;158:4. Rahim SA, Panju A, Pai M, Ginsberg J. Venous thromboembolism prophylaxis in medical inpatients: a retrospective chart review. Thromb Res. 2003;111:5. Goldhaber SZ, Tapson VF, for the DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol. 2004;93:
95Conclusions and Summary Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopeniaLong-term secondary prevention with LMWH has been shown to produce better outcomes than warfarinGuidelines and landmark trials support administration of LMWH in at risk patientsCancer patients are under-prophylaxed for VTEHealth system pharmacists can play a pivotal role in improving clinical outcomes in this patient population
96Venous Thromboembolism (VTE) Prophylaxis in the Clotting, Cancer, and Clinical StrategiesVenous Thromboembolism (VTE) Prophylaxis in theCancer Patient and BeyondGuidelines and Implications for Clinical PracticeJohn Fanikos, RPh, MBAAssistant Director of PharmacyBrigham and Women’s HospitalAssistant Clinical Professor of PharmacyNortheastern UniversityMassachusetts College of PharmacyBoston, MA
97Outline of Presentation Guidelines for VTE preventionPerformance to dateOpportunities for improvementGuidelines for VTE Treatment
98Prophylaxis Rates in Hospitalized Patients Amin A et al. J Thromb Haemost. 2007; 5:9898
99VTE, Cancer, and Survival N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer0.000.200.401.000.800.60DVT/PE and Malignant DiseaseMalignant DiseaseDVT/PE OnlyNonmalignant DiseaseNumber of DaysProbability of DeathLevitan N, et al. Medicine 1999;78:285
100Time Distribution of VTE Events Following Cancer Surgery @RISTOS Registry: prospective cohort N=23731210VTE Events86421-5 d6-10 d11-15 d16-20 d21-25 d26-30 d> 30 dAgnelli G et al. Ann Surg 2006; 243:89-95.100
101NCCN Clinical Practice Guidelines in Oncology™“…The panel of experts includes medical and surgical oncologists, hematologists, cardiologists, internists, radiologists. And a pharmacist.”Recommendations for VTE Prophylaxis & Treatment in Patients with Cancer
1021A is the highest possible grade 2004 ACCP RecommendationsCancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A)General, Gynecologic, Urologic SurgeryLow Dose Unfractionated Heparin 5,000 units TIDLMWH > 3,400 units DailyDalteparin 5,000 unitsEnoxaparin 40 mgTinzaparin 4,500 unitsGCS and/or IPCCancer patients with an acute medical illness receive prophylaxis that is appropriate for their current risk state (Grade 1A)Low Dose Unfractionated HeparinLMWHContraindication to anticoagulant prophylaxis (Grade 1C+)GCS or IPC[Geerts. Chest.Sept.2004/ p371S/c1/line 1-8][Geerts/ p338S/c1/Abstract/ line 4-8]In the 2004 guidelines on venous thromboembolism prophylaxis endorsed by the ACCP, Geerts and coworkers reviewed evidence from 11 studies on the use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in patients with general medical conditions1ACCP Grade 1A treatment options for deep vein thrombosis (DVT) prophylaxis in general medical patients with clinical risk factors for DVT/PE (including active cancer, bed rest, heart failure, severe lung disease, prior DVT/PE, sepsis, acute neurologic disease, or IBD)1LMWHLow-dose UFHThe investigators assigned a Grade of 1A to 2 for treatment options, defined as follows:1Grade 1: Benefits of a given intervention are certain to outweigh the risks, burdens, and costs of the interventionGrade 2: Less certainty that the benefits outweigh the risks, burdens, and costsMethodological quality of evidence subcategorized by letters A-CA: Randomized clinical trials (RCTs) with consistent resultsB: RCTs with inconsistent resultsC: Observational studies, generalizations from single patient group in an RCT compared to a similar patient group not in the RCT. More compelling evidence in this category is graded C+[1/Geerts. Chest.Sept.2004/ p371S/c1/line 1-8][1/Geerts/ p338S/c1/Abstract/ line 4-8]1A is the highest possible gradeIndicates that benefits outweigh risks, burdens, and costs, with consistent RCT level of evidenceGeerts WH et al. Chest. 2004;126(suppl):338S-400S___________________________________________________________________________________Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl):338S-400S.
103NCCN Practice Guidelines in VTE Disease At Risk Population Initial ProphylaxisContinue Prophylaxis After Discharge ?Prophylactic anticoagulation therapy (category 1) + sequential compression device (SCD)Adult patientDiagnosis or clinical suspicion of cancerInpatientNORelative contra-indication to anticoagulation treatmentMechanical prophylaxis (options)- SCD- Graduated compression stockingsYESModifiable risk factors: Lifestyle, smoking, tobacco, obesity, activity level/exerciseRISK FACTOR ASSESSMENTAgePrior VTEFamilial thrombophiliaActive cancerTraumaMajor surgical proceduresAcute or chronic medical illness requiring hospitalization or prolonged bed restCentral venous catheter/IV catheterCongestive heart failurePregnancyRegional bulky lymphadenopathy with extrinsic vascular compressionAGENTS ASSOCIATED WITH INCREASED RISKChemotherapyExogenous estrogen compounds- HRT- Oral contraceptives- Tamoxifen/Raloxifene- DiethystilbestrolThalidomide/lenalidomide
104NCCN Practice Guidelines in VTE Disease Inpatient Prophylactic Anticoagulation TherapyLMWH- Dalteparin 5,000 units subcutaneous daily- Enoxaparin 40 mg subcutaneous daily- Tinzaparin 4,500 units (fixed dose) subcutaneous daily or units/kg subcutaneous dailyPentasaccharide- Fondaparinux 2.5 mg subcutaneous dailyUnfractionated heparin 5,000 units subcutaneous 3 times daily
105NCCN Practice Guidelines in VTE Disease Relative Contraindications to Prophylactic orTherapeutic AnticoagulationRecent CNS bleed, intracranial or spinal lesion at high risk for bleedingActive bleeding (major): more than 2 units transfused in 24 hoursChronic, clinically significant measurable bleeding > 48 hoursThrombocytopenia (platelets < 50,000/mcL)Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis)Recent major operation at high risk for bleedingUnderlying coagulopathyClotting factor abnormalities- Elevated PT or aPTT (excluding lupus inhibitors)- Spinal anesthesia/lumbar punctureHigh risk for falls
106Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ? “Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation”Lyman GH et al. J Clin Oncol (25) 2007; 34:
107Incidence and Relative Risk of High-Grade VTE with Bevacizumab Tumor TypeNo. StudiesBevacizumabControlIncidenceRROverall13235/3795134/31676.31.38Colo-rectal496/131550/11287.31.56NSCLC78/122841/8626.61.24Breast Cancer220/59413/5613.91.47Renal Cell17/3372/3042.02.86Mesothelioma9/535/5517.01.89Pancreatic Cancer24/26823/2579.01.00SR Nalluri et al. JAMA 2008;300(19):
108Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy?“Routine prophylaxis is not recommended.”“Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis.”Lyman GH et al. J Clin Oncol (25) 2007; 34:
109Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ? All patients should be considered for thromboprophylaxis.Procedures greater than 30 minutes should receive pharmacologic prophylaxis.Mechanical methods should not be used as monotherapy.Prophylaxis should continue for at least 7-10 days post-op. Prolonged prophylaxis may be considered for cancer with high risk features.Lyman GH et al. J Clin Oncol (25) 2007; 34:
110Compliance With ACCP VTE Prophylaxis Guidelines Is Poor Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group9.9%6.7%35,12462,0125,00010,00070,000Number of patientsAt risk for DVT/PEReceived compliant care15.3%12.7%52.4%232491751388Orthopedic SurgeryAt-risk Medical ConditionsGeneral SurgeryUrologic SurgeryGynecologic Surgery[Yu.AHA.May [poster]p1/Fig 1, Fig 2][1/Yu.AHA.May [poster]p1/Fig 1, Fig 2]A study by Yu and colleagues showed that even when risk is recognized, the thromboprophylactic strategy chosen may be inadequateThe study assessed compliance with the 2001 ACCP guidelines for prophylaxis for DVT and PE. The authors looked at records from more than 120,000 adult hospital admissions between January 2001 and March 20051Orthopedic surgery patients (n=2324) had the highest rate of compliance, 52.4%1The rate of compliance for patients with at-risk medical conditions (n=62,012) was 15.3%. For general surgery patients (n=35,124), the rate of compliance was 12.7%1For urologic (n=1338) and gynecologic (n=9175) surgery patients, the rates of compliance were 9.9% and 6.7%, respectively1Overall, only 23.4% of patients received some form of prophylaxis and only 13.3% of patients received guideline-recommended prophylaxis1Thus, only about a quarter of patients received prophylaxis at all, and of those only about half received the prophylaxis recommended by ACCP guidelines for patients with their condition1Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based on the 6th American College of Chest Physicians (ACCP) guidelines.HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76_______________________________________________________________________________Yu H-T, Dylan ML, Lin J, Dubois RW. Prophylaxis of venous thromboembolism: do providers follow guidelines [poster]? Presented at the American Heart Association 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, May 7-9, 2006; Washington, DC.
111Reasons for Inadequate Duration of VTE Prophylaxis Started LateStarted late & Ended EarlyEnded EarlyAt-Risk Medical (n=5,994)1,347 (22.5)2,961 (49.4)1,686 (28.1)Abdominal Surgery (n=3,240)824 (25.4)1,764 (54.4)652 (20.1)Urologic surgery(n=158)18 (11.4)73 (46.2)67 (42.4)Gynecologic surgery (n=163)13 (8.0)43 (26.4)107 (65.6)Neurosurgery(n=250)66 (26.4)125 (50.0)59 (23.6)HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76
112Use of Thromboprophylaxis Predictors of theUse of ThromboprophylaxisEffect Odds Ratio (95% CI)Malignancy 0.40OthersInfectionBleeding RiskGenderHospital SizeAgeLOSCardiovascular DiseaseInternal MedicineRespiratoryAMCDuration of ImmobilityVTE Risk FactorsKahn SR et Al. Thromb Res 2007; 119:Odds Ratio
113Unfractionated Heparin Prophylaxis: BID vs TID—What Works, What Doesn’t? Meta-analysis:12 RCTsDVT, PE, all VTE events, BleedingProximal DVT plus PEBID VTE event rate:2.34 events per 1,000 patient daysTID event rate:0.86 events per 1,000 patient daysP=0.05NNT676 hospital prophylaxis days with UFH TID to prevent1 major bleed with 1,649 hospital prophylaxis days of TID dosingKing CS et al. CHEST 2007;131:
114Heparin, Low Molecular Weight Heparin Prophylaxis Meta-analysis36 randomized controlled trials23,000 hospitalized medical patientsUFH 5,000 units TID is more effective in preventing DVT than UFH BIDLow molecular weight heparin is 33% more effective than unfractionated heparin in preventing DVTRR for DVT 0.68 (p=0.004)LMWH vs UFHDVT RiskStudy Reduction (95% CI) Weight %Harenberg et al, ( )Turpie et al, ( )Dumas et al, ( )Bergmann & Neuhart ( )et al, 1996Harenberg et al, ( )Lechler et al, ( )Hillbom et al, ( )Kleber, et al ( )Diener et al, ( )Overall (95% CI) ( )Risk RatioLMWH Better LMWH WorseWein L et al. Arch Intern Med. 2007;167:
115BWH/DFCI Partners Cancer Care Experience Consecutive patients, < 60 days2 Nursing unitsLOS ranged from 3 days to 31 daysNumber of days where doses were omitted ranged from to 6 days
116VTE Incidence: More Common in the Outpatient Setting Medical records of residents (n=477,800)587 VTE events (104 per 100,000 population)30 Day recurrence 4.8 %Patients receiving prophylaxis during high risk periodsVTE Event LocationSpencer FA, et al. Jour Gen Int Med 2006; 21 (7):
117Thrombosis in Malignancy 7TH ACCP Consensus Conference Recommendations Initial Phase5-7 daysDalteparin 200/kg q24h(GRADE 1A)Chronic PhaseContinue anticoagulation (warfarin or LMWH) long-term or until malignancy resolves(GRADE 1C)days3 - 6 mos6 mos - indefiniteSubacute Phase3 - 6 monthsDalteparin* 150 units/kg q24h(GRADE 1A)* Dalteparin Approved for Extended Treatment to Reduce theRecurrence of Blood Clots in Patients with CancerBuller HR, et al. Chest 2004; 126 (suppl 3): 401s-428s
118Warfarin vs. Dalteparin for VTE Treatment in Malignancy Recurrent ThrombosisDalteparin: 9.0% of 336Warfarin: % of 336Dalteparin: 200 units/kg/dayx 1 mo, then 150 units/kg/dayWarfarin dosed to INR 2-3Duration: 6 months252015105P=0.002Oral anticoagulantProbability of Recurrent VenousThromboembolism (%)DalteparinDays after RandomizationNo. at RiskDalteparinOral anticoagulantLee AY et al. New Engl J Med 2003; 349:118
119Subgroup Analysis Dalteparin Warfarin P Value 12-month Cumulative Mortality RateDalteparinWarfarinP ValueMetastatic Disease (n=452)72%69%P = 0.46Non-metastatic Disease (n=150)20%36%P=0.03Failures defined as recurrent DVT.Lee AY et al. J Clin Oncol. 2005; 23:119
120Dalteparin Cost Effectiveness in Recurrent VTE Cost ParameterDalteparin (n=338)Warfarin (n=338)Drug2852269Laboratory303437Diagnostic Tests253267Unscheduled Visits286300Transfusions143208Major bleeding97.592.3VTE Recurrence228429Mean Cost Per Patient41622003Dranitsaris G. Pharmacoeconomics 2006; 24(6):
121NCCN Practice Guidelines—Venous Thromboembolic Disease Therapeutic Anticoagulation Treatment forDVT, PE, and Catheter-Associated ThrombosisImmediateLMWH- Dalteparin (200 units/kg subcutaneous daily)- Enoxaparin (1 mg/kg subcutaneous every 12 hrs)- Tinzaparin (175 units/kg subcutaneous daily)Pentasaccharide- Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [ lg]; 10 mg [>100 kg] subcutaneous dailyUnfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to x control)
122NCCN Practice Guidelines—Venous Thromboembolic Disease Therapeutic Anticoagulation Treatment forDVT, PE, and Catheter-Associated ThrombosisLong TermLMWH is preferred as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancerWarfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR )Duration of Long Term TherapyMinimum time of 3-6 mo for DVT and 6-12 mo for PEConsider indefinite anticoaugulation if active cancer or persistent risk factorsFor catheter associated thrombosis, anticoagulate as long as catheter is in place and for 1-3 mo after catheter removal
123What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE ? LMWH is the preferred approach for the initial 5-10 days.LMWH, given for at least 6 months, is the preferred for long-term anticoagulant therapy.After 6 months, anticoagulation therapy should be considered for select patients.For CNS malignancies, elderly patients anticoagulation is recommended with careful monitoring and dose adjustment.Lyman GH et al. J Clin Oncol (25) 2007; 34:
124Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?“Anticoagulants are not recommended to improve survival in patients with cancer without VTE.”Lyman GH et al. J Clin Oncol (25) 2007; 34:
125Antithrombotic Therapy Practices in U.S. Hospitals Survey of 38 U.S. Hospitalsn=939 DVT or PE50% patients reached INR >2 for 2 consecutive daysTherapyn (%)LMWH527 (56.1%)UFH562 (59.8%)UFH SC78 (8.3%)DTI6 (0.6%)Tapson V et al. Arch Intern Med 2005
126Self-Managed Long Term LMWH Therapy 2212 patients with proximal vein thrombosis assessed for eligibility1475 excluded for anticoagulant violations or inability to give written consent737 Randomized369 assigned to LMWH369 assigned to usual care with heparin and warfarin3 lost to follow-up1 withdrew consent3 lost to follow-up5 withdrew consent369 included in analysis369 included in analysisHull R. Am Jour Med 2007; 120:72-82
127Self-Managed Long Term LMWH Therapy OutcomesTinzaparin (n=369)Usual Care (n=368)Absolute Difference(95% CI)p-valueNew VTE at 3 Mos18 (4.9)21 (5.7)-0.8 ( )NSNew VTE at 12 Mos33 (8.9)36 (9.8)-0.8 ( )All Bleeding48 (13.0)73 (19.8)-6.8 ( )p=.011Major Bleeding12 (3.3)17 (4.6)-1.4 ( )Minor Bleeding56 (15.2)-5.5 ( )p=.022Stratified Bleeding-High Risk31/144 (21.5)39/146 (26.7)-5.2 (-15%-4.6%)Stratified Bleeding-Low Risk17/225 (7.6)34/222 (15.3)-7.8 ( %)p=.01Thrombocytopenia (<150)9 (2.4)1.6 ( )Bone Fracture4 (1.1)7 (1.9)-0.8 ( )Hull R. Am Jour Med 2007; 120:72-82
128LMWHs and Bleeding in Patients with Renal Dysfunction Dosage adjustmentsfor renal dysfunctionLim W et al. Ann Intern Med 2006; 144:673-84
129Barriers to Long-term Use of LMWH for Treatment of Cancer-associated VTEInitial treatmentLMWH for 3-6 months %UFH/LMWH for 5-7 days %followed by warfarinReasons LMWH not used long-termNot covered by medical insurance %Physician preference %Patient refused long-term injections %History of HIT %Severe renal insufficiency %Wittkowsky AK. J Thromb Haemost. 2006; 4:
130Examine your current practices of VTE prophylaxis and treatment ConclusionsExamine your current practices of VTE prophylaxis and treatmentReview available guidelines as a benchmarkConsider the use of a pharmacologic or mechanical interventionEvaluate use of Reminder or Risk Scoring SystemsUtilize the regimen providing the best efficacy in reducing events and offering best complianceFollow-up with patients to monitor and avoid adverse events and to ensure optimal outcomes
131Pharmacologic Prophylaxis of DVT in Special Populations A Year 2009 Update forThe Health System PharmacistPharmacologic Prophylaxis of DVT in Special PopulationsEdith Nutescu, PharmD, FCCPClinical Associate ProfessorPharmacy PracticeAffiliate Faculty, Center forPharmacoeconomic ResearchDirector, Antithrombosis CenterThe University of Illinois at ChicagoCollege of Pharmacy & Medical CenterChicago, IL
132ObjectivesDifferentiate data with various LMWHs in special populationsReview appropriate dosing and monitoring of LMWHs in patients with obesity and renal failureDiscuss cautions of using emerging agents in special populations
133Risk of Inadequate Therapy in High Risk Patients 524 VTE PatientsActive Cancer in 26%Only 1/3rd on LMWH monotherapyWeight > 100Kg in 15%Under-dosing of LMWH by > 10%36% of > pts 100Kg8% of pts < 100Kg (p < 0.001)CrCL < 30mL/min in 5%LMWH tx in 67%Cook LM, et.al. J Thromb Hemost 2007;5;
1348th ACCP Conference on Antithrombotic Therapy Obese Patients“In obese patients given LMWH prophylaxis or treatment, we suggest weight-based dosing (Grade 2C).”What is this weight-based dosing and how does it differ from typical dosing?At what weight do we move away from standard dosing and move to weight-based dosing?Hirsh J et al. Chest. 2008;133(suppl):141S-159S.
135Pharmacokinetic Characteristics of Low Molecular Weight Heparins Lipid solubility LOWPlasma protein binding HIGHTissue binding LOWVolume of Distribution 5-7 LLogical conclusion:IBW may be a better predictor of LMWH dosing than TBW
136LMWH: Maximum Weights Studied Kinetic StudiesClinical TrialsDalteparin190 kg128 kg*Enoxaparin144 kg194 kgTinzaparin165 kg88 kgFondaparinux175.5 kg* max dose 18, ,000 IU/dayDuplaga BA et al. Pharmacotherapy 2001; 21:Synergy Trial: Data on FileDavidson, et al. J Thromb Haem 2007;5:1191-4
137LMWH Pharmacokinetics in Obesity N= 30 (< 100kg)35 ( kg)Tinzaparin 175 IU/kgSQ single doseActual body weight correlates best with anticoagulant response to LMWHs as measured by anti-factor Xa levelsClin Pharmacol Ther 2002;72: Thromb Haemost 2002;87:
139Dalteparin Pharmacokinetics In Obesity Correlation Coefficient Between Vd and:LBW 0.05ABW 0.52TBW 0.55Correlation Coefficient Between Cl and:LBW 0.01ABW 0.32TBW 0.39Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7.Conclusion:TBW may be a better predictor of LMWH dose than IBW
140Dalteparin Pharmacokinetics In Obesity Dose: 200 U/kg qdDuration: 5 DaysMax TBW: 190kg<20% of IBW20-40% of IBW> 40% of IBWN131410Mean Dose (U)14,03017,64623,565Ant-Xa Activity (u/ml)Day 3 Peak1.010.971.12 NSDay 3 Trough0.120.110.11 NSConclusion: Body mass does not appear to have an important effect on the response to LMWH up to a weight of 190kg in patients with normal renal function.Wilson SJ et al. Hemostasis 2001; 31:42-8.
141LMWH Safety and Effectiveness Using TBW Enoxaparin In ACS (ESSENCE/TIMI IIb) 16.1%14.3%P=0.131.6%0.4%Obese: BMI > 30mg/m2Enox max weight 158 kgSpinler SA et al. Am Heart J 2003; 146:33-41
142Safety Of TBW-based Dosing of Dalteparin for Treatment of Acute VTE in Obese Patients N = 193 patients 3 month outcomes: major bleeding = 1.0% (n=2)> 90 kg recurrent VTE = 1.6% (n=3)WEIGHT(kg)NMeanDoseFull dose +/- 5%QD DosingBIDDosing90-994019,3003924165220,8504925174121,47021261524,30022925,250810626,92054> 15028,280Failures defined as recurrent DVT.Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2.
143Fondaparinux In Obesity Results From the Matisse Trials < 50kg: 5mg qd50-100kg: 7.5mg qd> 100kg: 10mg qdEnoxaparin:(Matisse DVT)1mg/kg q12hHeparin:(Matisse PE)Adjusted per aPTTNo weight-dependentdifference inefficacy or safetyDavidson BL et al. J Thrombosis Haemost 2007; 5:
144Body Weight and Anti-Xa Activity for Prophylactic Doses of LMWH N = 17 patients and 2 volunteersEnoxaparin 40mg SQ x1 doseAntiXa levels hourly x10 hoursRegression line95% CI for line95% CI for data points20015010050Area under the curve for 10 hBody Weight (kg)Frederiksen SG et al. Br J Surgery 2003; 90:547-8
145Fixed Dosing For VTE Prevention Dalteparin:Fixed Dosing For VTE PreventionSubgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill)BMI (kg/m2) Patients %Favors Dalteparin Favor Placebo<>Overall Prevent Trial0.010.10.551.010.0Relative RiskDalteparin 5,000 units daily was similarly effective in obese and non-obese patients (except pts with BMI>40) with no observed difference in mortality or major bleedingKucher N et al. Arch Int Med 2005;165:341-5.
146Enoxaparin VTE Prophylaxis in TKA/THA/Trauma 31.8%p<0.00116.7%N: Dose: 40 mg qd Obese : BMI>32kg/m2Samama MM et al. Thromb Haemost 1995; 73:977.
147Enoxaparin: VTE Prophylaxis in Bariatric Surgery 5.4%p<0.010.6%30mg bid: n=92BMI 51.7kg/m240mg bid: n=389BMI 50.3kg/m2Scholten Obes Surg 2002; 12:19-24.
148Dalteparin in Morbid Obesity: Bariatric Surgery 200180160140120P=0.031P=0.052N=135Bariatric SurgeryMean Weight: 148.8KgMean BMI: 53.7Dalteparin: 7,500 IU dailyP=0.444Body Weight (kg)Under target value<0.2 IU/mLn-=41Target value< IU/mLn-=81Over target value<>0.5 IU/mLn=13Anti-factor Xa levelNumber of patient (%)Body weight (kg)Below target value (<0.2 UI/ml)41 (30.4%)159.4 ± 35.8Target value (0.2–0.5 UI/ml)81 (60.0%)145.7 ± 28.4Above target value (>0.5 UI/ml)13 (9.6%)134.6 ± 24.2p value0.0152Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print]
149LMWH in Obesity: Summary Treatment: in controlled trials, LMWH dosing has been based on TBW (max kg)DalteparinDose based on TBWPI recommends dose cappingRecent clinical data supports TBW dosingQD or BID dosingEnoxaparinDose capping NOT recommendedBID dosing preferredTinzaparinDose based on TBW, NO dose adjustment or cappingAnti-Xa monitoring not necessary for TBW < 190kgProphylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients)Nutescu E, et.al. Ann Pharmacother; 2009; in press.
1508th ACCP Conference on Antithrombotic Therapy Renal Impairment For each of the antithrombotic agents, we recommend that clinicians follow manufacturer-suggested dosing guidelines (Grade 1C)We recommend that renal function be considered when making decisions about the use of and/or dose of LMWH or fondaparinux (Grade 1A)Options for patients with renal impairment (Grade 1B)Avoid agents that renal accumulateUse a lower doseMonitor the drug level or anticoagulant effectGeerts WH. Chest 2008;133(suppl):381S-453S.
151LMWH in Renal Dysfunction Manufacturer Recommendations Dalteparin“should be used with caution in patients with severe kidney insufficiency.”Monitor anti-Factor Xa for dose guiding with therapeutic dosesEnoxaparin“adjustment of dose is recommended for patients with severe renal impairment (CrCL < 30 mL/min).”Tinzaparin“patients with severe renal impairment should be dosed with caution.”Fondaparinux- Contraindicated in CrCL < 30mL/min
152Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n) Recent Meta-Analysis of LMWHs and Bleeding In Patients With Severe Renal DysfunctionStudy; yearPatients w/ renal insuff. (n/n)Patients w/ no renal insuff. (n/n)Peto OR (95%, CI)Weight (%)Collet, et al; 20010/281/832.010.26 (0.00 – 23.94)Paulas, et al; 20020/513/1496.020.26 (0.02 – 3.50)Siguret, et al; 20000/170/13Not estimableChow, et al; 20030/5Khazan, et al. (adj.); 20030/103/424.780.28 (0.01 – 5.16)(Prophylactic) 20033/363/4714.771.33 (0.25 – 7.05)(Therapeutic) 20032/173/618.623.09 (0.35 – 27.31)Spinler, et al; 20035/6974/3,43215.9310.05 (2.02 – 49.98)Green, et al; 20051/180/202.668.26 (0.16 – )Kruse & Lee; 20040/501/1202.220.24 (0.00 – 17.90)Macie, et al; 20042/76/2012.68(19.61 – 48,752.07)Peng, et al; 20040/70/43Thorevska, et al; 20047/6511/17135.561.85 (0.63 – 5.40)Bazinet, et al; 20051/362/1604.752.74 (0.15 – 51.73)Total (95%, CI)21/416107/4,555100.002.25 (1.19 – 4.27)Dosage adjustmentsfor renal dysfunctionFavors ↓’ed Favors ↑’edbleedingLim W, et al. Ann Intern Med. 2006;144:
153Sanderink GJCM. Thromb Res 2002;105:225-31. Enoxaparin PK and PD in Renal ImpairmentResult:Tmax: 3-4 hoursAmax: 10-35% higher in RI groupsCI/F”linearly correlated with CrClDay 4CL/F(L/h)Half-life(h)AUC (0-24)(h●IU/mL)Normals0.986.87Mild RI0.879.9420% ↑Moderate RI0.7611.321% ↑Severe RI0.5815.965% ↑Sanderink GJCM. Thromb Res 2002;105:
154LMWH Renal Dosing in NSTE ACS Patients Dose may be to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl ml/minAnti-Xa monitoringDoses “appeared safe”Further prospective evaluation needed56 UA pts with CrCl <60 ml/minEnoxaparin dose empirically and anti-Xa level measured after 3rd doseCrCl(ml/min)<30(n = 28)>30 and <60(n =28)Age76+/-373+/-3Enoxaparin (mg/kg/12h)0.640.84Anti-Xa (IU/ml)0.95Collet JP et al. International J Cardiol 2001;80:81-2.
155Clinical Use Of Recommended Enoxaparin Dosage in Renal Impairment N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h22.214.171.124.126.96.36.199.188.8.131.524321PEAK ANTI-Xa LEVELSTROUGH ANTI-Xa LEVELSAntifactor X1 Level (U/mL)Number of PatientsFirst doseSubsequent doses(second and third)Median % interquartile rangeTrough Antifactor Xa Level (U/mL)Trough Antifactor Xa Level (U/mL)Lachish T et al. Pharmacotherapy 2007; 27:
156Tinzaparin 175 U/kg Peak Anti-Xa Levels According to Renal Function No correlation between peak anti-Xa activity and ClcrNo accumulation of Anti-Xa activity after 10 days of therapySiguret V et al. Thromb Haemost 2000;84:800-4.
157Pharmacokinetics of Prophylactic Enoxaparin vs Tinzaparin Enoxaparin 40mg qdorTinazaparin 4500 IU qdN = 52 patientsMean age = 87.7 yrsMean wt = 52.3kgMean Clcr = 34.7ml/minMahe I et al. Thromb Haemost 2007; 97:581-6.
158Dalteparin 100 U/kg q12h Peak Anti-Xa Levels According to Renal Function No difference in peak anti-Xa activity between normal patients andpatients with renal impairement1.51.00.5Clcr > < 40Mean peakanti-Xa levelafter 5-6 dosesAntifactor Xa Level (U/mL)xxSubjects withoutRenal impairmentSubjects withRenal impairmentN=11N=11Shprecher AR et al. Pharmacotherapy 2005; 25:
159Pharmacokinetics of Prophylactic Doses of Dalteparin N = 115 elderly (age > 65) pts with acute medical illness and elevated SCrTx: dalteparin 5000 U or 2500 U SQ qd (risk-based) for VTE prophylaxisRenal FailureMild(n=12)Moderate(n=73)Severe(n=24)CrCL (ml/min)60-8930-59<30Day 6 peak anti-Xa0.0300.0330.048Minor Bleeding3Major BleedingP=0.72No evidence of accumulation of anti-Xa activityNo relationship between the degree of renal impairment and peak anti-Xa level on Day 6No association between creatinine clearance and anti-Xa levelsTincani E et al. Haematologica 2006; 91:976-9.
160Douketis, et al. Arch Intern Med. 2008 Sep 8;168(16):1805-12. Dalteparin Thromboprophylaxis in Critically Ill Patients with Severe Renal Insufficiency: The Direct StudyN=138 critically ill patientsCrCl < 30 ml/minMean CrCL 18.9ml/minDalteparin 5000 IU sc dailySerial anti Xa levels measured on days 3, 10, and 17Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mLResults:The median duration of dalteparin exposure was 7 (4-12) daysNo patient had a trough anti Xa level > 0.4 IU/mlBased on serial measurementspeak anti-Xa levels were 0.29 to 0.34 IU/mLtrough levels were lower than 0.06 IU/mLDouketis, et al. Arch Intern Med Sep 8;168(16):
161Dosing of LMWHs In Renal Impairment Recommendations FOR CrCL < 30 ml/minEnoxaparin:Prophylaxis doses: 30 mg sq QDTreatment doses: 1mg/Kg sq QDDalteparin and Tinzaparin:no specific dosing guidelinesNo or lower degree of accumulation expectedAnti-Factor Xa activity monitoringFOR CrCL mL/minNo specific recommendationsConcern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?)Monitoring anti-Xa ?Nutescu E, et.al. Ann Pharmacother; 2009; in press.
162Unresolved Issues in Renal Dosing of LMWHs CrCl (mL/min)Recommendations< 30Dose of enoxaparin should be adjusted; dalteparin and tinzaparin no short term accumulation expected.<LMWHs have not been adequately studied as repeated doses for prophylaxis and treatment indications; UFH is preferred in these patients.Issues with anti-factor Xa testing include:true therapeutic range, standardization, availability, recommendations for dose adjustment
163Anti-Xa Activity Level Monitoring Enoxaparin 1mg/kg SQ pharmacokinetic profilePeak (goal ~ U/ml) at 3-4 hrsTrough (goal < 0.5 U/ml) at hrsLaposata et al. Arch Pathol Lab Med. 1998;122:
164ANTI-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 settingsUse peak levels 4 hrs after SQ doseThrough levels in renal impairment maybe preferredUse chromogenic, not clot-based assaysPeak:for BID dosing: U/mlfor QD dosing: U/mlThrough: < 0.4 U/mlLaposata et al. Arch Pathol Lab Med. 1998;122:Nutescu E, et.al. Ann Pharmacother; 2009; in press.
165Fondaparinux Pharmacokinetics 100% bioavailableCmax = 0.34 µg/mL (SD: 0.04)Tmax = 1.7 h (SD: 0.4)T1/2 = 17.2 h (SD: 3.2)Elimination = RENAL0.350.30.25concentration (µg/mL)Pentasaccharide*0.20.150.10.05Plasma levels of Pentasaccharide* rise rapidly following subcutaneous administration.1Peak plasma level (Cmax) are reached within two hours of dosing (Tmax) and significant levels (Cmax/2) within 25 minutes; this ensures a rapid onset of antithrombotic activity following dosing of Pentasaccharide*.1The rapid rise in plasma level of Pentasaccharide* through the 24 hours following dosing allows once-daily dosing.1The low inter and intravariability of Pentasaccharide’s pharmacokinetics allowed a single regimen to be used for all patients included in Phase III trials for VTE prophylaxis.1,2,3,4,5*fondaparinuxDonat F, Duret JP, Santoni A, Cariou R, Neciari J, Magnani H et al. Pharmacokinetis of Org31540/SR90107A in young and elderly healthy subjects: a highly favourable pharmacokinetic profile. Thromb Haemost. July Abstract P3094Lassen M. The Ephesus Study: Comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) after elective hip replacement surgery Blood J Am Soc Hem. 2000; 96(11): Abstract 2109Eriksson BI.The Penthifra Study: Comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) after hip fracture surgery Blood J Am Soc Hem ; 96(11): Abstract 2110Turpie G. The Pentathlon 2000 Study: Comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) after elective hip replacement Blood J Am Soc Hem. 2000; 96(11): Abstract 2112Bauer K. The Pentamaks Study: Comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) after elective major knee surgery Blood J Am Soc Hem. 2000; 96(11): Abstract 21114812162024283236Time (h)Donat F, et al. Clin Pharmacokinetics 2002; 41 (suppl 2):1-9.
166Fondaparinux Use in Patients with Impaired Renal Function Total clearance lower than in patients with normal renal functionMild impairment ~25%Moderate impairment ~40%Severe impairment ~55%Fondaparinux: PI
167Full-dose Fondaparinux Risk Of Major Bleeding 4.8%3.8%Incidence (%)2.4%n=5041.6%n=1288n=1565Clcr80mL/minClcr50–80mL/minClcr30–50mL/minClcr< 30ml/minData on file, GlaxoSmithKline
168Influence of Renal Function Fondaparinux vs Enoxaparin in ACS OASIS-5:Fondaparinux 2.5mg qdvs enoxaparin 1mg/kg q12hfor 2-8 daysFox KAA et al. Ann Intern Med 2007; 147:
169Electronic Alerts: Future Horizons A Year 2009 Update forThe Health System PharmacistElectronic Alerts: Future HorizonsKaren Fiumara, PharmDMedication Safety OfficerBrigham and Women’s HospitalAdjunct Assistant Professor of Pharmacy PracticeMassachusetts College of Pharmacy and Allied Health SciencesBouve’ College of Health Sciences Northeastern UniversityBoston, MA
170BackgroundPast 10 years the prevention of medication errors has become a primary focus in healthcareIn 1995 Bates et al. published landmark study indicating 28% of hospital admissions are attributed to preventable medication errorsThe IOM report “To Err is Human” have led to increased research and development of both medical informatics and computerized alerting systemsBates DW et al. JAMA 1995;274:
171CPOE : Friend or Foe?Recently, institutions are beginning to critically assess electronic systems, such as CPOEVA Medical Center in Salt Lake City:74% of medication errors occur during prescribing11% during administration0% during transcriptionBates et al. study:56% of medication errors - prescribing24% of medication errors – administration6% of medication errors – transcriptionNebeker JR et al. Arch of Intern Med 2005;165:
172CPOE : Friend or Foe?VA Medical Center attributed low error rates during the transcription and administration to information system upgrades such as:Bar code technology during administration, EMAR and computerized drug-drug interaction and allergy screeningConcluded that their systems are working as designed but lack decision support within CPOE leading to high error rates during prescribingNebeker JR et al. Arch of Intern Med 2005;165:
173CPOE AlertsInstitutions that utilize decision support and computerized alerts during prescribing have reported high rates of physician overrideA study conducted at BIDMC reported that 94.2% of computerized alerts were overriddenReviewers concluded of the 189 rules studied, 36.5% of the rules were invalid and agreed with the physician’s decision 97.9% of the timeWeingart SN et al. Arch of Intern Med 2003;163:
174Saving CPOE from Extinction CPOE must evolve to keep up with the growing demand for effective medical informatics and technology solutionsNext generation of CPOE will utilize algorithms that take into account patient specific factors and generate prescribing recommendations to providersOne area in which CPOE has proven beneficial is VTE prophylaxis
175Medical Error Rates Two errors per day = 99% proficiency level If 99% was good enough:How do we transform health care into a high reliability industry?Airline industry = 2 unsafe landings per dayMail industry = 16,000 pieces of mail lost every hourBanking industry = 32,000 checks deducted from the wrong account per hourLeape LL. JAMA. 1994;272:
176BackgroundAt Brigham and Women’s Hospital, we have initiated a series of trials aimed at increasing prophylaxis by:Changing MD behavior andImproving the implementation of prophylaxis strategies
177Types of Interventions Electronic computer generated alerting systemsEfficacy of these alerting systems have been studied in:RCT trial of a 1-screen alertCohort study of a 3-screen alert
178First Generation Electronic Alerts BWH utilizes BICS (Brigham Integrated Computing System) for all order entry functionsAdmitting 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
179First Generation Alert: Development Aim: to increase rate of prophylaxis in patients at risk for DVT and PEDeveloped computer program to detect and identify which patients were at riskAlert the responsible physician of high risk patient (via e alert) and offer opportunity to order appropriate prophylaxis
180Study Schema All Adult Patients DVT Risk Score > 4 YES Presence of ProphylaxisNOGenerate Alert
182Randomization VTE Risk Score > 4 No Prophylaxis N = 2506 Control InterventionSingle Alertn = 1255ControlNo Alertn = 1251Kucher N, et al. NEJM 2005;352:
183Physician Notification of Alerts For patients randomized to the intervention arm, their responsible physician received an electronic alert at the moment they logged into the CPOE system. Once the physician clicks on the alert they are presented with multiple options.
185First Generation Computerized Alerts for VTE Prevention Utilization of computer generated alerts to house staff reduced the incidence of VTE by 41%VTE prophylaxis was prescribed in 33.5% of patients in the intervention groupFollowing study conclusion a follow up cohort study was conductedKucher N, et al. NEJM. 2005;352:
187BWH VTE Alerts: The Future Goals:Engage the house officer with an interactive alert to increase acceptance and gain feedbackUpdate the DVT prophylaxis template to meet current practice guidelinesProvide real-time knowledge links
188Interactive Techniques Provide objective data to the house officer that this alert positively impacts patient outcomeCreate opportunity to capture rationale for declining alertHypothesized that many physicians fear a risk of bleeding with anticoagulationProvide a final opportunity to order mechanical prophylaxisAlert attending physician if alert is not acknowledged after 24 hours
189DVT Alert ScreenThis alert screen is identical to the NEJM trial except of the inclusion of educational information about the NEJM article. A MD may also choose to review alert details, which
190Rule Logic – Alert Details Which displays the patient specific criteria and rule logic, that qualify the patient as high risk.
191Option AAfter reviewing the alert details The MD can then proceed to order DVT prophylaxis via an order set template
192The template allows the MD to select mechanical, pharmacological or combination prophylaxis.
193Option C or “Done”If at any point the user selects “exit”, “done” or “escape” they are presented with a screen that prompts for a reason for declining the alert
194The reasons provided are Patient is already receiving anticoagulants, risk of bleed outweighs benefits of anticoagulant therapyk, pt is CMO, Schedule of surgery or other.If med enters other, they must enter a reason that is at least 15 characters long. Once a reason has been selected….
195The user has a final opportunity to order mechanical prophylaxis via a second order entry template. The user is also provided with additional point of care information that mechanical prophylaxis does not increase risk of bleeding,
196Escalation and Timing of Alerts Alerts should be set up to generate each day at 8:30 AMIf an alert was not acknowledged after 24 hours the attending physician on record should be text paged.These enhanced VTE alerts are set to fire at 8:30am every day which corresponds to peak prescribing times and morning rounds and should the MD ignore the alert for >24 hours, the attending MD is then notified via text page.
197Quality Assurance Weekly reports are reviewed Allows core team to review all aspects of the alerts including:Type of action takenRate of overridesRational for declining the alertsResults coming soon
199VTE Prophylaxis: hALERT Multicentered RCT of human alerts (hALERT).Objective: to recruit hospitals that differ from BWH re: IT, community vs. academic, urban vs. suburban/rural, location within USA.Can a human alert be more effective than an electronic alert?
200MethodologyPatients admitted to the hospital are screen by human for increased VTE riskHigh risk patients are randomized to alert or no alertPhysicians of patients in alert group receive page alerting them of high risk statusRecords are checked for prophylaxis order 48 hours after alert90 day follow up for clinically significant VTE and clinically importing bleeding
201hALERT: Capturing New Prophylaxis Orders Enrolled patients must be reexamined in hours to determine whether prophylaxis orders were written.Capturing prophylaxis orders after enrollment applies to both the Intervention Group and to the Control Group.
202Human Alert TrialHuman (often RN or pharmacist) issues the Alert, not a computerThe attending physician, not the intern, receives the AlertDiversity of centers: community, suburban, throughout the USAWill attendings pay more attention than house staff?
203Conclusions Changing behavior is challenging Multi-disciplinary team involvement is critical to successful implementationNeed to engage providers and obtain feedbackDesigning “smart alerts” that include decision support functionality or “human alerts” that require face to face contact may be effective
205Patient Case—Infusion Pump Error Error Description57 YOM endstage CMPEF = 10%Heart transplant candidate with BIVADReceiving UFH 900 units per hour (9 mls/hr)New order to reduce Heparin 800 units per 10:22 PMInfusion pump set for 800 mls per hour8:45 PM aPTT = 75.11:13 AM Protamine 25mg1:28 AM aPTT = >1503:13 AM aPTT = >1503:32 AM Protamine 26mg2 Units PRBC4:08 AM aPTT = >1508:21 AM aPTT = 44.4The following patient case is a classic example of heparin errors that we often see. Patient is a 57 y/o male with endstage cardiomyopathy with biventricular assist device. Patient was receiving UFH at 900 units per hour. A new order was written to reduce the heparin to 800 units per hour. RN programmed infusion pump was set for 800 mls per hour. The RN programs the pump, leaves the room, goes back into the room approximately 1 hour later and the patient had received the entire bag 250 ml bag over less than ½ an hour. So the patient receives an entire 24 hours supply of heparin in ½ hour. These types of errors are usually reported as a “device error”. Our patient did have significant sequale in that he received protamine and PRBC, however did not experience a major bleeding episode.
206Medications Causing Harm BackgroundNational DataHeparin has been identified both nationally and internally at BWH as a medication frequently associated with ADERemoved access to different formulationsStandardized UFH ConcentrationCalculate infusion rates in OERankMedications Causing Harm1.Insulin2.Morphine3.Heparin4.Warfarin5.Potassium6.Furosemide7.Vancomycin8.Hydromorphone9.Meperidine10.DiltiazemUnfortunately, cases like this are not a rare exception. Both nationally as defined by MEDMARx and internally here at BWH heparin has been identified as a medication that is frequently associated with causing “harm”. At BWH heparin is routinely associated with medication errors and for quite some time heparin has been the second most likely medication to be associated with an adverse event. In light of these events we in pharmacy tried to decrease events by:Removing access to different formuationsStandardized UFH concentrations (25,000/250ml)Even programmed order entry to calculate the rate in an attempt to ellimiate some of the confusion surrounding med calculations which anyone who cares about patient safety will tell you is a real problem.MEDMARXSM The United States Pharmacopoeia (USP)Convention Inc.
207UFH Error Analysis: BWH 1 event per 1,000 patients52% - Administration related31% - Equipment failure, rate or dosing error23% - Infusion Pump6% - Prolonged LOS or significant harm***Patient Safety Initiative: Hospital invested 3 million dollars in state of the art infusion pumps***John Fanikos from the pharmacy department in conjuction with Dr. Goldhaber published a paper evaluating medication errors associated with anticoagulation therpay in the hospital. We found that the majority 52.5% of errors are administration related. These errors where often described at “equipment failure, rate or dosing errors”. These resulted in approximately 1 event per patients, which correlates to approximately one error per week. However, only a small % of these ADE were found to result in prolonged LOS or significant patient harm.We know that heparin is not the only IV medication that is associate with significant potential to cause ADE, and hospital admistration invested 3 million dollars in state of the art infusion pump technology in an attempt to increase pt safety.Realizing theFanikos J et al. Medication Errors associated with anticoagulation therapy in the hospital. Am J Cardiol 2004;94:
208ObjectivesEvaluate impact of “smart” infusion technology on anticoagulation administrationTo determine if infusion technology equipped with drug libraries may reduce medication errors
209Features of the “Smart” Pumps “Smart” pumps share safety features of older pumps including dose calculation functions, free-flow protection and occlusion alerts“Smart” pumps also equipped with a drug libraryProvide dose and rate limits on commonly used medicationsProvide users with overdose and underdose alerts based on predetermined limits defined by the drug library
214MethodsWe programmed the drug library to alert for overdoses or underdosesAlerts where subsequently recorded in the device’s electronic memory, along with the user’s next actionWe retrospectively reviewed all anticoagulant alerts and the user’s next action for all devices from 10/2003 through 1/2005MedicationUnderdose AlertOverdose AlertUFH<300 units/hour>2,800 units/hourArgatroban<0.5 mcg/kg/min>10 mcg/kg/minLepirudin<5 mg/hour>16.5 mg/hourBivalirudin<0.2 mg/kg/hour>1.8 mg/kg/hour
218ConclusionsThe drug library and its alerting system intercept programming errorsDespite alerts, data entry errors are frequently repeated by the userThe highest alert incidence occurs on weekdays between 2 PM and 4 PM, corresponding to Nursing Shift change