Presentation on theme: "1. 2 Learning Objectives After participating in this activity, participants should be able to: Assess the impact of risk factors and comorbidities on."— Presentation transcript:
2 Learning Objectives After participating in this activity, participants should be able to: Assess the impact of risk factors and comorbidities on the development of VTE Evaluate current clinical trial evidence for the use of anticoagulant treatments Implement current guideline-based recommendations for VTE prevention and treatment Develop strategies for meeting standards set by the Joint Commission/National Quality Forum
3 The Network for Continuing Medical Education requires that CME faculty disclose, during the planning of an activity, the existence of any personal financial or other relationships they or their spouses may have with the commercial supporter of the activity or with the manufacturer of any commercial product or service discussed in the activity. Disclosure Statement
5 Venous Thromboembolism Annual incidence of VTE in the US: Approximately 600,000 cases of VTE 1,2 Estimated 180,000 deaths due to DVT/PE 1 Annual number at risk for VTE in US hospitals: 7.7 million medical service inpatients 3 4.3 million surgical service inpatients 3 2/3 of VTE cases and deaths are hospital-acquired 1 1.US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Bethesda, MD: September 2008. 2.Anderson FA Jr, et al. Arch Intern Med. 1991;151(5):933-938. 3.Anderson FA Jr, et al. Am J Hematol. 2007;82(9):777-782. 4.Geerts WH, et al. Chest. 2008;133:381S-453S. PE is the leading preventable cause of hospital death 4 31% of US hospital discharges
6 Rising Incidence of VTE in Hospitalized Patients VTE rates are rising because –The population is getting older –The US obesity epidemic continues to grow –Patients are surviving longer with chronic disease associated with the risk of VTE
7 VTE in Hospitalized Patients Not Just a Surgical Problem 50%-70% of symptomatic VTEs occur in nonsurgical patients 1 70%-80% of fatal PEs occur in nonsurgical patients 1 DVT was detected by ultrasound in 33% of medical patients in the ICU during an 8-month screening study 2 PE: most preventable cause of hospital death and the number one strategy to improve patient safety in hospitals 1 1. Geerts WH, et al. Chest. 2008;133:381S-453S. 2. Hirsch DR, et al. JAMA. 1995;274:335-337.
8 DVT-FREE Registry: Distribution by Age and Gender Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering Committee. Am J Cardiol. 2004;93:259-262. 800 700 600 500 400 300 200 100 0 ≤20 Patients, n Age, y Men (n=2559) Women (n=2892) 21-3031-4041-5051-6061-7071-8081-90>90
9 DVT-FREE Registry: Distribution by BMI and Gender Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering Committee. Am J Cardiol. 2004;93:259-262. 800 700 600 500 400 300 200 100 0 ≤2031-3521-2526-30>35 Patients, n Body Mass Index, kg/m 2 Men (n=2095) Women (n=2344)
10 DVT-FREE Registry: Time From Most Recent Surgery to Diagnosis of DVT by Patient Status Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering Committee. Am J Cardiol. 2004;93:259-262. 40 35 30 25 20 15 10 0 0-5 Patients, % Time, d Outpatients (n=718) Inpatients (n=1351) 6-1011-1516-2021-2526-30>31 5
11 Outpatient and Inpatient VTE Are Linked An observational study of 1897 patients with a confirmed episode of VTE found that –74% of patients developed VTE in the outpatient setting Among those 74%, 60% were hospitalized (23% surgical; 37% medical) in the past 3 months Of those 60%, 67% experienced VTE within 1 month of hospital discharge –Among 516 patients with a recent hospitalization who subsequently developed VTE, less than half (43%) had received anticoagulant prophylaxis during their hospital stay Spencer FA, et al. Arch Intern Med. 2007;167(14):1471-1475.
12 Potential Mechanisms by Which Clinical Conditions Facilitate VTE Hypercoagulability Direct vessel injury Blood stasis Hypercoagulability Direct vessel injury Blood stasis Acute insult Increased baseline propensity for thrombosis Lopez JA, et al. Hematology. 2004;1:439-456.
13 Adapted from Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Risk Factors for VTE Surgery Trauma (major trauma or lower-extremity injury) Immobility, lower-extremity paresis Cancer (active or occult) Cancer therapy Venous compression Previous VTE Increasing age Pregnancy/postpartum period Smoking Estrogen-containing OCs or HRT Erythropoiesis-stimulating agents Acute medical illness Inflammatory bowel disease Nephrotic syndrome Myeloproliferative disorders Paroxysmal nocturnal hemoglobinuria Obesity Central venous catheterization Inherited or acquired thrombophilia
14 Acute Respiratory Disease and CHF Increase the Risk of VTE The prevalence of thromboembolic disease in patients hospitalized for respiratory disease is estimated at 8%-25% 1 COPD patients with DVT are older, more likely to be inpatients, more likely to be in the ICU and mechanically ventilated, and more often have concomitant PE 2 CHF has long been associated with an increased risk of VTE 3 –One of the few studies to quantify the risk of DVT in patients with CHF did find increased risk, with an OR of 1.8 4 VTE is an underestimated cause of morbidity and mortality in patients with CHF 3 1.Shetty R, et al. J Throm Thrombolysis. 2008;26:35-40. 2.Fraisse F, et al. Am J Respir Crit Care Med. 2000;161:1109-1114. 3.Howell MD, et al. J Clin Epidemiol. 2001;54(8):810-816. 4.Cogo A, et al. Arch Int Med. 1994;154:164-168.
15 The Importance of DVT Prophylaxis in Congestive Heart Failure 38.3 x greater 1.7 X greater 2.8 X greater LVEF >45%LVEF 20-44%LVEF <20% DVT/PE Risk LVEF = left ventricular ejection fraction. Howell MD, et al. J Clin Epidemiol. 2001;54:810-816.
16 Joint Commission/NQF Draft VTE Measures for 2009 6 VTE measures were endorsed by the NQF in May 2008 –VTE prophylaxis –ICU VTE prophylaxis –VTE patients with anticoagulation overlap therapy –VTE patients UFH dosages/platelet count monitoring by protocol (or nomogram) –VTE discharge instructions –Incidence of potentially preventable VTE Measures will be available for data collection and reporting for discharges beginning autumn 2009 Complete measure specifications available spring 2009 National Quality Forum. http://www.qualityforum.org/news/releases/051508-endorsed- measures.asp. Accessed November 6, 2008.
17 Surgical Care Improvement Project SCIP is a unique partnership between multiple organizations, including the American Academy of Orthopedic Surgeons, American Hospital Association, American College of Surgeons, Joint Commission, AHRQ, Centers for Disease Control and Prevention, and VA, among others The goal is to reduce the incidence of surgical complications nationally by 25% by the year 2010 VTE Performance Measures –Surgery patients with recommended VTE prophylaxis ordered –Surgery patients who received appropriate VTE prophylaxis within 24 hours prior to surgery to 24 hours after surgery MedQIC – Surgical Care Improvement Project. http://www.qualitynet.org/dcs/ContentServer?cid=1137346750659&pagename=Medqic/Content/Par entShellTemplate&parentName=TopicCat&c=MQParents. Accessed November 6, 2008.
18 Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Strategies for Prevention of VTE Pharmacologic –LMWH (eg, enoxaparin, dalteparin) –Low-dose UFH –Fondaparinux a –Vitamin K antagonist (eg, warfarin) Mechanical –Intermittent pneumatic compression –Graduated elastic compression stockings a Fondaparinux is not approved by the FDA for VTE prophylaxis in medical patients. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
19 Emerging Anticoagulants for the Management of VTE Indirect FXa inhibitor –Idraparinux Oral direct FXa inhibitors –Rivaroxaban –Apixaban Oral direct thrombin inhibitor –Dabigatran
20 Key ACCP 2008 Practice Guideline Recommendations Every hospital should develop a formal strategy that addresses the prevention of VTE (Grade 1A) Aspirin should not be used alone as thromboprophylaxis for any patient group (Grade 1A) Mechanical methods of thromboprophylaxis should be used primarily for patients at high bleeding risk (Grade 1A) or possibly as an adjunct to anticoagulant thromboprophylaxis (Grade 2A) Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
21 Key ACCP 2008 Practice Guideline Recommendations (cont) In patients admitted to the hospital with an acute medical illness, thromboprophylaxis with LMWH, low-dose UFH, or fondaparinux a is recommended (Grade 1A) On admission to the ICU, all patients should be assessed for their risk of VTE, and most should receive thromboprophylaxis (Grade 1A) Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines a Fondaparinux is not approved by the FDA for VTE prophylaxis in medical patients.
22 Thromboprophylaxis Recommendations for Hospital Patients — Balancing the Risk of Bleeding a High-risk patients include those who have had major trauma or spinal cord injury, major hip or knee surgery, or major surgery for cancer. Bleeding RiskVTE RiskRecommendation LowModerateLMWH or LDUH LowHigh a LMWH and/or fondaparinux, with or without GCS or IPC HighModerateGCS or IPC, LMWH or LDUH when risk decreases HighHigh a GCS or IPC, LMWH when risk decreases Adapted from Geerts WH, et al. J Crit Care. 2002;17:95-104.
23 Primary Prevention of VTE in Hospitalized Medical Patients
24 Risk of VTE in Hospitalized Medical Patients Patients hospitalized for acute medical illness have more than a 10-fold increased risk for VTE 1 Nursing home residents are more than twice as likely as nonresidents to develop DVT/PE 2 VTE prophylaxis remains underutilized or inadequate in hospitalized medical patients 3,4 –Underuse often occurs because of unwarranted safety concerns 5 1.Heit JA, et al. Arch Intern Med. 2000;160(6):809-815. 2.Heit JA, et al. Arch Intern Med. 2002;162(11):1245-1248. 3.Goldhaber SZ, Tapson VF. Am J Cardiol. 2004;93(2):259-262. 4.Anderson FA Jr, et al. Ann Intern Med. 1991;115(8):591-595. 5.US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Bethesda, MD: September 2008.
25 Recommendations for Prophylaxis in Medical Patients In acutely ill medical patients who have been admitted to the hospital with: 1,2 –congestive heart failure or severe respiratory disease –Or who are confined to bed and have ≥1 additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease LMWH (Grade 1A; IUA: enoxaparin 40 mg qd or dalteparin 5000 qd) Low-dose UFH (Grade 1A; IUA: 5000 IU tid) Fondaparinux (Grade 1A)* * Fondaparinux is not approved by the FDA for prophylaxis in medical patients. 1.International Consensus Statement. Int Angiol. 2006;25:101-161. 2.Geerts WH, et al. Chest. 2008;133:381S-453S. ACCP 2008 and IUA 2006 Guidelines
26 VTE Prophylaxis in Acutely Ill Medical Patients Primary Efficacy End Points: Implications for Clinical Practice 1.Samama MM, et al. N Engl J Med. 1999;341(11):793-800. 2.Leizorovicz A, et al. Circulation. 2004;110(7):874-879. 3.Cohen AT, et al. BMJ. 2006;332(7537):325-329. # Needed to Treat 10 45 20 TrialVTERRR MEDENOX 1 Distal and proximal63% venographic DVT + symptomatic VTE + fatal PE PREVENT 2 Compression45% ultrasonographic DVT + symptomatic VTE + fatal PE ARTEMIS 3 Distal and proximal47% venographic DVT + symptomatic VTE + fatal PE
27 VTE Prophylaxis in Hospitalized Medical Patients: 3 Meta-analyses Dentali et al 1 : 9 randomized trials (N=19,958) comparing anticoagulant prophylaxis with no treatment –Anticoagulation significantly reduced any PE by 57% and fatal PE by 62%, and reduced symptomatic DVT by 53% (nonsignificant) King et al 2 : 12 randomized trials (N=7978) comparing bid with tid UFH – The combined DVT + PE event rate was 2.34 per 1000 patient days with bid UFH and 0.86 per 1000 patients days with tid UFH (P=.05) –The risk for major bleeding was significantly increased with tid UFH (P<.001) Wein et al 3 : 36 randomized trials comparing the efficacy and safety of various prophylaxis agents –Both UFH and LMWH were associated with a reduced risk of DVT and PE; UFH tid was more effective than UFH bid for reducing the risk of DVT (RR 0.27 vs RR 0.52, respectively) –When directly compared with UFH, LMWH was associated with a lower risk of DVT (RR 0.68) 1.Dentali F, et al. Ann Intern Med. 2007;146(4):278-288. 2.King CS, et al. Chest. 2007;131(2):507-516. 3.Wein L, et al. Arch Intern Med. 2007;167(14):1476-1486.
28 Is Duration of VTE Prophylaxis Analogous to Duration of a Course of Antibiotics? IndicationAverage LOS, dDuration of Prophylaxis Acute medical illness3-56-11 d Abdominal surgery2-107-10 d Hip replacement2-67-10 d or 3 wk Knee replacement2-57-10 d Antibiotic Organism Process Components: 1.Failure to give the antibiotic 2.“Resistance” of the organism 3.Initial timing of the antibiotic 4.Duration of treatment
29 Hull RD, et al. Abstract presented at: ISTH, July 8-11, 2007, Geneva, Switzerland. EXCLAIM: Extended-duration Enoxaparin Prophylaxis in High-risk Medical Patients End pointsExtended prophylaxis n=2013 (%) Placebo n=2027 (%) RR reduction (%) P value VTE events2.84.944.001 Symptomatic0.31.173.004 No symptoms2.53.734.032 NNT = 46 patients to avoid one VTE event. NNT = 224 to result in one major bleeding event.
30 Prevention of VTE After Acute Ischemic Stroke: PREVAIL Study NIHSS = National Institutes of Health Stroke Scale. Reprinted with permission from Sherman DG, et al. Lancet. 2007;369:1347-1355. NIHSS Score <14NIHSS Score ≥14 Occurrence (95% CI)P P VTE Enoxaparin8.3% (5.90-10.70).00416.3% (10.53-21.97).004 UFH14.0% (10.91-17.02)29.7% (22.94-36.49) DVT Enoxaparin8.1% (5.73-10.48).00516.3% (10.53-21.97).005 UFH13.6% (10.54-16.58)29.1% (22.41-35.88)
31 Prevention of VTE in Patients With Heart Failure or Severe Respiratory Disease HF = heart failure. Kleber F-X, et al. Am Heart J. 2003;145:614-621. Percentage of Thrombolic Events 0 2 4 6 8 10 12 14 16 18 All PatientsResp DisHF Enoxaparin UFH
32 Prevention of VTE in High-Risk Hospitalized Medical Patients: THE PRIME Study Reprinted with permission from Lechler E, et al. Haemostasis. 1996;26(suppl 2):49-56. Intention-to-treatPer-protocol Enoxaparin (n=442) Heparin (n=443) Enoxaparin (n=393) Heparin (n=377) Thromboembolic events1 (0.2%)6 (1.4%)1 (0.3%)5 (1.3%) DVT1212 DVT + PE0212 PE0202 Test for superiorityP=.1235P=.1164 Test for equivalenceP=.0000048P=.00000306
33 Conclusions: THE PRIME Study Enoxaparin is at least as efficacious as standard heparin for DVT prophylaxis in high-risk hospitalized medical patients Treatment with enoxaparin resulted in fewer major bleeds and adverse events –Only 3 bleeds were considered to be treatment related; all occurred in the heparin group –Hematomas at the injection site exceeding 5 cm in diameter were recorded 22 times (4.6%) in the enoxaparin group and 52 times (10.8%) in the heparin group (P<.001) –Liver enzymes were significantly more often elevated with heparin compared with enoxaparin Lechler E, et al. Haemostasis. 1996;26(suppl 2):49-56.
34 The Importance of DVT Prophylaxis in Patients With Cancer VTE is one of the leading causes of death in cancer patients, occurring in 4% to 20% of patients Hospitalized patients with cancer and cancer patients receiving active therapy are at greatest risk for VTE –Cancer increased the risk of VTE 4.1-fold –Chemotherapy increased the risk 6.5-fold Major risk factors include older age, comorbid conditions, recent surgery or hospitalization, active chemotherapy or hormonal therapy All hospitalized cancer patients should be considered for prophylaxis Patients with cancer undergoing surgery should be considered for prophylaxis LMWH is the preferred drug Lyman GH, et al. J Clin Oncol. 2007;25:5490-5505.
35 Prophylaxis in Cancer Patients Cancer patients undergoing surgical procedures: routine thromboprophylaxis that is appropriate for the type of surgery (Grade 1A) Cancer patients who are bedridden with an acute medical illness: routine thromboprophylaxis as for other high-risk medical patients (Grade 1A) Cancer patients receiving chemotherapy or hormonal therapy: recommend against the routine use of thromboprophylaxis for the primary prevention of VTE (Grade 1C) Cancer patients overall: recommend against the routine use of primary thromboprophylaxis to try to improve survival (Grade 1B) Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
36 Despite Evidence, Medical Patients at Risk Remain Unprotected MedicalSurgical No. of patients 37,35630,827 At risk for VTE 42%64% Receiving ACCP Tx 40%59% ENDORSE 1 1.Cohen AT, et al. Presented at: 2007 Congress of the International Society on Thrombosis and Haemostasis; July 6-12, 2007; Geneva, Switzerland. 2.Tapson VF, et al. Chest. 2007;132(3):936-945. IMPROVE 2 United States Other Countries No. of patients 3,41011,746 VTE prophylaxis 1852 (54%)5788 (49%) LMWH476 (14%)4657 (40%) UFH717 (21%)1014 (9%)
37 Electronic Alerts to Prevent VTE in Hospitalized Patients P<.001 by the log-rank test for the comparison of the outcome between groups at 90 days. Reprinted with permission from Kucher N, et al. N Engl J Med. 2005;352:969-977. 0 92 94 98 100 30 Freedom From DVT or PE (%) 96 60900 Days 90 Intervention group Control group P<.001 No. at Risk Intervention group1255977900853 Control group1251976893839
38 Primary Prevention of VTE in Surgical Patients
39 General Surgery Recommendations Low-risk patients, minor procedure, no additional risk factors: recommend against specific thromboprophylaxis other than early and frequent ambulation (Grade 1A) Moderate-risk patients, major procedure for benign disease: LMWH, LDUH, or fondaparinux (Grade 1A) Higher-risk patients, major procedure for cancer: LMWH, LDUH 3 times/day, or fondaparinux (Grade 1A) Patients with multiple risk factors who are thought to be at high risk: LMWH, LDUH 3 times/day, or fondaparinux with GCS and/or IPC (Grade 1C) Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
40 General Surgery Recommendations (cont) Patients with high risk of bleeding: GCS or IPC (Grade 1A); pharmacologic therapy substituted or added to mechanical thromboprophylaxis once high bleeding risk decreases (Grade 1C) For patients undergoing major general surgery, continue thromboprophylaxis until discharge (Grade 1A) Selected high-risk patients, including some who have undergone major cancer surgery or have had VTE previously, continue thromboprophylaxis after discharge; consider LMWH for up to 28 days Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
41 UFH vs LMWH in Colorectal Surgery: A Meta-analysis In a meta-analysis that included 19 randomized controlled or clinical controlled trials comparing prophylactic interventions in patients who underwent colorectal surgery –UFH and LMWH (4 studies) were equally effective (POR 1.01) –The combination of graduated compression stockings and LMWH is better than LMWH alone (2 studies) (POR 4.17) The investigators concluded that graduated compression stockings + low-dose UFH or LMWH is the optimal thromboprophylaxis in colorectal surgery Borly L, et al. Colorectal Dis. 2005;7(2):122-127. POR, Peto Odds ratio.
42 Efficacy of LMWH in Patients Undergoing Cancer Surgery: ENOXACAN Results a 95% CI -9.2–2.3; b P=.02. 1. ENOXACAN Study Group. Br J Surg. 1997;84(8):1099-1103. 2. Bergqvist D, et al. N Engl J Med. 2002;346(13):975-980. ENOXACAN I 1 ENOXACAN II 2 18.2 a 17.6 2.9 14.7 14.4 4.1 0 2 4 6 8 10 12 14 16 18 20 Total VTEDVTMajor Bleeding Percent of Patients UFH Enoxaparin 12.0 b 10.2 0.0 4.8 4.2 0.4 0 2 4 6 8 10 12 14 16 18 20 All VTEDistal DVT Major Bleeding Percent of Patients Placebo Enoxaparin
43 Efficacy of Dalteparin in Cancer Surgery: Rate of Clinically Significant DVT or PE Reprinted with permission from DeBernardo RL Jr, et al. Obstet Gynecol. 2005;105(5 Pt 1):1006-1011. 12 10 8 6 4 2 0 8.9 1.2 7.7 2.9 10.5 0 Patients With DVT/PE, % All PatientsPneumobootsNo Pneumoboots Treatment Arm Dalteparin UFH P=.009 P=.25 P=.016
44 Guidelines for VTE Prophylaxis in Orthopedic Patients FIT, foot impulse technology; IPC, intermittent pneumatic compression. 1.Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2.International Consensus Statement. Int Angiol. 2006;25(2):101-161. 3.American Academy of Orthopaedic Surgeons Clinical Guideline, 2007. http://www.aaos.org/Research/guidelines/PE_guideline.pdf. Accessed October 24, 2008. ACCP 1 IUA 2 AAOS 3 Total hip replacement LMWH, fondaparinux, warfarin LMWH, fondaparinux, warfarin, IPC or FIT Aspirin, LMWH, fondaparinux, warfarin Total knee replacement LMWH, fondaparinux, warfarin LMWH or warfarinAspirin, LMWH, fondaparinux, warfarin Arthroscopic knee surgery LMWH for higher- risk patients LMWH or IPC if contraindications to LMWH Note that the ACCP and IUA specifically recommend against the use of aspirin alone as thromboprophylaxis Multiple traumaLMWH or IPCLMWH or IPC if contraindications to LMWH
45 VTE After Orthopedic Surgery VTE is common after major orthopedic surgery 1 Without prophylaxis, approximately 60% of patients have evidence of DVT at hospital discharge 1 Prevalence of asymptomatic DVT is greater than 2-fold higher after knee replacement than hip replacement 7 to 10 days after surgery 2 In patients who receive short-duration LMWH, the prevalence of DVT is 16% after hip replacement and 31% after knee replacement 1 Use of estrogen therapy increases the risk of VTE 3 1.Geerts WH, et al. Chest. 2001;119(1 suppl):132S-175S. 2.Douketis JA, et al. Arch Intern Med. 2002;162(13):1465-1471. 3.US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Bethesda, MD: September 2008.
46 3 2 1 0 % Incidence 142842567084 Days VTE Incidence Following Hip and Knee Replacement Time of Onset of DVT After THR 1 1.Reprinted with permission from Sikorski JM, et al. J Bone Joint Surg. 1981;63(2):171-177. 2.Reprinted with permission from White RH, et al. Arch Intern Med. 1998;158(14):1525-1531. Incidence of VTE Complications During 3 Mo After Surgery 2 0 5 10 15 20 25 30 246810121416 Post-op Day Total Proximal All VTE Primary Hip Primary Knee The incidence of thromboembolic events does not stabilize until approximately 10 weeks after THR
47 Prevention of VTE After Major Orthopedic Surgery: Rivaroxaban vs Enoxaparin Meta-analysis of 3 RECORD pivotal trials Turpie AG, et al. Presented at: American College of Chest Physicians 74th Annual Scientific Assembly (CHEST 2008); October 27, 2008; Philadelphia, PA. 0.4 0.5 0.2 0.3 0.8 1.3 0.2 0 1 2 2 Weeks Symptomatic VTE and Death Major Bleeding End of Period Percent of Patients Rivaroxaban Enoxaparin 2 WeeksEnd of Period P=.005 P<.001 P=NS
48 10.1 Thromboprophylaxis With Rivaroxaban vs Enoxaparin 30 mg q12h: RECORD4 0 2 4 6 8 10 12 Incidence, % Enoxaparin 30 mg q12h Rivaroxaban 10 mg once daily 6.9 2.0 1.2 0.7 0.3 0.7 Total VTE Major VTE Major Bleeding P=.012 Symptomatic VTE Turpie AG, et al. Presented at: the American Academy of Orthopaedic Surgeons (AAOS) 2009 Annual Meeting; February 27, 2009; Las Vegas, NV.
49 VTE Prevention After Hip Fracture Surgery Incidence of VTE by Day 11 Eriksson BI, et al. N Engl J Med. 2001;345(18):1298-1304. P<.001 for all fondaparinux vs enoxaparin comparisons. 8.3 7.9 0.9 6.7 19.1 18.8 4.3 15 0 5 10 15 20 25 30 VTEAny DVTProximal DVTDistal DVT Percent of Patients Fondaparinux Enoxaparin
50 Neurosurgery Recommendations Routine use of prophylaxis in all patients undergoing major neurosurgery (Grade 1A) –Optimal use of IPC (Grade 1A) –Acceptable alternatives to IPC: post-op LMWH (Grade 2A) or LDUH (Grade 2B) In patients with particularly high thrombosis risk, combine mechanical and pharmacologic method (GCS and/or IPC; post-op LMWH or LDUH) (Grade 2B) Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
51 Trauma Recommendations All major trauma patients should receive prophylaxis (Grade 1A) Initiate LMWH as soon as possible in the absence of major contraindications (Grade 1A) Use GCS +/- IPC when LMWH prophylaxis is delayed or contraindicated (Grade 1B) Consider extended prophylaxis with LMWH or VKA in major immobility (Grade 2C) Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
52 Management of VTE in Special Patient Populations
53 LMWH and Bleeding in Patients With Severe Renal Insufficiency: A Meta-analysis In a meta-analysis that included 18 studies using 3 preparations of LMWH –Peak anti-Xa levels measured 4 hours after a SC injection were statistically significantly higher in patients with a CrCl ≤30 mL/min compared with those with a CrCl >30 mL/min in studies that used a standard therapeutic dose of enoxaparin but not in studies of empirically dose-adjusted enoxaparin –LMWH was associated with a statistically significant increase in the risk for major bleeding in patients with a CrCl ≤30 mL/min compared with those with a CrCl >30 mL/min (P=.013) –When analyzed according to LMWH preparation, major bleeding was increased when a standard therapeutic of enoxaparin was used (8.3% vs 2.4%) but may not be increased when an empirically adjusted dose of enoxaparin is used (0.9% vs 1.9%; P=.23) Lim W, et al. Ann Intern Med. 2006;144(9):673-684.
54 Renal Impairment Recommendations Consider renal function when making decisions about the use and/or dose of LMWH, fondaparinux, and other antithrombotic drugs cleared by the kidneys (Grade 1A) –Particularly important in elderly patients, patients with diabetes mellitus, those at high risk for bleeding Depending on circumstances, options include (Grade 1B): –Avoid anticoagulants that bioaccumulate in the presence of renal impairment –Use a lower dose of the agent –Monitor the drug level or its anticoagulant effect Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines
55 Efficacy of Fixed Low-Dose Dalteparin in Obese vs Nonobese Patients Kucher N, et al. Arch Intern Med. 2005;165(3):341-345. NOTE: Fixed low-dose dalteparin was not effective in reducing the primary end point in patients with a BMI ≥40 kg/m 2. a Primary end point: symptomatic VTE, fatal PE, sudden death, or asymptomatic proximal DVT by day 21 RR, 0.64; 95% CI, 0.32-1.28 4.3 2.8 0 2 4 6 8 10 PlaceboDalteparin Patients With VTE Events a, % Obese Patients 5.2 2.8 PlaceboDalteparin Nonobese Patients RR, 0.53; 95% CI, 0.34-0.82
56 Inpatient Bariatric Surgery Recommendations Use routine thromboprophylaxis with LMWH, LDUH 3 times daily, fondaparinux, or the combination of 1 of these pharmacologic methods with optimally used IPC (Grade 1C) It is suggested that higher doses of LMWH or LDUH than usual for nonobese patients be used (Grade 2C) 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
58 Initial Management of DVT Short-term treatment with SC LMWH, IV UFH, or SC fondaparinux (Grade 1A) –LMWH SC once or twice daily over UFH as an outpatient if possible (Grade 1C) and as an inpatient if necessary (Grade 1A), unless renal failure (Grade 2C) –IV UFH: continuous infusion with aPTT monitoring (Grade 1C) If clinical suspicion of DVT is high, treatment should be initiated while awaiting results of diagnostic tests (Grade 1C) Treat for at least 5 d with LMWH, UFH, or fondaparinux until the INR ≥2.0 for 24 h (Grade 1C) Start warfarin on first treatment day together with LMWH, UFH, or fondaparinux (Grade 1A) Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S. 2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines
59 Treatment With LMWH vs UFH LMWH vs UFH 1 (based on a meta-analysis) –LMWH is more effective than UFH for initial treatment of VTE –LMWH significantly reduces the occurrence of major hemorrhage during initial treatment and overall mortality at follow up LMWH use is amenable to home therapy 2 (based on a meta-analysis) –Lower VTE recurrence rate than hospital treatment –Lower mortality –Lower major bleeding rate 1.van Dongen CJ, et al. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001100. 2.Othieno R, et al. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD003076.
60 Initial Treatment of PE For objectively confirmed PE, short-term treatment with SC LMWH, IV UFH, or SC fondaparinux (Grade 1A) For acute nonmassive PE, LMWH recommended over IV UFH (Grade 1A) If clinical suspicion of PE is high, treatment should be initiated while awaiting outcome of diagnostic tests (Grade 1C) Treat for at least 5 d with LMWH, UFH, or fondaparinux and until the INR is ≥2.0 for at least 24 h (Grade 1C) Start warfarin on first treatment day together with LMWH, UFH, or fondaparinux (Grade 1A) 2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S. Anticoagulant Therapy
61 Initial Treatment of PE (cont) All PE patients should undergo rapid risk stratification (Grade 1C) –When evidence of hemodynamic compromise, use thrombolytic therapy unless there are major contraindications owing to bleeding risk (Grade 1B) –In selected high-risk patients without hypotension judged to have a low risk of bleeding, use of thrombolytic therapy is recommended (Grade 2B) The decision to use thrombolytic therapy depends on the clinician’s assessment of PE severity, prognosis, and risk of bleeding –For the majority of patients with PE, thrombolytic therapy is not recommended (Grade 1B) 2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines Thrombolytic Therapy Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S.
62 Outpatient VTE Protocol Clinical Exclusionary Criteria Absolute Active bleeding or positive stool guiac Thrombocytopenia <100K Major surgery/trauma or CVA <2 weeks Phlegmasia Symptomatic PE Severe renal dysfunction Recent GI bleeding Hypertensive emergency History of heparin sensitivity or HIT Active or major comorbid illness Relative History of familial bleeding disorder Morbid obesity Iliofemoral DVT Pregnancy Underlying liver disorder Aged >75 y Acquired or congenital hypercoagulable state Based on compendium of RCTs and observational studies CVA, cerebrovascular accident; HIT, heparin-induced thrombocytopenia. Spyropoulos AC. Am J Manag Care. 2000;6(20 suppl):S1034-S1044.
63 Case Study 1 Thromboprophylaxis in a Patient Undergoing Total Joint Replacement History and Examination: 74-year-old woman scheduled for elective total hip replacement Otherwise healthy and no previous history of vascular or venous disease Currently uses oral estrogen therapy Laboratory evaluation at hospital admission was normal, as were a chest x-ray and ECG
64 Risk of DVT: Complications associated with total hip replacement are PE and postphlebitic syndrome Fatal PE occurs in 1 in 500 patients undergoing total hip replacement Asymptomatic DVT is much more common, occurring in 40% to 60% of patients; asymptomatic VTE occurs in 2% to 5% Case Study 1 Thromboprophylaxis in a Patient Undergoing Total Joint Replacement
65 Treatment: Adjusted dose warfarin with a target INR of 2.0 to 3.0, LMWH, or fondaparinux Treatment usually begins on the day of surgery (fondaparinux started after surgery) and continues for up to 35 days Risk of bleeding with prophylactic therapy is much lower than with therapeutic anticoagulation Early mobilization and compression stockings also may be used as adjunctive measures Use of estrogen therapy increases the risk of VTE Case Study 1 Thromboprophylaxis in a Patient Undergoing Total Joint Replacement
66 Case Study 2 Thromboprophylaxis in a Hospitalized Medical Patient History and Examination: 79-year-old woman in a skilled nursing facility History of CHF Reports shortness of breath over the past 24-48 hours Transferred to the ED Diagnostic evaluation revealed no PE on CT scan, but chest x-ray revealed pneumonia in right lung Vital signs: RR 24, HR 96, BP 156/76, normal temp Levofloxacin was begun for pneumonia
67 Risk of DVT: Inadequate or omitted VTE prophylaxis in hospitalized medical patients is common The majority of DVT develops in hospitalized medical rather than surgical patients VTE prophylaxis remains underutilized Ineffective regimens are often used Underuse often occurs because of inappropriate safety concerns Case Study 2 Thromboprophylaxis in a Hospitalized Medical Patient
68 Treatment: Prompt evaluation of the need for VTE prophylaxis is essential Pharmacological therapy is first-line therapy Results from the EXCLAIM study show that extended duration anticoagulation is appropriate in high-risk medical patients Appropriate options in this patient include: –Mechanical prophylaxis with IPC –LMWH –Fondaparinux* –UFH Case Study 2 Thromboprophylaxis in a Hospitalized Medical Patient * Fondaparinux is not approved by the FDA for prophylaxis in medical patients.
69 History and Examination: 68-year-old woman with Stage II breast cancer Post lumpectomy 3 months ago Now with left lower extremity proximal DVT Labs with normal hemogram and platelet count of 180K CrCl >50 cc/min Otherwise healthy and taking tamoxifen Case Study 3 Treatment in a Patient With Cancer
70 Risk of DVT: Patients with cancer have a 6-fold increased risk of VTE compared to those without cancer –Cancer also increases risk of recurrent VTE and hemorrhagic complications Case Study 3 Treatment in a Patient With Cancer
71 Treatment First-line therapy options: –LMWH heparin bridge to dose-adjusted VKA –Dalteparin 200 IU/kg q d 1 month, then 150 IU/kg q d –Enoxaparin 1 mg/kg q 12 h or 1.5 mg/kg q d, extended therapy –Fondaparinux 5 mg q d, extended therapy Continue treatment for at least 3 to 6 months Case Study 3 Treatment in a Patient With Cancer