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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
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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
Disclosure Statement 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.
Venous Thromboembolism Annual incidence of VTE in the US: • Approximately 600,000 cases of VTE1,2 • Estimated 180,000 deaths due to DVT/PE1 Annual number at risk for VTE in US hospitals: • 7.7 million medical service inpatients3 • 4.3 million surgical service inpatients3 • 2/3 of VTE cases and deaths are hospital-acquired1 31% of US hospital discharges PE is the leading preventable cause of hospital death4 • 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. • Anderson FA Jr, et al. Arch Intern Med. 1991;151(5):933-938. • Anderson FA Jr, et al. Am J Hematol. 2007;82(9):777-782. • Geerts WH, et al. Chest. 2008;133:381S-453S.
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
VTE in Hospitalized PatientsNot Just a Surgical Problem • 50%-70% of symptomatic VTEs occur in nonsurgical patients1 • 70%-80% of fatal PEs occur in nonsurgical patients1 • DVT was detected by ultrasound in 33% of medical patients in the ICU during an 8-month screening study2 • PE: most preventable cause of hospital death and the number one strategy to improve patient safety in hospitals1 1. Geerts WH, et al. Chest. 2008;133:381S-453S. 2. Hirsch DR, et al. JAMA. 1995;274:335-337.
DVT-FREE Registry: Distribution by Age and Gender 800 Men (n=2559) Women (n=2892) 700 600 500 Patients, n 400 300 200 100 0 ≤20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 >90 Age, y Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering Committee. Am J Cardiol. 2004;93:259-262.
DVT-FREE Registry:Distribution by BMI and Gender 800 Men (n=2095) Women (n=2344) 700 600 500 Patients, n 400 300 200 100 0 ≤20 21-25 26-30 31-35 >35 Body Mass Index, kg/m2 Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering Committee. Am J Cardiol. 2004;93:259-262.
DVT-FREE Registry: Time From Most Recent Surgery to Diagnosis of DVT by Patient Status 40 Outpatients (n=718) Inpatients (n=1351) 35 30 25 Patients, % 20 15 10 5 0 0-5 6-10 11-15 16-20 21-25 26-30 >31 Time, d Reprinted with permission from Goldhaber SZ, Tapson VF; for the DVT FREE Steering Committee. Am J Cardiol. 2004;93:259-262.
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.
Increased baseline propensity for thrombosis Acute insult Potential Mechanisms by Which Clinical Conditions Facilitate VTE Hypercoagulability Direct vessel injury Blood stasis Hypercoagulability Direct vessel injury Blood stasis Lopez JA, et al. Hematology. 2004;1:439-456.
Surgery Trauma (major trauma orlower-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 Risk Factors for VTE Adapted from Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
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 PE2 • CHF has long been associated with an increased risk of VTE3 • One of the few studies to quantify the risk of DVT in patients with CHF did find increased risk, with an OR of 1.84 • VTE is an underestimated cause of morbidity and mortality in patients with CHF3 • 1. Shetty R, et al. J Throm Thrombolysis. 2008;26:35-40. • Fraisse F, et al. Am J Respir Crit Care Med. 2000;161:1109-1114. • Howell MD, et al. J Clin Epidemiol. 2001;54(8):810-816. • Cogo A, et al. Arch Int Med. 1994;154:164-168.
The Importance of DVT Prophylaxisin Congestive Heart Failure 38.3 x greater DVT/PE Risk 2.8 X greater 1.7 X greater LVEF >45% LVEF 20-44% LVEF <20% LVEF = left ventricular ejection fraction. Howell MD, et al. J Clin Epidemiol. 2001;54:810-816.
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.
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/ParentShellTemplate&parentName=TopicCat&c=MQParents. Accessed November 6, 2008.
Pharmacologic LMWH (eg, enoxaparin, dalteparin) Low-dose UFH Fondaparinuxa Vitamin K antagonist (eg, warfarin) Mechanical Intermittent pneumatic compression Graduated elastic compression stockings 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines Strategies for Prevention of VTE aFondaparinux is not approved by the FDA for VTE prophylaxis in medical patients. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
Emerging Anticoagulants for the Management of VTE • Indirect FXa inhibitor • Idraparinux • Oral direct FXa inhibitors • Rivaroxaban • Apixaban • Oral direct thrombin inhibitor • Dabigatran
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines 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 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 fondaparinuxa 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) aFondaparinux is not approved by the FDA for VTE prophylaxis in medical patients. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.
Thromboprophylaxis Recommendations for Hospital Patients — Balancing the Risk of Bleeding aHigh-risk patients include those who have had major trauma or spinal cord injury, major hip or knee surgery, or major surgery for cancer. Adapted from Geerts WH, et al. J Crit Care. 2002;17:95-104.
Risk of VTE in Hospitalized Medical Patients • Patients hospitalized for acute medical illness have more than a 10-fold increased risk for VTE1 • Nursing home residents are more than twice as likely as nonresidents to develop DVT/PE2 • VTE prophylaxis remains underutilized or inadequate in hospitalized medical patients3,4 • Underuse often occurs because of unwarranted safety concerns5 • Heit JA, et al. Arch Intern Med. 2000;160(6):809-815. • Heit JA, et al. Arch Intern Med. 2002;162(11):1245-1248. • Goldhaber SZ, Tapson VF. Am J Cardiol. 2004;93(2):259-262. • Anderson FA Jr, et al. Ann Intern Med. 1991;115(8):591-595. • 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.
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, includingactive 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)* ACCP 2008 and IUA 2006 Guidelines • * Fondaparinux is not approved by the FDA for prophylaxis in medical patients. • International Consensus Statement. Int Angiol. 2006;25:101-161. • Geerts WH, et al. Chest. 2008;133:381S-453S.
VTE Prophylaxis in Acutely Ill Medical Patients Primary Efficacy End Points: Implications for Clinical Practice Trial VTE RRR MEDENOX1 Distal and proximal 63% venographic DVT + symptomatic VTE + fatal PE PREVENT2 Compression 45% ultrasonographic DVT + symptomatic VTE + fatal PE ARTEMIS3 Distal and proximal 47% venographic DVT + symptomatic VTE + fatal PE # Needed to Treat 10 45 20 • Samama MM, et al. N Engl J Med. 1999;341(11):793-800. • Leizorovicz A, et al. Circulation. 2004;110(7):874-879. • Cohen AT, et al. BMJ. 2006;332(7537):325-329.
VTE Prophylaxis in Hospitalized Medical Patients: 3 Meta-analyses • Dentali et al1: 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 al2: 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 al3: 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) • Dentali F, et al. Ann Intern Med. 2007;146(4):278-288. • King CS, et al. Chest. 2007;131(2):507-516. • Wein L, et al. Arch Intern Med. 2007;167(14):1476-1486.
Is Duration of VTE Prophylaxis Analogous to Duration of a Course of Antibiotics? Antibiotic Organism • Process Components: • Failure to give the antibiotic • “Resistance” of the organism • Initial timing of the antibiotic • Duration of treatment
EXCLAIM: Extended-duration Enoxaparin Prophylaxis in High-risk Medical Patients NNT = 46 patients to avoid one VTE event. NNT = 224 to result in one major bleeding event. HullRD, et al. Abstract presented at: ISTH, July 8-11, 2007, Geneva, Switzerland.
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.
Prevention of VTE in Patients With Heart Failure or Severe Respiratory Disease 18 16 Enoxaparin 14 UFH 12 10 Percentage of Thrombolic Events 8 6 4 2 0 All Patients Resp Dis HF HF = heart failure. Kleber F-X, et al. Am Heart J. 2003;145:614-621.
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.
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.
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.
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines 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.
Despite Evidence, Medical Patients at Risk Remain Unprotected ENDORSE1 IMPROVE2 • Cohen AT, et al. Presented at: 2007 Congress of the International Society on Thrombosis and Haemostasis; July 6-12, 2007; Geneva, Switzerland. • Tapson VF, et al. Chest. 2007;132(3):936-945.
Electronic Alerts to Prevent VTE in Hospitalized Patients 100 98 96 Intervention group Freedom From DVT or PE (%) 94 92 Control group 90 P<.001 0 0 30 60 90 Days 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.
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines 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 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.
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 POR, Peto Odds ratio. Borly L, et al. Colorectal Dis. 2005;7(2):122-127.
Efficacy of LMWH in Patients Undergoing Cancer Surgery: ENOXACAN Results ENOXACAN I1 ENOXACAN II2 20 20 18.2a Placebo Enoxaparin UFH Enoxaparin 17.6 18 18 14.7 16 14.4 16 14 14 12.0b 12 12 10.2 Percent of Patients 10 Percent of Patients 10 8 8 4.8 6 6 4.2 4.1 2.9 4 4 2 2 0.4 0.0 0 0 All VTE Distal DVT Major Bleeding Total VTE DVT MajorBleeding 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.
Efficacy of Dalteparin in Cancer Surgery: Rate of Clinically Significant DVT or PE P=.016 12 10.5 P=.009 10 P=.25 Dalteparin UFH 8.9 7.7 8 Patients With DVT/PE, % 6 4 2.9 2 1.2 0 0 All Patients Pneumoboots No Pneumoboots Treatment Arm Reprinted with permission from DeBernardo RL Jr, et al. Obstet Gynecol. 2005;105(5 Pt 1):1006-1011.
Guidelines for VTE Prophylaxis in Orthopedic Patients • FIT, foot impulse technology; IPC, intermittent pneumatic compression. • Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. • International Consensus Statement. Int Angiol. 2006;25(2):101-161. • American Academy of Orthopaedic Surgeons Clinical Guideline, 2007. http://www.aaos.org/Research/guidelines/PE_guideline.pdf. Accessed October 24, 2008.
VTE After Orthopedic Surgery • VTE is common after major orthopedic surgery1 • Without prophylaxis, approximately 60% of patients have evidence of DVT at hospital discharge1 • Prevalence of asymptomatic DVT is greater than 2-fold higher after knee replacement than hip replacement 7 to 10 days after surgery2 • In patients who receive short-duration LMWH, the prevalence of DVT is 16% after hip replacement and 31% after knee replacement1 • Use of estrogen therapy increases the risk of VTE3 • Geerts WH, et al. Chest. 2001;119(1 suppl):132S-175S. • Douketis JA, et al. Arch Intern Med. 2002;162(13):1465-1471. • 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.
VTE Incidence Following Hip and Knee Replacement Incidence of VTE Complications During 3 Mo After Surgery2 Time of Onset of DVT After THR1 30 3 All VTE 25 2 20 Total % Incidence 15 Proximal 1 10 Primary Hip Primary Knee 5 0 0 2 4 6 8 10 12 14 16 14 28 42 56 70 84 Post-op Day Days The incidence of thromboembolic events does notstabilize until approximately 10 weeks after THR • Reprinted with permission from Sikorski JM, et al. J Bone Joint Surg. 1981;63(2):171-177. • Reprinted with permission from White RH, et al. Arch Intern Med. 1998;158(14):1525-1531.
Prevention of VTE After Major Orthopedic Surgery: Rivaroxaban vs Enoxaparin Meta-analysis of 3 RECORD pivotal trials 2 Rivaroxaban P<.001 Enoxaparin 1.3 P=.005 Percent of Patients 1 0.8 P=NS P=NS 0.5 0.4 0.3 0.2 0.2 0.2 0 2 Weeks End of Period 2 Weeks End of Period Major Bleeding Symptomatic VTE and Death Turpie AG, et al. Presented at: American College of Chest Physicians 74th Annual Scientific Assembly (CHEST 2008); October 27, 2008; Philadelphia, PA.
Thromboprophylaxis With Rivaroxaban vs Enoxaparin 30 mg q12h: RECORD4 12 P=.012 10.1 Rivaroxaban 10 mg once daily 10 Enoxaparin 30 mg q12h 8 6.9 Incidence, % 6 4 2.0 1.2 2 1.2 0.7 0.7 0.3 0 Major Bleeding SymptomaticVTE Major VTE Total VTE Turpie AG, et al. Presented at: the American Academy of Orthopaedic Surgeons (AAOS) 2009 Annual Meeting; February 27, 2009; Las Vegas, NV.
VTE Prevention After Hip Fracture Surgery Incidence of VTE by Day 11 30 Fondaparinux 25 Enoxaparin 19.1 18.8 20 15 Percent of Patients 15 8.3 10 7.9 6.7 4.3 5 0.9 0 VTE Any DVT Proximal DVT Distal DVT P<.001 for all fondaparinux vs enoxaparin comparisons. Eriksson BI, et al. N Engl J Med. 2001;345(18):1298-1304.
2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines 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.