"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Charles L Bennett, MD, PhD, MPP Northwestern University Chicago.

"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations"
Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

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 Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

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. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Faculty Disclosure Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Venous Thromboembolism
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 Pulmonary embolism (PE) resulting from deep vein thrombosis (DVT)─collectively referred to as venous thromboembolism (VTE)─is the leading preventable cause of hospital death in the United States.1 Although a 1991 study that extrapolated findings from 16 short-stay hospitals in Worcester, Massachusetts, found that approximately 270,000 individuals were hospitalized for VTE in 1991,2 the true incidence rate is probably closer to 600,000 VTE cases annually, as VTE is often undiagnosed.3 At least 100,000─and perhaps as many as 180,000─individuals annually die directly or indirectly as a result of PE or DVT.3 An analysis of inpatients, using the 2003 Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project and based on VTE criteria established by the Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic and Thrombolytic Therapy, estimated that more than 12 million patients (comprising 31% of US hospital discharges in 2003) were at risk for VTE.4 A total of 7.7 million medical inpatients and 4.3 million surgical patients met ACCP guideline criteria for VTE risk. Effective prophylaxis can significantly reduce the incidence of VTE. 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): Anderson FA Jr, et al. Am J Hematol. 2007;82(9): Geerts WH, et al. Chest. 2008;133:381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:381S-453S. US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. US Dept of Health and Human Services; Bethesda, MD: September Accessed September 16, 2008. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991;151(5): Anderson FA Jr, Zayaruzny M, Heit JA, Fidan D, Cohen AT. Estimated annual numbers of US acute-care hospital patients at risk for venous thromboembolism. Am J Hematol. 2007;82(9): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Rising Incidence of VTE in Hospitalized Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 rates in hospitalized patients are rising because the population is getting older (older age increases the risk of VTE), the obesity epidemic in the United States continues to grow (obesity also increases VTE risk), and patients are surviving longer with chronic disease associated with the risk of VTE. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

VTE in Hospitalized Patients Not Just a Surgical Problem
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" VTE in Hospitalized Patients Not 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 Although the risk of deep vein thrombosis (DVT) is thought to be most commonly associated with surgical patients, 50% to 70% of symptomatic thromboembolic events and 70% to 80% of cases of fatal PE occur in nonsurgical patients.1 Patients in the medical intensive care unit (ICU) are at particularly high risk for DVT. During an 8-month screening study, DVT was detected by ultrasound in 33% of 100 patients admitted to the medical ICU with an anticipated minimum stay of 48 hours.2 PE is the 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: Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:381S-453S. Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA. 1995;274: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

DVT-FREE Registry: Distribution by Age and Gender
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" DVT-FREE Registry: Distribution by Age and Gender ART: pl 800 700 Men (n=2559) Women (n=2892) 600 500 Patients, n 400 300 200 Goldhaber et al enrolled 5451 patients with ultrasound-confirmed DVT, including 2892 women and 2559 men, from 183 United States sites in their prospective registry. The 5 most frequent comorbidities were hypertension (50%), surgery within 3 months (38%), immobility within 30 days (34%), cancer (32%), and obesity (27%). Of the 2726 patients who had their DVT diagnosed while in the hospital, only 1147 (42%) received prophylaxis within 30 days before diagnosis. This figure shows the age distribution for men and women. The mean age was 64 ± 17 years. There were more women than men ≥70 years of age (P<.0001). 100 ≤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: 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: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

DVT-FREE Registry: Distribution by BMI and Gender
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" DVT-FREE Registry: Distribution by BMI and Gender 800 Men (n=2095) Women (n=2344) 700 600 500 Patients, n 400 300 200 Overweight and obesity were common. Body mass index (BMI) was calculated for 81% of all patients (n=4439). The mean BMI was 28.3 ± 7.3 kg/m2. One third of patients were obese (BMI >30 kg/m2), and 31% were overweight (BMI 25 kg/m2 to 30 kg/m2). 100 ≤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: 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: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

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 A total of 2094 (38%) developed DVT 3 months after surgery. The median time from surgery to diagnosis of DVT was 8 days for patients who had their DVT diagnosed while in the hospital and 21 days for those who had their DVT diagnosed while outpatients (P<.0001). 5 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: 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: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Outpatient and Inpatient VTE Are Linked
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 and colleagues conducted an observational study in Worcester, Massachusetts, to determine the frequency of VTE occurring in outpatients, the prevalence of risk factors for VTE, and the use of VTE prophylaxis. A total of 1897 patients had a confirmed episode of VTE. Overall, 74% of cases of VTE occurred in outpatients. A substantial portion (60%) of these patients had been hospitalized within the previous 3 months—23% for surgery and 37% for medical hospitalization. Among the 60% of patients who had recently been hospitalized, 67% were diagnosed with VTE within 1 month after hospital discharge. Other major risk factors for VTE in the outpatient setting included active malignant neoplasms (29%) or previous VT (20%). Only 43% of 516 recently hospitalized patients who subsequently developed VTE had received VTE prophylaxis. Spencer FA, et al. Arch Intern Med. 2007;167(14): Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007;167(14): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Potential Mechanisms by Which Clinical Conditions Facilitate VTE
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Potential Mechanisms by Which Clinical Conditions Facilitate VTE Increased baseline propensity for thrombosis Hypercoagulability Direct vessel injury Blood stasis Acute insult Hypercoagulability Direct vessel injury Blood stasis Risk factors and clinical conditions that impact the risk of DVT are classified as increasing the occurrence of thrombosis or precipitating an acute thrombotic event. These conditions promote thrombosis by inducing hypercoagulability, directly injuring the vessel wall, or inducing blood stasis. Lopez JA, et al. Hematology. 2004;1: Lopez JA, Kearon C, Lee AYY. Deep venous thrombosis. Hematology. 2004;1: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Risk Factors for VTE Surgery
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 The clinical risk factors for venous thromboembolism (VTE) listed on the slide are indications for VTE prophylaxis, based on the recommendations of experts. For surgical patients, the incidence of deep-vein thrombosis is affected by these preexisting factors as well as by factors related to the procedure itself, including the site, technique, and duration of the procedure, the type of anesthetic, the presence of infection, and the degree of postoperative immobilization. Adapted from Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergvist D, Pineo GF, et al. Prevention of venous thromboembolism. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Acute Respiratory Disease and CHF Increase the Risk of VTE
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 Although there are no precise data on the prevalence of thromboembolic disease in patients hospitalized for pulmonary disease, it has been estimated at 8% to 25%.1 COPD patients with DVT constitute a group of patients with a higher medical acuity, more likely to be diagnosed with concomitant PE, and more likely to managed with IVC filter insertion. Congestive heart failure is particularly important to consider because it may be difficult to distinguish from COPD, and these entities often co-exist.2 CHF has long been associated with an increased risk of VTE.3 In one of the few studies to quantify the risk of DVT in patients with CHF, the risk was increased, with an odds ratio of 1.0.4 Reports in the literature suggest that 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. Fraisse F, et al. Am J Respir Crit Care Med. 2000;161: Howell MD, et al. J Clin Epidemiol. 2001;54(8): Cogo A, et al. Arch Int Med. 1994;154: Fraisse F, Holzapfel L, Couland JM, et al. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. Am J Respir Crit Care Med. 2000;161(4 Pt 1): Shetty R, Seddighzadeh A, Piazza G, Goldhaber SZ. Chronic obstructive pulmonary disease and deep vein thrombosis: a prevalent combination. J Throm Thrombolysis. 2008;26:35-40. Howell MD, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol. 2001;54(8): Cogo A, Bernardi E, Prandoni P, et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Int Med. 1994;154: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

The Importance of DVT Prophylaxis in Congestive Heart Failure
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" The Importance of DVT Prophylaxis in Congestive Heart Failure 38.3 x greater DVT/PE Risk 2.8 X greater A case-control study was conducted to determine if congestive heart failure (CHF) was an independent risk factor for VTE in outpatients. Diagnoses of VTE and CHF required a definitive procedure. CHF was an independent predictor of VTE risk, and the risk increased with decreasing left ventricular ejection fraction (LVEF). These results support the use of anticoagulation in patients with CHF. 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: Howell MS, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol. 2001;54: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Joint Commission/NQF Draft VTE Measures for 2009
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 In May 2008, the National Quality Forum (NQF) endorsed 48 voluntary consensus standards focusing on measuring the performance of acute care hospitals, 6 of which were VTE measures: 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 All measures will be available for data collection and reporting for discharges beginning autumn 2009, and it is anticipated that complete measure specifications will be available in the spring of 2009. NQF-endorsed voluntary consensus standards are widely viewed as the “gold standard” for measurement of healthcare quality. National Quality Forum. Accessed November 6, 2008. National Quality Forum. National Quality Forum endorses consensus standards for quality of hospital care. Available at: Accessed November 6, 2008. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Surgical Care Improvement Project
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 The Surgical Care Improvement Project (SCIP) is a national quality partnership of organizations focused on improving surgical care by significantly reducing surgical complications. It 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 SCIP goal is to reduce the incidence of surgical complications nationally by 25% by the year 2010. Partners in SCIP believe that a meaningful reduction in surgical complications depends on surgeons, anesthesiologists, perioperative nurses, pharmacists, infection control professionals, and hospital executives working together to intensify their commitment to making surgical care improvement a priority. Hospitals can report on any of 4 major areas: surgical site infections, cardiovascular events, respiratory complications, and venous thromboembolism (VTE). The SCIP performance measures for VTE are: 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. Accessed November 6, 2008. Surgical Care Improvement Project. Accessed November 6, 2008. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Strategies for Prevention of VTE
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines Strategies for Prevention of VTE Pharmacologic LMWH (eg, enoxaparin, dalteparin) Low-dose UFH Fondaparinuxa Vitamin K antagonist (eg, warfarin) Mechanical Intermittent pneumatic compression Graduated elastic compression stockings The 8th edition of the American College of Chest Physicians evidence-based clinical practice guidelines for the prevention of venous thromboembolism recommended both nonpharmacologic and pharmacologic approaches to prevent DVT and PE. For patients undergoing major general surgery, thromboprophylaxis with a LMWH, low-dose UFH, or fondaparinux is recommended (each Grade 1A). Routine thromboprophylaxis with LMWH, low-dose UFH, fondaparinux, or intermittent pneumatic compression is recommended for all patients undergoing major gynecologic surgery or major, open urologic procedures (Grade 1A). For patients undergoing elective hip or knee arthroplasty, the guideline committee recommends one of the following 3 anticoagulant agents: LMWH, fondaparinux, or a vitamin K antagonist (each Grade 1A). For patients undergoing hip fracture surgery, the guideline committee recommends the routine use of fondaparinux (Grade 1A), LMWH (Grade 1B), a VKA (target INR, 2.5; range, 2.0 to 3.0; Grade 1B), or low-dose UFH (Grade 1B). Thromboprophylaxis with LMWH, low-dose UFH, or fondaparinux (each Grade 1A) is recommended for patients admitted to the hospital with an acute medical illness. (Note: Fondaparinux is not approved by the FDA for VTE prophylaxis in medical patients.) aFondaparinux is not approved by the FDA for VTE prophylaxis in medical patients. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 Suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Emerging Anticoagulants for the Management of VTE
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Emerging Anticoagulants for the Management of VTE Indirect FXa inhibitor Idraparinux Oral direct FXa inhibitors Rivaroxaban Apixaban Oral direct thrombin inhibitor Dabigatran Idraparinux is a long-acting, injectable, factor Xa inhibitor. Its clinical development has had some challenges. However, a new formulation with biotinylated idraparinux has been developed and may offer an improved safety and pharmacokinetic profile. Data from the EQUINOX trial demonstrated that the biotinylated idraparinux (idrabiotaparinux) performed well compared with idraparinux. In 753 patients with documented, acute, symptomatic DVT, treatment with idrabiotaparinux demonstrated a lower rate of recurrent VTE than treatment with idraparinux. There was also a lower rate of clinically significant bleeding with idrabiotaparinux.1 Future trials are being planned in orthopedic surgery patients. Rivaroxaban is an oral, reversible factor Xa inhibitor. The phase III RECORD program compared rivaroxaban to enoxaparin in over 12,500 patients worldwide undergoing orthopedic surgery.2-5 Data from patients undergoing total hip (THR) and knee replacement (TKR) confirmed that rivaroxaban was superior to enoxaparin given at 40 mg/day for the prevention of VTE, without an increase in major bleeding. There were no clinically important or consistent liver enzyme elevations. Bayer has recently applied to the FDA and EMEA for approval of the drug for thromboprophylaxis in orthopedic patients. Apixaban, an oral, direct, reversible factor Xa inhibitor, is under evaluation for the prevention and treatment of VTE. In the APROPOS study of patients undergoing TKR, apixaban had a lower composite rate of DVT, PE, and all-cause mortality when compared with enoxaparin or warfarin.6 In the ADVANCE-1 study of patients undergoing TKR, however, apixaban failed to meet criteria for noninferiority when compared with enoxaparin.7 Apixaban is now being evaluated for VTE prophylaxis in acutely ill medical patients. Dabigatran, a direct thrombin inhibitor, is currently in a phase 3 trial. In the RE-NOVATE trial, dabigatran was equivalent to enoxaparin in reducing DVT, PE, and all-cause mortality after THR.8 Dabigatran was as effective as enoxaparin for preventing VTE and all-cause mortality following TKR surgery in the RE-MODEL study, but failed to show equivalence to higher-dose enoxaparin (60 mg) in the RE-MOBILIZE trial.9,10 Buller H, Destors JM, Gallus AS, et al. Idrabiotaparinux, a biotinylated long-acting anticoagulant, in the treatment of deep venous thrombosis (EQUINOX study): safety, efficacy, and reversibility by aviden. Blood. 2008;112:18. Eriksson BI, Borris LC, Friedman RJ, et al. Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty: the RECORD1 trial. ASH Annual Meeting Abstracts. 2007;110(11):6 Kakkar AK, Brenner B, Dahl OE, et al. Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with enoxaparin after total hip arthroplasty: the RECORD2 trial. ASH Annual Meeting Abstracts. 2007;110(11):307. Lassen MR, Turpie AGG, Rosencher N, et al. Rivaroxaban—an oral, direct factor Xa inhibitor—for thromboprophylaxis after total knee arthroplasty: the RECORD3 trial. ASH Annual Meeting Abstract. 2007;110(11):308. Turpie A, Bauer K, Davidson B, et al. Comparison of revaroxaban—an oral, direct factor Xa inhibitor—and subcutaneous enoxaparin for thromboprophylaxis after total knee replacement (RECORD4: a phase 3 study). European Federation of National Associations of Orthopaedics and Traumatology 2008 Annual Meeting: May 29-June1, 2008; Nice, France. Abstract F85. Lassen MR, Davidson BL, Gallus A, et al. The efficacy and safety of apixiban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost. 2007;5: Bristol-Myers Squibb and Pfizer. Bristol-Myers Squibb and Pfizer provide update on apixaban clinical development program [press release]. August 26, Available at Eriksson BI, Rosencher N, Kurth AA, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double blind, non-inferiority trial. Lancet. 2007;370: Eriksson BI, Dahl OE, Kurth AA, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5: Friedman RJ, Caprini JA, Comp PC, et al. Dabigatran etexilate versus enoxaparin in preventing venous thromboembolism following total knee arthroplasty Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Key ACCP 2008 Practice Guideline Recommendations
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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) Among the key recommendations from the 8th edition of the American College of Chest Physicians evidence-based clinical practice guidelines for the prevention of venous thromboembolism is the recommendation that every hospital develop a formal strategy that addresses the prevention of venous thromboembolism (Grade 1A). The guidelines also recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A). In addition, 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. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Key ACCP 2008 Practice Guideline Recommendations (cont)
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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) In patients admitted to the hospital with an acute medical illness, the ACCP 2008 practice guidelines for the prevention of venous thromboembolism recommend thromboprophylaxis with LMWH, low-dose UFH, or fondaparinux (Grade 1A). On admission to the intensive care unit, the guidelines recommend that all patients be assessed for their risk of VTE, and that most 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. Geerts WH, Bergvist D, Pineo GF, et al. Prevention of venous thromboembolism. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Thromboprophylaxis Recommendations for Hospital Patients — Balancing the Risk of Bleeding Bleeding Risk VTE Risk Recommendation Low Moderate LMWH or LDUH Higha LMWH and/or fondaparinux, with or without GCS or IPC High GCS or IPC, LMWH or LDUH when risk decreases GCS or IPC, LMWH when risk decreases Decisions regarding the initiation of thromboprophylaxis and selection of the specific method of thromboprophylaxis should be individualized and based on each patient’s risks for bleeding and thrombosis. 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: Geerts WH, Cook D, Selby R, et al. Venous thromboembolism and its prevention in critical care. J Crit Care. 2002;17: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Primary Prevention of VTE in Hospitalized Medical Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Primary Prevention of VTE in Hospitalized Medical Patients Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Risk of VTE in Hospitalized Medical Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 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 and PE, and they account for more than 13% of all such events that occur outside the hospital.2 High-risk patients and those with identifiable symptoms are not routinely receiving prophylaxis that could help to prevent the development of DVT and/or PE. A large epidemiologic study of 5451 patients with ultrasound-confirmed DVT found that the majority had been given no prophylaxis prior to their diagnosis despite being at high risk.3 Another study of 2017 patients in 16 short-stay Massachusetts hospitals found that only 32% of high-risk patients received appropriate prophylaxis, with rates across the hospitals ranging from 9% to 56%.4 Underuse often occurs because of unwarranted safety concerns.5 Heit JA, et al. Arch Intern Med. 2000;160(6): Heit JA, et al. Arch Intern Med. 2002;162(11): Goldhaber SZ, Tapson VF. Am J Cardiol. 2004;93(2): Anderson FA Jr, et al. Ann Intern Med. 1991;115(8): 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. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160(6): Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med. 2002;162(11): Goldhaber SZ, Tapson VF; DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol. 2004;93(2): Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Forcier A, Patwardhan NA. Physician practices in the prevention of venous thromboembolism. Ann Intern Med. 1991;115(8): US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. US Dept of Health and Human Services; Bethesda, MD: September Accessed September 16, 2008. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Recommendations for Prophylaxis in Medical Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Recommendations for Prophylaxis in Medical Patients ACCP 2008 and IUA 2006 Guidelines 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)* Guidelines for prevention and treatment of VTE issued by the ACCP in 2008 and the International Union of Angiology (IUA) in 2006 are consistent in their recommendations for medical patients. Acutely ill medical patients who are admitted to the hospital and are at risk because of age, comorbid illness, immobility, or other risk factors should receive prophylaxis with either LMWH, low-dose UFH, or fondaparinux. Of note, fondaparinux is not approved by the US Food and Drug Administration (FDA) for the prophylaxis of VTE in medical patients. * Fondaparinux is not approved by the FDA for prophylaxis in medical patients. International Consensus Statement. Int Angiol. 2006;25: Geerts WH, et al. Chest. 2008;133:381S-453S. International Union of Angiology. Prevention and treatment of venous thromboembolism International Consensus Statement. Int Angiol. 2006;25: Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

VTE Prophylaxis in Acutely Ill Medical Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 Three randomized, placebo-controlled trials evaluated VTE prophylaxis with enoxaparin, dalteparin, or fondaparinux in acutely ill medical patients older than age 40 years.1-3 All three studies showed a substantial and significant reduction in the relative risk of VTE within 1 to 2 weeks after starting anticoagulation. The substantial differences in number needed to treat for the studies reflect a lower- risk population in the PREVENT trial and the inclusion of asymptomatic DVT in the MEDENOX and ARTEMIS trials. 20 Samama MM, et al. N Engl J Med. 1999;341(11): Leizorovicz A, et al. Circulation. 2004;110(7): Cohen AT, et al. BMJ. 2006;332(7537): Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999;341(11): Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ; PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7): Cohen AT, Davidson BL, Gallus AS, et al; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. 2006;332(7537): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

VTE Prophylaxis in Hospitalized Medical Patients: 3 Meta-analyses
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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) A meta-analysis by Dentali et al, which involved 9 randomized trials consisting of more than 19,000 at-risk hospitalized medical patients, found anticoagulant prophylaxis effective in preventing symptomatic VTE in at-risk hospitalized medical patients. Anticoagulation significantly reduced any PE by 57% and fatal PE by 62%, along with a nonsignificant reduction in symptomatic DVT.1 King et al conducted a meta-analysis to compare the efficacy of VTE prophylaxis with twice- vs three-times daily UFH. Twelve randomized, controlled trials were included, and the incidence of DVT, PE, all VTE events, and bleeding events was determined. The combined DVT + PE event rate was 2.34 per 1000 patient days with twice daily UFH and 0.86 per 1000 patient days with three times daily UFH (P=.05). The risk for major bleeding was significantly increased with three-times daily heparin (P<.001).2 The meta-analysis conducted by Wein et al included 36 randomized controlled trials of prophylaxis for VTE in hospitalized medical patients. Compared with the control, both UFH and LMWH were associated with a reduced risk of DVT and PE. UFH 5000 U three times daily was more effective than 5000 U twice daily for reducing the risk of DVT (RR, 0.27; 95% CI, vs RR 0.52; 95% CI ). LMWH was associated with a lower risk of DVT than UFH (RR, 0.68; 95% CI, ). Neither LMWH nor UFH reduced mortality. Dentali F, et al. Ann Intern Med. 2007;146(4): King CS, et al. Chest. 2007;131(2): Wein L, et al. Arch Intern Med. 2007;167(14): Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med. 2007;146(4): King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a metaanalysis. Chest. 2007;131(2): Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167(14): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Duration of Prophylaxis
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Is Duration of VTE Prophylaxis Analogous to Duration of a Course of Antibiotics? Indication Average LOS, d Duration of Prophylaxis Acute medical illness 3-5 6-11 d Abdominal surgery 2-10 7-10 d Hip replacement 2-6 7-10 d or 3 wk Knee replacement 2-5 Antibiotic Organism If a patient who is on an antibiotic is admitted to the hospital, and by day 3 is ready to be discharged, would you stop the antibiotic at that point? Of course not — the patient should remain on the antibiotic for the duration of a course, 7 to 10 days. Or would you see a patient with pneumonia in the ED and wait until the next morning when he/she is on the hospital floor before starting antibiotics? You should think about VTE prophylaxis much the same way. Process Components: Failure to give the antibiotic “Resistance” of the organism Initial timing of the antibiotic Duration of treatment Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Extended prophylaxis n=2013 (%)
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" EXCLAIM: Extended-duration Enoxaparin Prophylaxis in High-risk Medical Patients End points Extended prophylaxis n=2013 (%) Placebo n=2027 (%) RR reduction (%) P value VTE events 2.8 4.9 44 .001 Symptomatic 0.3 1.1 73 .004 No symptoms 2.5 3.7 34 .032 The EXCLAIM study was a multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial that compared extended-duration prophylaxis with enoxaparin and the standard regimen of enoxaparin for prevention of VTE in acutely ill medical patients with recent reduced mobility. Patients were aged ≥40 years, recently immobilized (≤3 days) and had an acute medical illness, with reduced mobility. After 10 days of open-label enoxaparin, patients were randomized to enoxaparin or placebo for another 28 days. The primary efficacy end point was the incidence of asymptomatic proximal DVT, symptomatic DVT, symptomatic PE, or fatal PE during the double-blind period. Of 5,049 patients, 2,013 received extended-duration enoxaparin and 2,027 received placebo. The rates of all VTE events and symptomatic or asymptomatic events were significantly reduced with enoxaparin vs placebo. Major bleeding occurred in 12 patients receiving enoxaparin and 3 patients receiving placebo (0.6% vs 0.1%; P=.0192). NNT = 46 patients to avoid one VTE event. NNT = 224 to result in one major bleeding event. Hull RD, et al. Abstract presented at: ISTH, July 8-11, 2007, Geneva, Switzerland. Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism (VTE) prophylaxis in acutely ill medical patients with recent reduced mobility: The EXCLAIM Study. Abstract presented at: the International Society for Thrombosis and Haemostasis Annual Meeting, July 8-11, 2007, Geneva, Switzerland. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Prevention of VTE After Acute Ischemic Stroke: PREVAIL Study
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Prevention of VTE After Acute Ischemic Stroke: PREVAIL Study NIHSS Score <14 NIHSS Score ≥14 Occurrence (95% CI) P VTE Enoxaparin 8.3% ( ) .004 16.3% ( ) UFH 14.0% ( ) 29.7% ( ) DVT 8.1% ( ) .005 13.6% ( ) 29.1% ( ) VTE is a common but preventable complication of acute ischemic stroke, and is associated with increased mortality and long-term morbidity. The PREVAIL study was a large-scale, multinational, open-label, randomized comparison of the efficacy and safety of enoxaparin with UFH for VTE prophylaxis in patients with acute ischemic stroke. Within 48 hours of the onset of stroke symptoms, the 1762 patients were randomized to receive either enoxaparin 40 mg subcutaneously once daily or UFH 5000 U subcutaneously every 12 hours for 10 days. The study treatments were not blinded. Patients were stratified by National Institutes of Stroke Scale (NIHSS) score (severe stroke ≥14, less severe stroke <14). The primary efficacy end point was the cumulative occurrence of confirmed VTE, defined as the composite of symptomatic or asymptomatic DVT, or symptomatic or fatal PE during the study treatment phase (up to day 14. Enoxaparin reduced the risk of VTE by 43% compared with UFH (68 [10%] vs 121 [18%]; relative risk 0.57, 95% CI , P=.0001). This reduction was consistent for patients with an NIHSS score of 14 or more or less than 14. The occurrence of bleeding was similar with enoxaparin (69, or 8%) or UFH (71, or 8%; P=.83). The frequency of symptomatic intracranial and major extracranial hemorrhage was small and closely similar between groups (enoxaparin 11 [1%] vs UFH 6 [1%], P=.23). There was no difference for symptomatic intracranial hemorrhage between groups. The rate of major extracranial bleeding was higher with enoxaparin than with UFH (7 [1%] vs 0; P=.015). NIHSS = National Institutes of Health Stroke Scale. Reprinted with permission from Sherman DG, et al. Lancet. 2007;369: Sherman DG, Albers GW, Bladin C, et al, on behalf of the PREVAIL Investigators. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet. 2007;369: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Percentage of Thrombolic Events
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 THE-PRINCE study was a multicenter, controlled, randomized, open parallel-group trial conducted in Germany that compared the efficacy and safety of low-molecular–weight heparin with UFH for prevention of VTE in 451 patients with heart failure or severe respiratory disease. The primary efficacy end point was a thromboembolic event up to 1 day after the treatment period. Patients were randomized to treatment with either enoxaparin 40 mg once daily or UFH 5000 IU 3 times daily for 10 ±2 days. The incidence of thromboembolic events was 8.4% with enoxaparin and 10.4% with UFH. Enoxaparin was at least as effective as UFH, with a 1-sided equivalence region of -4% (90% CI -2.5–6.5, P=.015). Enoxaparin was associated with fewer deaths, less bleeding, and significantly fewer adverse events (45.8% vs 53.8%, P=.044). 4 2 All Patients Resp Dis HF HF = heart failure. Kleber F-X, et al. Am Heart J. 2003;145: Kleber F-X, Witt C, Vogel G, Koppenhagen K, Schomkaer U, Flosbach CW, for THE-PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J. 2003;145: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Prevention of VTE in High-Risk Hospitalized Medical Patients: THE PRIME Study Intention-to-treat Per-protocol Enoxaparin (n=442) Heparin (n=443) (n=393) Heparin (n=377) Thromboembolic events 1 (0.2%) 6 (1.4%) 1 (0.3%) 5 (1.3%) DVT 1 2 DVT + PE PE Test for superiority P=.1235 P=.1164 Test for equivalence P= P= THE PRIME study was a multicenter, randomized, controlled double-blind trial investigating the efficacy and safety of enoxaparin 40 mg once daily subcutaneously vs calcium-heparin (Ca-heparin) 5000 IU three times daily subcutaneously in the prevention of thromboembolism in a high-risk group of 959 hospitalized patients over a period of 7 days. In the intention-to-treat analysis, there was no significant difference in the rate of thromboembolic events between the two groups (P=.1235). There was also no significant between-group differences in the per-protocol analysis (P=.1164). An explorative analysis of the two groups with a statistical test for equivalence proved to be highly significant, as shown in this slide. A total of 15 bleedings were documented in each treatment group. Only 3 bleedings were considered to be treatment-related; these all occurred in the Ca-heparin group. More hematomas at the injection site exceeding 5 cm in diameter occurred in the Ca-heparin than in the enoxaparin group (P<.001). Liver elevations were also significantly more frequently elevated with Ca-heparin compared with enoxaparin. Reprinted with permission from Lechler E, et al. Haemostasis. 1996;26(suppl 2):49-56. Lechler E, Schramm W, Flosbach CW, THE PRIME Study Group. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). Haemostasis. 1996;26(suppl 2):49-56. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Conclusions: THE PRIME Study
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 This trial proves that enoxaparin is at least as efficacious as Ca-heparin in the prophylaxis of DVT in hospitalized medical patients at high risk for DVT. Moreover, there were fewer adverse events and few major bleeds in patients treated with enoxaparin. A total of 15 bleeds were documented in each treatment group. Only 3 bleeds were considered to be treatment-related; these all occurred in the Ca-heparin group. More hematomas at the injection site exceeding 5 cm in diameter occurred in the Ca-heparin than in the enoxaparin group (P<.001). Liver elevations were also significantly more often elevated with Ca-heparin compared with enoxaparin. Lechler E, et al. Haemostasis. 1996;26(suppl 2):49-56. Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The PRIME Study Group. Haemostasis. 1996;26(suppl 2):49-56. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

The Importance of DVT Prophylaxis in Patients With Cancer
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 The American Society of Clinical Oncology (ASCO) issued guidelines for prophylaxis and treatment of VTE in cancer patients. Among the recommendations are that all cancer patients who are hospitalized or are undergoing cancer surgery should be considered for prophylaxis, and the preferred drug is low-molecular-weight heparin (LMWH). Lyman GH, et al. J Clin Oncol. 2007;25: Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer. J Clin Oncol. 2007;25: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Prophylaxis in Cancer Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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) Current ACCP guidelines note that the use of appropriate thromboprophylaxis in hospitalized cancer patients with additional VTE risk factors provides an important opportunity to reduce the substantial burden of this complication. Prevention of VTE is important not only because VTE may be more difficult to diagnose in cancer patients, but also because the treatment of VTE in these patients may be less effective and associated with more bleeding complications. Cancer patients undergoing surgery should receive aggressive thromboprophylaxis appropriate for the type of surgery. Cancer patients with an acute medical illness who are bedridden should receive thromboprophylaxis as recommended for medical patients. Thromboprophylaxis is also indicated in selected palliative care patients in order to prevent further reduction in quality of life, but cancer patients who are fully ambulatory should not routinely be given thromboprophylaxis. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Despite Evidence, Medical Patients at Risk Remain Unprotected
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Despite Evidence, Medical Patients at Risk Remain Unprotected ENDORSE1 IMPROVE2 Medical Surgical No. of patients 37,356 30,827 At risk for VTE 42% 64% Receiving ACCP Tx 40% 59% United States Other Countries No. of patients 3,410 11,746 VTE prophylaxis 1852 (54%) 5788 (49%) LMWH 476 (14%) 4657 (40%) UFH 717 (21%) 1014 (9%) The ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study evaluated the proportion of medical and surgical patients at risk for VTE who received prophylaxis.1 Patients were enrolled from 358 randomly selected hospitals in 32 countries. Of the 68,183 patients enrolled, a mean of 52% were at risk for VTE, including 64% of surgical and 42% of medical patients. However, only 59% of surgical and 40% of medical patients were receiving prophylaxis. The IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) study evaluated risk and prophylaxis use in the United States compared with other countries.2 From July 2002 to September 30, 2006, 15,156 patients were enrolled from 52 hospitals in 12 countries. Only 54% of at-risk US patients and 49% of at-risk patients outside the United States received VTE prophylaxis. Intermittent pneumatic compression was the most common form of medical prophylaxis used in the United States, although it was used very rarely in other countries (22% vs 0.2%, respectively). Unfractionated heparin was the most frequent pharmacological approach used in the United States (21% of patients), with low-molecular–weight heparin used most frequently in other participating countries (40%). 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): Cohen AT, Tapson VF, Bergmann JF, et al. A large-scale, global observational study of venous thromboembolism risk and prophylaxis in the acute hospital care setting: the ENDORSE study. Presented at: 2007 Congress of the International Society on Thrombosis and Haemostasis; July 6-12, 2007; Geneva, Switzerland. Abstract ISTH 2007 O-S-002. Tapson VF, Decoucus H, Pini M, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients. Findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest. 2007;132(3): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Electronic Alerts to Prevent VTE in Hospitalized Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 Kuchler and colleagues evaluated a computer linked to a patient database and designed to identify consecutive hospitalized patients at increased risk for VTE. The program used eight common risk factors to determine each patient’s risk profile for VTE, each factor weighted according to a point scale: cancer, prior VTE, and hypercoagulability were assigned a score of 3; major surgery was assigned a score of 2; advanced age, obesity, bed rest, and use of hormone therapy or oral contraceptives were assigned a score of 1. An increased risk of VTE was defined as a cumulative risk score of at least 4. The primary end point was clinically diagnosed DVT or PE at 90 days. A total of 1255 patients were randomly assigned to the intervention group, in which the responsible physician was alerted to a patient’s risk of DVT; 1251 patients were assigned to a control group, in which no alert was issued. Kaplan-Meier estimates of the absence of VTE at 90 days (shown in figure) were 94.1% and 90.6%, respectively for the intervention group vs control group (P<.001). More patients in the intervention group than in the control group received mechanical prophylaxis or pharmacologic prophylaxis. The primary end point occurred in 4.9% of the intervention group vs 8.2% of the control group. The computer alert reduced the risk of DVT or PE at 90 days by 41% (P=.001). 30 60 90 Days No. at Risk Intervention group 1255 977 900 853 Control group 1251 976 893 839 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: Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005;352: Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Primary Prevention of VTE in Surgical Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Primary Prevention of VTE in Surgical Patients Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

General Surgery Recommendations
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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) According to the ACCP 2008 guidelines, the type of surgery is the primary determinant of the risk of DVT, and most patients undergoing outpatient surgery have low rates of DVT. Factors that affect the risk of VTE in general surgery patients include traditional risk factors such as cancer, previous VTE, obesity, delayed mobilization; increasing age; type of anesthesia; duration of surgery; and postoperative infection. The guidelines recommend against additional thromboprophylaxis other than early and frequent ambulation in low-risk general surgery patients who have no additional risk factors. For moderate-risk general surgery patients undergoing a major procedure for benign disease, thromboprophylaxis with LMWH, LDUH, or fondaparinux is recommended. For higher-risk patients undergoing a major procedure for cancer, the guidelines recommend thromboprophylaxis with LMWH, LDUH three times daily, or fondaparinux. For patients with multiple risk factors who are thought to be at particularly high risk, the guidelines recommend pharmacologic therapy (LMWH, LDUH three times daily, or fondaparinux) combined with the optimal use of a mechanical method (GCS and/or IPC). Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

General Surgery Recommendations (cont)
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 For general surgery patients with a high risk of bleeding, the ACCP guidelines recommend the optimal use of mechanical thromboprophylaxis with properly fitted GCS or IPC. When the high bleeding risk decreases, pharmacologic thromboprophylaxis may be substituted or added to mechanical thromboprophylaxis. For patients undergoing major general surgery, the guidelines recommend continuation of thromboprophylaxis until discharge from the hospital. In selected high-risk patients, including some who have undergone major cancer surgery or have had VTE previously, the guidelines suggesting continuing thromboprophylaxis after discharge; LMWH for up to 28 days should be considered. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

UFH vs LMWH in Colorectal Surgery: A Meta-analysis
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 This meta-analysis of interventions for prophylaxis against VTE in colorectal surgery reviewed 19 studies. In 4 studies, LMWH and UFH were equally effective (Peto Odds ratio [POR] 1.01; 95% CI, ). In 2 studies, the combination of graduated compression stockings and LMWH was better than LMWH alone (POR 4.17; 95% CI, ). The authors concluded that the optimal thromboprophylaxis in colorectal surgery is the combination of graduated compression stockings and low-dose UFH or LMWH. POR, Peto Odds ratio. Borly L, et al. Colorectal Dis. 2005;7(2): Borly L, Wille-Jorgensen P, Rasmussen MS. Systematic review of thromboprophylaxis in colorectal surgery─an update. Colorectal Dis. 2005;7(2): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Efficacy of LMWH in Patients Undergoing Cancer Surgery: ENOXACAN Results ENOXACAN I1 ENOXACAN II2 20 18.2a 20 17.6 UFH Enoxaparin Placebo Enoxaparin 18 18 16 14.7 14.4 16 14 14 12.0b 12 12 10.2 Percent of Patients 10 Percent of Patients 10 8 8 6 6 4.8 4.1 4.2 The efficacy of enoxaparin for prophylaxis in elective cancer surgery was evaluated in 2 studies. In ENOXACAN I, enoxaparin and UFH were compared for the prevention of DVT in patients undergoing elective abdominal or pelvic surgery for cancer.1 Of 631 evaluable patients, VTE events occurred in 18.2% of patients treated with UFH and 14.7% of those treated with enoxaparin (95% confidence interval of the difference, -9.2–2.3%). No differences in mortality or bleeding complications were observed. ENOXACAN II was a double-blind, multicenter trial that evaluated the optimal duration of enoxaparin prophylaxis against VTE in 332 patients undergoing surgery for abdominal or pelvic cancer. Patients received enoxaparin for 6 to 10 days after surgery and then were randomized to enoxaparin or placebo for another 21 days.2 The rates of VTE at 21 days were 12.0% with placebo and 4.8% with enoxaparin (P=.02). This difference persisted at 3 months (13.8% vs 5.5%; P=.01). No significant differences were observed in the incidence of bleeding or other complications during the double-blind or follow-up periods. Thus, the study showed that enoxaparin prophylaxis for 4 weeks after surgery for abdominal or pelvic cancer is safe and significantly reduces the incidence of VTE as compared with enoxaparin prophylaxis for 1 week. 4 2.9 4 2 2 0.0 0.4 Total VTE DVT Major Bleeding All VTE Distal DVT Major Bleeding a 95% CI -9.2–2.3; b P=.02. 1. ENOXACAN Study Group. Br J Surg. 1997;84(8): 2. Bergqvist D, et al. N Engl J Med. 2002;346(13): ENOXACAN Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg. 1997;84(8): Bergqvist D, Agnelli G, Cohen AT, et al; ENOXACAN II Investigators. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346(13): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Efficacy of Dalteparin in Cancer Surgery: Rate of Clinically Significant DVT or PE P=.016 12 10.5 P=.009 10 P=.25 8.9 Dalteparin UFH 7.7 8 Patients With DVT/PE, % 6 4 2.9 DeBernardo and colleagues studied dalteparin vs UFH in women undergoing surgery for gynecologic malignancy. In this retrospective analysis, 103 patients received dalteparin and 11 received UFH. The study was not randomized, but researchers controlled for relevant variables and found no significant between-group differences. Rates of clinically significant DVT or PE were 8.9% in patients who received dalteparin compared with 1.2% in patients who received UFH (P=.009). The addition of pneumatic compression did not significantly decrease the thrombotic events in patients receiving dalteparin. The proportion of patients with thrombosis using these devices in conjunction with dalteparin was 7.7% compared with 10.5% of women using dalteparin alone (P=.62). In patients given UFH, the use of pneumatic compression devices did not change the incidence of thrombotic events (2.9% vs 0%; P=.22). Thus, the study found that LMWH dalteparin is inadequate postoperative prophylaxis in women undergoing surgery for gynecologic cancer. 2 1.2 All Patients Pneumoboots No Pneumoboots Treatment Arm Reprinted with permission from DeBernardo RL Jr, et al. Obstet Gynecol. 2005;105(5 Pt 1): DeBernardo RL Jr, Perkins RB, Littell RD, Krasner CN, Duska LR. Low-molecular-weight heparin (dalteparin) in women with gynecologic malignancy. Obstet Gynecol. 2005;105(5 Pt 1): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Guidelines for VTE Prophylaxis in Orthopedic Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Guidelines for VTE Prophylaxis in Orthopedic Patients ACCP1 IUA2 AAOS3 Total hip replacement LMWH, fondaparinux, warfarin LMWH, fondaparinux, warfarin, IPC or FIT Aspirin, LMWH, fondaparinux, warfarin Total knee replacement LMWH or 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 trauma LMWH or IPC This slide compares guidelines for VTE prophylaxis in common orthopedic conditions from 3 different associations, the American College of Chest Physicians (ACCP),1 the International Union of Angiology (IUA),2 and the American Academy of Orthopaedic Surgeons (AAOS).3 Note that the AAOS3 includes aspirin in their recommendations for total hip and knee replacement procedures, whereas the ACCP1 and IUA2 specifically recommend against the use of aspirin. 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): American Academy of Orthopaedic Surgeons Clinical Guideline, Accessed October 24, 2008. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol. 2006;25(2): American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty. Accessed October 24, 2008. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

VTE After Orthopedic Surgery
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 VTE is a common occurrence after major orthopedic surgery. Without prophylaxis, approximately 60% of patients have evidence of DVT at hospital discharge.1 The prevalence of asymptomatic DVT is greater than 2-fold higher after knee replacement than hip replacement 7 to 10 days after surgery.2 In the subsequent 3 months, however, symptomatic VTE is more likely to occur after hip replacement. 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 Geerts WH, et al. Chest. 2001;119(1 suppl):132S-175S. Douketis JA, et al. Arch Intern Med. 2002;162(13): 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. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest. 2001;119(1 suppl):132S-175S. Douketis JD, Eikelboom JW, Quinlan DJ, Willan AR, Crowther MA. Short-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes. Arch Intern Med. 2002;162(13): US Dept of Health and Human Services. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. US Dept of Health and Human Services; Bethesda, MD: September Accessed September 16, 2008. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

VTE Incidence Following Hip and Knee Replacement
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 20 2 Total 15 % Incidence Proximal 10 1 Primary Hip 5 Primary Knee Sikorski et al1 conducted a long-term prospective study of the natural history and etiology of DVT in 499 patients after total hip replacement. In patients who received no prophylaxis, 107 (48%) patients developed DVT; however, of these, only 6 developed DVT in the first 2 days after surgery (shown in figure on the left). The onset reached a peak on the fourth day and by the end of the first week, 82 patients had thrombosis. There was a second small peak of incidence occurring on day 13; in the second week, 25 patients developed thrombi (23% of all thrombi and 11% of all patients). The risk of thrombosis was over by day 17. The patients were subdivided into a group with thrombosis limited to the calf veins and those associated with the femoral vein irrespective of whether the femoral component originated in the calf or the thigh. In the first week, the peak incidence of femoral thrombosis was the same as the overall pattern. However, the risk of femoral thrombosis had disappeared by day 11. Eighty-seven percent of all femoral clots occurred during the first week.1 White et al2 identified cases diagnosed as having DVT or PE within 3 months of unilateral total hip or knee arthroplasty using a hospital discharge database. The figure on the right shows the incidence of thromboembolic complications over the first 3 months after surgery. Among 19,586 primary hip and 24,059 primary knee arthroplasties, the cumulative incidence of DVT or PE within 3 months of surgery was 556 (2.8%) after hip arthroplasty and 508 (2.1%) after knee arthroplasty. The diagnosis of thromboembolism was made after hospital discharge in 76% and 47% of the total hip and total knee arthroplasty cases, respectively (P<.001), with a median time of diagnosis of 17 days and 7 days after surgery, respectively (P<.001). As seen in the figure on the right, the incidence of thromboembolic events decreased to a stable rate approximately 4 weeks after knee arthroplasty, whereas the rate became stable approximately 10 weeks after hip arthroplasty. 2 4 6 8 10 12 14 16 14 28 42 56 70 84 Post-op Day Days The incidence of thromboembolic events does not stabilize until approximately 10 weeks after THR Reprinted with permission from Sikorski JM, et al. J Bone Joint Surg. 1981;63(2): Reprinted with permission from White RH, et al. Arch Intern Med. 1998;158(14): Sikorski JM, Hampson WG, Staddon GE. The natural history and aetiology of deep vein thrombosis after total hip replacement. J Bone Joint Surg. 1981;63(2): White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998;158(14): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Meta-analysis of 3 RECORD pivotal trials Symptomatic VTE and Death
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 This meta-analysis evaluated the efficacy of rivaroxaban for the prevention of symptomatic VTE in the 3 completed pivotal RECORD studies, which compared rivaroxaban with enoxaparin 40 mg once daily in patients undergoing hip or knee replacement surgery. Patients (n=9581) were randomized to receive oral rivaroxaban (10 mg once daily starting at least 6 to 8 hours after surgery) or subcutaneous enoxaparin (40 mg once daily starting the evening before surgery). In RECORD1, all patients undergoing total hip replacement (THR) received extended thromboprophylaxis for 35 days. In RECORD2, patients undergoing THR received rivaroxaban for 35 days or enoxaparin for 10 to 14 days. In RECORD3, patients undergoing total knee replacement received prophylaxis for 10 to 14 days. In all 3 studies, the rivaroxaban regimens significantly reduced the incidence of the primary outcome (the composite of any DVT, nonfatal PE, and death) and major VTE (proximal DVT, nonfatal PE, and VTE-related death) compared with the enoxaparin regimens, without increasing the risk of bleeding. This meta-analysis evaluated the effect of rivaroxaban on the composite of symptomatic VTE (DVT and PE) and death, and major bleeding at 2 weeks (predefined) and at the end of the planned medication period, in the safety population. Rivaroxaban significantly reduced the incidence of symptomatic VTE and death compared with enoxaparin (2 weeks: 0.4% vs 0.8%, respectively; OR, 0.44; 95% CIs, 0.23, 0.79; P=.005). The rivaroxaban regimens were more effective at the end of the planned study medication (0.5% vs 1.3%, respectively; OR, 0.38; 95% CIs, 0.22, 0.62; P<.001). Both groups had similar rates of major bleeding (2 weeks: 0.2% vs 0.2%, respectively; P=.662; end of planned study medication: 0.3% vs 0.2%, respectively; P=.305). 0.2 0.2 0.2 2 Weeks End of Period 2 Weeks End of Period Symptomatic VTE and Death Major Bleeding Turpie AG, et al. Presented at: American College of Chest Physicians 74th Annual Scientific Assembly (CHEST 2008); October 27, 2008; Philadelphia, PA. Turpie AG, Lassen MR, Kakkar AK, et al. Oral, once-daily rivaroxaban for the prevention of symptomatic venous thromboembolism after major orthopaedic surgery: a meta-analysis of three pivotal studies. Presented at: American College of Chest Physicians 74th Annual Scientific Assembly (CHEST 2008); October 27, 2008; Philadelphia, PA. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Thromboprophylaxis With Rivaroxaban vs Enoxaparin 30 mg q12h: RECORD4
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 RECORD4 was designed to determine the efficacy and safety of rivaroxaban compared with enoxaparin, 30 mg every 12 hours (q12h), after TKR. Patients (N=3148) were randomized to receive oral rivaroxaban 10 mg once daily (initiated 6 to 8 hours after surgery) or SC enoxaparin 30 mg q12h (initiated 12 to 24 hours after surgery) for 10 to 14 days. The primary efficacy outcome was the composite of DVT detected by mandatory, bilateral venography, nonfatal PE, and all-cause mortality up to day 13 ± 4. Secondary outcomes included major VTE (composite of proximal DVT, nonfatal PE, and VTE-related death) and symptomatic VTE. Safety outcomes included on-treatment major and nonmajor bleeding. Rivaroxaban significantly reduced the incidence of the primary efficacy outcome compared with enoxaparin (6.9% vs 10.1%, respectively; P=.012; relative risk reduction [RRR] 31%). The corresponding rates for major VTE were 1.2% versus 2.0%, respectively (P=.124) and for symptomatic VTE were 0.7% versus 1.2%, respectively (P=.187). No significant differences in bleeding incidence were observed between rivaroxaban and enoxaparin (major bleeding: 0.7% versus 0.3%, respectively, P=.110; clinically relevant nonmajor bleeding: 3.0% versus 2.3%, respectively, P=.179). Rivaroxaban 10 mg once daily significantly reduced the incidence of VTE compared with 30 mg enoxaparin q12h, with a similar, low rate of bleeding, following TKR. 2 1.2 1.2 0.7 0.7 0.3 Total VTE Major VTE Symptomatic VTE Major Bleeding Turpie AG, et al. Presented at: the American Academy of Orthopaedic Surgeons (AAOS) 2009 Annual Meeting; February 27, 2009; Las Vegas, NV. Turpie AG, et al. Presented at: the American Academy of Orthopaedic Surgeons (AAOS) 2009 Annual Meeting; February 27, 2009; Las Vegas, NV. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

VTE Prevention After Hip Fracture Surgery
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 10 8.3 7.9 6.7 This study randomly assigned 1711 patients undergoing surgery for hip fracture to treatment with either 40 mg of enoxaparin once daily or 2.5 mg of subcutaneous fondaparinux once daily for at least 5 days for VTE prophylaxis. The primary efficacy outcome was VTE up to postoperative day 11. At postoperative day 11, the incidence of VTE was 8.3% with fondaparinux compared with 19.1% with enoxaparin (P<.001). The incidence of total, proximal, and distal DVT also was significantly lower in the fondaparinux group (P<.001 for all 3 comparisons). No significant differences were observed between treatments in the incidence of death or clinically relevant bleeding. 4.3 5 0.9 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): Eriksson BI, Bauer KA, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med. 2001;345(18): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Neurosurgery Recommendations
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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) Patients undergoing major neurosurgery are at moderately increased risk for postoperative VTE and warrant the routine use of thromboprophylaxis. IPC is recommended; other acceptable options include the use of perioperative LDUH or postoperative LMWH. LMWH and GCS is more efficacious than GCS alone; LDUH and mechanical prophylaxis also appears to be highly effective. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Trauma Recommendations
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines 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) Among hospitalized patients, those recovering from major trauma are in the highest risk group for VTE. However, there have been relatively few randomized trials of thromboprophylaxis in trauma patients. According to ACCP Guidelines, all trauma patients should receive VTE prophylaxis with LMWH as soon as possible. In those patients where LMWH is contraindicated or in whom LMWH prophylaxis was delayed, GCS with or without IPC should be used. If the patient will be immobilized for an extended period, extended prophylaxis with LMWH or vitamin K analogue should be considered. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Management of VTE in Special Patient Populations
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Management of VTE in Special Patient Populations Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

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 and colleagues conducted a meta-analysis to compare the risk for major bleeding in LMWH-treated patients with a creatinine clearance of 30 mL/min or less versus those with a creatinine clearance of greater than 30 mL/min by using standard weight-adjusted therapeutic doses, empirically adjusted doses, or prophylactic doses of LMWH. A total of 18 studies using 3 preparations of LMWH were included. The analysis found that patients not on dialysis who have a creatinine clearance of 30 mL/min or less have elevated levels of anti-Xa and an increased risk of bleeding when receiving standard doses of enoxaparin. Conclusions about other LMWHs were not possible because of limited data. Lim W, et al. Ann Intern Med. 2006;144(9): Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med. 2006;144(9): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Renal Impairment Recommendations
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines 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 Renal clearance is the primary mode of elimination for several anticoagulants, including LMWH, fondaparinux, and the direct thrombin inhibitors. Reduced creatinine clearance may cause these drugs to accumulate, increasing the risk of bleeding. However, because there is considerable variability in the relationship between renal impairment and drug accumulation even for various LMWHs, the ACCP guidelines recommend that each agent be evaluated separately. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Efficacy of Fixed Low-Dose Dalteparin in Obese vs Nonobese Patients
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Efficacy of Fixed Low-Dose Dalteparin in Obese vs Nonobese Patients 10 Obese Patients Nonobese Patients 8 RR, 0.53; 95% CI, RR, 0.64; 95% CI, 6 5.2 4.3 Patients With VTE Eventsa, % 4 2.8 2.8 2 The original PREVENT trial found that a fixed dose of dalteparin was effective in reducing VTE events by 45% (relative risk [RR] 0.55; 95% CI, ) in patients aged 40 years or older who require hospitalization for an acute medical illness. This subgroup analysis of the PREVENT trial was conducted to determine whether this fixed dose was as effective in obese patients as in nonobese patients. The authors retrospectively analyzed data from 3706 hospitalized patients included in the PREVENT trial who received dalteparin 5000 IU/day or placebo. Obesity was defined as a BMI greater than 30 kg/m2 for men and 28.6 kg/m2 for women, and 30.4% of the overall population met these criteria. In obese patients, the primary end point—a composite of symptomatic VTE, fatal pulmonary embolism, sudden death, or asymptomatic proximal DVT by day 21— occurred in 2.8% of the dalteparin group compared with 4.3% in the placebo group (RR 0.64; 95% CI, ). In nonobese patients, the primary end point occurred in 2.8% of the dalteparin group and 5.2% of the placebo group (RR 0.53, 95% CI ). Dalteparin was therefore effective in obese patients, with an RRR of 36% across BMI subgroups, except for those patients with a BMI greater than 40 kg/m2. This indicates that perhaps a fixed low dose of dalteparin may not be appropriate in the morbidly obese population, particularly in those with additional risk factors. Dalteparin was deemed safe in the obese population, in that no increase in mortality (4.6% vs 2.7%, P=.14) or increase in major hemorrhage (0% vs 0.7%, P>.99) versus placebo, was observed by day 21. This study’s findings imply a low fixed dose of dalteparin is safe and effective in preventing VTE among hospitalized patients with acute medical illness and is not significantly affected by BMI, unless patients have a BMI greater than 40 kg/m2. Placebo Dalteparin Placebo Dalteparin NOTE: Fixed low-dose dalteparin was not effective in reducing the primary end point in patients with a BMI ≥40 kg/m2. aPrimary end point: symptomatic VTE, fatal PE, sudden death, or asymptomatic proximal DVT by day 21 Kucher N, et al. Arch Intern Med. 2005;165(3): Kucher N, Leizorovicz A, Vaitkus PT, et al. Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial. Arch Intern Med. 2005;165(3): Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Inpatient Bariatric Surgery Recommendations
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 2008 ACCP Prevention of Venous Thromboembolism Practice Guidelines 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) The ACCP guidelines recommend that the thromboprophylaxis recommendations for higher-risk general surgical patients be used to guide decision making in bariatric surgery patients. The guidelines suggest that higher than standard doses of LMWH or LDUH be used. Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Treatment of VTE Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Initial Management of DVT
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines 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) Based on ACCP guidelines, initial management of DVT includes short-term treatment with SC LMWH, IV UFH, monitored SC UFH, fixed dose-SC UFH, or SC fondaparinux. If the clinical suspicion is high, treatment should be initiated immediately before results from diagnostic tests are available. Treatment with LMWH, UFH, or fondaparinux should be continued for at least 5 days while warfarin is started and the dose is adjusted to achieve a stable INR >2.0. Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):454S-545S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Treatment With LMWH vs UFH
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Treatment With LMWH vs UFH LMWH vs UFH1 (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 therapy2 (based on a meta-analysis) Lower VTE recurrence rate than hospital treatment Lower mortality Lower major bleeding rate A meta-analysis of randomized controlled trials comparing LMWH and adjusted-dose UFH found that LMWH was more effective than UFH for initial treatment of VTE and that LMWH significantly reduces the occurrence of major hemorrhage during initial treatment and overall mortality at follow up.1 A follow-up meta-analysis of outpatient vs inpatient treatment of DVT found that use of LMWH at home was more effective than UFH or LMWH in the hospital, with a lower VTE recurrence rate, lower mortality, and lower major bleeding rate.2 van Dongen CJ, et al. Cochrane Database Syst Rev Oct 18;(4):CD Othieno R, et al. Cochrane Database Syst Rev Jul 18;(3):CD van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev Oct 18;(4):CD Othieno R, Abu Affan M, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev Jul 18;(3):CD Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Initial Treatment of PE
2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines "Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Initial Treatment of PE Anticoagulant Therapy 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) For patients with objectively confirmed PE, short-term treatment with SC LMWH, IV UFH, or SC fondaparinux is recommended (Grade 1A) by the 2008 ACCP practice guidelines. In patients with acute nonmassive PE, the guidelines recommend initial treatment with LMWH over IV UFH (Grade 1A). For patients in whom there is a high clinical suspicion of PE, the guidelines recommend treatment with anticoagulants while awaiting outcome of diagnostic tests (Grade 1C). In patients with acute PE, the guidelines recommend initial treatment with LMWH, UFH, or fondaparinux for at least 5 d and until the INR is ≥2.0 for at least 24 h (Grade 1C). In patients with acute PE, the guidelines recommend initiation of VKA together with LMWH, UFH, or fondaparinux on the first treatment day (Grade 1A). Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):454S-545S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Initial Treatment of PE (cont)
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines Initial Treatment of PE (cont) Thrombolytic Therapy 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) All patients with PE should undergo rapid risk stratification (Grade 1C). – For patients with evidence of hemodynamic compromise, the guidelines recommend use of thrombolytic therapy unless there are major contraindications owing to bleeding risk (Grade 1B). Thrombolysis in these patients should not be delayed because irreversible cardiogenic shock may ensue – In selected high-risk patients without hypotension who are judged to have a low risk of bleeding, administration 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) Kearon C, et al. Chest. 2008;133(6 suppl):454S-545S. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):454S-545S. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Outpatient VTE Protocol Clinical Exclusionary Criteria
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Outpatient VTE Protocol Clinical Exclusionary Criteria Based on compendium of RCTs and observational studies 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 Clinical exclusionary risk factors for outpatient treatment of DVT shown here are based on a published meta-analysis and experience at Lovelace Medical Center in New Mexico. Evidence from clinical findings suggests that patients without absolute exclusionary risk factors can successfully be treated with LMWH as outpatients. Results show that 61% of patients were eligible for outpatient therapy and had fewer recurrences of VTE (1.9%) than comorbid matched patients who were hospitalized with traditional UFH therapy the previous year (4.1%). These findings suggest that LMWH is safe and effective for the home treatment of VTE in a managed care setting when patient selection criteria and risk stratification strategies are maintained. CVA, cerebrovascular accident; HIT, heparin-induced thrombocytopenia. Spyropoulos AC. Am J Manag Care. 2000;6(20 suppl):S1034-S1044. Spyropoulos AC. Outpatient-based treatment protocols in the management of venous thromboembolic disease. Am J Manag Care. 2000;6(20 Suppl):S1034-S1044. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

History and Examination:
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Fatal PE occurs in 1 in 500 patients undergoing total hip replacement
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Case Study 1 Thromboprophylaxis in a Patient Undergoing Total Joint Replacement 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% Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Use of estrogen therapy increases the risk of VTE
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Case Study 1 Thromboprophylaxis in a Patient Undergoing Total Joint Replacement 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 Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Case Study 2 Thromboprophylaxis in a Hospitalized Medical Patient
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" 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 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 Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Case Study 2 Thromboprophylaxis in a Hospitalized Medical Patient 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 Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Case Study 2 Thromboprophylaxis in a Hospitalized Medical Patient 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 * Fondaparinux is not approved by the FDA for prophylaxis in medical patients. Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Case Study 3 Treatment in a Patient With Cancer
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Case Study 3 Treatment in a Patient With Cancer 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 Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Case Study 3 Treatment in a Patient With Cancer 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 Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Case Study 3 Treatment in a Patient With Cancer 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 Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Question-and-Answer Session
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Question-and-Answer Session Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

Thank you for participating!
"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Thank you for participating! Charles L Bennett, MD, PhD, MPP Northwestern University Chicago

"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Charles L Bennett, MD, PhD, MPP Northwestern University Chicago.

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"Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Charles L Bennett, MD, PhD, MPP Northwestern University Chicago.

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Presentation on theme: ""Meeting the Challenges of VTV: Strategies for Implementing Guideline-based Recommendations" Charles L Bennett, MD, PhD, MPP Northwestern University Chicago."— Presentation transcript:

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