American Journal of Health-System Pharmacy

doi: 10.1093/ajhp/64.suppl_7.30pmid: N/A

Learning objectives After studying these articles, the reader should be able to Name three risk factors for venous thromboembolism (VTE), compare and contrast the types of strategies to improve VTE risk assessment and the use of VTE prophylaxis, and recommend a VTE prophylactic regimen for an individual based on his or her risk. Recommend a VTE treatment regimen for a patient and explain how severe renal impairment and excessive body weight might affect that regimen. Name a shortcoming in acute and discharge medication use for patients with non-ST-segment elevation acute coronary syndrome (ACS) that was identified in the CRUSADE registry and characterize trends in adherence to American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for managing non-ST-segment elevation. Explain the current thinking about the place in therapy of bivalirudin in patients with non-ST-segment elevation ACS who are undergoing an invasive intervention. Discuss the results of recent studies of clopidogrel in patients with ST-segment elevation myocardial infarction (MI) that are not reflected in current ACC/AHA guidelines for managing ST-segment elevation MI, and name a new therapeutic option for anticoagulation in a patient with ST-segment elevation MI who receives fibrinolytic therapy. Identify a limitation of guidelines for VTE and ACS, and explain the evolution of evidence-based quality measures. Describe a current initiative to improve the quality of care for VTE, and name a VTE process measure for which reporting to the Centers for Medicare and Medicare Services (CMS) was required beginning January 1, 2007. Self-assessment questions For each question there is only one best answer. Which of the following is a risk factor for VTE? Diabetes mellitus. Dyslipidemia. Obesity. Parkinson’s disease. Which of the following types of strategies to improve VTE risk assessment and the use of VTE prophylaxis involves categorizing a patient’s risk based on his or her risk factors for VTE? Risk assessment scoring systems. Risk recognition systems. Prophylaxis default systems. Universal risk systems. Which of the following best characterizes the recommendation of the American College of Chest Physicians (ACCP) for the use of mechanical prophylaxis of VTE in medical patients? It should be reserved for medical patients with risk factors for VTE and a contraindication to anticoagulant prophylaxis. It should be reserved for medical patients at risk for limb gangrene. It should be used only in medical patients with risk factors for VTE who receive low-dose unfractionated heparin or low-molecular-weight heparin (LMWH). It should be used in all medical patients with risk factors for VTE. Which of the following have been demonstrated from LMWH therapy in studies comparing it with unfractionated heparin (UFH) for VTE prophylaxis? A reduced risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and death, but an increased risk of major hemorrhage and heparin-induced thrombocytopenia (HIT). A comparable risk of DVT, PE, and death, but an increased risk of major hemorrhage and HIT. A comparable risk of DVT, PE, and death, but a reduced risk of major hemorrhage and HIT. A reduced risk of DVT, PE, death, major hemorrhage, and HIT. Which of the following is the minimum duration of anticoagulation therapy during the acute phase in patients with VTE recommended by ACCP? 1 day. 2 days. 3 days. 5 days. The use of LMWH for initial VTE treatment is recommended over UFH by ACCP because of a lower risk of: Major bleeding. Mortality. Recurrent VTE. Thrombocytopenia. Which of the following regimens is best recommended for treatment of a 70-kg patient with VTE? Fondaparinux 2.5 mg subcutaneously (s.c.) once daily alone. Fondaparinux 2.5 mg s.c. once daily plus warfarin. Fondaparinux 5.0 mg s.c. alone. Fondaparinux 7.5 mg s.c. plus warfarin. Which of the following is the duration of warfarin therapy recommended by ACCP for patients with a first DVT episode that is idiopathic? At least 14 days. At least 3–6 months. At least 6–12 months. Indefinite. Which of the following is the duration of LMWH therapy recommended by ACCP for treatment of a patient with cancer and VTE? Until the international normalized ratio is stable and exceeds 2.0. 6–14 days. At least 3–6 months. Indefinite. Reducing the dosage of enoxaparin for patients with severe renal impairment provides: Cost savings. Greater safety. Greater efficacy. Greater convenience. Which of the following statements about weight-based dosing of LMWH is correct? It is customarily used for VTE prophylaxis but not treatment, and weight-based dosing might improve the efficacy of treatment in obese patients. It is customarily used for VTE treatment but not prophylaxis, and weight-based dosing might improve the efficacy of prophylaxis in obese patients. It is customarily used for VTE treatment but not prophylaxis, and capping the dosage used for treatment might avoid adverse effects in obese patients. It is customarily used for VTE prophylaxis but not treatment, and capping the dosage used for prophylaxis might avoid adverse effects in obese patients. Which of the following medications were identified in the CRUSADE registry as most in need of improvement in use during the first 24 hours after hospitalization of patients with non-ST-segment elevation ACS who undergo early invasive cardiac procedures? Aspirin and beta blockers. Glycoprotein (GP) IIb/IIIa inhibitors and clopidogrel. UFH and LMWH. Lipid-lowering agents and angiotensin converting-enzyme (ACE) inhibitors. Which of the following medications was identified in the CRUSADE registry as most in need of improvement in discharge prescribing for patients with non-ST-segment elevation ACS? ACE inhibitors. Clopidogrel. GP IIb/IIIa inhibitors. Lipid-lowering agents. Which of the following types of patients was identified as most at risk of harm from excessive doses of GP IIb/IIIa inhibitors in the CRUSADE registry? Elderly men with congestive heart failure (CHF). Elderly women with CHF. Elderly men with renal insufficiency. Elderly women with renal insufficiency. Which of the following statements best characterizes recent trends in adherence to ACC/AHA guidelines for managing non-ST-segment elevation MI identified in the CRUSADE registry? Adherence has improved, and it is high. Adherence has improved, but considerable improvement is still needed. Adherence has worsened, largely because of frequent revisions to guidelines. Adherence has worsened, largely because of the release of conflicting guidelines from other sources. Which of the following statements best summarizes the findings from the ACUITY study in moderate-to high-risk patients with non-ST-segment elevation ACS who are undergoing an invasive intervention? Bivalirudin plus a GP IIb/IIIa inhibitor is a suitable alternative to UFH or enoxaparin plus a GP IIb/IIIa inhibitor, and bivalirudin alone may be preferred because of a lower risk of major bleeding. Bivalirudin alone is a suitable alternative to UFH or enoxaparin plus a GP IIb/IIIa inhibitor, and bivalirudin plus a GP IIb/IIIa inhibitor may be preferred because of a lower risk of major bleeding. UFH or enoxaparin plus a GP IIb/IIIa inhibitor is preferred over bivalirudin with or without a GP IIb/IIIa inhibitor because of greater efficacy and comparable safety. UFH or enoxaparin plus a GP IIb/IIIa inhibitor is preferred over bivalirudin with or without a GP IIb/IIIa inhibitor because of comparable efficacy and greater safety. Which of the following statements reflects the conclusions drawn from the CLARITY-TIMI 28 study about the use of clopidogrel with respect to percutaneous coronary intervention (PCI) in patients with ST-segment elevation MI who receive fibrinolytic therapy? Clopidogrel is useful only before PCI. Clopidogrel is useful only after PCI. Clopidogrel is useful both before and after PCI. Clopidogrel is not useful before or after PCI. Which of the following anticoagulant therapies appeared to reduce the risk of death and reinfarction without increasing the risk of severe bleeding compared with UFH in patients with ST-segment elevation MI? Bivalirudin 0.25 mg/kg/hr intravenously (i.v.). Clopidogrel 300 mg orally as a loading dose followed by 75 mg orally once daily. Enoxaparin 30 mg as an i.v. bolus followed by 1 mg/kg s.c. every 12 hours. Fondaparinux 2.5 mg s.c. once daily. Which of the following is the greatest limitation of guidelines for VTE and ACS? The difficulty publicizing them. The lack of scientific data to support them. The lack of opportunity for clinical judgment. The tendency to rapidly become out of date. AJHP continuing education AJHP CE process The continuing-education (CE) test for this supplement can only be taken online through ASHP’s CE Testing Center. If you score 70% or better on the test, you will be able to immediately print your own CE statement for your records. You will have two opportunities to pass the CE test, and you may stop and return to the test at any time before submitting your final answers. ASHP will keep a record of the credits you have earned from this and other CE activities, and you will be able to view your own transcript through the online CE service. Instructions Continuing education credit for selected AJHP supplements, including this supplement, is free for both members and nonmembers. Go to http://ce.ashp.org and select “Enter CE Testing Center.” ASHP members and registered users should type in their 8-digit ASHP ID and password, click on “Register for Tests,” and then follow the instructions to select the supplement for which CE credit is desired. To find the desired title most easily, put the cursor at the top of the page and use the browser to search for one key word in the title. Nonmember customers who are not yet registered should click on the “Become a Registered User” link at the bottom of the page to obtain their ASHP ID and password. Then go back to http://ce.ashp.org, select “Enter CE Testing Center,” and proceed as described above. Registered users are welcome to browse the list of other available AJHP CE articles and supplements, all of which are free for ASHP members. Nonmembers can follow the instructions to gain access to CE offerings for which there is a fee. Supplement: Improving the quality of care for venous thromboembolism and acute coronary syndrome: Using evidence-based guidelines and performance measures ACPE#: 204-000-07-004-H01 CE credit: 2.0 hours (0.2 CEU) Expiration date: June 1, 2010 The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Questions? Call ASHP Processing Center:866-279-0681 (toll free)+1-240-646-7082 (international callers) Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Spinler, Sarah, A.

doi: 10.2146/ajhp070109pmid: 17519441

Abstract Purpose. To describe data and insights from a national quality improvement initiative known as Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines (CRUSADE), for managing non-ST-segment elevation acute coronary syndrome (ACS), as well as the findings and implications of Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), a study of bivalirudin with or without a glycoprotein (GP) IIb/IIIa inhibitor in patients with non-ST-segment elevation ACS who were undergoing an invasive intervention, and the results of two recent studies of clopidogrel in patients with ST-segment elevation myocardial infarction (MI) that are not reflected in current ACC/AHA guidelines for managing ST-segment elevation MI. Summary. Data from the CRUSADE registry suggest that there is room for improvement in the use of GP IIb/IIIa inhibitors and clopidogrel during the first 24 hours of hospitalization in patients with non-ST-segment elevation ACS who undergo early invasive cardiac procedures, and in the prescribing of angiotensin converting-enzyme (ACE) inhibitors at the time of discharge. Adherence to ACC/AHA guidelines for non-ST-segment elevation ACS has improved over time but further improvement is needed. Failure to reduce the dose of a GP IIb/IIIa for patients with renal insufficiency resulting in excessive dosing of GP IIb/IIIa inhibitors increases the risk of major bleeding and is particularly common among the elderly, women, and patients with renal insufficiency. The ACUITY study suggests that bivalirudin plus a GP IIb/IIIa inhibitor is a suitable alternative to standard therapy for moderate- to high-risk patients with non-ST-segment elevation ACS who are undergoing early invasive intervention, and bivalirudin alone may be preferred because of a lower risk of major bleeding. However, interpretation of the ACUITY results is complicated by numerous methodologic concerns, so the role of bivalirudin in managing non-ST-segment elevation ACS is still evolving. In patients with ST-segment elevation, clopidogrel provides an early benefit in reopening occluded coronary arteries and a late benefit in reducing cardiovascular mortality and morbidity without increasing the risk of bleeding. Clopidogrel treatment is warranted before as well as after percutaneous coronary intervention in patients with ST-segment elevation MI who receive fibrinolytic therapy. Adding clopidogrel to fibrinolytic therapy and other standard therapy reduces mortality without increasing the risk of bleeding. Conclusion. Evidence-based guidelines provide recommendations for the management of ACS, but the pace of clinical research is rapid and current guidelines do not reflect the latest research findings. Pharmacists need to stay abreast of new developments and ensure that clinical practice reflects these developments. Angioplasty, Angiotensin-converting-enzyme inhibitors, Anticoagulants, Bivalirudin, Clopidogrel, Coronary disease, Dosage, Fibrinolytic agents, Geriatrics, Kidney failure, Mortality, Patient care, Platelet aggregation inhibitors, Protocols, Quality assurance, Toxicity Acute coronary syndrome (ACS) is a group of clinical symptoms compatible with acute myocardial ischemia (i.e., angina due to insufficient blood and oxygen supply to the myocardium that results from coronary artery disease [CAD]) at rest and is caused by either a complete or partial occlusion of a coronary artery by a thrombus composed of platelets and fibrin.1 Patients with ACS may be classified on the basis of the 12-lead electrocardiogram (ECG) with either ST segment elevation (STE) or non-ST segment elevation (NSTE). Patients with STE ACS have a higher risk of early mortality compared to patients with NSTE ACS. Patients with ACS may be diagnosed with myocardial infarction (MI) with evidence of an elevated plasma troponin (a protein associated with cardiac muscle damage) concentration, indicating myocardial necrosis occurred. Patients with STE ACS have a complete thrombotic occlusion of a coronary artery and require prompt restoration of myocardial perfusion by opening an occluded coronary artery using fibrinolytic therapy or percutaneous coronary intervention (PCI). Primary PCI of STE ACS usually involves angioplasty and insertion of an intracoronary stent. Patients with NSTE ACS and elevated troponin have an NSTE MI, and those patients without an elevated troponin have unstable angina. The goals of therapy are to promote coronary artery blood flow and reduce risk of infarction in the case of NSTE ACS and reduce the risk reinfarction in both STE ACS and NSTE. Antithrombotic therapy plays a key role in achieving these goals in treatment of ACS. CRUSADE Registry A national quality improvement initiative known as CRUSADE—Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines—began in 2001.2 By the end of the second quarter of 2006, more than 400 hospitals had participated in the initiative and 180,842 patients had enrolled in the CRUSADE registry.2 In 2007, this registry has merged with the National Registry of Myocardial Infarction to create one large ACS registry, the NCDR-ACTION Registry ™ that is managed by the ACC. High-risk patients with non-ST-segment elevation ACS—ischemic symptoms at rest and either elevated cardiac biomarkers (such as elevated troponin concentration) or NSTE ischemic ECG changes (e.g., ST-segment depression or transient ST-segment elevation)—were enrolled in the CRUSADE registry. The baseline characteristics of the 180,842 CRUSADE enrollees—female gender (40%), diabetes mellitus (33%), prior MI (30%), prior congestive heart failure (18%), prior PCI (21%), prior coronary artery bypass graft (19%), and ST segment depression (34%)—were similar to those of enrollees in other registries of patients with non-ST-segment elevation ACS.2,–5 In the 6923 patients enrolled in the second quarter of 2006, 27% had ST-segment depression (a risk factor for CAD), and 93% had positive cardiac markers, such as troponin (i.e., evidence of MI) at the time of presentation at the hospital. Signs of congestive heart failure (CHF), tachycardia, and hypotension were the presenting characteristics in 22%, 21%, and 4% of patients, respectively.2 In-hospital outcomes recorded in the CRUSADE registry for the 12-month period from July 1, 2005, through June 30, 2006, include death (3.9%), reinfarction (1.8%), CHF (7.0%), cardiogenic shock (2.2%), stroke (0.6%), and red blood cell (RBC) transfusion (9.4%).2 The RBC transfusion rate does not include coronary artery bypass graft (CABG)-related transfusions. A goal of the CRUSADE initiative is to evaluate and improve adherence to ACC/AHA guidelines for the management of unstable angina and NSTE MI, which were published most recently in 2002 and are scheduled to be updated in 2007.6 The CRUSADE registry documents current practices in acute treatment during the first 24 hours after hospitalization, which may involve the use of aspirin, clopidogrel, beta blockers, glycoprotein (GP) IIb/IIIa inhibitors, and anticoagulants such as unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux (a pentasaccharide inhibitor of activated coagulation factor X that was introduced since the ACC/AHA guidelines were published).2 The registry also records discharge therapy for patients with non-ST-segment elevation ACS, which may include aspirin, clopidogrel, beta blockers, angiotensin converting-enzyme (ACE) inhibitors, statins or other lipid-lowering therapy, smoking cessation, and cardiac rehabilitation. In the 6923 patients enrolled in CRUSADE during the second quarter of 2006, the rate of use of aspirin, beta blockers, heparin (UFH or LMWH), GP IIb/IIIa inhibitors, and clopidogrel for acute therapy in patients without contraindications was 96%, 92%, 87%, 45%, and 60%, respectively.2 The ACC/AHA guidelines recommend GP IIb/IIIa inhibitors (along with aspirin and heparin) in patients undergoing catheterization and PCI.6 Clopidogrel is recommended in all patients with NSTE ACS, especially those undergoing PCI, who are not at high risk for bleeding.6 In the 6923 CRUSADE enrollees who had no contraindication to catheterization, 84% underwent catheterization, including 68% within 48 hours after hospitalization; 54% underwent PCI, including 44% within 48 hours after hospitalization; and 11% underwent CABG.2 Therefore, the CRUSADE registry data suggest that there is room for improvement in the acute use of GP IIb/IIIa inhibitors and clopidogrel in patients with non-ST-segment elevation ACS who undergo early invasive cardiac procedures. Discharge medication use also was documented in the 6923 patients enrolled in CRUSADE during the second quarter of 2006.2 Aspirin and beta blockers were used at the time of discharge by 96% and 94% of patients without contraindications, respectively. Lipid-lowering agents were used by 90% of eligible patients (i.e., patients with known hyperlipidemia or elevated total cholesterol or low-density lipoprotein cholesterol concentrations) without contraindications. The percentage of eligible patients receiving clopidogrel at the time of discharge (73%) was higher than the percentage receiving the drug as acute therapy, probably reflecting the large percentage of patients undergoing PCI. Only 65% of patients who were eligible to receive ACE inhibitors (i.e., patients with a left ventricular ejection fraction less than 40%, CHF, diabetes mellitus, or hypertension) received such therapy at the time of discharge, despite recent recommendations from AHA and ACC for the use of these agent in most patients with CAD.7 These findings suggest the need for improvement in the prescribing of ACE inhibitors at the time of discharge of patients with non-ST-segment elevation ACS. Adherence to the 2002 ACC/AHA guidelines was analyzed in 113,595 CRUSADE enrollees over 11 calendar quarters between 2002 and 2004.8 There was a significant increase over time in the percentage of enrollees receiving all guideline-recommended therapies from 16% in the first quarter to 33% in the eleventh quarter. Increases over time in guideline adherence were observed in the use of both acute therapies (from 30–48%) and discharge therapies (from 30–50%). These changes reflect the often lengthy time for incorporation of new guidelines into practice, but the figures suggest the need for continued efforts to increase guideline adherence. Considerable improvement is still needed. The impact of dosing of UFH, LMWH, and GP IIb/IIIa inhibitors on major bleeding (defined as a hematocrit drop ≥12%, need for transfusion, or intracranial bleeding) was examined in a prospective observational analysis of 30,136 CRUSADE enrollees at 387 hospitals.9 Excessive dosing was defined based on ACC/AHA guidelines, clinical trial results, and package inserts as a bolus dose of UFH exceeding 70 units/kg, an infusion rate of UFH exceeding 15 unit/kg/hour, a subcutaneous dose of the LMWH enoxaparin exceeding 1.05 mg/kg (i.e., > 105% of the recommended dose), and the administration of full weight-based doses of the GP IIb/IIIa inhibitor eptifibatide or tirofiban to patients with a creatinine clearance less than 50 mL/min or 30 mL/min, respectively (i.e., failure to reduce the GP IIb/IIIa inhibitor dose for patients with renal impairment). Forty-two percent of enrollees received at least one excess initial dose of UFH, LMWH, or GP IIb/IIIa inhibitor, including 33% with an excess UFH dose, 14% with an excess LMWH dose, and 27% with an excess GP IIb/IIIa inhibitor dose. The risk of major bleeding was increased by excessive dosing of UFH, LMWH, or GP IIb/IIIa inhibitor compared with appropriate dosing.9 Elderly patients (age ≥ 75 years) were more likely than younger patients and women were more likely than men to receive an excessive dose of GP IIb/IIIa inhibitors.9 Compared with appropriate GP IIb/IIIa inhibitor dosing, excess dosing significantly increased the risk of major bleeding in both women and men.10 However, the increase in major bleeding risk attributed to excess dosing was much higher in women than in men (11.6% with appropriate dosing versus 19.6% with excessive dosing in women, p < 0.0001 versus 5.6% with appropriate versus 14.8% with excessive dosing in men, p < 0.0001).10 In patients with a creatinine clearance less than 50 mL/min, the likelihood of an excess dose of GP IIb/IIIa inhibitor was higher in the presence of a serum creatinine concentration of 2.0 mg/dL or less than in the presence of a serum creatinine concentration exceeding 2.0 mg/dL (90.8% versus 62.9%), suggesting that reduced creatinine clearance is less recognized in this patient group.10 These findings suggest that greater attention needs to be devoted to proper dosing of GP IIb/IIIa inhibitors for the elderly, women, and patients with renal insufficiency. Identifying renal insufficiency using creatinine clearance is preferred over serum creatinine because it is possible to have a normal or near normal serum creatinine concentration in the presence of renal insufficiency. Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Study The safety and efficacy of the direct thrombin inhibitor bivalirudin were evaluated in the ACUITY study, a multicenter, randomized, controlled, non-inferiority study of approximately 13,819 adults with non-ST-segment elevation ACS who were likely to undergo a strategy of early angiography and revascularization (Table 11).11,12 Patients were randomly assigned to one of three treatment groups: (1) GP IIb/IIIa inhibitor plus either UFH or enoxaparin (the control group receiving the standard of care), (2) bivalirudin plus a GP IIb/IIIa inhibitor, or (3) bivalirudin alone. All patients received aspirin. Clopidogrel was given at the discretion of the physician in accordance with local practice. The choice of UFH or enoxaparin in the control group was made according the local custom at the institution and, all patients at a particular institution received the same drug. The choice of GP IIb/IIIa inhibitor also was made based on local practice, although the use of more than one different GP IIb/IIIa inhibitor was permitted at a particular institution. Patients in the GP IIb/IIIa inhibitor plus UFH or enoxaparin group and patients in the bivalirudin plus GP IIb/IIIa inhibitor group were randomly assigned to receive the GP IIb/IIIa inhibitor immediately after randomization (i.e., “upstream”) or on a deferred basis in the cardiac catheterization laboratory (i.e., “downstream”) only if PCI was indicated. Patients in all treatment groups were referred for PCI, CABG, or medical management at the time of angiography at the discretion of the physician. Patients who did not undergo angiography within 72 hours after randomization were excluded from the analysis. Table 1. ACUITY Study Inclusion and Exclusion Criteria11,–13 CAD = coronary artery disease; INR = international normalized ratio; MI = myocardial infarction; TIMI = Thrombolysis in Myocardial Infarction Inclusion Criteria • Age ≥ 18 yr • Chest pain lasting ≥ 10 min in the preceding 24-hour period • At least one of the following: New ST segment depression Transient ST segment elevation of 1 mm or more An elevated troponin I, troponin T, or creatine kinase MB level Documented CAD All four other TIMI risk criteria age ≥ 65 years use of aspirin within the prior 7 days ge; two angina episodes with the prior 24 hours ≥ three CAD risk factors • Written informed consent Exclusion Criteria • Acute MI associated with ST segment elevation or shock • Bleeding diathesis or major bleeding within 2 weeks before the current angina episode • Thrombocytopenia (a platelet count <100,000/mm3) • INR >1.5 • Creatinine clearance <30 mL/min • Recent administration of abciximab or ≥ 2 doses of LMWH (although recent use of UFH, eptifibatide, tirofiban, or a single LMWH dose was allowed) • Allergy to drugs or contrast media CAD = coronary artery disease; INR = international normalized ratio; MI = myocardial infarction; TIMI = Thrombolysis in Myocardial Infarction Inclusion Criteria • Age ≥ 18 yr • Chest pain lasting ≥ 10 min in the preceding 24-hour period • At least one of the following: New ST segment depression Transient ST segment elevation of 1 mm or more An elevated troponin I, troponin T, or creatine kinase MB level Documented CAD All four other TIMI risk criteria age ≥ 65 years use of aspirin within the prior 7 days ge; two angina episodes with the prior 24 hours ≥ three CAD risk factors • Written informed consent Exclusion Criteria • Acute MI associated with ST segment elevation or shock • Bleeding diathesis or major bleeding within 2 weeks before the current angina episode • Thrombocytopenia (a platelet count <100,000/mm3) • INR >1.5 • Creatinine clearance <30 mL/min • Recent administration of abciximab or ≥ 2 doses of LMWH (although recent use of UFH, eptifibatide, tirofiban, or a single LMWH dose was allowed) • Allergy to drugs or contrast media Open in new tab Table 1. ACUITY Study Inclusion and Exclusion Criteria11,–13 CAD = coronary artery disease; INR = international normalized ratio; MI = myocardial infarction; TIMI = Thrombolysis in Myocardial Infarction Inclusion Criteria • Age ≥ 18 yr • Chest pain lasting ≥ 10 min in the preceding 24-hour period • At least one of the following: New ST segment depression Transient ST segment elevation of 1 mm or more An elevated troponin I, troponin T, or creatine kinase MB level Documented CAD All four other TIMI risk criteria age ≥ 65 years use of aspirin within the prior 7 days ge; two angina episodes with the prior 24 hours ≥ three CAD risk factors • Written informed consent Exclusion Criteria • Acute MI associated with ST segment elevation or shock • Bleeding diathesis or major bleeding within 2 weeks before the current angina episode • Thrombocytopenia (a platelet count <100,000/mm3) • INR >1.5 • Creatinine clearance <30 mL/min • Recent administration of abciximab or ≥ 2 doses of LMWH (although recent use of UFH, eptifibatide, tirofiban, or a single LMWH dose was allowed) • Allergy to drugs or contrast media CAD = coronary artery disease; INR = international normalized ratio; MI = myocardial infarction; TIMI = Thrombolysis in Myocardial Infarction Inclusion Criteria • Age ≥ 18 yr • Chest pain lasting ≥ 10 min in the preceding 24-hour period • At least one of the following: New ST segment depression Transient ST segment elevation of 1 mm or more An elevated troponin I, troponin T, or creatine kinase MB level Documented CAD All four other TIMI risk criteria age ≥ 65 years use of aspirin within the prior 7 days ge; two angina episodes with the prior 24 hours ≥ three CAD risk factors • Written informed consent Exclusion Criteria • Acute MI associated with ST segment elevation or shock • Bleeding diathesis or major bleeding within 2 weeks before the current angina episode • Thrombocytopenia (a platelet count <100,000/mm3) • INR >1.5 • Creatinine clearance <30 mL/min • Recent administration of abciximab or ≥ 2 doses of LMWH (although recent use of UFH, eptifibatide, tirofiban, or a single LMWH dose was allowed) • Allergy to drugs or contrast media Open in new tab The provisional use of GP IIb/IIIa inhibitors was allowed for severe breakthrough ischemia before angiography in patients in the bivalirudin alone group and patients in the other two treatment groups who had been assigned to deferred GP IIb/IIIa inhibitor therapy. The provisional use of GP IIb/IIIa inhibitors also was permitted in patients in the bivalirudin alone group who experienced procedural complications while undergoing PCI (i.e., “bail out” use). Three co-primary end points were measured 30 days after randomization: (1) composite ischemia, including death from any cause, MI, or unplanned revascularization for ischemia; (2) major bleeding unrelated to CABG; and (3) net clinical outcome, which was the occurrence of the composite ischemia end point or major bleeding.12 Major bleeding was defined as a decrease in hemoglobin concentration by more than 3 g/dL with an overt bleeding source or more than 4 g/dL without an overt bleeding source, intracranial, retroperitoneal, or intraocular bleeding, access site bleeding that required intervention, a hematoma with a diameter of 5 cm or more, reoperation for bleeding, or the transfusion of a blood product.12 ACUITY results Fifty-nine percent of ACUITY participants had cardiac biomarker elevations (i.e., evidence of MI) and 41% had unstable angina.12 Patients’ risk of death and ischemic events was rated using the Thrombolysis in Myocardial Infarction (TIMI) risk scoring system, a 7-point, validated system for scoring these risks in patients with unstable angina or non-ST-segment elevation MI.13 The percentage of ACUITY enrollees with a high TIMI risk score (5–7), moderate TIMI risk score (3–4), and low TIMI risk score (0–2) was 30%, 55%, and 16%, respectively.12 Thus, low-risk patients were enrolled despite plans to enroll only moderate- and high-risk patients. The percentage of patients referred for PCI, CABG, and medical management at the time of angiography was 56%, 11%, and 33%, respectively. Bivalirudin plus a GP IIb/IIIa inhibitor was judged non-inferior to UFH/enoxaparin plus a GP IIb/IIIa inhibitor in all three primary end points, with similar 30-day rates of the net clinical outcome (11.8% and 11.7%, respectively, p < 0.001), composite ischemia (7.7% and 7.3%, respectively, p = 0.007), and major bleeding (5.3% and 5.7%, respectively, p < 0.001).12 When bivalirudin alone was compared with UFH/enoxaparin plus a GP IIb/IIIa inhibitor, both the 30-day rate of the net clinical outcome (10.1% and 11.7%, p < 0.001) and the 30-day rate of major bleeding (3.0% and 5.7%, p < 0.001) were lower with bivalirudin. Bivalirudin alone was non-inferior to UFH/enoxaparin plus a GP IIb/IIIa inhibitor in the 30-day rate of composite ischemia (7.8% and 7.3%, respectively, p = 0.01). These findings suggest that bivalirudin plus a GP IIb/IIIa inhibitor is a suitable alternative to UFH/enoxaparin plus a GP IIb/IIIa inhibitor for moderate- to high-risk patients with unstable angina or non-ST-segment elevation ACS who are undergoing early invasive intervention. Bivalirudin alone may be preferred over UFH/enoxaparin plus a GP IIb/IIIa inhibitor in these patients because of a lower risk of major bleeding. Criticisms of ACUITY Interpretation of the results of ACUITY is complicated by methodologic shortcomings. For example, GP IIb/IIIa inhibitors were used on a provisional basis for “bail out” in 9% of patients in the bivalirudin alone group. More than 14 hours elapsed between hospital admission and randomization, a time during which almost 65% of patients received anticoagulant treatment that could have had a confounding effect on the study outcome. At the time of randomization, patients underwent a brief washout period (30 minutes to 12 hours depending on agent)11 that may have been insufficient to negate the effect of some antithrombotic therapies (e.g., enoxaparin, which has a long duration of activity).14 The average time from randomization to angiography was less than 6 hours. Since most patients received no anticoagulation after the procedure, this trial compared outcomes between arms of therapy in which anticoagulants were administered for a very brief time. In the control group, patients receiving enoxaparin and patients receiving UFH were combined for the initial analysis, which could have masked differences in safety or efficacy. The risk of bleeding is a particular concern because of the results of other comparative studies suggesting a higher risk from enoxaparin than from UFH.5 A further analysis of the ACUITY data found no significant difference between patients receiving enoxaparin and patients receiving UFH in the 30-day rate of major bleeding (5.5% with enoxaparin and 5.9% with UFH) or the other two primary end points.12 The ACUITY trial included non-inferiority analyses. An extensive review of the merits and hazards of non-inferiority trials is beyond the scope of this review and the reader is referred to a more extensive discussion of the ACUITY trial.15 The ACUITY non-inferiority analysis was specified a priori with a 25% non-inferiority margin that allowed bivalirudin to be judged non-inferior despite end points up to 25% worse than those in the control group. That is, the upper boundary of the 95% confidence interval (CI) would not exceed 1.25.11 The 30-day rate for composite ischemia was slightly worse in the bivalirudin alone group than in the UFH/LMWH plus a GP IIb/IIIa inhibitor group and, since the 95% upper CI limit was 1.24 (risk ratio 1.08, 95% CI 0.93–1.24), this outcome still met the criteria for non-inferiority. A more narrow non-inferiority margin (e.g., 10% or an upper 95% CI boundary of 1.10) might have yielded different results and interpretation. 15 Two recent NSTE ACS non-inferiority trials, SYNERGY and A to Z, used non-inferiority margins of 10% and 11%, respectively.5,16 Whether the degree of risk in the ACUITY participants was sufficiently high to draw valid conclusions about the usefulness of bivalirudin in patients with unstable angina or non-ST-segment elevation ACS who are undergoing early invasive intervention might be questioned because some low-risk patients were enrolled for whom GP IIb/IIIa inhibitor and bivalirudin therapy might not be warranted. A substantial percentage of enrollees were managed medically (32%) without a need for PCI or CABG.11 Selection among the available GP IIb/IIIa inhibitors and dosing are considerations in interpreting ACUITY results. There were potentially important differences in the type of GP IIb/IIIa inhibitor used among the groups randomly assigned to receive routine upstream and deferred GP IIb/IIIa inhibitor therapy. ACUITY was a multi-national study with geographic differences in use of these agents (e.g., eptifibatide is the most widely used GP IIb/IIIa inhibitor in the United States, but tirofiban is used widely in Europe). Roughly one in three patients assigned to routine upstream GP IIb/IIIa inhibitor use received tirofiban, and two thirds of the patients received eptifibatide.17 Abciximab is a GP IIb/IIIa inhibitor that usually is not administered prior to angiography. In patients assigned to deferred GP IIb/IIIa inhibitor therapy, about one third of patients received abciximab during PCI. Only 4.5% of patients assigned to deferred GP IIb/IIIa inhibitor therapy received tirofiban, and another 62.1% of patients received eptifibatide.17 In clinical trials of tirofiban, the drug was initiated 48 hours before angiography and PCI.18 The administration of tirofiban within 6 hours before angiography in ACUITY could have compromised outcomes as clinical trials of tirofiban have generally administered the drug for at least 48 hours prior to PCI.19,20 Moreover, the likelihood that the tirofiban dose was adequate is debatable and unknown from the ACUITY study report. The likelihood that tirofiban and eptifibatide doses were reduced properly for patients with renal insufficiency also is a possible concern. The definition of major bleeding (particularly inclusion of large hematomas, which are not uncommon at the access site in the groin where the cardiac catheter is inserted into the femoral artery to perform angiography) used in ACUITY might be questioned because it differs from the definitions used in other studies.21 The reduction in hemoglobin concentration by more than 3 g/dL used as a criterion in the ACUITY study also is a criterion for minor bleeding in TIMI studies whereas a reduction by more than 5 g/dL constitutes TIMI major bleeding.22 The suitability of giving equal weight to hematoma (as part of major bleeding) and death and MI (as part of composite ischemia) in measuring the net clinical outcome as an end point in the ACUITY study might be questioned. Analysis of the ACUITY 30-day data for minor bleeding (defined as ecchymoses, epistaxis, bleeding at the puncture site, or gastrointestinal, genitourinary, hemopericardial, pulmonary, or other bleeding) and TIMI minor and major bleeding did find significantly lower rates in the bivalirudin alone group compared with the UFH/LMWH plus a GP IIb/IIIa inhibitor group, however.12 The 30-day cumulative need for blood transfusions also was significantly reduced by bivalirudin alone compared with UFH/enoxaparin plus a GP IIb/IIIa inhibitor (1.6% versus 2.6%, p < 0.001).12 The relationship between definition of bleeding and 12-month mortality was explored using a database of patients undergoing PCI and participating in a study of bivalirudin known as REPLACE-2.21,23 A significant increase in 12-month mortality was associated with bleeding regardless of the definition of bleeding used. A higher odds ratio for 12-month mortality (6.1) was associated with a restrictive definition of bleeding (i.e., a definition that takes into consideration only the most severe signs, symptoms, or changes in laboratory values) compared with an odds ratio of 1.6 for a liberal definition (i.e., a definition that takes into consideration mild as well as severe signs, symptoms, and laboratory values).23 Restrictive definitions of bleeding (e.g., TIMI major bleeding) are the most commonly used definitions. While a more liberal definition of bleeding was used in ACUITY, it appears that major bleeds, regardless of how defined, seem to negatively impact patient outcome. Bleeding is an important measure of quality in the treatment of moderate- to high-risk patients with non-ST-segment elevation ACS who are undergoing early invasive intervention, regardless of the definition of bleeding used. Case study one JS is a 44-year-old man who presents to the emergency department with a complaint of squeezing chest pain at rest, the severity of which he rates as 7 on a 10-point scale with 10 as the worst pain imaginable. He experienced an MI six months ago. JS’s medications include aspirin 325 mg/daily, atorvastatin 80 mg/day, ramipril 10 mg/day, and extended-release metoprolol 100 mg/day, all of which he takes orally as single daily doses. JS is a nonsmoker who weighs 80 kg. His vital signs include a systolic and diastolic blood pressure of 110/70 mm Hg and a heart rate of 90 beats/minute. An ECG reveals a 2-mm ST segment depression in the inferior leads, and JS’s troponin levels are elevated. His estimated creatinine clearance is 88 mL/min. JS was promptly given aspirin 325 mg orally, three 0.4-mg sublingual nitroglycerin doses at 5-minute intervals, clopidogrel 300 mg, nitroglycerin 5 μg/min by continuous intravenous (i.v.) infusion, and metoprolol 5 mg by i.v. injection. The ST segment depression continued with little reduction in the chest pain (rated 6 on a 10-point scale). JS had a presentation that was consistent with non-ST-segment elevation ACS. His ST segment depression, elevated troponin level, history of MI, use of aspirin within the past seven days, and unrelenting angina suggested that he was at high risk for death or ischemic events. Therapeutic options for JS include any one of the three regimens that were used in the ACUITY study: (1) UFH 4000 units (60 units/kg with a maximum dose of 4000 units) by bolus i.v. injection followed by i.v. infusion of 950 units/hr (i.e., 12 units/kg/hr, maximum infusion rate of 1000 units/hr) plus eptifibatide 2 μg/kg/min (either initiated in the emergency department at the time of PCI), (2) enoxaparin 80 mg subcutaneously (s.c.) twice daily plus eptifibatide 2 μg/kg/min (initiated in the emergency department or at the time of PCI), and (3) bivalirudin 0.1 mg/kg as an i.v. bolus followed by 0.25 mg/kg/hr with a second bolus of 0.5 mg/kg and an increase in infusion rate to 1.75 mg/kg/hr at the time of PCI.12 Because JS did not have renal insufficiency, no dosage adjustments in enoxaparin or eptifibatide were needed. Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS) 5 Study Fondaparinux 2.5 mg s.c. once daily might have been an alternative for JS, although use of the drug in patients with non-ST-segment elevation ACS is not yet approved by FDA and it is not addressed by ACC/AHA guidelines. It was given an “approvable” letter by the FDA, but final approval and labeling are pending. In a randomized, double-blind, double-dummy study known as OASIS-5, fondaparinux 2.5 mg s.c. once daily was compared with enoxaparin 1 mg/kg s.c. twice daily for an average of 6 days in 20,078 patients with unstable angina or non-ST-segment elevation ACS.24 The enoxaparin dose was reduced to 1 mg/kg once daily in patients with creatinine clearance values less than 30 mL/min. A non-inferiority boundary of 1.185, or a non-inferiority margin of 18.5%, was used to evaluate the efficacy of fondaparinux for preventing the primary outcome (death, MI, or refractory ischemia). Fondaparinux was non-inferior to enoxaparin in efficacy for preventing the primary outcome.24 The incidence of the primary outcome after 9 days was 5.8% with fondaparinux and 5.7% with enoxaparin, a difference that was not significant (p = 0.007 for non-inferiority or hazard ratio = 1.01). The risk of major bleeding after nine days was significantly lower in the fondaparinux group (2.2%) than in the enoxaparin group (4.1%, p < 0.001). Approximately 40% of patients in each treatment group underwent PCI. The efficacy of fondaparinux and enoxaparin in preventing the primary outcome in patients undergoing PCI was similar after 9 days (9.3% with fondaparinux and 8.6% with enoxaparin) after 30 days (10.4% and 9.6%, respectively), and at the end of the study (12.9% and 12.3%, respectively). The rate of major bleeding 48 hours after PCI was significantly lower with fondaparinux (1.6%) than with enoxaparin (3.6%). The study protocol was amended to allow an increase in the fondaparinux dosage in the fondaparinux group and the use of UFH in the enoxaparin group because of problems with catheter thrombosis in patients undergoing PCI. The major bleeding rate 48 hours after PCI remained significantly lower in the fondaparinux group (1.4%) than in the enoxaparin group (3.4%, p < 0.001) after protocol amendment. The addition of 70 units/kg i.v. bolus of UFH to enoxaparin as well as the failure to use the enoxaparin PCI dosage that was found non-inferior to UFH in another study (0.3 mg/kg i.v. before PCI)5 rather than combining two different anticoagulants might in part explain the high rate of major bleeding after PCI with enoxaparin in this study.5 Additional comparative studies of fondaparinux dosing in PCI are warranted to establish the proper dosing/timing. In the case of JS, he received UFH, and proceeded to early diagnostic cardiac angiography, i.e. “cardiac catheterization” within six hours of hospital presentation. At cardiac angiography, a 90% proximal right coronary artery thrombotic occlusion was observed. He underwent successful PCI with intracoronary stent placement while receiving UFH and “downstream” eptifibatide as per the current ACC/AHA NSTE ACS guidelines.6 His angina symptoms and the ECG changes resolved with no signs or symptoms of bleeding. JS was discharged from the hospital the following morning with instructions to continue his medications as prescribed before the hospitalization with the addition of clopidogrel 75 mg orally once daily. Patients with ST-segment elevation ACS Patients with ST-segment elevation ACS typically receive fibrinolytic therapy or undergo PCI (or both).25 The most recent guidelines for the management of ST-segment elevation MI were published in 2004 before the results of two important clinical trials of the use of clopidogrel along with standard therapy (i.e., aspirin, beta blockers, and ACE inhibitors) in patients with ST-segment elevation MI were available.25,–27 Clopidogrel as Adjunctive Reperfusion Therapy—Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) The CLARITY-TIMI-28 study was conducted in 23 countries (although most participating hospitals were in the United States) and involved 3491 patients 18 to 75 years of age who presented within 12 hours after the onset of ST-segment elevation MI.26 The patients were randomly assigned to receive clopidogrel (300 mg orally as a loading dose followed by 75 mg orally once daily for 2–8 days) or placebo. All patients also received fibrinolytic therapy, aspirin, and if appropriate, heparin (UFH or LMWH), and they underwent angiography 2–8 days after fibrinolytic therapy (patients undergoing primary PCI were excluded from the study). The primary efficacy end point was a composite of a TIMI flow grade of zero or one during angiography (i.e., evidence of artery occlusion), death, or recurrent MI. The TIMI flow grade describes epicardial blood flow on a scale with zero for complete occlusion, one for penetration of the obstruction with no distal perfusion, two for partial perfusion of the artery with delayed flow, and three for full perfusion with normal flow.28 The rate of the primary efficacy end point (evaluated at the start of angiography in most patients) was significantly lower in the clopidogrel group (15%) than in the placebo group (22%), representing a 36% odds reduction (p < 0.001).26 A significant reduction in the percentage of patients with a TIMI flow grade of zero or one also was observed with the use of clopidogrel compared with placebo (12% versus 18%, respectively, p < 0.001). There were no significant differences between treatment groups in the rate of recurrent MI or death, although the rate of recurrent MI was slightly lower in the clopidogrel group (2.5%) than in the placebo group (3.6%, p = 0.08). The cumulative rate of a composite of death from cardiovascular causes, recurrent MI, or recurrent ischemia leading to the need for urgent revascularization after 30 days was significantly lower in the clopidogrel group than in the placebo group, with a 20% reduction in the odds of the composite end point (p = 0.03).26 There were no significant differences between the treatment groups in the incidence of TIMI major or minor bleeding or intracranial hemorrhage evaluated the day after angiography or the incidence of major or minor bleeding after 30 days. The incidence of TIMI major bleeding evaluated the day after angiography was 1.3% in the clopidogrel group and 1.1% in the placebo group (p = 0.64). The frequency of TIMI minor bleeding was 1.6% in the clopidogrel group and 0.9% in the placebo group (p = 0.1). At 30 days, the incidence of TIMI major bleeding was 1.9% in the clopidogrel group and 1.7% in the placebo group (p = 0.80). Thus, clopidogrel provided an early benefit in reopening occluded coronary arteries and a late benefit in reducing cardiovascular mortality and morbidity without increasing the risk of bleeding. Bleeding had been a concern because other studies in patients with non-ST-segment elevation ACS found that adding clopidogrel to aspirin therapy increases the risk of bleeding.4 A subgroup analysis was conducted of 1863 CLARITY-TIMI 28 patients who underwent PCI after angiography a median of three days after fibrinolytic therapy.29 Most (95%) of these patients underwent coronary artery stent placement and received open-label clopidogrel in accordance with current ACC/AHA guidelines.25 The subgroup analysis allowed comparison of clopidogrel pretreatment before PCI (the CLARITY-TIMI 28 clopidogrel group) with clopidogrel use beginning at the time of PCI and stent insertion (the CLARITY-TIMI 28 placebo group). The incidence of a composite of cardiovascular death, recurrent MI, or stroke from PCI 30 days after randomization was significantly lower with clopidogrel pretreatment (3.6%) than placebo (6.2%, p = 0.008), representing an odds reduction of 46%. There was no significant difference in the rate of TIMI major or minor bleeding (2.0% with clopidogrel pretreatment and 1.9% with placebo, p > 0.99). These findings suggest that clopidogrel treatment is warranted before as well as after PCI in patients with ST-segment elevation MI who receive fibrinolytic therapy. Clopidogrel and metoprolol in myocardial infarction trial (COMMIT) COMMIT, the second of the two studies of clopidogrel use in patients with ST-segment elevation MI was larger than the CLARITY-TIMI 28 study and it was conducted only in China.27 In the COMMIT study, 45,852 patients admitted to the hospital within 24 hours after the onset of a suspected acute MI (including 93% who had ST-segment elevation or bundle branch block and 7% with ST segment depression) were randomly assigned to receive clopidogrel 75 mg daily (without a loading dose) or a matching placebo for 28 days or until hospital discharge. All patients received aspirin therapy. Patients undergoing primary PCI were excluded. Approximately 25% of patients received fibrinolytic therapy before or after randomization, with an equal percentage of patients receiving fibrinolytic therapy in the groups of patients randomized to clopidogrel or placebo. A composite of death, reinfarction, or stroke at the time of discharge or the end of the scheduled 28-day treatment period was a primary efficacy end point. The average length of hospital stay was 15 days. In both treatment groups in COMMIT, the mean age was 61 years and 26% of patients were 70 years of age or older.27 The incidence of the composite end point was 9.3% with clopidogrel and 10.1% with placebo, reflecting a significant 9% reduction in death, reinfarction, or stroke from clopidogrel.27 The incidence of death also was significantly reduced from 8.1% with placebo to 7.5% with clopidogrel (p > 0.03). The incidence of reinfarction was significantly reduced from 2.4% with placebo to 2.1% with clopidogrel (p = 0.02). There was no significant difference between treatment groups in the incidence of stroke (1.1% with placebo and 0.9% with clopidogrel, p = 0.11). There also were no significant differences between treatment groups in the incidence of fatal (0.32% in each, p = 0.92) or non-fatal cerebral (0.22% with placebo and 0.27% with clopidogrel, p = 0.35) or non-cerebral hemorrhage. The incidence of any bleeding during the in-hospital treatment period was low and similar between groups, 0.58% in the clopidogrel group and 0.55% in the placebo group (p = 0.59). The benefits from clopidogrel were not affected by the use of fibrinolytic therapy as there was no heterogeneity in the results for the composite end point of death, MI, or stroke between patients receiving and those not receiving fibrinolytic agents. Thus, adding clopidogrel to standard treatment (i.e., aspirin) with or without fibrinolytic therapy) reduces mortality without increasing the risk of bleeding. Changes to clopidogrel labeling and guidelines The use of clopidogrel in patients with ST-segment elevation acute MI was approved by the Food and Drug Administration (FDA) in August 2006 based on the findings from the CLARITY-TIMI 28 and COMMIT studies.30 The drug already had been approved by FDA for use in patients with non-ST-segment elevation ACS (unstable angina/non-Q-wave MI), including patients who are to be managed medically and those who are to be managed with PCI (with or without stents) or CABG.30 The clopidogrel product labeling describes the option of either a 300-mg loading dose of clopidogrel as was done in the CLARITY-TIMI 28 study or initiating therapy with 75 mg/day as was done in COMMIT. The ACC/AHA guidelines for the management of ST-segment elevation MI are expected to be updated in 2007 to reflect the results of these studies. Whether the new guidelines will recommend a loading dose of clopidogrel remains to be determined. There were no age restrictions in the COMMIT study, and a substantial percentage of the participants were elderly. Patients more than 75 years of age were not enrolled in the CLARITY-TIMI 28 study, so no experience was gained with the use of the 300-mg loading dose in older patients. While there is no specific dose reduction recommendations in the clopidogrel product label, the safety of clopidogrel, aspirin and a fibrinolytic has not been evaluated in patients over the age of 75 years, so perhaps should be avoided at this time until the updated ACC/AHA practice guideline is published. The optimal duration of clopidogrel therapy is unclear for patients who do not undergo PCI and stent insertion. In CLARITY TIMI-28, patients who did not undergo PCI received clopidogrel for up to eight days while in COMMIT clopidogrel was given only during hospitalization, which averaged 15 days. Whether the updated ACC/AHA guidelines will specify a duration of therapy patients not undergoing PCI remains to be seen. New recommendations from the ACC/AHA and other professional associations recommend that clopidogrel be continued for a minimum of 30 days in patients receiving a bare metal intracoronary stent and for at least 12 months following a drug-eluting intracoronary stent. Case study two RJ was a 64-year-old man with who presented to the emergency department complaining of crushing chest pain, the severity of which he rated 10 on a 10-point scale with 10 as the worst pain imaginable. The pain began an hour ago while RJ was watching television (i.e., at rest). RJ had a 10-year history of hypertension and took aspirin 325 mg once daily and losartan 50 mg once daily. RJ weighed 90 kg and his vital signs included a systolic and diastolic blood pressure of 140/90 mm Hg and a heart rate of 88 beats/minute. The ECG showed a 2-mm ST segment elevation in the anterior leads. The result of a laboratory test for troponin was negative (i.e., the troponin level is not elevated). His estimated creatinine clearance was 78 mL/min. The emergency department staff quickly concluded that RJ was experiencing an ST-segment elevation MI based on his symptoms and ECG findings. His troponin test result was negative only because he arrived at the emergency department very early after the onset of chest pain, before there was time for the protein to distribute from the myocardium into the systemic circulation. RJ was promptly given aspirin 325 mg, three 0.4-mg sublingual nitroglycerin doses at 5-minute intervals, nitroglycerin 5 μg/min by continuous i.v. infusion, and metoprolol 5 mg and morphine sulfate 1 mg by i.v. injection. The ST segment elevation and severe chest pain continued without any change despite treatment. Primary PCI was not an option because there was no cardiac catheterization laboratory at the hospital, and transfer to another hospital was not feasible. Therefore, the decision was made to administer the fibrinolytic agent tenecteplase. The results of the CLARITY-TIMI 28 and COMMIT suggest that RJ stands to benefit from receiving clopidogrel (75 mg/day with or without a 300-mg loading dose). Use of a GP IIb/IIIa inhibitor alone or in combination with clopidogrel is not indicated in RJ because it can increase the risk of intracranial hemorrhage and bleeding when combined with a fibrinolytic agent without decreasing mortality, especially in older patients like RJ.25 If a cardiac catheterization laboratory had been available and RJ had ST-segment depression (i.e., high-risk non-ST-segment elevation ACS), use of a GP IIb/IIIa inhibitor with clopidogrel would have been appropriate.6 Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment—Thrombolysis in Myocardial Infarction (EXTRACT TIMI 25) EXTRACT TIMI 25 provides insight into the anticoagulation therapy that might be suitable for RJ. In this study, 20,506 patients with ST-segment elevation MI who were scheduled to undergo fibrinolysis were randomly assigned to receive UFH (60 units/kg not to exceed 4000 units as an i.v. bolus followed by 12 units/kg/hr i.v. for at least 48 hours) or enoxaparin (30 mg as an i.v. bolus followed by 1 mg/kg s.c. every 12 hours) throughout the hospitalization. 31 In patients 75 years of age or older, the enoxaparin i.v. bolus dose was omitted and 0.75 mg/kg was given s.c. every 12 hours. In patients weighing more than 100 kg, the first two doses of enoxaparin were “capped” at a maximum of 100 mg. The primary efficacy end point (death from any cause or nonfatal recurrent MI within 30 days after randomization) occurred in 12% of patients in the UFH group and 10% of patients in the enoxaparin group, reflecting a significant 17% reduction in relative risk with enoxaparin (p < 0.001). The incidence of major bleeding after 30 days was significantly higher in the enoxaparin group (2.1%) than in the UFH group (1.4%, p < 0.001). There was no significant difference between treatment groups in the frequency of intracranial hemorrhage (0.7% with enoxaparin and 0.6% with UFH, p = 0.29). The 2004 ACC/AHA guidelines for the management of ST-segment elevation MI suggest enoxaparin as an alternative to UFH for patients less than 75 years of age who are receiving fibrinolytic therapy, provided that renal dysfunction is not present.25 Therefore, RJ, who is 64 years old without chronic kidney disease, could receive either UFH (4000 units as an i.v. bolus followed by 1000 units/hr i.v.) or enoxaparin 30 mg as an i.v. bolus followed by 90 mg s.c. every 12 hours. Bivalirudin would not be an option as an alternative to UFH for RJ. The current guidelines recommend bivalirudin plus a fibrinolytic agent only in patients with a history of heparin-induced thrombocytopenia25 based upon a trial of bivalirudin plus streptokinase where bivalirudin dem onstrated similar efficacy but more bleeding than UFH.32 Fondaparinux 2.5 mg s.c. once daily is another alternative for RJ, although the drug does not appear in the current ACC/AHA guidelines.25 OASIS-6 Study In a recent randomized, double-blind study of 12,092 patients with ST-segment elevation MI, fondaparinux 2.5 mg once daily for up to 8 days was compared with UFH or placebo.33 The UFH dose was 60 units/kg not to exceed 4000 units as an i.v. loading dose followed by 12 units/kg/hr not to exceed 1000 units/hr for 24–48 hours with dosage adjustments to maintain an activated partial thromboplastin time 1.5–2.0 times the control value. A composite of death or reinfarction after 30 days was the primary efficacy end point. The median bolus dose of UFH was 4875 units. The risk of the primary efficacy end point was significantly reduced by 14% from 11.2% in the control group (i.e., UFH or placebo) to 9.7% in the fondaparinux group (p = 0.008). The risk of severe hemorrhage was 1.3% in the control group and 1.0% in the fondaparinux group, a difference that is not significant (p = 0.15). The use of fondaparinux is unlikely to be adopted in clinical practice for three reasons. First, there was no significant difference between the two groups in severe bleeding. Second, the control group included patients who received no anticoagulant therapy where it was logical that fondaparinux would be better than placebo. Compared with UFH, there was no significant difference in the rate of death or MI at any time point evaluated. Third, there was no efficacy benefit from fondaparinux in the subgroup of patients who underwent in-hospital PCI. The 30-day rate of death or MI was 6.0% with fondaparinux and 4.9% with UFH or placebo in this subgroup (p = 0.04). Implications for pharmacists Many therapeutic options are available for patients with ACS, but current ACC/AHA guidelines do not reflect all of these options because of the rapid pace of clinical research. The role of bivalirudin in non-ST-segment elevation ACS is still evolving. Fondaparinux plays a larger role in patients who do not undergo PCI than in patients who do. Clopidogrel plays a role in all patients with ACS, including patients with non-ST-segment ACS (regardless of whether PCI is used) and patients with ST-segment elevation MI (including patients receiving fibrinolytic therapy and those undergoing primary PCI). Enoxaparin is a possible alternative for patients with ST-segment elevation MI who are receiving fibrinolytic therapy. Staying abreast of clinical trial results and ensuring that the proper dosages of antithrombotic medications are used are among the contributions that pharmacists can make in optimizing therapeutic outcomes in patients with ACS. Patients should be monitored for bleeding during antithrombotic therapy. Conclusion Evidence-based guidelines for the management of ACS are continually evolving. Applying these guidelines and the results of recent clinical research to clinical practice will improve therapeutic outcomes. Footnotes Based on the proceedings of a symposium held December 3, 2006, during the ASHP Midyear Clinical Meeting, Anaheim, CA, and supported by an educational grant from sanofi-aventis US. Dr. Spinler received an honorarium for her participation in the symposium and for the preparation of this article. Dr. Spinler reports that she serves on the speakers bureau for Bristol-Myers Squibb and Schering Plough, on the speakers bureau and as a consultant for sanofi-aventis, and as a consultant for The Medicines Company. References 1 American Heart Association. 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Platelet glycoprotein IIb/IIIa Inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet . 2002 ; 359 : 189 –98. Crossref Search ADS PubMed 17 Stone GW. Prospective, randomized comparison of routine upfront initiation versus selective use of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes: the ACUITY Timing Trial. clinicaltrialresults.org (accessed 2007 Feb 28). 18 Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med . 1998 ; 338 : 1488 –97. Crossref Search ADS PubMed 19 McCullough PA, Gibson CM, Dibattiste PM et al. Timing of angiography and revascularization in acute coronary syndromes: an analysis of the TACTICS-TIMI-18 trial. J Interv Cardiol . 2004 ; 17 : 81 –6. Crossref Search ADS PubMed 20 Topol EJ, Moliterno DJ, Herrmann HC et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med . 2001 ; 344 : 1888 –94. Crossref Search ADS PubMed 21 Lincoff AM, Kleiman NS, Kereiakes DJ et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaeous coronary revascularization: REPLACE-2 randomized trial. JAMA . 2004 ; 292 : 696 –703. Crossref Search ADS PubMed 22 Bovill EG, Terrin ML, Stump DC et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med . 1991 ; 115 : 256 –65. Crossref Search ADS PubMed 23 Chew DP, Bhatt DL, Lincoff AM et al. Clinical end point definitions after percutaneous coronary intervention and their relationship to late mortality: an assessment by attributable risk. Heart . 2006 ; 92 : 945 –50. Crossref Search ADS PubMed 24 Yusuf S, Mehta SR, Chrolavicius S et al for the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med . 2006 ; 354 : 1464 –76. Crossref Search ADS PubMed 25 Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol . 2004 ; 44 : 671 –719. Crossref Search ADS PubMed 26 Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med . 2005 ; 352 : 1179 –89. Crossref Search ADS PubMed 27 Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet . 2005 ; 366 : 1607 –21. Crossref Search ADS PubMed 28 Gibson CM, Schomig A. Coronary and myocardial angiography: angiographic assessment of both epicardial and myocardial perfusion. Circulation . 2004 ; 109 : 3096 –105. Crossref Search ADS PubMed 29 Sabatine MS, Cannon CP, Gibson CM et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA . 2005 ; 294 : 1224 –32. Crossref Search ADS PubMed 30 Plavix package insert. New York, NY: Sanofi-Synthelabo; August 2006 . 31 Antman EM, Morrow DA, McCabe CH et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med . 2006 ; 354 : 1477 –88. Crossref Search ADS PubMed 32 White H, Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet . 2001 ; 358 : 1855 –63. Crossref Search ADS PubMed 33 Yusuf S, Mehta SR, Chrolavicius S et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA . 2006 ; 295 : 1519 –30. Crossref Search ADS PubMed Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Groce, James, B.

doi: 10.2146/ajhp070110pmid: 17519443

Abstract Purpose. The evolution of evidence-based quality measures in healthcare, specific performance measures that have been developed by various groups for the prevention and treatment of venous thromboembolism (VTE), the objectives and potential benefits of a national quality improvement initiative designed to improve the care of high-risk patients with acute coronary syndrome (ACS), the reporting of performance data to the public to guide consumer choice, and the recent growth in pay-for-performance programs are described. Summary. Efforts to develop evidence-based quality measures began in the mid to late 1990s and have led to the creation of various safe practices, indicators, standards, and quality measures and initiatives. The prevention and treatment of VTE and the management of ACS have been the focus of some of these initiatives. Reporting of data for two surgery-related VTE process measures to the Centers for Medicare and Medicaid Services began January 1, 2007, and two additional measures may be used in the future. The Joint Commission and National Quality Forum have proposed eight core measures for the prevention and care of VTE that could eventually be used in hospital accreditation decisions. A national quality improvement initiative, CRUSADE, provides participating hospitals with feedback about performance in caring for high-risk patients with non-ST-segment elevation ACS. Reporting of performance data to the public facilitates healthcare decision making by consumers. The use of pay-for-performance programs that provide incentives and rewards for meeting quality goals has grown rapidly in recent years. Conclusion. The various initiatives under way using evidence-based performance measures to evaluate quality of care for VTE and ACS have the potential to improve patient outcomes. Accreditation, Coronary disease, Hospitals, Patient care, Protocols, Quality assurance, Reimbursement, Risk management, Thromboembolism The impetus for developing evidence-based quality measures began in the mid to late 1990s, when the need for quality improvement was first recognized. Quality measures that define safe practices were created. Implementation of these quality measures led to the assessment of hospital performance and the reporting of findings to the public, which allowed consumers to evaluate and compare healthcare system performance. Today’s pay for performance evolved from this public reporting. It offers the potential for rewards for the provision of quality health services by individual healthcare practitioners and healthcare systems from the Centers for Medicare and Medicaid Services (CMS) and insurers. Legislation and governmental efforts in the mid 1990s led to creation in the late 1990s and early 2000s of various safe practices, indicators, standards, and quality measures, implementation of which is under way today. Legislation included the National Technology Transfer and Advancement Act, which was signed into law in 1996, directing federal agencies and state and local governments to increase their reliance on voluntary standards and reduce their dependence on in-house standards.1 The 1998 Office of Management and Budget circular no. A-119 revised established policies on federal use and development of voluntary consensus standards.2 The 1998 final report of the President’s Advisory Commission on Consumer Protection and Quality in the Health Care Industry, Quality First: Better Health Care for All Americans, recommended steps to provide a national commitment to improving healthcare quality.3 Safe practices, indicators, standards, and quality measures developed in the late 1990s and early 2000s include the 2003 National Quality Forum (NQF) safe practices for better healthcare, the 2003 release of the Agency for Healthcare Research and Quality patient safety indicators, and the 2004 collaboration of the Joint Commission (formerly the Joint Commission on Accreditation of Healthcare Organizations) and NQF to develop national consensus standards for the prevention and care of deep vein thrombosis (DVT), a set of standardized, inpatient measures.4,–6 Physician performance measures were developed by the American Medical Association (AMA) and the National Committee for Quality Assurance (NCQA) with the collaboration of CMS and the endorsement of NQF in 2005.7 Several initiatives currently are under way to implement the safe practices, indicators, standards, and quality measures developed in the late 1990s and early 2000s. Minnesota is the first state with mandatory reporting of 27 preventable hospital adverse events in hospitals.8 These adverse events were identified by NQF. Physician voluntary reporting of some AMA/NCQA physician performance measures to CMS began in early January 2006.9 The CMS Surgical Care Improvement Project (SCIP) is a national initiative to improve the safety of surgical care through the reduction of postoperative complications.10 Hospitals were required to submit SCIP data starting with discharges that occurred in the first quarter of calendar year 2007 to obtain reimbursement from CMS.10 CMS has added three SCIP measures for fiscal year 2007 related to venous thromboembolism (VTE) prophylaxis and prophylactic antibiotic selection for surgical patients.10 The Leapfrog Group is a consortium of more than 150 Fortune 500 companies and other large private and public U.S. healthcare purchasers that promotes improvements in the safety, quality, and affordability of healthcare for Americans.11 Quality measures identified by the Leapfrog Group currently are used in more than 900 hospitals. Venous thromboembolism Several of the AMA/NCQA physician performance measures address VTE in surgical patients.12 Voluntary reporting of these measures to CMS began in January 2006, with plans for Medicare pay for performance in 2008. The NQF has endorsed 20 national consensus standards for prevention and care of VTE.13 These consensus standards include a policy measure (known as safe practice no. 17), two process (performance) measures, and 17 key characteristics of preferred practices. The policy measure requires that “Every healthcare facility shall have a written policy appropriate for its scope that is evidence-based and drives continuous quality improvement related to VTE risk assessment, prophylaxis, diagnosis, and treatment.” The two process (performance) measures are surgery-related measures used for the CMS SCIP: (1) surgery patients with recommended VTE prophylaxis ordered (SCIP VTE-1), and (2) surgery patients who received appropriate VTE prophylaxis within 24 hours prior to or 24 hours after surgery (SCIP-2). The policy measure and two process measures currently are in use in the private and public sectors in the United States. Hospitals were required to report data for SCIP VTE-1 and SCIP VTE-2 to CMS beginning January 1, 2007, to receive the full market basket increase in their payment rates for 2008.10 Failure to submit the required data will result in a 2% reduction in market basket updates.10 A hospital market basket includes a set of expenditures— specific goods or services—used to calculate a price index for a provider. Medicare payments are updated annually to reflect inflation based upon price versus the market basket.14 Monetary penalties will be assessed to those who do not report on the Medicare SCIP VTE measures. Poor reporting will also be “penalized” as the results will be posted for viewing by the public and healthcare community on the Hospital Compare Web site beginning in December of 2007.15 Two additional SCIP VTE measures have been developed for possible future use. Intra- or postoperative pulmonary embolism (PE) diagnosed during the index hospitalization and within 30 days of surgery is SCIP VTE-3. Intra- or postoperative DVT diagnosed during the index hospitalization and within 30 days of surgery is SCIP VTE-4.16 Neither of these measures is reported to CMS at the present time. Eight proposed Joint Commission/ NQF core measures for the prevention and care of VTE are listed in Table 11. Audience response technology employed during the live symposium revealed that many clinicians expect that initial patient assessment within 24 hours after hospital admission will have the greatest contribution to improving patient care. By contrast, the audience also thought that documentation of inferior vena cava filter insertion and the incidence of potentially preventable hospital-acquired VTE are measures that may be least likely to improve patient care. Table 1. Joint Commission/NQF Proposed Core Measures for Prevention and Care of Venous Thromboembolism6,a aICU = intensive care unit; VTE = venous thromboembolism. Risk Assessment/Prophylaxis 1. Documentation of VTE risk assessment/prophylaxis within 24 hours of hospital admission 2. Documentation of VTE risk assessment/prophylaxis within 24 hours of transfer to ICU Treatment 3. Documentation of inferior vena cava filter insertion 4. VTE patients with overlap of warfarin and parenteral anticoagulation therapy 5. VTE patients receiving unfractionated heparin with platelet count monitoring 6. VTE patients receiving unfractionated heparin management by nomogram/protocol 7. VTE discharge instructions Outcome 8. Incidence of potentially preventable hospital-acquired VTE aICU = intensive care unit; VTE = venous thromboembolism. Risk Assessment/Prophylaxis 1. Documentation of VTE risk assessment/prophylaxis within 24 hours of hospital admission 2. Documentation of VTE risk assessment/prophylaxis within 24 hours of transfer to ICU Treatment 3. Documentation of inferior vena cava filter insertion 4. VTE patients with overlap of warfarin and parenteral anticoagulation therapy 5. VTE patients receiving unfractionated heparin with platelet count monitoring 6. VTE patients receiving unfractionated heparin management by nomogram/protocol 7. VTE discharge instructions Outcome 8. Incidence of potentially preventable hospital-acquired VTE Open in new tab Table 1. Joint Commission/NQF Proposed Core Measures for Prevention and Care of Venous Thromboembolism6,a aICU = intensive care unit; VTE = venous thromboembolism. Risk Assessment/Prophylaxis 1. Documentation of VTE risk assessment/prophylaxis within 24 hours of hospital admission 2. Documentation of VTE risk assessment/prophylaxis within 24 hours of transfer to ICU Treatment 3. Documentation of inferior vena cava filter insertion 4. VTE patients with overlap of warfarin and parenteral anticoagulation therapy 5. VTE patients receiving unfractionated heparin with platelet count monitoring 6. VTE patients receiving unfractionated heparin management by nomogram/protocol 7. VTE discharge instructions Outcome 8. Incidence of potentially preventable hospital-acquired VTE aICU = intensive care unit; VTE = venous thromboembolism. Risk Assessment/Prophylaxis 1. Documentation of VTE risk assessment/prophylaxis within 24 hours of hospital admission 2. Documentation of VTE risk assessment/prophylaxis within 24 hours of transfer to ICU Treatment 3. Documentation of inferior vena cava filter insertion 4. VTE patients with overlap of warfarin and parenteral anticoagulation therapy 5. VTE patients receiving unfractionated heparin with platelet count monitoring 6. VTE patients receiving unfractionated heparin management by nomogram/protocol 7. VTE discharge instructions Outcome 8. Incidence of potentially preventable hospital-acquired VTE Open in new tab Approximately 55 hospitals have been randomly selected for pilot testing of the proposed core measures to evaluate the reliability of the individual measures and associated data elements, assess data collection efforts (including time and estimated cost), enhance measure specifications, and assess sampling strategies.6 The pilot testing was to take place between January and June 2007. If everything goes as planned, the Joint Commission and NQF will release a set of usable consensus measures in late 2007 or early 2008.17 The Joint Commission will expect the core measures to be applied in practice.18 A Leapfrog hospital quality and safety survey was conducted in 2006 to educate and inform participants about patient safety and the importance of comparing provider performance, and recognize and reward providers.17 The survey was based on 30 safe practices identified by the NQF, including patient evaluation for risk of developing DVT/VTE at the time of admission and regularly thereafter, and use of clinically appropriate methods for preventing DVT/VTE. The use of dedicated antithrombotic (anticoagulation) services that facilitate coordinated care management to ensure that antithrombotic (anticoagulation) therapy is effective and safe is another NQF safe practice included in the Leapfrog survey. This measure is one of Leapfrog’s four key quality and safety practices (i.e., leaps). One insurer and four Fortune 500 companies who are members of the Leapfrog Group committed to paying more than $2 million in bonuses to hospitals that met certain Leapfrog safety standards.19 These safety standards were for the use of computerized physician order entry and staffing of intensive care units with physicians who are board-certified or board-eligible in critical care medicine. Payments to hospitals for meeting other safety standards in providing contract services are likely. Acute coronary syndrome A national quality improvement initiative—Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/ American Heart Association (ACC/ AHA) Guidelines (CRUSADE)—is under way to improve the care of highrisk patients with non-ST-segment elevation acute coronary syndrome (ACS) (see the article by Spinler in this supplement).20 Collecting data related to patient management practice patterns in the U.S. and using the data for targeted educational interventions to promote adherence to the ACC/AHA guidelines for management of patients with unstable angina and non-ST-segment elevation myocardial infarction are among the strategies used in the CRUSADE initiative.21 The objectives of the CRUSADE initiative are to determine the current state of awareness of and adherence to the ACC/AHA guidelines, implement quality improvement initiatives to promote the guideline recommendations, and improve clinical outcomes for high-risk patients with non-ST-segment elevation ACS through early risk stratification and implementation of evidence-based care both in the hospital and after hospital discharge.20 More than 400 hospitals are participating in the initiative. A collaborative effort among the pharmacy, emergency medicine, cardiology, quality improvement, and other departments is required. Confidential quarterly feedback reports on a hospital’s adherence to ACC/AHA guidelines will be provided to allow assessment of the effectiveness of quality improvement initiatives in the institution and comparison of performance with benchmark data at similar hospitals, top-performing hospitals, and all hospitals participating in CRUSADE. In the future, the Joint Commission’s hospital accreditation decisions could hinge on performance. The potential benefits of participation in the CRUSADE initiative include improved risk stratification and clinical outcomes in patients with non-ST-segment elevation ACS, and insight into reasons for a lack of guideline adherence and ways to improve adherence. Other possible positive outcomes of CRUSADE participation include gaining insight into the effectiveness of collaborative quality improvement efforts that might translate into other aspects of patient care and be used to help identify areas for improvement, and the ability to rate hospital performance relative to other hospitals, leading to pay for performance. Public reporting and consumer choice Hospital performance data are available to the public from several sources to facilitate healthcare decision making by consumers. These sources include CMS, Joint Commission, and the Leapfrog Group. Hospital Compare (www.hospitalcompare.hhs.gov/) is a web-based tool that allows comparisons of organizational performance using quality data obtained from hospitals that voluntarily participate in a national project called Hospital Quality Alliance: Improving Care Through Information. Performance of a particular hospital can be compared with that of other hospitals in the state and nation. Quality Check (www.qualitycheck.org) is a web-based tool with performance reports for healthcare organizations and programs accredited by the Joint Commission. It allows performance comparisons among the Joint Commission-accredited organizations in the same state or the entire nation. A web-based database with the results of the Leapfrog hospital quality and safety survey (www.leapfroggroup.org/cp) can be searched and used to compare performance among various participating hospitals in a particular geographic area. Pay for performance Pay-for-performance programs provide physicians and hospitals with financial incentives and rewards for meeting quality goals and improving patient outcomes. The number of physician and hospital pay-for-performance programs has increased rapidly over the past several years (Figure 11).22 In 2003, CMS initiated the Premier Hospital Quality Incentive Demonstration, a three-year project to reward top-performing hospitals with approximately $21 million in bonuses.23 In 2004, hospitals in Indiana received $13 million in rewards for the results of an innovative quality improvement program developed by Anthem Blue Cross and Blue Shield. In California, approximately $100 million was expected to be distributed as bonuses to physician groups in the six largest health plans through the Integrated Health Association pay-for-performance program beginning in late 2004. These bonuses were for clinical quality, patient satisfaction, and information technology investment.23 Figure 1. Open in new tabDownload slide Figure 1. Open in new tabDownload slide Conclusion The use of evidence-based performance measures for VTE and ACS has the potential to improve patient care. Performance measures will become the benchmark for pay for performance, and in the future, possibly hospital accreditation. Footnotes Based on the proceedings of a symposium held December 3, 2006, during the ASHP Midyear Clinical Meeting, Anaheim, CA, and supported by an educational grant from sanofi-aventis US. Dr. Groce received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Groce reports that he serves on the speakers bureau and as a consultant for Bristol-Myers Squibb, as a consultant for Eisai Pharmaceuticals, on the speakers bureau and as a consultant for sanofi-aventis, and as a consultant for The Medicines Company. References 1 National Technology Transfer and Advancement Act frequently asked questions. ts.nist.gov/Standards/Conformity/nttaa-qa.cfm (accessed 2006 Dec 28). 2 Office of Management and Budget circular No. A-119 revised. February 10, 1998. www.whitehouse.gov/omb/circulars/a119/a119.html (accessed 2006 Dec 28). 3 President’s Advisory Commission on Consumer Protection and Quality in the Health Care Industry. www.hcqualitycommission.gov/ (accessed 2006 Dec 28). 4 National Quality Forum safe practices for better healthcare. www.qualityforum.org/projects/completed/safe_practices.asp (accessed 2006 Dec 28). 5 Agency for Healthcare Research and Quality patient safety indicators. www.qualityindicators.ahrq.gov/psi_overview.htm (accessed 2006 Dec 28). 6 Joint Commission on Accreditation of Healthcare Organizations. National Consensus Standards for Prevention and Care of Venous Thromboembolism (VTE). October 18, 2006. www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/National+Consensus1Standards1for1Prevention1and1Care1of1Venous1Thromboembolism1%28VTE%29.htm (accessed 2006 Dec 28). 7 NQF endorses AMA/Physician Consortium and NCQA quality measures. August 9, 2005. www.ama-assn.org/ama/pub/category/15422.html (accessed 2006 Dec 28). 8 Gov. Pawlenty signs legislation creating new system for reporting adverse events in hospitals. June 6, 2003. www.bhcag.com/vertical/Sites/%7B887602D0-6B1A-468C-B400-ED58BF42138D%7D/uploads/%7B400016E3-5CC9-4C9A-B25D-57E4B619AA0B%7D.DOC (accessed 2006 Dec 28). 9 Centers for Medicare and Medicaid Services. Physician voluntary reporting program (PVRP): background and general information. October 16, 2006. www.cms.hhs.gov/PVRP/Downloads/PVRPBackground.pdf (accessed 2006 Dec 28). 10 Centers for Medicare and Medicaid Services. Details for hospital quality reporting expansion provisions in CY 2007 hospital outpatient prospective payment system proposed rule. August 8, 2006. www.cms.hhs.gov/apps/media/press/factsheet.asp?Counter=1942&intNumPerPage=10&checkDate=&checkKey=&srchType=&numDays=3500&srchOpt=0&srchData=&keywordType=All&chkNewsType=6&intPage=&showAll=&pYear=&year=&desc=false&cboOrder=date (accessed 2006 Dec 28). 11 The Leapfrog Group fact sheet. www.leapfroggroup.org/about_us/leapfrog-factsheet (accessed 2006 Dec 28). 12 2007 Physician Voluntary Reporting Program (PVRP) measure specifications. www.cms.hhs.gov/PVRP/Downloads/PVRPMeasureSpecifications.pdf (accessed 2006 Dec 28). 13 The National Quality Forum. National Quality Forum endorses consensus standards for prevention and care of venous thromboembolism. May 18, 2006. www.qualityforum.org/pdf/news/DVT5-18-06.pdf (accessed 2006 Dec 28). 14 Centers for Medicare and Medicaid Services. Market Basket Definitions and General Information. www.cms.hhs.gov/MedicareProgramRatesStats/downloads/info.pdf (accessed 2007 Jan 17). 15 Centers for Medicare and Medicaid Services. Hospital Quality Alliance 2004–2007 Measure Build-out Table. www.cms.hhs.gov/HospitalQualityInits/downloads/HospitalHQA2004_2007200512.pdf (accessed 2007 Jan 17). 16 Centers for Medicare and Medicaid Services Surgical Care Improvement Project & American College of Surgeons National Surgical Quality Improvement Program frequently asked questions. June 1, 2006. www.mainequalityforum.gov/SCIP%20Submit%20datescmsscipfaqs.pdf (accessed 2006 Dec 28). 17 The Leapfrog Group hospital quality and safety survey: what’s new in the 2006 survey (version 3.2). leapfrog.medstat.com/pdf/Final.pdf (accessed 2006 Dec 28). 18 Gebhart F. New standards for DVT coming. mediwire.skyscape.com/main/Default.aspx?P=Content&ArticleID=200946 (accessed 2006 Dec 28). 19 Empire Blue Cross Blue Shield. Join Empire Blue Cross Blue Shield to Recognize and Reward Hospitals that Achieve Leapfrog Safety Standards. October 19, 2001. www.empireblue.com/wps/portal/ehpfooter?content_path=shared/noapplication/f0/s0/t0/pw_ad069498.htm&label=October%2019,%202001 (accessed 2006 Dec 28). 20 Crusade national quality improvement initiative. www.crusadeqi.com/ (accessed 2007 Jan 4). 21 Braunwald E, Antman EM, Beasley JW et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction–summary article: a report of the American College of Cardiology/ American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol . 2002 ; 40 : 1366 –74. Crossref Search ADS PubMed 22 Enhancing provider dynamics: pay-for-performance. www.bcbs.com/mcrg/chap3/pay/pay_2.html (accessed 2006 Dec 28). 23 Lee TH, Galvin R, Miller ME. Paying for performance in health care: getting a better deal? nhpf.ags.com/pdfs_fs/FS_07-09-04.Payfor-Performance.pdf (accessed 2006 Dec 28). 24 Anthem Blue Cross and Blue Shield pays out $13 million extra in 2004 through Hospital Quality Program. April 25, 2005. www.anthem.com/wps/portal/ahpfooter?content_path=shared/noapplication/f0/s0/t0/pw_a035879.htm&label= (accessed 2006 Dec 28). Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.

Nutescu, Edith, A.

doi: 10.2146/ajhp070108pmid: 17519445

Abstract Purpose. The long-term complications of deep vein thrombosis (DVT), assessment of risk for venous thromboembolism (VTE) in medical and surgical patients, recommendations in evidence-based guidelines for VTE prophylaxis in surgical and medical patients and the treatment of VTE, and a new alternative for VTE prophylaxis and treatment are discussed. Summary. Pulmonary embolism (PE) is an acute complication of DVT, and recurrent DVT, post-thrombotic syndrome, and death are long-term complications of DVT. The need to assess VTE risk and provide VTE prophylaxis are well recognized in surgical patients. However, VTE prophylaxis is underutilized in medical patients despite the fact that DVT is common and guidelines for prophylaxis are available, partly because the condition often is asymptomatic in these patients. The risk for VTE increases as the number of risk factors increases, so the aggressiveness of VTE prophylaxis in medical and surgical patients increases as the risk of VTE increases. The most recent American College of Chest Physicians (ACCP) guidelines recommend low-dose unfractionated heparin or low-molecular-weight heparin (LMWH) for VTE prophylaxis in acutely ill medical patients. The treatment of VTE recommended by ACCP involves short-term LMWH or unfractionated heparin therapy plus long-term oral warfarin therapy. The pentasaccharide, factor Xa inhibitor, fondaparinux is a new alternative for VTE prophylaxis and treatment. Reducing LMWH doses for patients with severe renal impairment may offer a safety advantage. Fixed doses of LMWH are customarily used for VTE prophylaxis regardless of body weight or body mass index, but weight-based dosing with larger doses for obese patients may be more effective than fixed doses. Conclusion. Efforts to assess VTE risk and apply evidence-based guidelines for VTE prophylaxis and treatment in medical patients as well as surgical patients can improve patient care and outcomes. Findings from recent clinical research provide clinicians with clarification about the optimal prophylactic and treatment strategies, and future guidelines will reflect these findings. American College of Chest Physicians, Anticoagulants, Critical illness, Dosage, Fondaparinux, Heparins, Kidney failure, Protocols, Risk management, Surgery, Thromboembolism, Warfarin, Weight Venous thromboembolism (VTE) is the most common preventable cause of hospital death. It has been referred to as a silent killer because only a small percentage of patients with VTE exhibit signs or symptoms of VTE. This scenario was the case for David Bloom, the 40-year-old NBC news correspondent who died suddenly after experiencing lower extremity cramping that led to pulmonary embolism (PE) while he was covering the war in Iraq. Approximately 50–80% of cases of deep vein thrombosis (DVT) are asymptomatic, and more than 70% of PE go undetected until a postmortem examination is performed after sudden death.1,–3 Sudden death often is the first sign of PE. The most serious acute complication of DVT is PE (i.e., embolus formation and pulmonary artery occlusion). Long-term complications after DVT include recurrent DVT, post-thrombotic syndrome (persistent edema, pain, purpura, dermatitis, pruritus, cellulitis, and ulceration), and death. These outcomes can develop despite treatment (Table 11).4 Post-thrombotic syndrome can lead to lower extremity amputation, with a large adverse impact on quality of life. Table 1. Long-Term Complications After a First Episode of Deep Vein Thrombosis4,a,b Cumulative Incidence Time Elapsed (yr) Recurrent DVT (%) Post-thrombotic Syndrome (%) Survival Rate (%) aDVT = deep vein thrombosis. bThe figures in this table are from a prospective cohort study of 528 patients with a first DVT who received at least three months of oral anticoagulant therapy. 2 17 25 80 5 24 30 74 8 30 30 69 Cumulative Incidence Time Elapsed (yr) Recurrent DVT (%) Post-thrombotic Syndrome (%) Survival Rate (%) aDVT = deep vein thrombosis. bThe figures in this table are from a prospective cohort study of 528 patients with a first DVT who received at least three months of oral anticoagulant therapy. 2 17 25 80 5 24 30 74 8 30 30 69 Open in new tab Table 1. Long-Term Complications After a First Episode of Deep Vein Thrombosis4,a,b Cumulative Incidence Time Elapsed (yr) Recurrent DVT (%) Post-thrombotic Syndrome (%) Survival Rate (%) aDVT = deep vein thrombosis. bThe figures in this table are from a prospective cohort study of 528 patients with a first DVT who received at least three months of oral anticoagulant therapy. 2 17 25 80 5 24 30 74 8 30 30 69 Cumulative Incidence Time Elapsed (yr) Recurrent DVT (%) Post-thrombotic Syndrome (%) Survival Rate (%) aDVT = deep vein thrombosis. bThe figures in this table are from a prospective cohort study of 528 patients with a first DVT who received at least three months of oral anticoagulant therapy. 2 17 25 80 5 24 30 74 8 30 30 69 Open in new tab Risk assessment VTE in hospitalized patients is often thought of as a consequence of surgery because major surgery is a risk factor, but medical patients also are at risk. Non-surgical patients account for 70–80% of fatal PE and 50–70% of symptomatic thromboembolic events.5 In an eight-month prospective screening study, DVT was detected by ultrasound in 33% of adults admitted to a medical intensive care unit.6 Ten percent of hospital deaths are caused by PE, suggesting that there is room for improvement in identifying patients at risk for VTE and providing VTE prophylaxis.5 The high incidence of DVT in medical patients and the high percentage of patients with VTE who are asymptomatic underscore the importance of assessing the risk for VTE in hospital patients and identifying patients at risk so that prophylactic strategies can be implemented. In untreated acutely ill medical patients, the incidence of VTE is 15%, which is comparable to the 10–20% risk of calf DVT in surgical patients who are categorized as being at moderate risk (Table 22).5,7 The incidence of proximal DVT in untreated acutely ill medical patients is 5%, which is comparable to the 4–8% risk of proximal DVT in surgical patients who are categorized as being at high risk (Table 2 2).5,7 Proximal DVT is particularly important because thrombi in this location are more likely to embolize to the lungs and cause PE. Table 2. Recommended VTE Prophylaxis for Surgical Patients5,a,b Risk Level Proximal DVT (%) Definition Prophylaxis aGCS = graduated compression stockings; IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; VTE = venous thromboembolism; yr = years; ES = elastic stockings. bRecommendations from the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Low 0.4 Minor surgery in patients <40 yr with no additional risk factors Early ambulation Moderate 2–4 Minor surgery in patients with additional risk factors or surgery in patients 40–60 yr with no additional risk factors LDUH (q 12 hr) 
 LMWH (≤3400 U/day)
 IPC
 ES High 4–8 Surgery in patients >60 yr or 40–60 yr with additional risk factors (cancer, prior VTE) LDUH (q 8 hr)
 LMWH (>3400 U/day)
 IPC Highest 10–20 Surgery in patients with multiple risk factors (age >40, cancer, prior VTE)
 Hip or knee arthroplasty
 Hip fracture surgery
 Major trauma
 Spinal cord injury LMWH (>3400 U/day)
 Oral anticoagulants (INR =2 − 3)
 IPC/ES + LMWH/LDUH
 Fondaparinux Risk Level Proximal DVT (%) Definition Prophylaxis aGCS = graduated compression stockings; IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; VTE = venous thromboembolism; yr = years; ES = elastic stockings. bRecommendations from the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Low 0.4 Minor surgery in patients <40 yr with no additional risk factors Early ambulation Moderate 2–4 Minor surgery in patients with additional risk factors or surgery in patients 40–60 yr with no additional risk factors LDUH (q 12 hr) 
 LMWH (≤3400 U/day)
 IPC
 ES High 4–8 Surgery in patients >60 yr or 40–60 yr with additional risk factors (cancer, prior VTE) LDUH (q 8 hr)
 LMWH (>3400 U/day)
 IPC Highest 10–20 Surgery in patients with multiple risk factors (age >40, cancer, prior VTE)
 Hip or knee arthroplasty
 Hip fracture surgery
 Major trauma
 Spinal cord injury LMWH (>3400 U/day)
 Oral anticoagulants (INR =2 − 3)
 IPC/ES + LMWH/LDUH
 Fondaparinux Open in new tab Table 2. Recommended VTE Prophylaxis for Surgical Patients5,a,b Risk Level Proximal DVT (%) Definition Prophylaxis aGCS = graduated compression stockings; IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; VTE = venous thromboembolism; yr = years; ES = elastic stockings. bRecommendations from the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Low 0.4 Minor surgery in patients <40 yr with no additional risk factors Early ambulation Moderate 2–4 Minor surgery in patients with additional risk factors or surgery in patients 40–60 yr with no additional risk factors LDUH (q 12 hr) 
 LMWH (≤3400 U/day)
 IPC
 ES High 4–8 Surgery in patients >60 yr or 40–60 yr with additional risk factors (cancer, prior VTE) LDUH (q 8 hr)
 LMWH (>3400 U/day)
 IPC Highest 10–20 Surgery in patients with multiple risk factors (age >40, cancer, prior VTE)
 Hip or knee arthroplasty
 Hip fracture surgery
 Major trauma
 Spinal cord injury LMWH (>3400 U/day)
 Oral anticoagulants (INR =2 − 3)
 IPC/ES + LMWH/LDUH
 Fondaparinux Risk Level Proximal DVT (%) Definition Prophylaxis aGCS = graduated compression stockings; IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin; LMWH = low-molecular-weight heparin; VTE = venous thromboembolism; yr = years; ES = elastic stockings. bRecommendations from the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Low 0.4 Minor surgery in patients <40 yr with no additional risk factors Early ambulation Moderate 2–4 Minor surgery in patients with additional risk factors or surgery in patients 40–60 yr with no additional risk factors LDUH (q 12 hr) 
 LMWH (≤3400 U/day)
 IPC
 ES High 4–8 Surgery in patients >60 yr or 40–60 yr with additional risk factors (cancer, prior VTE) LDUH (q 8 hr)
 LMWH (>3400 U/day)
 IPC Highest 10–20 Surgery in patients with multiple risk factors (age >40, cancer, prior VTE)
 Hip or knee arthroplasty
 Hip fracture surgery
 Major trauma
 Spinal cord injury LMWH (>3400 U/day)
 Oral anticoagulants (INR =2 − 3)
 IPC/ES + LMWH/LDUH
 Fondaparinux Open in new tab Providing primary prophylaxis to asymptomatic persons is problematic unless there is a basis for risk assessment. Fortunately, many risk factors for VTE have been identified (Table 33), and these risk factors can be used as the basis for risk assessment. The risk for DVT increases with increases in the number of risk factors (Figure 11).9 Table 3. Risk Factors for VTE5,8,a aVTE = venous thromboembolism. • Increasing age (>40 yr) • Prolonged immobility, stroke, or paralysis • Previous VTE • Cancer and/or its treatment • Major surgery (abdomen, pelvis, lower extremity) • Trauma (pelvis, hip, or lower extremity) • Obesity • Smoking • Varicose veins • Cardiac or pulmonary failure • Recent myocardial infarction • Central venous catheter use • Inflammatory bowel disease • Nephrotic syndrome • Pregnancy and the postpartum period • Estrogen therapy • Acute medical illness • Infection • Thrombophilia aVTE = venous thromboembolism. • Increasing age (>40 yr) • Prolonged immobility, stroke, or paralysis • Previous VTE • Cancer and/or its treatment • Major surgery (abdomen, pelvis, lower extremity) • Trauma (pelvis, hip, or lower extremity) • Obesity • Smoking • Varicose veins • Cardiac or pulmonary failure • Recent myocardial infarction • Central venous catheter use • Inflammatory bowel disease • Nephrotic syndrome • Pregnancy and the postpartum period • Estrogen therapy • Acute medical illness • Infection • Thrombophilia Open in new tab Table 3. Risk Factors for VTE5,8,a aVTE = venous thromboembolism. • Increasing age (>40 yr) • Prolonged immobility, stroke, or paralysis • Previous VTE • Cancer and/or its treatment • Major surgery (abdomen, pelvis, lower extremity) • Trauma (pelvis, hip, or lower extremity) • Obesity • Smoking • Varicose veins • Cardiac or pulmonary failure • Recent myocardial infarction • Central venous catheter use • Inflammatory bowel disease • Nephrotic syndrome • Pregnancy and the postpartum period • Estrogen therapy • Acute medical illness • Infection • Thrombophilia aVTE = venous thromboembolism. • Increasing age (>40 yr) • Prolonged immobility, stroke, or paralysis • Previous VTE • Cancer and/or its treatment • Major surgery (abdomen, pelvis, lower extremity) • Trauma (pelvis, hip, or lower extremity) • Obesity • Smoking • Varicose veins • Cardiac or pulmonary failure • Recent myocardial infarction • Central venous catheter use • Inflammatory bowel disease • Nephrotic syndrome • Pregnancy and the postpartum period • Estrogen therapy • Acute medical illness • Infection • Thrombophilia Open in new tab Figure 1. Open in new tabDownload slide Risk of Deep Vein Thrombosis (DVT) Increases with the Number of Risk Factors. Proportion of Patients with DVT Was Confirmed by Objective Testing. Reprinted with Permission from Reference 9. Figure 1. Open in new tabDownload slide Risk of Deep Vein Thrombosis (DVT) Increases with the Number of Risk Factors. Proportion of Patients with DVT Was Confirmed by Objective Testing. Reprinted with Permission from Reference 9. Risk assessment strategies Three types of strategies may be used to improve VTE risk assessment and the use of VTE prophylaxis when it is warranted: (1) risk assessment scoring systems, (2) risk recognition systems, and (3) prophylaxis default systems. Risk assessment scoring systems categorize a patient’s risk based on his or her risk factors for VTE. Such scoring systems often use a point system, with different point values for different risk factors (i.e., the risk factors are weighted according to their contribution to risk).10,11 Preprinted risk scoring forms or computerized programs with alert functions may be used to identify high-risk patients for whom VTE prophylaxis is indicated. Automated calculations based on International Classification of Diseases, 9th revision codes also are sometimes used to identify patients for VTE prophylaxis. Risk recognition systems identify patients at risk for VTE based on certain criteria associated with VTE without scoring an individual’s risk for VTE. Prophylaxis is provided to all patients meeting the criteria unless they have a contraindication to use of prophylaxis. Prophylaxis default systems, usually built in electronic medical records or electronic order entry, provide prophylaxis to all patients meeting certain pre-determined criteria associated with VTE without scoring individual risk. Prophylaxis is later discontinued for patients who no longer meet those criteria. Most risk assessment strategies translate the VTE risk into recommendations for use of specific prophylactic regimens if needed, taking into consideration contraindications to the use of prophylaxis.10 Ideally, the strategy for risk assessment and the prophylactic regimen are evidence-based and prospectively validated. Considerable guidance on prophylactic regimens is available from authoritative sources, particularly the evidence-based guidelines for prevention of VTE from the Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy (Table 22).5 The aggressiveness of prophylaxis increases as the risk of VTE increases. Prophylaxis in medical patients The use of mechanical prophylaxis with intermittent pneumatic compression (IPC) or graduated compression stockings (GCS) in medical patients is somewhat controversial because clinical data supporting its use are limited in this patient population, patient adherence is poor, and the cost of IPC is relatively high. However, the lack of a risk of bleeding is a major advantage of mechanical prophylaxis.5 Therefore, mechanical prophylaxis with IPC or GCS is recommended by ACCP for medical patients with risk factors for VTE and a contraindication to anticoagulant prophylaxis.5 According to ACCP, acutely ill patients with CHF or severe respiratory disease or who are confined to bed with one or more additional risk factor (e.g., cancer, previous VTE, sepsis) should receive low-dose unfractionated heparin (LDUH) or low-molecular-weight heparin (LMWH) for VTE prophylaxis.5 The ACCP recommendations do not specify a dosing frequency for LDUH leading to clinical controversy in the appropriate dosing of UFH for this indication. The ACCP recommendations were published before the results of a study demonstrating the efficacy of fondaparinux, a pentasaccharide inhibitor of activated coagulation factor X (Xa), for prevention of VTE in older acute medical inpatients were released.12 Use of fondaparinux for this purpose in this patient population is not yet approved by the Food and Drug Administration (FDA).13 A meta-analysis of seven controlled trials of either unfractionated heparin (UFH) or LMWH in 15,095 medical patients found significant reductions in the risk of DVT (by 56%) and PE (by 58%) with the use of UFH or LMWH compared with control treatment.14 There was no significant impact on the incidence of major hemorrhage or death. The efficacy of the LMWH enoxaparin, the LMWH dalteparin, and the factor Xa inhibitor fondaparinux for preventing VTE in acutely ill medical patients was demonstrated in three separate large, randomized, double-blind, placebo-controlled studies.7,12,15 Significant reductions in the relative risk of VTE were associated with active treatment in all three studies. A 63% reduction in the relative risk of VTE was associated with enoxaparin 40 mg given subcutaneously (s.c.) once daily for 6–14 days in a study known as Prophylaxis in Medical Patients with Enoxaprin (MEDENOX).7 A 45% reduction in the relative risk of VTE was associated with dalteparin sodium 5000 units given s.c. once daily for 14 days in a study known as “Dalteparin for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients (PREVENT).15 In the Arixtra® for Thromboembolism Prevention in a Medical Indications Study (ARTEMIS), a 47% reduction in the relative risk of VTE was associated with fondaparinux sodium 2.5 mg s.c. given once daily for 6–14 days.12 The results of these studies collectively demonstrate that failing to provide VTE prophylaxis is not wise in acutely ill medical patients. The ACCP guidelines do not specify a duration of therapy for VTE prophylaxis in medical patients because the optimal duration is not known5; however, the duration of prophylaxis ranged from 6 to 14 days in recent studies.7,12,15 Studies of extended prophylaxis in patients with persistent risk factors currently are underway in medically ill patients. Comparisons of the efficacy, safety, and cost of LMWH with UFH are needed to make decisions about selecting the best VTE prophylactic therapy for medical patients. In a meta-analysis of nine clinical trials comparing LMWH with UFH in a total of 4669 medical patients, there was no significant difference between LMWH and UFH in efficacy for preventing DVT, PE, or death. However, LMWH significantly reduced the risk of major hemorrhage by 52% compared with UFH.14 Heparin-induced thrombocytopenia (HIT) is a potentially serious complication of LMWH and UFH therapy. A meta-analysis was conducted of two randomized, controlled studies and three prospective, nonrandomized studies in which the incidence of HIT was compared in a total of 2478 surgical patients receiving LMWH or UFH.16,–21 The absolute risk of HIT was 0.2% with LMWH and 2.6% with UFH, a difference that is significant. Three large registries have demonstrated that VTE prophylaxis is underused in hospitalized medical patients despite ACCP recommendations. 5,22,–24 In the DVT FREE registry of medical and surgical patients with DVT, only 42% of 2726 patients with DVT diagnosed in the hospital had received prophylaxis within the preceding 30 days.22 In the RIETE registry of patients with acute VTE, only 28% of 756 acutely ill medical patients had received VTE prophylaxis compared with 67% of 884 surgical patients.23 In the International Medical Prevention Registry on Venous Thromboembolism (a registry known as the IMPROVE), 41% of 4315 acutely ill medical patients received VTE prophylaxis, of which 25% of patients with no risk factors, 49% of patients with one risk factor, and 67% of patients with two or more risk factors.24 Various strategies have been used to increase VTE prophylaxis rates in medically ill patients. At a tertiary care university-affiliated teaching hospital, the VTE prophylaxis rate in medically ill patients was compared before and after implementation of an intervention designed to increase awareness of the need for prophylaxis. The intervention involved the use of a patient admission or medical history form with a VTE risk-assessment scheme, use of an admission order set listing optimal VTE prophylactic regimens, and the provision of education sessions about VTE prophylaxis for house staff and clinical pharmacists.25 Patients were stratified at the time of admission on the basis of risk for developing VTE into a high-risk group and a low-risk group. Before the intervention phase, 75% of patients were considered at high risk, but only 43% of those high-risk patients received VTE prophylaxis. After the intervention, a similar percentage (79%) of patients was considered at high risk for VTE, but the VTE prophylaxis rate had increased to 72%. Improvement in the VTE prophylaxis rate also was observed in the low-risk group after implementation of the intervention compared with the period before the intervention. The impact of a computer program designed to assess VTE risk and alert physicians about patients at risk for DVT was evaluated in a randomized, controlled study of 2506 medical and surgical patients at a tertiary care teaching hospital where computerized physician order entry was used.26 The computer system was linked to the hospital’s VTE prophylaxis guidelines, which were based on published guidelines. Patients were randomly assigned to an intervention group or a control group. An electronic alert about the risk of VTE was sent to the physician responsible for each of the 1255 patients in the intervention group. Decisions about use of VTE prophylaxis were left to the physician’s judgment. No electronic alert was sent to physicians caring for the 1251 patients in the control group. The rate of VTE prophylaxis was significantly higher in the intervention group (34%) than in the control group (15%).26 The intervention significantly reduced the risk of VTE after 90 days by 41%, with no significant increase in the risk of major hemorrhage after 30 days (the incidence of major hemorrhage was 1.5% in both groups). Case study 1 CM is a 65-year-old African American woman who was admitted to the hospital for an exacerbation of congestive heart failure (CHF). She weighed 98 kg and was 5’2" tall. Her medical history included chronic obstructive pulmonary disease (COPD), sleep apnea, 60 packyears of cigarette smoking, and bilateral varicose veins in her lower extremities. Vital signs included a respiratory rate of 22 breaths/minute, systolic and diastolic blood pressure of 110/66 mm Hg, heart rate of 78 beats/minute, temperature of 102.1°F, and oxygen saturation of 89%. A chest x-ray showed pulmonary edema with bilateral pleural effusions and right lower lobe infiltrates. Laboratory values were within normal limits. CM had no known drug allergies. CM is an acutely ill medical patient who is at moderate or high risk of VTE because of her advanced age, CHF, COPD, varicose veins, obesity, and smoking. According to ACCP guidelines, she should receive LDUH or LMWH for VTE prophylaxis.5 Fondaparinux is a possible alternative. CM might receive one of several regimens that have been used in clinical studies: UFH 5000 units s.c. two or three times daily, enoxaparin 40 mg s.c. once daily, dalteparin 5000 units s.c. once daily, or fondaparinux 2.5 mg s.c. once daily.5,7,12,15 Because CM’s risk factors for VTE are likely to persist and keep her at moderate or high risk for VTE, prophylaxis for 14 days or perhaps even longer, if her risk factors continue, is warranted. Treatment If VTE develops, treatment should be initiated as soon as possible once the diagnosis is confirmed by objective tests.27 According to ACCP, initial treatment in the acute phase involves the use of anticoagulation therapy to prevent thrombus extension and early and late recurrence of DVT and PE.27 Long-term treatment in the chronic phase involves continuation of anticoagulation because the incidence of symptomatic thrombus extension or VTE recurrence in patients with DVT is 15–50% without such treatment.27 Anticoagulant therapy options for VTE treatment include intravenous (i.v.) or s.c. UFH, s.c. LMWH (dalteparin, enoxaparin, and tinzaparin, although dalteparin is not approved by FDA for the treatment of VTE yet is approved in Canada and other countries for this indication), the s.c. pentasaccharide factor Xa inhibitor fondaparinux, and the oral vitamin K antagonist warfarin.27 Parenteral therapy provides more rapid anticoagulation than oral therapy, so at least five days of i.v. or s.c. UFH, s.c. LMWH (Table 44), or s.c. fondaparinux should be administered in the acute phase of VTE.27 Oral warfarin should be initiated at the same time as UFH, LMWH, or fondaparinux, and it should be continued during the chronic phase, with a target international normalized ratio (INR) of 2.0–3.0.27 Once the INR is stable and the INR exceeds 2.0, UFH, LMWH, or fondaparinux therapy may be discontinued. Table 4. LMWH Dosing Regimens for the Treatment of VTE27,–30,a aLMWH = low-molecular-weight heparin, s.c. = subcutaneously, VTE = venous thromboembolism. • Dalteparin sodium 200 units/kg s.c. once daily or 100 units/kg s.c. every 12 hours • Enoxaparin sodium 1 mg/kg s.c. every 12 hours or 1.5 mg/kg s.c. once daily • Tinzaparin sodium 175 units/kg s.c. once daily aLMWH = low-molecular-weight heparin, s.c. = subcutaneously, VTE = venous thromboembolism. • Dalteparin sodium 200 units/kg s.c. once daily or 100 units/kg s.c. every 12 hours • Enoxaparin sodium 1 mg/kg s.c. every 12 hours or 1.5 mg/kg s.c. once daily • Tinzaparin sodium 175 units/kg s.c. once daily Open in new tab Table 4. LMWH Dosing Regimens for the Treatment of VTE27,–30,a aLMWH = low-molecular-weight heparin, s.c. = subcutaneously, VTE = venous thromboembolism. • Dalteparin sodium 200 units/kg s.c. once daily or 100 units/kg s.c. every 12 hours • Enoxaparin sodium 1 mg/kg s.c. every 12 hours or 1.5 mg/kg s.c. once daily • Tinzaparin sodium 175 units/kg s.c. once daily aLMWH = low-molecular-weight heparin, s.c. = subcutaneously, VTE = venous thromboembolism. • Dalteparin sodium 200 units/kg s.c. once daily or 100 units/kg s.c. every 12 hours • Enoxaparin sodium 1 mg/kg s.c. every 12 hours or 1.5 mg/kg s.c. once daily • Tinzaparin sodium 175 units/kg s.c. once daily Open in new tab According to ACCP, the use of a vena cava filter (i.e., vena cava interruption) should be reserved for patients with contraindications to or complications from anticoagulant therapy and patients with recurrent VTE despite the use of anticoagulation. 27 Thrombolytic therapy and thrombectomy (i.e., surgical removal of a thrombus) are reserved for patients at risk for venous limb gangrene or patients who are hemodynamically unstable. A meta-analysis of 13 randomized controlled trials comparing UFH with LMWH for VTE treatment found no significant differences in the incidence of recurrent VTE, recurrent PE, major bleeding, minor bleeding, or thrombocytopenia.31 The mortality risk was 24% lower with LMWH than with UFH, a difference that is significant. The use of LMWH for initial VTE treatment is recommended over UFH by ACCP, preferably on an outpatient basis or as an inpatient if necessary.27 These recommendations are based on studies demonstrating that LMWH therapy at home is as safe and effective as and associated with shorter hospital stays, lower costs, and better quality of life than UFH therapy in the hospital. Two large, three-month, non-inferiority studies compared the efficacy and safety of fondaparinux (5.0 mg for patients weighing <50 kg, 7.5 mg for patients weighing 50–100 kg, and 10.0 mg for patients weighing >100 kg) with LMWH or UFH for the treatment of DVT32 or PE.33 In both studies, treatment with fondaparinux and LMWH or UFH was continued for at least five days and until warfarin induced an INR greater than 2.0. In 2205 patients with acute symptomatic DVT, s.c. fondaparinux once daily was at least as effective and safe as enoxaparin 1 mg/kg s.c. twice daily for preventing symptomatic recurrent VTE complications.32 In 2213 patients with acute symptomatic PE, s.c. fondaparinux once daily was at least as safe and effective as a continuous i.v. infusion of UFH for preventing symptomatic, recurrent PE (nonfatal or fatal) and new or recurrent DVT.33 In both studies, the rates of major bleeding and death were similar in the two treatment groups.32,33 The efficacy of long-term treatment using the LMWH dalteparin for preventing VTE recurrence was compared with warfarin in a randomized controlled study of 672 patients with cancer and acute, symptomatic VTE.28 Patients were randomly assigned to receive dalteparin alone for six months (200 units/kg s.c. once daily for one month followed by approximately 150 units/kg s.c. once daily for five months) or dalteparin 200 units/kg s.c once daily for five to seven days plus warfarin (with a target INR 2.5) for six months (the warfarin group). The incidence of recurrent VTE over the six-month study period was 8% in the dalteparin group and 16% in the warfarin group, representing a 52% reduction in risk of VTE recurrence with long-term dalteparin therapy. There was no significant difference between the two treatment groups in the incidence of major bleeding (6% in the dalteparin group and 4% in the warfarin group). These findings and those from other studies led ACCP to recommend long-term LMWH therapy for at least the first three to six months in patients with cancer and VTE.27,30 Anticoagulant therapy should be continued indefinitely in these patients or until the cancer resolves.27 The duration of long-term anticoagulation (i.e., warfarin) treatment for VTE recommended by ACCP depends on the presence of risk factors. In patients with a first DVT or PE episode caused by a transient (i.e., reversible) risk factor, therapy should be continued for at least three months.27 At least 6–12 months of warfarin therapy are recommended for patients with a first DVT episode that is idiopathic. Warfarin treatment for an indefinite period is recommended for patients with a first episode of PE that is idiopathic and patients with two or more episodes of DVT or PE. Patients with a first episode of DVT or PE and documented deficiency of antithrombin, protein C, or protein S; a mutation in the factor V Leiden or prothrombin P20210 gene; homocysteinemia; or elevated factor VIII levels should be treated with warfarin for 6–12 months or possibly indefinitely because these factors increase the risk of VTE recurrence.27 Patients with a first episode of DVT or PE and documented antiphospholipid antibodies (a risk factor for VTE recurrence) or two or more thrombophilic conditions (e.g., a combination of factor V Leiden and prothrombin P20210 gene mutations) should be treated for 12 months or possibly indefinitely. Challenges in dosing LMWH Determining the appropriate dosage of LMWH to use in certain high-risk patient populations can present a challenge. These patient populations include patients with renal impairment, patients with obesity, and the elderly, who often have age-related renal impairment. All LMWH products are eliminated by the kidneys, but the extent to which each specific drug accumulates in patients with renal impairment varies.34,–36 The clinical effects of LMWH are mediated in part by inhibition of coagulation factor Xa. Anti-factor Xa activity can be measured and used in pharmacokinetic analyses of LMWH products. For enoxaparin, there is a linear relationship between anti-factor Xa plasma clearance and creatinine clearance. The area under the anti-factor Xa activity-time curve (AUC) is a measure of drug exposure (i.e., accumulation in patients with renal impairment). In patients with severe renal impairment (creatinine clearance <30 mL/min), the AUC at steady state is increased by 65% on average after multiple single daily 40-mg s.c. enoxaparin doses compared with patients with normal renal function.35 Anti-factor Xa clearance of dalteparin was significantly reduced in eight patients with moderate or severe renal insufficiency (13–57 mL/min) after single 50-units/kg i.v. injections compared with eight healthy individuals.37 Reductions in tinzaparin clearance based on anti-factor Xa activity by 24% have been observed after single 75-units/kg i.v. doses in patients with severe renal impairment compared with healthy volunteers. 36 The degree of accumulation appears lower with dalteparin and tinzaparin from that reported with enoxaparin. Specific instructions for dosage adjustments in patients with renal impairment (Table 55) are available only for enoxaparin in patients with severe renal impairment; no guidance is provided for the other two LMWH products or enoxaparin dosing in patients with moderate renal impairment (creatinine clearance 30–50 mL/min) or end-stage renal disease.35 The product labeling for dalteparin and tinzaparin states that the drugs should be dosed with caution in patients with severe renal impairment or insufficiency34,36; however, the degree of accumulation is expected to be lower than with enoxaparin or fondaparinux. Fondaparinux is contraindicated in patients with severe renal impairment.13 Table 5. Recommended Dosage Adjustments for Enoxaparin in Patients with Severe Renal Impairment 35,a,b,c Indication Dosage in Patients with Normal Renal Function Dosage in Patients with Severe Renal Impairmentb aDVT = deep vein thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism. bCreatinine clearance <30 mL/min. (Data in patients with CrCI <20 ml/min is very limited; consider use of UFH in these patients.) cAll doses are administered subcutaneously. Prophylaxis in abdominal or hip replacement surgery 40 mg once daily 30 mg once daily Prophylaxis in hip or knee replacement surgery 30 mg every 12 hr 30 mg once daily Prophylaxis in medical patients during acute illness 40 mg once daily 30 mg once daily Inpatient treatment of acute DVT with or without PE, when administrered in conjunction with warfarin sodium 1.5 mg/kg once daily or 1 mg/kg every 12 hr 1 mg/kg once daily Outpatient treatment of acute DVT without PE when adminstered in conjunction with warfarin sodium 1 mg/kg every 12 hr 1 mg/kg once daily Indication Dosage in Patients with Normal Renal Function Dosage in Patients with Severe Renal Impairmentb aDVT = deep vein thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism. bCreatinine clearance <30 mL/min. (Data in patients with CrCI <20 ml/min is very limited; consider use of UFH in these patients.) cAll doses are administered subcutaneously. Prophylaxis in abdominal or hip replacement surgery 40 mg once daily 30 mg once daily Prophylaxis in hip or knee replacement surgery 30 mg every 12 hr 30 mg once daily Prophylaxis in medical patients during acute illness 40 mg once daily 30 mg once daily Inpatient treatment of acute DVT with or without PE, when administrered in conjunction with warfarin sodium 1.5 mg/kg once daily or 1 mg/kg every 12 hr 1 mg/kg once daily Outpatient treatment of acute DVT without PE when adminstered in conjunction with warfarin sodium 1 mg/kg every 12 hr 1 mg/kg once daily Open in new tab Table 5. Recommended Dosage Adjustments for Enoxaparin in Patients with Severe Renal Impairment 35,a,b,c Indication Dosage in Patients with Normal Renal Function Dosage in Patients with Severe Renal Impairmentb aDVT = deep vein thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism. bCreatinine clearance <30 mL/min. (Data in patients with CrCI <20 ml/min is very limited; consider use of UFH in these patients.) cAll doses are administered subcutaneously. Prophylaxis in abdominal or hip replacement surgery 40 mg once daily 30 mg once daily Prophylaxis in hip or knee replacement surgery 30 mg every 12 hr 30 mg once daily Prophylaxis in medical patients during acute illness 40 mg once daily 30 mg once daily Inpatient treatment of acute DVT with or without PE, when administrered in conjunction with warfarin sodium 1.5 mg/kg once daily or 1 mg/kg every 12 hr 1 mg/kg once daily Outpatient treatment of acute DVT without PE when adminstered in conjunction with warfarin sodium 1 mg/kg every 12 hr 1 mg/kg once daily Indication Dosage in Patients with Normal Renal Function Dosage in Patients with Severe Renal Impairmentb aDVT = deep vein thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism. bCreatinine clearance <30 mL/min. (Data in patients with CrCI <20 ml/min is very limited; consider use of UFH in these patients.) cAll doses are administered subcutaneously. Prophylaxis in abdominal or hip replacement surgery 40 mg once daily 30 mg once daily Prophylaxis in hip or knee replacement surgery 30 mg every 12 hr 30 mg once daily Prophylaxis in medical patients during acute illness 40 mg once daily 30 mg once daily Inpatient treatment of acute DVT with or without PE, when administrered in conjunction with warfarin sodium 1.5 mg/kg once daily or 1 mg/kg every 12 hr 1 mg/kg once daily Outpatient treatment of acute DVT without PE when adminstered in conjunction with warfarin sodium 1 mg/kg every 12 hr 1 mg/kg once daily Open in new tab In a meta-analysis of 12 studies of LMWH, an increased risk of major bleeding was associated with the use of LMWH in patients with severe renal impairment compared with patients with higher creatinine clearance values.38 In a secondary analysis of four studies of fixed enoxaparin doses, the risk of major bleeding was increased in patients with severe renal impairment compared with patients with better renal function. However, in three studies in which enoxaparin dosing was empirically adjusted on the basis of creatinine clearance or measured anti-factor Xa levels, the risk of major bleeding was not increased by severe renal impairment. These findings suggest a safety advantage to reducing the dosage of enoxaparin for patients with severe renal impairment. No conclusions were drawn about other LMWH products. Fixed doses of LMWH are customarily used for VTE prophylaxis, regardless of body weight or body mass index (BMI), but weight-based dosing of LMWH is customarily used for VTE treatment. Weight-based dosing is part of the product labeling only for enoxaparin and tinzaparin when these drugs are used for VTE treatment. Fixed enoxaparin doses are used for VTE prophylaxis, and tinzaparin is approved by FDA for VTE treatment only, not for prophylaxis.35,36 Dalteparin is not approved by FDA for VTE treatment, although weight-based doses have been evaluated for this indication.28 Fixed dalteparin doses are used for VTE prophylaxis.34 The impact of body weight on the anti-factor Xa activity of single 40-mg s.c. enoxaparin doses was measured at hourly intervals over a 10-hour period in 17 patients requiring VTE prophylaxis and two healthy volunteers.39 As body weight increased, the AUC for anti-factor Xa activity over time decreased. In a study of the use of enoxaparin (40 mg s.c. once daily) for VTE prophylaxis in 807 obese (defined as a BMI >32 kg/m2) and non-obese male and female orthopedic patients with total knee replacement, total hip replacement, or trauma, the incidence of VTE was significantly higher (32%) in obese patients than non-obese patients (17%).40 These findings suggest the need for larger enoxaparin doses in obese patients who require VTE prophylaxis than the fixed doses recommended for all patients. A subgroup analysis was conducted of 1118 obese patients (defined as a BMI ≥30 kg/m2 for men and ≥28.6 kg/m2 for women) and 2588 non-obese participants in PREVENT, the randomized, doubleblind, placebo-controlled study demonstrating the efficacy of fixed doses of dalteparin 5000 units/day s.c. for 14 days for preventing VTE in acutely ill medical patients.15,41 The incidence of VTE was the same (2.8%) in obese patients and non-obese patients. However, the effect of dalteparin was attenuated by BMI values of 40 kg/m2 or higher. Consideration of a 25% increase in the LMWH dosage for VTE prophylaxis in very obese patients was suggested by ACCP, unless clear data are unavailable to guide dosing.42 Part of the difficulty in determining which body weights warrant adjustment in LMWH dosages in the United States may be attributed to the fact that many of the early studies demonstrating the efficacy of these drugs for VTE prophylaxis were conducted in Europe where the average body weight is lower than it is in the United States. In the past, some practitioners chose to limit the dosage of LMWH used for VTE treatment (i.e., capped the doses used) because of concerns that weight-based dosing might result in increased exposure and adverse effects in obese patients, although dose caps were controversial.43,44 In a randomized, open-label, two-way crossover study, enoxaparin 1.5 mg/kg s.c. once daily for four days or a single 1.5-mg/kg i.v. infusion over six hours was administered to 24 obese volunteers and 24 non-obese volunteers who were matched for age, sex, and height.45 The AUC and maximum anti-factor Xa activity were similar in the two treatment groups, although the time to maximum anti-factor Xa activity was one hour longer in the obese volunteers compared with the non-obese volunteers. Body weight and BMI had no effect on tinzaparin pharmacokinetics in a study of single 175- and 75-units/kg s.c. doses in 37 healthy heavy-weight subjects (101–165 kg and 26–61 kg/m2).46 Comparison of the data with historical control data from normal-weight subjects (<100 kg) suggested that weight-adjusted tinzaparin dosing produces a predictable pharmacokinetic response regardless of body weight or BMI. These and other pharmacokinetic studies support the use of the weight-based dosing recommendations for VTE treatment in the product labeling for enoxaparin and tinzaparin (dalteparin is not approved by FDA for VTE treatment; however, pharmacokinetic data with this agent also support dosing based on actual body weight). Capping the dosage in obese patients does not appear warranted. Case study 2 SD is a 38-year-old Caucasian woman who comes to the emergency department complaining of chest pain, shortness of breath, and lightheadedness that developed the preceding evening and worsened over the past several hours. These symptoms were preceded by left calf pain that began about three days ago. SD weighs 120 kg and is 5’5" tall. Her past medical history includes type 2 diabetes mellitus and hypertension. Her medications include lisinopril 20 mg orally once daily, rosiglitazone 4 mg orally twice daily, enteric-coated aspirin 325 mg orally once daily, and an oral contraceptive containing ethinyl estradiol 50 μg plus ethynodiol diacetate 1 mg once daily for 21 days of every 28-day period. SD’s mother died of a stroke, and her paternal grandmother had a history of blood clots in her legs. SD’s vital signs include a temperature of 99.9 °F, systolic and diastolic blood pressure of 125/77 mmHg, heart rate of 102 beats/minute, and respiratory rate of 24 breaths/minute. Laboratory values were within normal limits. An electrocardiogram showed normal sinus rhythm. The chest X-ray showed a slightly enlarged heart, and results of a ventilation-perfusion scan suggested a high probability of PE. The treatment options for PE in SD who is obese and has normal renal function are weight-based and include enoxaparin 120 mg s.c. every 12 hours, dalteparin 24,000 units s.c. once daily, tinzaparin 21,000 units s.c. once daily, and fondaparinux 10 mg s.c. once daily.27,–29,33 Oral warfarin should be initiated simultaneously. Once the INR is stable and it exceeds 2.0, the LMWH or fondaparinux therapy may be discontinued. Conclusion Clinicians need to assess the risk for VTE in medical patients as well as surgical patients, and apply evidence-based guidelines for the prevention and treatment of VTE to clinical practice. The findings from recent clinical research about the optimal strategies for preventing and treating VTE should be taken into consideration. These efforts will optimize clinical outcomes. Footnotes Based on the proceedings of a symposium held December 3, 2006, during the ASHP Midyear Clinical Meeting, Anaheim, CA, and supported by an educational grant from sanofi-aventis US. Dr. Nutescu received an honorarium for her participation in the symposium and for the preparation of this article. Dr. Nutescu reports that she has received research support from GlaxoSmithKline, serves on the speakers bureau for sanofi-aventis, and serves on the speakers bureau for Eisai Pharmaceuticals. References 1 Lethen H, Flachskampf FA, Schneider R et al. Frequency of deep vein thrombosis in patients with patent foramen ovale and ischemic stroke or transient ischemic attack. Am J Cardiol . 1997 ; 80 : 1066 –9. Crossref Search ADS PubMed 2 Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest . 1995 ; 108 : 978 –81. Crossref Search ADS PubMed 3 Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? J R Soc Med . 1989 ; 82 : 203 –5. Crossref Search ADS PubMed 4 Prandoni P, Villalta S, Bagatella P et al. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica . 1997 ; 82 : 423 –8. PubMed 5 Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest . 2004 ; 126 (3 suppl): 338S –400S. Crossref Search ADS PubMed 6 Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA . 1995 ; 274 : 335 . Crossref Search ADS PubMed 7 Samama MM, Cohen AT, Darmon JY et al. comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. 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Groce, James, B.

doi: 10.2146/ajhp070107pmid: N/A

Introduction The Institute of Medicine defines practice guidelines as systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific circumstances.1 Not to mention guidelines improve the consistency and efficiency of healthcare and close the gap between actual clinical practice and the practices that are supported by scientific evidence.2 Not to mention guidelines are of greatest benefit when practitioners are unclear about what practices are appropriate and scientific evidence is available to facilitate decision making. Guideline development requires a wide variety of skills and expertise.3 Literature searching and retrieval, epidemiology, biostatistics, health services research, clinical experience, group collaboration, writing, and editing are among these skills and expertise. Guidelines have limitations.2 In some cases, recommendations in guidelines are deemed inappropriate (or inappropriate for an individual) because of inadequate, misleading, or misinterpreted scientific evidence. The composition, clinical experience, and biases of the guideline-development group can influence recommendations.2 Guidelines can quickly become out of date when the pace of clinical research is rapid. Clinicians may be concerned about their liability for failing to adhere to guidelines.2,4 This scenario has not yet become a reality and remains theoretical, but it is a commonly voiced concern. Guidelines ideally are evidence-based. However, they sometimes are eminence-based or based on the judgment of an individual. Recommendations in guidelines must be acceptable and accepted by clinicians and patients. Guidelines should provide extensive, critical, and well-balanced information on the benefits and limitations of various diagnostic and therapeutic interventions that physicians and patients can use to make decisions in individual cases. Clinical judgment is required when applying guidelines to a specific patient situation, even when recommendations are supported by strong evidence. Socioeconomic factors should be considered in applying recommendations. Guidelines should elicit changes in professional behavior.5 The development of evidence-based guidelines does not ensure their use in practice, and publication of guidelines in professional journals, sending targeted mailings to healthcare professionals, and other methods for disseminating guidelines seldom result in changes in professional behavior.5 Lack of familiarity with guidelines, lack of awareness of the burden of disease, the perceived risk of adverse effects, local hospital protocols that are inconsistent with guidelines, and medico-legal and economic issues are among the factors that influence physician behavior and could present barriers to the implementation of guidelines. 4 Educational programs may be required to overcome these barriers and influence professional behavior.5 The strategy for implementing guidelines in an institution depends on the available resources and the perceived barriers to providing care associated with guideline use. Evidence-based guidelines evolved from clinical studies (Figure 11). Continued evolution of evidence-based guidelines led to the development of consensus standards and then hospital and physician quality measures, which have been used in many healthcare systems. Practice and outcomes reporting was an outgrowth of these measures, and this reporting ultimately led to pay for performance (i.e., financial incentives and rewards for hospitals and physicians for meeting quality objectives). Figure 1. Open in new tabDownload slide Evolution of Evidence-Based Guidelines Figure 1. Open in new tabDownload slide Evolution of Evidence-Based Guidelines Venous thromboembolism (VTE) is a major public health problem in the United States, with more than 200,000 new cases each year.6 About one third of patients in whom VTE is symptomatic also experience pulmonary embolism (PE), and the other two thirds of patients experience deep vein thrombosis alone. Thirty percent of patients with VTE die within 30 days, 20% suffer sudden death from PE, and 30% develop recurrent VTE within 10 years.6 More than 250,000 Americans are hospitalized with VTE each year. The economic burden of VTE amounts to nearly $500 million annually in the United States.7 Acute coronary syndrome (ACS)— ST-segment elevation myocardial infarction (MI), non-ST-segment elevation MI, or unstable angina—is a common and costly condition in the United States. In 2003, 879,000 Americans were discharged from U.S. hospitals with ACS, including 767,000 with MI and 112,000 with unstable angina.6 A retrospective analysis of the total costs during the first year after diagnosis of ACS in 13,731 managed care patients quantified the costs at $2312 per patient-month of followup, with 72% of the costs for hospitalizations and 7% for pharmacy costs.8 Evidence-based guidelines have been developed for the prevention and treatment of VTE and the management of ACS. The first article in this supplement discusses the assessment of VTE risk, the recommendations in current evidence-based guidelines for VTE prophylaxis and treatment, and a new alternative for VTE prophylaxis and treatment that is not addressed in current American College of Chest Physicians guidelines. The second article provides insights from a national quality improvement initiative designed to assess and improve adherence to guidelines for managing non-ST-segment elevation ACS and the implications of several important studies that are not reflected in current guidelines for managing ST-segment elevation MI. Finally, the translation of evidence-based guidelines into performance measures used to evaluate the quality of care provided to patients with VTE or ACS is addressed in the third article. Footnotes Based on the proceedings of a symposium held December 3, 2006, during the ASHP Midyear Clinical Meeting, Anaheim, CA, and supported by an educational grant from sanofi-aventis US. Dr. Groce received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Groce reports that he serves on the speakers bureau and as a consultant for Bristol-Myers Squibb, as a consultant for Eisai Pharmaceuticals, on the speakers bureau and as a consultant for sanofi-aventis, and as a consultant for The Medicines Company. References 1 Field MJ, Lohr KN, eds. Clinical practice guidelines: directions for a new program. Washington, DC: The National Academies Press; 1990 . 2 Woolf SH, Grol R, Hutchinson A et al. Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ . 1999 ; 318 : 527 –30. Crossref Search ADS PubMed 3 Shekelle PG, Woolf SH, Eccles M et al. Clinical guidelines: developing guidelines. BMJ . 1999 ; 318 : 593 –6. Crossref Search ADS PubMed 4 Hurwitz B. Legal and political considerations of clinical practice guidelines. BMJ . 1999 ; 318 : 661 –4. Crossref Search ADS PubMed 5 Feder G, Eccles M, Grol R et al. Clinical guidelines: using clinical guidelines. BMJ . 1999 ; 318 : 728 –30. Crossref Search ADS PubMed 6 Thom T, Haase N, Rosamond W et al. Heart Disease and Stroke Statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation . 2006 ; 113 : 85 –151. 7 Hawkins D. Pharmacoeconomics of thrombosis management. Pharmacotherapy . 2004 ; 24 (7 pt 2): 95S –99S. Crossref Search ADS PubMed 8 Etemad LR, McCollam PL. Total first-year costs of acute coronary syndrome in a managed care setting. J Manag Care Pharm . 2005 ; 11 : 300 –6. PubMed Copyright © 2007. American Society of Health-System Pharmacists, Inc. All rights reserved.