Contemporary Hospitalists' Guide to Anticoagulation

Second Edition

Contemporary Hospitalists’ Guide to

Anticoagulation

™

Steven B. Deitelzweig, MD, MMM System Chairman of Hospital Medicine Vice President, Medical Affairs Member, Section of Vascular Medicine, Ochsner Health System Clinical Associate Professor of Medicine, Tulane University New Orleans, LA

Alpesh N. Amin, MD, MBA Professor and Chair, Department of Medicine Executive Director, Hospitalist Program University of California, Irvine

Contemporary Hospitalists’ Guide to

Anticoagulation

™

Steven B. Deitelzweig, MD, MMM System Chairman of Hospital Medicine Vice President, Medical Affairs Member, Section of Vascular Medicine Ochsner Health System Clinical Associate Professor of Medicine Tulane University New Orleans, Louisiana

Alpesh N. Amin, MD, MBA Professor and Chair, Department of Medicine Executive Director, Hospitalist Program University of California, Irvine Second Edition Published by Handbooks in Health Care Co., Newtown, Pennsylvania, USA

This book is not intended to replace or to be used as a substitute for the complete prescribing information prepared by each manufacturer for each drug. Because of possible variations in drug indications, in dosage information, in newly described toxicities, in drug/drug interactions, and in other items of importance, reference to such complete prescribing information is definitely recommended before any of the drugs discussed are used or prescribed.

International Standard Book Number: 978-1-935103-77-6 Library of Congress Catalog Card Number: 2010931905 Contemporary Hospitalists’ Guide to Anticoagulation™. Copyright© 2011, 2009 by Handbooks in Health Care Co., a Division of AMM Co., Inc. All rights reserved. Printed in Canada. No part of this book may be used or reproduced in any manner whatsoever, including but not limited to electronic or mechanical means such as photocopying, recording, or using any information storage or retrieval system, without written permission, except in the case of brief quotations embodied in critical articles and reviews. For information, write Handbooks in Health Care, 6 Penns Trail, Suite 215, Newtown, Pennsylvania 18940, (215) 860-9600. Web site: www.HHCbooks.com 2

Authors and Contributors

This book has been prepared and is presented as a service to the medical community. The information provided reflects the knowledge, experience, and personal opinions of the lead authors, Steven B. Deitelzweig, MD, MMM, System Chairman of Hospital Medicine, Vice President of Medical Affairs, Member, Section of Vascular Medicine, Ochsner Health System, and Clinical Associate Professor of Medicine, Tulane University, New Orleans, Louisiana, and Alpesh N. Amin, MD, MBA, Professor and Chair, Department of Medicine, and Executive Director, Hospitalist Program, University of California, Irvine. The information provided also reflects the knowledge, experience, and personal opinions of the contributing authors, Jason C. Robin, MD, Fellow, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL; Andrew F. Shorr, MD, MPH, Associate Director, Pulmonary and Critical Care Medicine, Washington Hospital Center, Associate Professor of Medicine, Georgetown University, Washington DC; Dan J. Fintel, MD, Professor of Medicine, Northwestern University Feinberg School of Medicine, Director, Coronary Care Unit, Bluhm Cardiovascular Institute; Alok A. Khorana, MD, Associate Professor and Vice-Chief, Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY; Gregory C. Connolly, MD, Fellow, Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester; Charles E. “Kurt” Mahan, PharmD, RPh, Director of Hospital Pharmacy, Cardinal Health Pharmacy Services, Lovelace Medical Center, Clinical Assistant Professor of Pharmacy, University of New Mexico Health Sciences Center; Alex C. Spyropoulos, MD, Associate Professor 3

of Medicine, McMaster University, Hamilton, Ontario, Canada; Geno J. Merli, MD, Professor of Medicine, Director, Jefferson Center for Vascular Diseases, Jefferson Medical College, and Chief Medical Officer, Thomas Jefferson University Hospital, Philadelphia, PA; Sylvia C. W. McKean, MD, Senior Hospitalist, Brigham and Women’s Hospital, and Associate Professor of Medicine, Harvard Medical School, Boston, MA; Adam C. Schaffer, MD, Hospitalist, Brigham and Women’s Hospital, Instructor in Medicine, Harvard Medical School, Boston; Franklin Michota Jr, MD, Director of Academic Affairs, Department of Hospital Medicine, Cleveland Clinic, Cleveland, OH; Surma D. Jain, MD, Assistant Clinical Professor of Medicine, Louisiana State University Health Sciences Center, Ochsner Health System, New Orleans, LA; David E. Taylor, MD, Associate Clinical Professor of Medicine, Louisiana State University Health Sciences Center, Chairman, Pulmonary Medicine, Ochsner Health System, New Orleans; Debbie Simonson, PharmD, Director of Pharmacy, Ochsner Health System, New Orleans; Parmis Khatibi, PharmD, Anticoagulation and Antithrombotic Specialist, University of California, Irvine Medical Center; Thomas W. Young, MD, Pediatric Cardiology, Ochsner Health System, New Orleans; and Chee M. Chan, MD, Director, Medical Intermediate Care Unit, Department of Pulmonary and Critical Care Medicine, Washington Hospital Center, Washington, DC.

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Table of Contents Chapter 1 The Importance of Antithrombosis in Hospital Medicine ........7 Steven B. Deitelzweig, Alpesh N. Amin

Chapter 2 Current Recommendations for Prevention of Deep Venous Thrombosis .....................................................12 Suma D. Jain, David E. Taylor

Chapter 3 Acute and Chronic Deep Vein Thrombosis: Epidemiology, Diagnosis, Treatment, and Prognosis .............28 Steven B. Deitelzweig, Alpesh N. Amin

Chapter 4 Upper Extremity Thrombosis, Superficial Thrombophlebitis, and Thrombosis at Rare Sites ..................46 Adam C. Schaffer, Sylvia C.W. McKean

Chapter 5 Pulmonary Embolism: Epidemiology, Diagnosis, and Treatment ................................92 Chee M. Chan, Andrew F. Shorr

Chapter 6 Perioperative Concerns: Orthopedics, General Surgery, Surgical Oncology, and Obstetrics ...........140 Franklin Michota Jr 5

Chapter 7 Cardiovascular and Antithrombotic Management: Acute Coronary Syndromes, Arrhythmias, and Cerebrovascular Diseases................................................165 Jason C. Robin, Dan J. Fintel

Chapter 8 Heparin-Induced Thrombocytopenia .....................................210 Geno J. Merli , Alpesh N. Amin, Steven B. Deitelzweig

Chapter 9 Anticoagulants in Pediatrics ..................................................237 Thomas W. Young

Chapter 10 Anticoagulation and National Patient Safety Goals............260 Debbie Simonson, Parmis Khatibi, Steven B. Deitelzweig, Alpesh N. Amin

Chapter 11 Anticoagulation in Cancer Patients ........................................290 Gregory C. Connolly, Alok A. Khorana

Chapter 12 Brave New World: Antithrombotics on the Horizon ...........314 Charles E. Mahan, Alex C. Spyropoulos, Erica A. Baca, Alpesh N. Amin, Steven B. Deitelzweig

Chapter 13 Frequently Asked Questions in Antithrombotic Management..............................................367 Alpesh N. Amin, Steven B. Deitelzweig Index .........................................................................................379 6

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Chapter 1

The Importance of Antithrombosis in Hospital Medicine Steven B. Deitelzweig, Alpesh N. Amin

V

enous thromboembolism (VTE) affects approximately 2 million people in the United States, resulting in more than 600,000 pulmonary embolisms (PEs) per year. The annual death toll from VTE has been estimated to be 300,000 persons per year, with two thirds of VTEs being hospital acquired. The annual cost associated with VTE is estimated to be $15.5 billion per year. Despite knowledge of the risk factors for VTE, it has been shown that appropriate preventive measures in medical and surgical patients are underused. High rates of VTE remain despite evidence from clinical trials showing that VTE can be safely and effectively reduced by VTE prophylaxis in at-risk medical and surgical patients. However, awareness of the importance of preventing VTE is growing in the US.

Importance of Guidelines For acute coronary syndromes (ACS), the most recent non–ST-segment elevation (NSTE) and ST-segment elevation myocardial infarction (STEMI)/ ACS guidelines should be understood and used by hospitalists and others practicing in the hospital setting. The recommendations in the 2007 American College of Cardiology/American 7

Heart Association (ACC/AHA) Guidelines1 for the management of NSTE ACS strongly support the upstream use of clopidogrel (Plavix®). This guidance is clearly durable because it was based less on new data on clopidogrel than on a combination of broad clinical experience; clopidogrel’s ease of administration; the broader use of drug-eluting stents; and clopidogrel’s link to new antithrombotic regimens, such as bivalirudin in the Acute Catherization and Urgent Intervention Triage Strategy (ACUITY) trial. The recommendations in the 2007 ACC/AHA Focused Update to the 2004 Guidelines for the Management of STEMI2 likewise give strong support to the upstream use of clopidogrel, whether the patient is managed with fibrinolysis or primary percutaneous coronary intervention. Familiarity with these newer guidelines may be important when treating patients who present after STEMI to the emergency department with recurrent ischemic symptoms. These guidelines are explored in this text. Many organizations, including the Centers for Medicare and Medicaid Services, the National Quality Forum, The Joint Commission, and the Agency for Healthcare Research and Quality, have developed ‘negative reimbursement’ incentive programs, public reporting initiatives, performance measures, and quality indicators that are designed to help improve anticoagulant care. However, it remains the responsibility of individual hospitals and hospitalists to identify specific areas in which they can improve to achieve the various quality initiative targets (process and outcome measures). An important factor that contributes to the suboptimal use of anticoagulants is poor knowledge of evidence-based guidelines among health-care professionals. Therefore, to meet performance measures, strategies must be developed and implemented to increase awareness and understanding of the guidelines. Multifaceted, integrated initiatives involving risk assessment tools, decision support, electronic alert systems, 8

clinical pathways, and hospitalwide education, with a mechanism for audit and feedback, may help ensure that all health-care professionals comply with anticoagulation policies and initiatives.

Management Options for Prevention and Treatment of Venous Thromboembolic Disease The challenges within hospital medicine involving anticoagulation have enormous implications for hospitalists, with the potential for significant improvement in both morbidity and mortality when pharmaceuticals (antithrombotics and thrombolytics) and devices are appropriately used. Hospitalists are integral in leading efforts to drive appropriate use of antithrombotics that allow for safe and effective delivery and improvement in quality outcomes within their institutions. Options for therapy have never been so varied. This handbook, Contemporary Hospitalists’ Guide to Anticoagulation™, addresses current and evolving management options for prevention and treatment of venous thromboembolic disease, including cancer, thrombosis at rare sites, and perioperative management in both adults and children. A practical handbook that delivers evidence-based approaches to the management of heparin-induced thrombocytopenia (HIT) and ACS by highlighting the important studies and consensus recommendations that are shaping current clinical practice should assist hospitalists. Unfractionated heparins (UFH), low-molecular-weight heparins (LMWH), vitamin K antagonists (warfarin), selective Xa inhibitors (fondaparinux), direct thrombin inhibitors, antiplatelets, fibrinolytics, and several evolving agents will affect the future of both venous thromboembolic and arterial disease management. Current management options for the treatment of both deep vein thrombosis (DVT) and PE, based on key studies and the 8th American College of Chest Physicians (ACCP) consensus recommendations,3 are discussed in depth in 9

1

this book. We know that excellent outcomes and patient satisfaction can be achieved in inpatients and outpatients with the use of LMWHs and other agents for thrombotic conditions. The goals of DVT treatment are not limited to prevention of thrombus propagation, embolization, and recurrence. Today’s management must also consider reestablishment of venous patency and the prevention of the postthrombotic (chronic venous insufficiency) syndrome. It is important to recognize the two phases in the treatment of patients with symptomatic VTE: acute (or initial) treatment and chronic (or secondary) prophylaxis. One of the serious problems often confronted clinically with all forms of heparin is HIT, which occurs at an incidence of 3.5% with UFH and 0.6% with LMWH. Typically, the diagnosis of HIT is suggested by a 50% reduction in the platelet count after at least 5 days of heparin administration when compared with pretreatment platelet counts or an absolute reduction to 100,000/mm3. If this complication occurs or is suspected, a direct thrombin inhibitor such as hirudin (Refludan®) or argatroban (Argatroban® IV) should be administered because of the potential for cross-reactivity with other heparins and LMWHs. For chronic VTE management, individualization remains the rule for both the duration and intensity of oral anticoagulant therapy. The recommendations are based on the risk for recurrent VTE if treatment is discontinued and the risk for bleeding if treatment is continued. Current guidelines and ACCP recommendations should be incorporated into practice, but how best to do this is an important task for hospitals, and hospitalists are often requested to champion these efforts. Newer anticoagulants target individual components of the coagulation cascade and include direct and indirect factor Xa inhibitors, heparinoids, oral and parenteral direct thrombin inhibitors, tissue factor pathway inhibitors, and nematode anticoagulant peptide C2. All of these agents 10

have the potential for replacing traditional agents for VTE management and are undergoing research. Thus, it is essential that clinicians, including hospitalists, emergency physicians, and cardiologists who treat patients with VTE, understand the potential significant sequelae in managing patients with this condition. The treatment of patients with VTE remains clinically demanding. Patient care may be improved and the rate of rehospitalization reduced with improved outcomes through educational programs for hospitalists who focus on current evidence-based treatment of patients with VTE.

References 1. Anderson JL, Adams AD, Antman EM, et al: ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/ Non–ST-Elevation Myocardial Infarction. Circulation 2007;116: e148-e304. 2. Antman EM, Hand M, Armstrong PW, et al: 2007 ACC/AHA focused update to the 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction. Circulation 2008;117:296-329. 3. Kearon C, Kahn SR, Agnelli G, et al: Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008;133:454S-545S.

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Chapter 2

Current Recommendations for Prevention of Deep Venous Thrombosis Suma D. Jain, David E. Taylor

H

undreds of randomized, controlled studies have demonstrated that prophylaxis against venous thromboembolism (VTE) is efficacious. Despite this evidence and expert recommendations, more than 50% of medical and surgical inpatients do not receive thromboprophylaxis or are treated suboptimally.1 The incidence of deep vein thrombosis (DVT) has been reported to be as high as 48 per 100,000 medical and surgical inpatients. Likewise, the incidence of pulmonary embolism (PE) is reported to be 23 per 100,000 with an in-hospital fatality rate of 12%.2 VTE is considered one of the most preventable causes of comorbidity and mortality in hospitalized patients. As a result, The Joint Commission (formerly the Joint Commission on the Accreditation of Healthcare Organizations [JCAHO]) now expects hospitals to demonstrate compliance with recommendations for DVT prevention. Similarly, beginning in 2009, the Center for Medicare and Medicaid Services will not reimburse hospitals for the added costs of care for patients who develop DVT after orthopedic surgeries. Unfortunately, the symptoms and signs of DVT are typically nonspecific, and thromboembolic disease is often not recognized until more severe complications occur, includ12

ing PE or postphlebitic syndrome. Certain patient populations are at particularly increased risk for DVT, including patients who have experienced prior VTE events, those who have had surgery, those who have cancer, and those who are experiencing prolonged immobility. This chapter provides an overview of the approaches to risk stratification and prevention of DVT and PE in hospitalized nonsurgical patients. Another useful resource to guide clinicians in the management of patients with VTE is the 8th edition of the American College of Chest Physicians EvidenceBased Clinical Practice Guidelines, which was released in June 2008.3

Rationale for Prophylaxis in Hospitalized Patients The risk of VTE is high in many hospitalized patients not receiving prophylaxis. General medical and surgical patients have a DVT prevalence of 10% to 40%. The prevalence in patients with spinal cord injury, patients who have had orthopedic surgery, and trauma patients has been reported to be as high as 80%.2 Although most hospitalized patients have at least one identifiable predisposing factor for DVT, Goldhaber1 reported that 16% of patients with documented DVT had no comorbidities. The most common risks described in that study were hypertension, surgery within the past 3 months, immobility within the past 30 days, cancer, and obesity (Table 2-1). Hospital morbidity associated with DVT includes extended hospitalization, prolonged treatment, and chronic complications such as long-term anticoagulation, postphlebitic syndrome, and risk of repeat VTE in the future. In addition, the mortality risk associated with PE justifies the use of thromboprophylaxis in most hospitalized patients (Table 2-2). Given these risks of VTE in hospitalized patients, many trials have examined the effectiveness of thromboprophylaxis. Based on patient outcomes and cost effectiveness, these studies support routine preven13

2

Table 2-1: Risk Factors for Venous Thromboembolism • Surgery • Trauma (major trauma or lower extremity injury) • Immobility or lower extremity paresis • Cancer (active or occult) • Cancer therapy • Venous compression • Previous VTE • Increasing age • Pregnancy and postpartum period • Use of estrogen-containing oral contraceptives or HRT • Use of SERMs • Use of erythropoiesis-stimulating agents • Acute medical illness • Inflammatory bowel disease • Nephrotic syndrome • Myeloproliferative disorders • Paroxysmal nocturnal hemoglobinuria • Obesity • Central venous catheterization • Inherited or acquired thrombophilia HRT=hormone replacement therapy, SERM=selective estrogen receptor modulator, VTE=venous thromboembolism Adapted from Geerts et al.3

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Table 2-2: Approximate Risks of Deep Vein Thrombosis in Hospitalized Patients Patient Group

DVT Prevalence (%)

Medical patients

10-20

Stroke

20-50

Critical care patients

10-80

General surgery

15-40

Major gynecologic surgery

15-40

Major urologic surgery

15-40

Neurosurgery

15-40

Hip or knee arthroplasty; hip fracture surgery

40-60

Major trauma

40-80

Spinal cord injury

60-80

2

Adapted from Geerts et al.3

tive treatment for hospitalized patients at increased risk for VTE.

Methods of Primary Thromboprophylaxis Pharmacologic Methods (Table 2-3) Low-Dose Unfractionated Heparin Unfractionated heparin (UFH) is an indirect thrombin inhibitor that binds antithrombin, converting it from a slow to a rapid inactivator of thrombin and other coagulation factors, specifically Xa. Although the earliest studies evaluating the efficacy of low-dose UFH (LDUH) for 15

Table 2-3: Pharmacologic Methods of Anticoagulation Anticoagulant • LDUH

Dosage 5000 IU SC b.i.d. 5000 IU SC t.i.d.

• LMWHs – Enoxaparin

40 mg/d SC

– Dalteparin

5000 IU/d SC

– Tinzaparin

75 IU/kg/d or 4500 IU/d SC

• Anti-Factor Xa (Xa inhibitors) – Fondaparinux

2.5 mg/d SC

• Direct Thrombin Inhibitors – Desirudin

15 mg SC b.i.d.

b.i.d.=twice a day, t.i.d.=three times a day, LDUH=low-dose unfractionated heparin, LMWH=low-molecular-weight heparin, SC=subcutaneous

DVT prophylaxis were performed more than 30 years ago, it remains a safe and effective method of VTE prevention.4 Initial regimens of LDUH—generally 5000 U UFH subcutaneously (SC) given two or three times daily—were referred to as “mini-dose” heparin. There is no strong evidence that thrice-daily LDUH is more effective than twice-daily administration. The reduced cost, ease of administration, and low frequency of bleeding complications make LDUH a good choice for thromboprophylaxis in many patients at intermediate risk for VTE. The most 16

serious side effect of heparin is heparin-induced thrombocytopenia (HIT), which is caused by an immune-mediated activation of platelets that results in thrombocytopenia and thrombosis. In most cases, discontinuation of the drug and use of another anticoagulant is sufficient to reverse HIT. Low-Molecular-Weight Heparin Low-molecular-weight heparins (LMWHs) have a mean molecular weight of 4000 to 5000 Daltons compared with 15,000 Daltons for UFH. Similar to UFH, LMW heparins bind and augment the activity of antithrombin, but LMWH preferentially inhibits factors Xa and IIa. Thus, LMWH does not affect traditional measures of coagulation, including prothrombin time, International Normalized Ratio, or activated partial thromboplastin time. Instead, anti-Xa levels can be measured to assess the anticoagulation activity of LMWH. Compared with UFH, LMWH has multiple advantages, including greater SC bioavailability, a longer duration of anticoagulation effect that allows once-daily dosing, and a lower incidence of HIT. Numerous studies have demonstrated LMWH to be equally as efficacious as LDUFH for DVT prophylaxis in hospitalized medical patients. However, in patients with ischemic stroke5 and multiple trauma,6 LMWH has shown superiority to LDUFH in prevention of DVT without resulting in increased hemorrhagic complications. Fondaparinux Fondaparinux (Arixtra®) belongs to a new class of anticoagulants referred to as Xa inhibitors and is the first selective Xa inhibitor to be approved by the Food and Drug Administration (FDA) for the prevention and treatment of VTE. Fondaparinux selectively binds with specific affinity for antithrombin to produce more anti-Xa activity and a longer half-life than LMWH. In contrast, heparins act on 17

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antithrombin but also have activity against factors IIa, Xa, IXa, XIa, and XIIa. Four multicenter, randomized, controlled trials evaluated the use of fondaparinux versus LMWH (enoxaparin, Lovenox®) in preventing DVT after major orthopedic procedures (hip fracture, hip replacement, knee surgery). A meta-analysis of these trials showed a reduction in the VTE incidence from 13.7% in the enoxaparin group to 6.8% in the fondaparinux group.7 The PEGASUS (Pentasaccharide in General Surgery Study) trial evaluated the use of fondaparinux versus LMWH (dalteparin, Fragmin®) in patients undergoing abdominal surgery.8 The two preventive regimens were found to be equally efficacious and safe. Fondaparinux is FDA approved for VTE prophylaxis after hip fracture surgery, total hip replacement, total knee replacement, and major abdominal surgery. For VTE prevention, fondaparinux may be administered once daily at a fixed dose of 2.5 mg SC but is contraindicated in patients with renal insufficiency (creatinine clearance <30 mL/min). Fondaparinux has a 1A recommendation for the prevention of VTE in at-risk medical patients based on the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,3 even though it is not FDA approved for this use. Warfarin Oral anticoagulation with warfarin (Coumadin®) has been used for VTE prophylaxis in high-risk postsurgical patients. However, because of the prolonged time to attain its anticoagulation effect and studies showing lower efficacy in orthopedic patients compared with use of LMWH, warfarin for VTE prevention is less common. Two studies9 comparing warfarin to LMWH (dalteparin) in patients undergoing hip arthroplasty showed dalteparin to be statistically more effective in reducing the risk of DVT than warfarin. 18

Direct Thrombin Inhibitors Desirudin (Iprivask®) is indicated in the United States for prevention of DVT that may lead to PE in patients undergoing elective total hip replacement surgery. Desirudin is a hirudin analogue that uses recombinant DNA technology. Desirudin is a specific, potent inhibitor of human α-thrombin; it exerts minimal effect on other coagulation factors and digestive enzymes, and binds tightly to thrombin in a stable 1:1 manner. The resulting thrombin-desirudin complex inhibits both fluid phase and clot-bound thrombin. Desirudin also prevents fibrinogen clotting, and inhibits accelerated prothrombin generation, the activation of coagulation factors V, VIII, and XIII, and thrombin-induced platelet activation. Unlike heparin-based anticoagulation, desirudin is: (1) independent of plasma cofactors and is not inactivated by antiheparin proteins (such as platelet factor 4 [PF4]), and (2) not dependent on antithrombin to exert its activity. Thrombin inhibition with desirudin results in dose-dependent aPTT prolongation.10 Desirudin is FDA approved for prophylactic therapy in total hip replacement patients. In this setting, two large, multicenter, randomized clinical trials found desirudin to be significantly more effective at reducing DVT incidence and overall TE events (a composite of DVT, PE, unexplained death, or death related to thromboembolism) than either UFH or LMWH (enoxaparin).10-12 Mechanical Methods Mechanical methods of thromboprophylaxis include graduated compression stockings (GCS), intermittent pneumatic compression (IPC), and a venous foot pump (VFP). The mechanism of action for these modalities is to prevent venous stasis; IPC also stimulates endogenous fibrinolysis.13 These methods have the advantage of not increasing the risk of bleeding in hospitalized patients. In addition, they appear to be efficacious in preventing VTE in certain low-risk populations for whom bleeding risk is 19

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Table 2-4: Medical Methods for Preventing Deep Vein Thrombosis Venous Thromboembolism Risk Factors in Medical Patients Congestive heart failure Severe respiratory disease Immobility (>50% of the time?) Active cancer Prior VTE Sepsis Acute neurologic disease (including stroke) Inflammatory bowel disease

Patients With Increased Risk of Bleeding Active bleeding High risk for bleeding Impaired coagulation GCS=graduated compression stockings, IPC=intermittent pneumatic compression, SC=subcutaneous, VFP=venous foot pump, VTE=venous thromboembolism

unacceptably high (elective neurosurgery). Most studies examining mechanical thromboprophylaxis have been conducted in surgical patients and have found that it is effective in reducing the incidence of VTE compared with using no preventive interventions. GCS have been shown to reduce 20

2 Venous Thromboembolism Prophylaxis LDUH: 5000 U SC b.i.d. LMWH Enoxaparin: 40 mg/d SC Dalteparin: 5000 IU/d SC Tinzaparin: 75 IU/kg/d or 4500 IU/d SC Fondaparinux: 2.5 mg/d Desirudin: 15 mg SC b.i.d

GCS, IPC, or VFP until the patient is able to receive pharmacologic methods of prophylaxis

the relative risk of DVT by 64% in general surgical patients and by 57% after total hip replacement.14 Also, the use of mechanical measures in addition to pharmacologic prophylaxis is likely to be more effective than heparin prophylaxis alone.14 Mechanical thromboprophylaxis is also thought to 21

be effective for medical patients with coagulopathy and an unacceptably high risk of bleeding, although no studies have specifically assessed this. The disadvantages of mechanical thromboprophylaxis are substantial, including lower efficacy in high-risk patients, poor compliance by patients and staff, and a greater effect on calf versus proximal DVT.3 In addition, mechanical methods should be used with caution in patients with peripheral vascular disease and ischemia of the extremities. General Medical Methods VTE prophylaxis is used less frequently in medical compared with surgical patients, even though most hospitalized medical patients have at least one risk factor for VTE, and the incidence of VTE among hospitalized medical patients ranges from 10% to 40%.13 A recent study15 found that medical patients who developed DVT received prophylaxis half as often as nonmedical patients. In the same study, medical patients with DVT developed PE significantly more often than nonmedical patients with DVT. A metaanalysis of nine randomized, controlled trials evaluating the use of VTE prevention in hospitalized medical patients showed that prophylaxis decreased the rate of DVT and statistically decreased the rate of fatal and nonfatal PE by half. No differences were noted in other complications, including bleeding and all-cause mortality.16 Four studies17-20 evaluating LMWH versus LDUH in medical patients found no differences in the rates of DVT or bleeding complications. In addition, a meta-analysis21 evaluating twice- versus thrice-daily LDUH administration demonstrated no difference in the rates of DVT or PE, although the rate of bleeding complications was significantly greater in the thrice-daily group. Although the guidelines for VTE prophylaxis in medical patients are less defined than in surgical populations, specific risk factors have arisen repeatedly when studying 22

comorbidities. Comorbid conditions such as congestive heart failure, obesity, surgery within the past 3 months, immobility within the past 30 days, cancer, obesity, sepsis, history of VTE, chronic obstructive pulmonary disease, and neurologic disease (including stroke) have all been shown to significantly increase the risk of VTE in medical patients.1,15,22 Current consensus statement guidelines provide prophylaxis recommendations determined by risk factors. Patients admitted to the hospital with at least one of these risk factors should receive thromboprophylaxis with LMWH, LDUH, or fondaparinux. When anticoagulation is contraindicated, such as in patients with active bleeding, a high risk of bleeding, or impaired coagulation, prophylaxis should include mechanical measures with either GCS or IPC (Table 2-4).2

Specific Recommendations in Other Nonsurgical Patients Cancer Patients Cancer patients have a significantly increased risk of VTE compared with patients without cancer,23 despite appropriate pharmacologic preventive measures, as well as for VTE recurrence after anticoagulation.24 In cancer patients with VTE, the 1-year survival rate is less than 15%,25 while those receiving chemotherapy have an increased incidence of VTE ranging from 11% to 20% depending on the type of medication given.25 Current guidelines recommend thromboprophylaxis for hospitalized, immobile cancer patients, similar to the recommendations for other high-risk patients. The use of central venous catheters in patients with cancer predisposes them to an even higher risk of upper extremity DVT. However, multiple studies evaluating the use of thromboprophylaxis have not shown any benefit, so routine treatment is not recommended to prevent catheterassociated DVT in cancer patients. 23

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Critical Care Patients Most intensive care unit (ICU) patients have at least one risk factor for VTE, including sepsis, stroke, immobility, or respiratory failure. However, critically ill patients are also at increased risk of bleeding complications from anticoagulation. Multiple studies have established the increased incidence of VTE in ICU patients as documented by Doppler compression ultrasonography of the lower extremities, with rates reported between 12% and 31%.3 Although there are theoretical concerns about the decreased efficacy of thromboprophylaxis in patients receiving vasopressors, the actual effect is unclear. The guidelines recommend the use of routine thromboprophylaxis in most ICU patients.3 For patients at increased risk of bleeding, guidelines recommend mechanical prophylaxis until the risk decreases, at which time pharmacologic prophylaxis should be added.3 Patients With Renal Impairment Renal insufficiency is a common medical comorbidity in hospitalized patients. Renal impairment is a significant consideration in prescribing VTE prophylaxis because LMWH, fondaparinux, and desirudin are primarily cleared via renal excretion. Not surprisingly, levels of anticoagulant medications may accumulate and lead to an increased risk of bleeding in patients with renal insufficiency. The guidelines recommend that renal function be considered when prescribing thromboprophylaxis. Specific suggestions include reduced dosing of LMWH and desirudin while avoiding fondaparinux in patients with renal impairment. At a minimum, clinicians should consider monitoring anticoagulant effect (Xa levels or aPTT) when using these medications in patients with renal impairment.

References 1. Goldhaber SZ, Tapson VF, DVT FREE Steering Committee: A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol 93(2):259-262.

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2. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al: A populationbased perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151(5):933-938. 3. Geerts WH, Bergqvist D, Graham F, et al: Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest 2008;133(suppl 6):381S-453S. 4. Gallus AS, Hirsh J, O’Brien SE, et al: Prevention of venous thrombosis with small, subcutaneous doses of heparin. JAMA 1976;235: 1980-1982. 5. Sherman DG, Albers GW, Bladin C, et al: The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007; 369:1347-1355. 6. Geerts WH, Jay, RM, Code, KI, et al: A comparison of lowdose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996;335:701-707. 7. Turpie AG, Bauer KA, Eriksson BI, et al: Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162(16):1833-1840. 8. Agnelli G, Bergqvist D, Cohen AT, et al: Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005;92:1212-1220. 9. Francis CW, Pellegrini VD, Totterman S, et al: Prevention of deep-vein thrombosis after total hip arthroplasty: comparison of warfarin and dalteparin. J Bone Joint Surg Am 1997;79:1365-1372. 10. Matheson AJ, Goa KL: Desirudin: a review of its use in the management of thrombotic disorders. Drugs 2000;60:679-700. 11. Eriksson BI, Ekman S, Kalebo P, et al: Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996;347:635-639. 12. Eriksson BI, Wille-Jørgensen P, Kälebo P, et al: A comparison of recombinant hirudin with a low-molecular-weight heparin to

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prevent thromboembolic complications after total hip replacement. N Engl J Med 1997;337:1329-1335. 13. Comerota AJ, Chouhan V, Harada RN, et al: The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis. Ann Surg 1997;226(3):306-313; discussion 313-314. 14. Agu O, Hamilton G, Baker D: Graduated compression stockings in the prevention of venous thromboembolism. Br J Surg 1999; 86(8):992-1004. 15. Piazza G, Seddighzadeh A, Goldhaber SZ: Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent. Chest 2007;132(2):554-561. 16. Dentali F, Douketis JD, Gianni M, et al: Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007;146: 278-288. 17. Bergmann JF, Neuhart E: A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute medical illness. Thromb Haemost 1996;76: 529-534. 18. Harenberg J, Roebruck P, Heene DL: Subcutaneous lowmolecular-weight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients. Haemostasis 1996;26: 127-139. 19. Lechler E, Schramm W, Flosbach CW: The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin): the Prime Study Group. Haemostasis 1996;26(suppl 2):49-56. 20. Kleber FX, Witt C, Vogel G, et al: Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003;145:614-621. 21. King CS, Holley AB, Jackson JL, et al: Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a metaanalysis. Chest 2007;131:507-516. 22. Heit JA, Silverstein MD, Mohr DN, et al: Risk factors for deep vein thrombosis and pulmonary embolism: a population-based casecontrol study. Arch Intern Med 2000;160(6):809-815.

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23. Heit KJA, Silverstein MD, Mohr DN, et al: Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809-815. 24. Elting LS, Escalante CP, Cooksley C, et al: Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med 2004;164:1653-1661. 25. Haddad TC, Greeno EW: Chemotherapy-induced thrombosis. Thromb Res 2006;118:555-568.

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Chapter 3

Acute and Chronic Deep Vein Thrombosis: Epidemiology, Diagnosis, Treatment, and Prognosis Steven B. Deitelzweig, Alpesh N. Amin

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resentation of deep vein thrombosis (DVT) is varied. Many patients with life-threatening conditions are asymptomatic, and only one third of cases of proximal DVT are clinically recognized. The true prevalence of DVT may be as high as 2 million patients per year. A serious morbid sequela of DVT is postthrombotic syndrome, or postthrombotic chronic venous insufficiency (CVI), which is characterized by chronic limb pain, edema, and ulceration of the lower extremities. Postthrombotic syndrome develops in 30% of patients within 8 years of an initial DVT and contributes to the substantial cost of management.1

Pathogenesis Venous thrombi typically form along the valve cusps within the soleal sinuses of the calf as a result of platelet aggregation and altered venous flow dynamics. They may overwhelm the endogenous fibrinolytic system within minutes. The propensity of the thrombus to embolize is greatest in the early or “loose” phase (first 7 days) when 28

the thrombus is composed of red blood cells, white blood cells, and platelets within a fibrin mesh. The organizational process continues through collateralization or retraction, ultimately leading to an often irreversible intimal injury during the recanalization phase.

History and Physical Examination A number of clinical studies have established that DVT cannot be reliably diagnosed based on the patient’s history and physical examination, even in high-risk patients. Patients with DVT may or may not experience the classic symptoms of edema, erythema, or limb pain. Homan’s sign (pain with dorsiflexion of the foot) and Moses’ sign (reproducible pain with calf manipulation), two commonly reported physical examination findings by trainees and ancillary health-care professionals, are neither sensitive nor specific for the diagnosis of DVT. Risk Factors Risk factors for venous thromboembolism (VTE) are increasingly common as the population ages and becomes more overweight and the prevalence of malignancy continues to increase. Virtually any patient admitted to a hospital for an underlying illness is at risk for VTE. Several institutions have adopted VTE risk assessment protocols to systematically identify and evaluate patients who require prophylaxis. To optimize outcomes, these risk assessment tools must incorporate current clinical evidence in a manner that is simple to execute and universally applicable. One novel and effective method is through the use of electronic alerts. In a large study2 of hospitalized patients at risk for VTE, an electronic alert system notified admitting physicians of the need for prophylaxis against VTE. The “control patient” physicians did not receive alerts. After 90 days, there was a statistically significant reduction in documented VTE rates among the patients whose physicians were alerted.2 (DVT prevention is discussed in Chapter 2.) 29

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Diagnosis of Deep Vein Thrombosis The diagnosis of acute DVT relies on objective testing. Compression ultrasonography is by far the most common technique used for suspected DVT. Impedance plethysmography has been essentially replaced by ultrasonography. Compression Duplex Ultrasonography Evidence from multiple, prospective, randomized clinical trials indicates that compression ultrasonography is highly sensitive and specific for symptomatic, proximal, acute DVT but is insensitive for asymptomatic acute DVT and isolated calf DVT. The diagnosis of DVT with ultrasonography relies on the lack of compressibility of the thrombosed venous segments, the appearance of collateral venous flow, and a thrombosed venous segment. More than a decade ago, the sensitivity and specificity of compression ultrasonography for symptomatic proximal DVT was demonstrated to be well above 90%.3-5 Limitations were also recognized, including the insensitivity for asymptomatic DVT, operator dependence, difficulty in accurately distinguishing acute from remote DVT in symptomatic patients, and the insensitivity for calf DVT. Ultrasonography is relatively inexpensive and is the preferred diagnostic modality for straightforward cases of symptomatic suspected proximal DVT. In cases in which there is a high clinical suspicion for DVT in the face of negative venous duplex ultrasound examination results, using serial ultrasonography is a reasonable strategy.6 Contrast Venography Contrast venography remains the gold-standard technique for the diagnosis of DVT but is still considered a second-line test. It is used when noninvasive testing is nondiagnostic or impossible to perform. Contrast venography is generally safe and accurate but is an invasive procedure that may result in superficial phlebitis, DVT, contrast-induced renal insufficiency, or hypersensitivity reactions.7 30

Magnetic Resonance and Computed Tomographic Venographic Imaging Magnetic resonance imaging (MRI) is being used increasingly to diagnose DVT and may be an accurate noninvasive alternative to contrast venography. Its major advantage is excellent resolution of the inferior vena cava (IVC) and pelvic veins. It appears to be at least as accurate as contrast venography and ultrasonography for imaging of the proximal deep veins and is perhaps more sensitive for pelvic vein thrombosis. MRI offers the opportunity for simultaneous bilateral lower extremity imaging, and it may accurately distinguish acute from chronic DVT. Newer techniques have improved the accuracy of MR venography for the diagnosis of DVT.8 Spiral computed tomography scanning has also been studied for suspected acute DVT. These techniques may fit into diagnostic algorithms for DVT, but these algorithms are institution specific, depending on resources and expertise with certain techniques.

Treatment of Venous Thromboembolic Disease The goals of DVT treatment are not just limited to prevention of thrombus propagation, embolization, and recurrence. Today’s management must consider reestablishment of venous patency and the prevention of the postthrombotic (CVI) syndrome. Various pharmacologic strategies have been studied with different efficacy and safety outcomes, including unfractionated heparins (UFHs), low-molecular-weight heparins (LMWH), warfarin, fondaparinux, and several newer agents. The two phases in the treatment of patients with symptomatic VTE are the acute (or initial treatment) and chronic (or secondary prophylaxis) phases. Acute treatment options include continuous intravenous (IV) UFH infusion, subcutaneous (SC) LMWH, SC selective Xa inhibitors, retrievable or permanent IVC filters, and thrombolytic therapy. 31

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Management of Acute Venous Thromboembolism Antithrombotic Agents Unfractionated Heparin. All heparins are heterogeneous mixtures of glycosaminoglycans derived from animal products that catalyze the blood enzyme antithrombin. UFH has a narrow therapeutic window and has been cited as a common cause of drug-related deaths in hospitalized patients. Significant bleeding occurs in 7% to 30% of patients on IV UFH, and complication rates of 1% to 2% per day have been reported.9 UFH prevents extension of thrombus and reduces the risk of subsequent embolization. The importance of achieving an adequate intensity of anticoagulation with heparin was emphasized by noting a recurrent VTE rate of at least 29% without therapeutic anticoagulation.10,11 Raschke et al11 reported a weight-based dosing protocol that resulted in a 95% likelihood of therapeutic heparin effect using an IV bolus of 80 U/kg followed by continuous IV infusion of 18 U/kg/hr. Using the activated partial thromboplastin time (aPTT) or another indirect assay (anti-Xa), the dosage of heparin should be adjusted to maintain an anticoagulant intensity above the lower limit of a defined therapeutic range.12 In situations in which the aPTT is unreliable (ie, circulating anticoagulant, factor deficiency), heparin levels via either thrombin or protamine titration are useful, aiming for a target of 0.2 to 0.4 U/mL or an anti-Xa level of 0.5 to 1.1 U/mL as evidence of adequate anticoagulation. Warfarin ( Coumadin ®), the most commonly used oral vitamin K antagonist (VKA) used in the US, is the mainstay of long-term anticoagulant therapy. Warfarin is commonly initiated within the first 24 to 48 hours at a dosage of 5.0 mg/day to 7.5 mg/day. The disadvantages of “loading doses” of 10 mg/day of warfarin have been well described, including a high incidence of “supratherapeutic” anticoagulation (36% overshoot phenomenon) at 60 hours, requiring correction.13 Both heparin and warfarin 32

must be used concomitantly for at least 5 days until the International Normalized Ratio (INR) is within therapeutic range (2.0 to 3.0), preferably for 2 consecutive days, at which time heparin administration can be discontinued.14 This regimen has been shown to reduce the incidence of acute hypercoagulability.15 The rationale for this is based on the short half-life of vitamin K–dependent factors protein C and protein S as well as factors VII, IX, and X. If oral VKAs are initiated while the intrinsic coagulation cascade is not inhibited, protein C deficiency will occur within 8 to 12 hours, which is a prothrombotic state. The risk of major hemorrhage with UFH is higher with intermittent than with continuous IV infusion. For this reason, close monitoring of anticoagulant effect is critical. When evaluating the risks of anticoagulationinduced hemorrhage, the intensity of anticoagulation is the strongest predictor.16 Other factors include advancing age, concomitant antiplatelet therapy, and a history of bleeding. Bleeding with UFH can be managed by close observation because UFH’s half-life is only 90 min. If hemodynamic compromise is developing, reversal of heparin effects with IV protamine sulfate is helpful. The standard dose is 1 mg of protamine for every 100 U of UFH administered. Protamine sulfate administration must be closely monitored because serious side effects, including anaphylaxis, hypotension, and possibly bleeding, may occur. It is advised to administer a test dose before fulldose therapy is started. A serious adverse effect with all forms of heparin is heparin-induced thrombocytopenia (HIT) and ultimate thrombosis. This is reviewed in detail in Chapter 8. Finally, because of an increase in osteoclast activating factor, heparin-induced osteoporosis can be a serious complication, especially with long-term administration (eg, pregnant patients with pregnancy-induced venous thrombosis in the first trimester). The risk of osteoporosis 33

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occurs less frequently with prolonged administration of LMWH than with UFH.17 The absolute contraindications to anticoagulant therapy include intracranial hemorrhage, active internal bleeding, peptic ulcer disease with hemorrhage, malignant hypertension, intracranial neoplasm, recent and significant trauma or surgery, and history of HIT. Low-Molecular-Weight Heparins. LMWHs have become the primary therapeutic options for patients with acute VTE. LMWHs possess a number of significant advantages over UFH. Their prolonged half-life, independent of dose, allows for a predictable dose response via SC injection once or twice daily, most often without monitoring (anti-Xa level). LMWHs have fewer pentasaccharide units, the high-affinity binding sites for antithrombin III. The anti-factor Xa:IIa ratio is 1:1 for UFH and from 2:1 to 4:1 for LMWHs.18 Several major randomized, prospective, multicenter trials and meta-analyses performed in the mid-1990s demonstrated a nonstatistically significant advantage of LMWH over UFH in the treatment of patients with acute VTE. Leizorovicz et al19 examined 2,045 patients in 16 controlled trials and found that the trend for VTE recurrence, bleeding, and mortality favored LMWH, with relative risk ratios of 0.66, 0.65, and 0.72, respectively.19,20 other studies have shown significantly less thrombus progression in patients treated with LMWH compared with those treated with UFH.21 LMWHs have been used as primary therapy for acute VTE in outpatients. Two large, randomized trials comparing enoxaparin (Lovenox®) and nadroparin (Fraxiparine®) demonstrated safety and efficacy in low-risk outpatient groups.22,23 When enoxaparin was administered at a dosage of 1 mg/kg SC twice daily, 5.3% of the 247 LMWH patients developed recurrent thromboembolism compared with 6.7% of the 253 patients treated with standard IV UFH (P=NS). There were no significant major bleeding rates 34

among the 2 treatment groups. This study suggests that LMWH may significantly alter the current therapeutic approach to DVT, allowing patients to be safely and effectively managed at home, potentially increasing patient convenience, and markedly reducing health-care costs. Enoxaparin is approved by the Food and Drug Administration (FDA) at a dosage of 1 mg/kg given SC twice daily or 1.5 mg/kg once daily to inpatients with DVT with or without pulmonary embolism (PE) and to outpatients at a dosage of 1 mg/kg twice daily for DVT without PE. Dalteparin (Fragmin®) is not yet approved for the treatment of VTE but has been used in dosages of 100 anti-factor Xa U/kg given SC twice daily and 200 antiXa U/kg given once daily for the management of DVT. Tinzaparin (Innohep®) is FDA labeled at a dosage of 175 IU/kg for DVT with or without PE. LMWHs have a significant cost and patient convenience advantage over UFH, but not all outpatients with VTE should be treated with LMWHs. Careful patient selection is the most important component to a successful outpatient treatment program. Patients without a history of VTE or bleeding who have demonstrated compliance are excellent outpatient candidates. For outpatient acute VTE management, warfarin therapy should mimic that of inpatient strategies and should be instituted on the first day of LMWH therapy.24 Factor Xa Inhibitors (Pentasaccharides). Fondaparinux (Arixtra®) is a synthetic analogue of a unique pentasaccharide sequence that mediates the interaction of heparin with antithrombin. Fondaparinux has been approved by the FDA for the treatment of patients with DVT. It inhibits both free and platelet-bound factor Xa. It also binds antithrombin with high affinity and is highly bioavailable, with a plasma half-life of 17 hours that permits once-daily administration. Despite the potential advantage of a prolonged halflife, the lack of reversibility in the face of fondaparinux35

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induced hemorrhage has limited the widespread use of this effective agent. The drug is excreted unchanged in urine, so it is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min). It does not bind platelet factor 4 and therefore should not cause HIT. Chapter 11 examines many other agents on the horizon. Newer anticoagulants target individual components of the coagulation cascade and include heparinoids, direct thrombin inhibitors, oral SNAC (sodium-N-amino caprylate) and SNAD (sodium N-amino decanoate) heparins, tissue factor pathway inhibitors, nematode anticoagulant peptide C2, and other investigational agents. These agents have the potential to change the paradigm of therapy for patients with acute VTE. Thrombolytic Therapy The limitation of standard anticoagulation for VTE has been the lack of restoration of deep venous patency and preservation of venous valvular function. Therefore, investigations of thrombolytic agents (commonly used as initial therapy for acute myocardial infarction) for use in patients with acute venous thromboembolic disease have been ongoing for more than 30 years. Despite the limited utility of thrombolytic therapy for DVT and PE, three FDA-approved thrombolytic agent regimens for PE use weight-based strategies. The data regarding thrombolytic therapy for DVT are less robust. Most clinicians have used a strategy of catheterdirected administration of the thrombolytic agent directly into the thrombus. But no agent is approved for use by the FDA. Thrombolysis should be considered for patients with acute massive iliofemoral venous thrombi (<28 days old). Bjarnason et al25 reported a 66% to 100% lysis rate compared with only 33% if the thrombus was present for more than 4 weeks. Theoretically, this will result in preservation of venous valvular function and a reduced incidence 36

of postthrombotic syndrome.26 Mechanical thrombectomy devices have been evaluated for therapy of large occlusive acute venous thrombi either in the lower extremities or pulmonary vasculature.27 Thrombolytic therapy is contraindicated in patients at risk for hemorrhage. Intracranial hemorrhage is the most devastating complication of thrombolytic therapy and is generally believed to occur in approximately 2% of patients. Retroperitoneal hemorrhage may result from a vascular puncture above the inguinal ligament, and even though it is often clinically silent, it may be life threatening. Malignant hypertension, recent stroke, surgery, biopsy, or arteriotomy of a noncompressible site are all contraindications to thrombolytic therapy but may offer VTE patients the option to use mechanical thrombectomy devices. Inferior Vena Cava Interruption IVC filter placement may be performed to minimize the risk of PE from lower extremity DVT. The primary indications for IVC filter placement include absolute contraindications to anticoagulation or recurrent embolism while the patient is receiving therapeutic doses of anticoagulation. A number of filter designs exist and can be inserted via the jugular or femoral veins. Recently, retrievable filters have been approved for use in the US. A retrievable IVC filter can be left indwelling as a permanent device, or it may be retrieved when the clinical need for mechanical IVC interruption no longer exists. The complications associated with IVC filters may include insertion-related complications, filter migration, direct thrombus extension through the filter, and IVC thrombosis. In addition, although IVC filters are effective at reducing the risk of PE, they are associated with an increased long-term risk of DVT formation.28 Given the apparent long-term risks of IVC filters, appropriate indications must exist, and standard anticoagulation should still be the mainstay of therapy.29 37

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DVT Treatment Plan Inferior Vena Cava (IVC) Filter Outpatient LMWH

Anticoagulation

Lysis

Risk Stratify 2-Day Hospital LMWH

5-Day Antithrombin Therapy

Figure 3-1: The American College of Physicians and the American Academy of Family Physicians guidelines for the acute management of DVT. Adapted from Snow V et al.30

The American College of Physicians and the American Academy of Family Physicians have put forth guidelines for the acute management of DVT (Figure 3-1). Chronic Venous Insufficiency CVI is an important manifestation of DVT. Although it is very common, it is often overlooked by hospitalists and cardiovascular specialists alike. Although some define CVI as venous varicosities, the more serious manifestations of venous stasis ulceration (affecting 0.3% of the adult population)31 require more meticulous care. CVI occurs in 92 per 100,000 hospital admissions, with 55% of patients being women and with a length of stay of 7 days.32 Patients with severe manifestations require repeated physician office visits and hospitalizations, resulting in loss of productivity and reduced quality of life.33 Patients who recover from acute DVT often suffer from reduced quality of life early after initial therapy.34 DVI is a result of malfunction of the normal venous physiology and anatomy. In normal states, the superficial 38

and deep veins of the lower extremities work against gravity and variable intrathoracic and intra-abdominal pressure to propel deoxygenated blood to the right side of the heart. Multiple “communicating” veins traverse the fascial planes in the thigh and calf. Each of these deep and superficial veins has multiple “one-way” venous valves that work in concert with the calf muscle pump action to aid in the appropriate emptying of blood from the lower extremities. When these valves become dysfunctional, predominantly because of primary valvular processes (rare) or after venous thrombosis (common), venous blood tends to follow the impact of gravitational forces, allowing venous blood to flow into the lower limb. This results in significant venous hypertension because emptied venous blood rapidly flows in a retrograde direction into the lower limb. Formal definitions of the presence and severity of CVI have been proposed by multiple groups. The most widely accepted is the CEAP (referring to clinical, etiology, anatomic location, and pathology) classification (Table 3-1).35 The diagnosis of CVI requires knowledge of the clinical and objective hemodynamic and physiologic manifestations of the disease. Clinical evidence of venous telangiectasis, reticular veins, and venous varicosities are important to note. Pigmentation of the distal medial aspect of the calf, lipodermatosclerosis, and atrophie blanche (hypopigmentation of the skin at an area of prior ulceration) suggest advanced CVI. Frank venous stasis ulcers have a characteristic location, commonly over the medial malleolus of the ankle, at the area of greatest venous hypertension. The ulcer is often moist, beefy red, and relatively painless. Without appropriate therapy, these ulcerations may have significant exudates on the surface. The differential diagnosis of CVI is often similar to that of limb edema, requiring the clinician to consider local (lymphedema, lipedema, ruptured popliteal [“baker’s”] cysts) and systemic (congestive heart failure, renal or 39

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Table 3-1: The CEAP Classification for Chronic Venous Insufficiency Classification

Clinical Description

Clinical No venous disease Telangiectasis Varicose vein Edema Lipodermatosclerosis or hyperpigmentation Healed ulcer Active ulcer Etiologic Congenital Primary Secondary Anatomic Distribution Superficial Deep

Perforator Pathophysiology Reflux Obstruction Both

Present since birth Undetermined cause Associated with postthrombotic syndrome or trauma Great or short saphenous veins Cava, iliac, gonadal, femoral, profunda, popliteal, tibial, or muscular veins Thigh or calf perforating veins Axial and perforating veins Acute or chronic Valvular dysfunction and thrombus

CEAP=clinical, etiology, anatomic location, and pathology

40

hepatic dysfunction) causes for edema. When ulceration is noted, the differential diagnosis requires discerning between arterial, venous, and neurotrophic causes. Objective testing often begins with venous duplex ultrasonography, which provides a definitive diagnosis of acute or remote venous thrombus, as well as a detailed venous “map” of segments of venous valvular incompetence. Air plethysmography (APG) is an important diagnostic test that provides physiologic information about the location and severity of CVI. This noninvasive test uses changes in limb volume by determining air displacement in the limb. APG may assess obstruction, venous refill, and poor calf muscle pump function.36 Treatment of CVI is based on the principles of prevention with aggressive management of acute proximal venous thrombosis; good skin care and optimization of wound care; maintenance of a moist, clean environment; reverse venous hypertension; weight loss; and aerobic exercise. Patients who present with acute proximal DVT are commonly managed with standard anticoagulation. However, because DVT results in CVI in many patients within 3 years of diagnosis, intervention with catheter-delivered thrombolytic therapy may result in prevention of venous valvular dysfunction and CVI.37 Compression therapy and weight loss remain the two most important maneuvers for reducing venous hypertension. Depending on the severity of the CEAP score, varying degrees of compression garments may be used, ranging from 20 to 50 mm Hg. In fact, compression therapy and meticulous wound care for venous stasis ulcers result in healing in 93% of patients.38 If conservative measures fail or if the patient cannot remain compliant, invasive therapy is often required. Patients with CEAP scores of 4 to 6 commonly require some form of invasive intervention. Invasive therapy ranges from injection venous sclerotherapy using duplex ultrasound guidance,39 endovenous ablation of venous varicosities 41

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with radiofrequency,40 laser,41 or venous surgery.42 The most common surgical treatment is removal of the great saphenous vein with high ligation at the level of the saphenofemoral junction, resulting in dramatic improvement in symptoms and promoting healing of recalcitrant venous ulcers.43

References 1. Barritt DW, Jordan SC: Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1960;18:13091312. 2. Kucher N, Koo S, Quiroz R, et al: Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med 2005;352:969-977. 3. Tapson VF, Witty LA: Massive pulmonary embolism: diagnostic and therapeutic strategies. Clin Chest Med 1996;16:329-340. 4. Tick LW, Ton E, van Voorthuizen T, et al: Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test, compression ultrasonography, and D-dimer test. Am J Med 2002;113(8):630-635. 5. Weinmann EE, Salzman EW: Deep-vein thrombosis. N Engl J Med 1994;331:1630-1641. 6. Prandoni P, Cogo A, Bernardi E, et al: A simple ultrasound approach for detection of recurrent proximal vein thrombosis. Circulation 1993;88(4 pt 1):1730-1735. 7. Aitken AGF, Godden DJ: Real-time ultrasound diagnosis of deep vein thrombosis: a comparison with venography. Clin Radiol 1987;38:309-313. 8. Fraser DG, Moody AR, Davidson IR, et al: Deep venous thrombosis: diagnosis by using venous enhanced subtracted peak arterial MR venography versus conventional venography. Radiology 2003;226:812-820. 9. Hirsh J, Dalen JE, Deykin D, et al: Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992;102(suppl 4):337S-351S. 10. Hull R, Delmore T, Genton E, et al: Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 1979;301:855-858.

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11. Raschke RA, Reilly BM, Guidry JR, et al: The weight-based heparin dosing nomogram compared with a standard care nomogram. Ann Intern Med 1993;119:874-881. 12. Brill-Edwards P, Ginsberg JS, Johnston M, et al: Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993;119: 104-109. 13. Harrison L, Johnston M, Massicotte MP, et al: Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997;126:133-136. 14. Hull RD, Raskob GE, Rosenbloom D, et al: Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990;22:1260-1264. 15. Rosenberg RD: Biochemistry and pharmacology of low molecular weight heparin. Semin Hematol 1997;34(4 suppl 4):2-8. 16. Hull R, Hirsh J, Jay R, et al: Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982;301:1671-1681. 17. Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombocytopenia is more common with unfractionated heparin than with low molecular weight heparin [abstract]. Thromb Haemost 1993;332:69:1330-1335. 18. Muir JM, Hirsh J, Weitz JI, et al: A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats. Blood 1997;89:3236-3242. 19. Leizorovicz A, Simonneau G, Decousus H, et al: Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep vein thrombosis: a meta-analysis. Br Med J 1994;309:299-304. 20. Dolovich LR, Ginsberg JS, Douketis JD, et al: A meta-analysis comparing low-molecular-weight heparin with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000;160: 181-188. 21. Breddin HK, Hach-Wunderle V, Nakov R, et al and the CORTES Investigators: Clivarin: Assessment of Regression of Thrombosis, Efficacy, and Safety. Effects of a low-molecular-weight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med 2001;344:626-631.

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22. Levine M, Gent M, Hirsh J, et al: A comparison of lowmolecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-681. 23. Koopman MM, Prandoni P, Piovella F, et al: Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996;334:682-687. 24. Kovacs MJ, Rodger M, Anderson DR, et al: Comparison of 10-mg and 5-mg warfarin initiation nomograms together with lowmolecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003;138:714-719. 25. Bjarnason H, Kruse JR, Asinger DA, et al: Iliofemoral deep venous thrombosis: safety and efficacy outcome during 5 years of catheter-directed thrombolytic therapy. J Vasc Interv Radiol 1997;8:405-418. 26. Laiho MK, Oinonen A, Sugano N, et al: Preservation of venous valve function after catheter-directed and systemic thrombolysis for deep venous thrombosis. Eur J Vasc Endovasc Surg 2004;28: 391-396. 27. Vendantham V, Vesely TM, Sicard GA, et al: Pharmacomechanical thrombolysis and early stent placement for iliofemoral deep vein thrombosis. J Vasc Interv Radiol 2004;15:565-574. 28. The PREPIC study group: Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism. Circulation 2005;112:416-422. 29. Jaff MR, Goldhaber SZ, Tapson VF: High utilization rate of vena cava filters in deep vein thrombosis. Thromb Haemost 2005;93: 1117-1119. 30. Snow, V, Qaseem A, Barry P, et al: Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2007;146:204-210. 31. Fowkes FG, Evans CJ, Lee AJ: Prevalence and risk factors for chronic venous insufficiency. Angiology 2001;52(suppl):S5-S15. 32. Tsai S, Dubovny A, Wainess R, et al: Severe chronic venous insufficiency: magnitude of the problem and consequences. Ann Vasc Surg 2005;19:705-711.

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33. Rhodes JM, Gloviczki P, Canton LG, et al: Factors affecting clinical outcomes after endoscopic perforator vein ablation. Am J Surg 1998;176:162-167. 34. Kahn SR, Ducruet T, Lamping DL, et al: Prospective evaluation of health-related quality of life in patients with deep venous thrombosis. Arch Intern Med 2005;165:1173-1178. 35. Porter JM, Moneta GL: Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995;21:635-645. 36. Criado E, Daniel PF, Marston W, et al: Physiologic variations in lower extremity venous valvular function. Ann Vasc Surg 1995;9: 102-108. 37. Silleson H, Just S, Jorgensen M, et al: Catheter directed thrombolysis for treatment of ilio-femoral deep venous thrombosis is durable, preserves venous valve function and may prevent chronic venous insufficiency. Eur J Vasc Endovasc Surg 2005;30:556-562. 38. Mayberry JC, Moneta GL, Taylor LM, et al: Fifteen-year results of ambulatory compression therapy for chronic venous ulcers. Surgery 1991;109:575-581. 39. Breu FX, Guggenbichler S: European consensus meeting on foam sclerotherapy. Dermatol Surg 2004;30:709-717. 40. Merchant RF, Pichot O, Closure Study Group: Long-term outcomes of endovenous radiofrequency obliteration of saphenous reflux as a treatment for superficial venous insufficiency. J Vasc Surg 2005;42:502-509. 41. Huang Y, Jiang M, Li W, et al: Endovenous laser treatment combined with a surgical strategy for treatment of venous insufficiency in lower extremity: a report of 208 cases. J Vasc Surg 2005;42: 494-501. 42. Blomgren L, Johanssen G, Dahlberg-Akerman A, et al: Changes in superficial and perforating vein reflux after varicose vein surgery. J Vasc Surg 2005;42:315-320. 43. Sarin S, Scurr JH, Coleridge Smith PD: Stripping of the long saphenous vein in the treatment of primary varicose veins. Br J Surg 1994;81:1455-1458.

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Chapter 4

Upper Extremity Thrombosis, Superficial Thrombophlebitis, and Thrombosis at Rare Sites Adam C. Schaffer, Sylvia C.W. McKean

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ertain principles regarding risk factors and treatment are common to thromboses at most (but not all) of these sites: the upper extremities; the superficial vasculature of the lower extremities; and the less common venous thromboses of the gastrointestinal (GI), renal, and the cerebrovascular systems (Table 4-1). The most prominent risk factors are discussed in each individual section, but many of them apply to most of the thromboses discussed in this chapter. In patients in whom the risk factor for venous thrombosis is not apparent, a search for one is appropriate, and in most cases, a full workup for thrombophilias should be undertaken. Therapeutically, for most of the thromboses mentioned in this chapter, initial anticoagulation with a heparin regimen is appropriate. A notable exception is the treatment of thromboses related to heparin-induced thrombocytopenia (HIT), which is a consideration when thrombosis occurs at unusual sites. In patients with HIT, heparin (including lowmolecular-weight heparin [LMWH]) is contradindicated.1 The goal of anticoagulation is primarily to prevent extension of the thrombus and to mitigate the risk of thromboembolic events (eg, pulmonary emboli). In general, anticoagulation does not eliminate the thrombus. In some of the cases dis46

cussed in this chapter, therapy, such as thrombolytics, can be used to attempt to achieve recanalization.

Upper Extremity Venous Thrombosis Deep vein thrombosis (DVT) of the upper extremity usually involves the axillary or subclavian veins (or both). Spontaneous upper extremity DVT (UEDVT) includes thrombosis related to strenuous exercise and idiopathic thrombosis. Catheter-associated UEDVT includes thromboses related to acute or chronic venous cannulation by a central venous catheter (CVC) for intravenous (IV) medication, total parenteral nutrition, hemodialysis, or hemodynamic monitoring. UEDVT may also be seen in association with pacemaker electrodes. UEDVT in the setting of indwelling venous catheters is treated differently than spontaneous UEDVT, so these are discussed in separate sections in this chapter. Some authors advocate making a slight distinction between primary UEDVT, in which no predisposing factor can be identified, and secondary UEDVT, which includes not only catheter-related UEDVT but also patients with predisposing conditions such as malignancies. In one series of 120 patients with UEDVT that used this classification scheme, 61% were primary and 39% were secondary. The most common secondary cause, after indwelling catheters, was malignancies, accounting for 11% of cases.2 Once thought to be a relatively benign condition that could be managed conservatively, UEDVT is now appreciated as a potentially serious condition that may lead to pulmonary emboli (PE).3,4Additional reported complications of UEDVT include chronic venous insufficiency (pain and swelling), venous gangrene, superior vena cava (SVC) syndrome, and catheter infection.5 Upper Extremity Thrombosis (Spontaneous) Most spontaneous UEDVT occurs in the axillary vein, subclavian vein, or both. Primary thrombosis involving 47

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Table 4-1: General Risk Factors for Venous Thromboses Hypercoagulable States • Inherited – Protein C deficiency – Protein S deficiency – Factor V Leiden mutation – Antithrombin III deficiency – Prothrombin mutation G20210A – Hyperhomocysteinemia • Acquired – Antiphospholipid syndrome – Heparin-induced thrombocytopenia Hematologic Disorders • • • •

Polycythemia vera Thrombocythemia Myeloproliferative disorders Paroxysmal nocturnal hemoglobinuria

Inflammatory Disorders • • • • • • • •

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Inflammatory bowel disease Peritonitis Sepsis Vasculitis Diverticulitis Nephrotic syndrome Pancreatitis Septic thrombophlebitis

Malignancy • Systemic hypercoagulability from malignancy • Mechanical effects such as extrinsic compression by tumor • Chemotherapeutic agents

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Women’s Health • Pregnancy • Postpartum • Hormone replacement therapy • Hormonal contraceptives Trauma Catheters Postoperative state Immobility Dehydration Hospitalization Age

Adapted from Asghar,156 Kumar et al,128 Joffe et al,9 Martinelli et al,14 and Menon et al.134

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the axillary–subclavian veins is also referred to as PagetSchroetter syndrome. Hughes described 320 cases of this condition in a 1949 paper.6 The proportion of all DVTs that occur in the upper extremity has been estimated from 1.3% to 4.0%,7 with one outlier estimate of 18%.8 In a retrospective study of hospitalized patients in a community teaching hospital, 0.18% of adult patients were diagnosed with UEDVT.8 UEDVT is an uncommon disorder, with one study in Sweden estimating a frequency of primary UEDVT of 2 cases per 100,000 persons per year.2 Common signs and symptoms of UEDVT include (in order of decreasing frequency) edema, pain, and erythema of the affected limb,9,10 mild cyanosis of the affected limb, a palpable cord, dyspnea, chest pain, and cough.4,9 If the UEDVT occurs in the setting of a thoracic outlet syndrome, then symptoms associated with brachial plexus compression may occur, including pain in the medial aspect of the forearm and hand.11,12 Risk Factors Analysis of data from 268 patients with UEDVT found the most common risk factors were cancer, immobilization, history of DVT, and recent major surgery. Although these risk factors are similar to those seen in lower extremity DVT, history of DVT and recent major surgery are significantly more important risk factors for lower extremity DVT than for UEDVT.9 Other risk factors for UEDVT include infection, renal failure, and chemotherapy.10 Thrombophilias are another important risk factor for UEDVT.13 One study designed to assess for thrombophilias in UEDVT patients, which excluded patients with malignancies and previous lower extremity DVT, found that the most common thrombophilias were factor V Leiden and prothrombin G20210A mutations.14 Another setting in which UEDVT may occur is in young, otherwise healthy people, such as athletes, who undertake vigorous, repetitive activity. 50

Presumably, as a result of repetitive compression of the upper extremity veins and microtrauma to the vessel wall, these patients may develop UEDVT, usually in the dominant upper extremity.15,16 This gives rise to another term sometimes used to describe UEDVT, effort thrombosis, which is considered a type of primary UEDVT. Complications and Sequelae The incidence of PE in patients with UEDVT is approximately 12%, with estimates ranging from 9% to 36%.7,17 Other complications associated with UEDVT include the postthrombotic syndrome18 and, in rare cases, venous gangrene.19 Postthrombotic syndrome, which occurs in approximately 15% of patients with UEDVT, encompasses symptoms such as pain, swelling, paresthesias, and significant functional limitation in the affected arm. Residual thrombosis after treatment may increase the likelihood of postthrombotic syndrome.18 Compression stockings may be used to treat patients with postthrombotic syndrome.11,18 Venous gangrene occurs in patients with cancer or another hypercoagulable state, and results from massive occlusion of venous outflow from the extremity, resulting in tissue ischemia and necrosis. Detectable arterial pulses in the affected limb help differentiate this condition from arterial thrombosis.19 Infection of the thrombus, leading to a septic thrombophlebitis, may also occur, primarily in patients with indwelling catheters.20 Diagnosis For screening patients suspected of having UEDVT, ultrasonography is an appropriate initial imaging modality.11,21 Using venography as the gold standard, Prandoni et al17 evaluated different ultrasound techniques to diagnose UEDVT and found that compression ultrasonography had a sensitivity and specificity of 96% and 93.5%, respectively, and color-flow Doppler imaging had a sensitivity and specificity of 100% and 93%, respectively. Simple 51

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Doppler ultrasonography fared less well, with a sensitivity and specificity of 81% and 77%, respectively.17,20 However, ultrasonography may poorly image the segment of the vein subject to the acoustic shadow of the clavicle and may sometimes not detect nonocclusive thrombi.22,23 There is significant variation in the reported sensitivity and specificity of ultrasonography in diagnosing UEDVT. Given that no study has examined whether it is safe to withhold anticoagulation in patients suspected of having UEDVT who have negative Doppler study results, some recommend following up with venography, especially if the clinical suspicion of UEDVT is high.24 But a number of drawbacks are associated with venography, including the need to obtain access to the vein in the suspect arm, which may be edematous, and the need for administration of IV contrast.11 Limited data exist on the use of computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of UEDVT. One study of 16 patients concluded that MRI was reliable for diagnosing UEDVT,25 but another study involving 28 patients found MRI to be specific but insensitive, missing a number of nonobstructive mural thrombi (which was also a problem with ultrasonography in the study).23 Too little data have been published on CT diagnosis of UEDVT to define its role.26,27 D-dimer testing is not helpful in making the diagnosis of UEDVT. In a study of 52 patients suspected of having UEDVT, the sensitivity of D-dimer testing was 100%, and the specificity was 14%. This positive predictive value of the D-dimer in this setting was 32%.28 Using a derivation sample of 140 patients hospitalized for possible UEDVT, Constans et al29 developed a clinical prediction score for the diagnosis of UEDVT. The four factors in the score are: (1) venous material (defined as a catheter or other access device in the subclavian or jugular vein or a pacemaker), (2) localized pain, (3) unilateral pitting edema, and (4) that an alternative diagnosis was at least as plausible. When scoring, factors 1 to 3 are each positive 1 point, and 52

factor 4 is negative 1 point. A score of -1 or 0 means the patient has a low probability of UEDVT, a score of 1 is an intermediate probability, and a score of 2 or 3 is high probability. Using this model, the area under the curve on the receiver operating characteristics plot was 0.70.29 Treatment For initial anticoagulation, IV unfractionated heparin (UFH) may be used. Heparin should be transitioned to warfarin (Coumadin®), with a goal International Normalized Ratio (INR) of 2.0 to 3.0. The minimum duration of anticoagulation should be 3 months,4 but 6 months is advisable if the patient has a coagulation abnormality.11 LMWH has been studied for anticoagulation of UEDVT and was found to yield good results.30,31 In addition to anticoagulation, the other treatment options include thrombolysis, either directed or systemic, and resection of the first rib, if it is believed to be playing a role in causing compression of the venous outflow of the upper extremity. There are varying opinions on the role of the more aggressive therapies. Machleder32 advocates what he refers to as a “staged multidisciplinary approach,” in which catheter-directed thrombolysis is undertaken along with anticoagulation as soon as a UEDVT is detected, and then surgery to remove the first rib at least 1 month later. The reason for this delay is to allow for the affected vessel to heal after thrombolysis and for any inflammation to diminish before surgery. Using this aggressive approach with 76 patients (most of whom were younger and many of whom were athletes), he found that none of the patients who had undergone thrombolysis and surgery had recurrent thrombosis and 84% were without significant disability.32 Others argue that catheter-directed thrombolysis should be used and that surgery to alleviate any thoracic inlet compression (usually partial first-rib resection) should occur promptly, within a few days of the thrombolysis.33-37 Still others promote catheterdirected thrombolysis without decompression surgery.38 53

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An alternative, more conservative, approach involves anticoagulation alone. In one series of 20 patients with UEDVT treated with anticoagulation alone, after 42 months only 5 patients had residual symptoms, all of them mild.39 Another series of 95 patients with UEDVT compared anticoagulation alone with systemic thrombolysis in addition to anticoagulation. The patients who received systemic thrombolysis had a good technical success rate, with 88% of them achieving recanalization. However, 21% of the patients who underwent systemic thrombolysis had bleeding complications. No bleeding complications were observed in the group treated with anticoagulation alone. At follow-up, the patients who received thrombolysis were significantly less likely to have a thrombosed upper extremity vein, but this decreased incidence did not translate into a significantly reduced rate of symptomatic postthrombotic syndrome. Therefore, the authors concluded that “conservative treatment may be favoured.”40 One intervention that does not appear to be beneficial is venous stenting, which has been found to be a risk factor for recurrent thrombosis, possibly because of the risk of stent fracture with repetitive compression.41 The literature on the treatment of patients with UEDVT is made up primarily of relatively small case series, which prevents definitive conclusions from being drawn. Part of the variability in the conclusions of the different case series likely stems from differences in the populations studied, with some of the studies looking only at younger patients with UEDVT in the setting of repetitive exertion—the classic “effort thrombosis”—but other studies including older patients with comorbidities. The preponderance of this methodologically limited literature appears to favor the more aggressive approach with catheter-directed thrombolysis and possibly decompression surgery in addition to anticoagulation. Thrombolysis is most beneficial in acute thromboses (<7 days) and may not be beneficial in older thromboses.5 In younger, healthy 54

patients with UEDVT, the more aggressive treatment approach is probably advisable, given that these patients are unlikely to have contraindications to these interventions and are most likely to want everything possible to be done to minimize any residual symptoms or functional limitations. Alternatively, patients with significant comorbidities, such as a malignancy, that place them at increased risk from the more aggressive interventions and that may shorten their lives may be more appropriate for anticoagulation alone.4,11 An algorithm showing the treatment approach advocated by Sajid et al42 is shown in Figure 4-1. In UEDVT patients in whom anticoagulation is contraindicated and in those who have thrombus extension or PE despite being on anticoagulation, insertion of an SVC Greenfield filter may be considered. 43,44 The largest reported series of SVC Greenfield filters inserted for UEDVT, which included 72 patients, concluded that their use was safe, and no patient in the series had PE or SVC thrombosis.43 There is, however, a case report of a significant complication (cardiac tamponade) in a trauma patient with an UEDVT into whom an SVC Greenfield filter was placed.45

Upper Extremity Thrombosis (Central Venous Catheter Related) The presence of a CVC markedly increases the risk of an UEDVT, with an adjusted odds ratio (OR) of 1,136.46 Estimates of the rate of thrombosis in association with CVCs range from 4% to 68%. An older summary of the various estimates of the rate of CVC-related UEDVT calculated a mean rate of 18.9%.47 More recent estimates of the UEDVT rate in association with CVCs have studied cancer patients and have prospectively looked for UEDVT, regardless of whether symptoms were present, and have therefore arrived at higher estimates, ranging from 27.3% to 66.0%.48 CVCs may damage the vessel wall, as may the infusate, and CVCs may also interfere with blood flow, 55

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leading to stasis.11 Factors that may make CVC-related thrombosis more likely include a larger bore CVC, number of venipunctures, malposition of the CVC, and the duration that the CVC is left in place.7,49 The material of the CVC may also influence the likelihood of UEDVT, with polyethylene- or Teflon-coated CVCs less likely to be associated with thrombosis than those made from polyurethane and silicone.49 Cancer patients are the dominant population in which this CVC-related UEDVT occurs, given the dual risk of the CVC itself and the hypercoagulability resulting from cancer and the population in which this issue has been most studied. In addition, certain chemotherapeutic agents, such as 5-fluorouracil, increase the risk of thrombosis.50 The adjusted OR of UEDVT in cancer patients is 43.6.46 The presence of pacemaker wire raises some of the same issues as the presence of CVCs. The rate of total occlusion of the upper extremity veins 6 months after implantation of a pacemaker is 6%, with other patients having lesser degrees of stenosis. Having had a previous temporary pacer lead may be a risk factor.51-53 Clinical Presentation and Complications The signs and symptoms of UEDVT in patients with CVCs are similar to those without catheters and include edema, pain, and erythema.10 Jaw pain, swelling of the head and neck, headache, and numbness may also be present.54 A significant proportion of cancer patients with CVC-related UEDVT may be asymptomatic, and were in the majority in a number of studies.54 Indeed, the symptoms of UEDVT may be milder in patients who have CVC-associated DVT compared with spontaneous UEDVT because the former may develop more slowly and be more likely to be nonocclusive.55 PEs are a major concern. One prospective study that assessed 86 consecutive patients for the presence of PE within 24 hours of the diagnosis of catheter-related UEDVT regardless of pulmonary symptoms, found that 56

15% had PE. Two of the 13 patients with PE died despite treatment with heparin.56 In addition to the risk of PE, CVC-related UEDVT appears to increase the risk of catheter-related sepsis.57 Diagnosis Diagnostically, the same principles apply as when UEDVT not associated with a CVC is suspected. In studies examining the value of ultrasonography in diagnosing UEDVT in patients with CVCs, one questioned ultrasonography’s sensitivity,58 but a larger, more recent study found that ultrasonography had a sensitivity of 94% and a specificity of 96%.59 Ultrasonography is therefore the appropriate initial test. If the results are positive, then the diagnostic evaluation is complete. If the results are negative and the clinical suspicion for DVT persists, then venography should be considered. Treatment There is a lack of consensus about what the appropriate treatment is for CVC-related UEDVT in cancer patients. In the absence of contraindications, anticoagulation is appropriate, with expert opinion holding that the duration of anticoagulation should be at least 6 months and consist of 5 to 7 days of UFH or LMWH as a bridge to warfarin.48,60 For patients with cancer and DVT of the lower extremity or PE, the CLOT (Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism) trial found a lower incidence of recurrent venous thromboembolism with 6 months of LMWH compared with warfarin.61 Others found a decreased incidence of HIT in patients treated with LMWH62,63 compared with warfarin. Removal of the CVC is reasonable if it can be done without jeopardizing the patient’s treatment. The availability of other CVC access sites needs to be considered in deciding 57

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58 UEDVT

Primary UEDVT <1-week-old thrombus • Anticoagulation • Fibrinolysis or thrombectomy • Optional: stenting or surgery

Secondary UEDVT/catheter related >1-week-old thrombus • Anticoagulation • Surgery

Catheter dependent

Catheter independent • Anticoagulation • Remove catheter With infection/line sepsis • Remove catheter • Anticoagulation

<1-week-old thrombus <2-cm thrombus • Anticoagulation • Fibrinolysis or thrombectomy • Preservation of catheter

Without infection

>1-week-old thrombus >2-cm thrombus • Anticoagulation • Remove catheter

Figure 4-1: An approach to managing upper extremity deep vein thrombosis (UEDVT). Adapted from Sajid MS, Ahmed N, Desai M, et al.42

whether to remove the CVC because the site from which the CVC is removed should not be used again for CVC access, and using the same site in the future may be technically unfeasible.64 Although some have reported good results with catheter-directed thrombolysis with CVC-related UEDVT patients,65 most authors are hesitant to give thrombolytics to these patients. The reason is that there is a dearth of data that thrombolysis is beneficial in this setting, and most of these patients tend to have underlying malignancies, which may increase the risk from thrombolysis and mean the patient has a limited life expectancy.48,60 Placement of a Greenfield filter in the SVC is an option, as it is for spontaneous UEDVT, in patients with a contraindication to anticoagulation or who have thrombus extension or PE on anticoagulation.43,44 One exception is cases of HIT, for which a Greenfield filter is not adequate treatment.1 Another controversial issue is the role of prophylaxis to prevent the formation of UEDVT. The largest trial to evaluate the effect of low-, fixed-dose warfarin in preventing UEDVT in cancer patients with CVCs enrolled 255 patients who required catheters for at least 7 days. They were randomized to receive either 1 mg/day of warfarin or placebo. Although there was no significant difference in the rate of bleeding between the two arms, the patients receiving warfarin did not have a significant reduction in the primary end point, which was symptomatic, radiographically confirmed UEDVT at the site of the catheter.66 A trial of LMWH randomized cancer patients undergoing at least 12 weeks of chemotherapy to receive either LMWH or placebo daily. Using a primary end point of symptomatic UEDVT, PE, or catheter obstruction requiring removal of the catheter, this study found no benefit to low-dose LMWH. Also, there was no significant difference in the two groups in the incidence of bleeding complications.67 Two meta-analyses on the value of thromboprophylaxis in patients with UEDVT have reached conflicting conclusions. One meta-analysis, which included only patients with 59

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malignancies, concluded that thromboprophylaxis did not decrease the risk of UEDVT.68 In contrast, another metaanalysis, which was not limited to cancer patients, including patients receiving total parenteral nutrition, concluded that thromboprophylaxis did reduce the risk of UEDVT.69 Therefore, in the absence of clear evidence, thromboprophylaxis cannot be recommended as routine practice to prevent UEDVT in cancer patients with catheters.

Superficial Thrombophlebitis Superficial thrombophlebitis refers to inflammation, often associated with thrombosis, of the superficial veins. Commonly occurring in varicose veins of the lower extremities, superficial thrombophlebitis may also result from seemingly minor trauma or from IV infusions. Less frequently, it occurs in association with thromboangiitis obliterans (Buerger’s disease)70 or with malignancy (Trousseau’s syndrome),71 in which settings the superficial thrombophlebitis is often migratory. Its overall incidence is not well defined, but one estimated range of 3% to 11% has been published.72 Clinical Presentation Common signs and symptoms of superficial thrombophlebitis include a palpable cord, along with surrounding evidence of inflammation, such as warmth, erythema, and pain.73,74 Varicose veins are the most common predisposing factor for superficial thrombophlebitis. Many of the other risk factors mirror those for lower extremity DVT and include immobility, postsurgical state, active malignancy, pregnancy, and obesity.75 Thrombophilias, including protein S deficiency76 and anticardiolipin antibodies,77 are associated with superficial thrombophlebitis.78 Another risk factor is the presence of peripheral IV catheters. It is controversial whether regularly changing peripheral IV catheters helps reduce catheter-associated phlebitis,79,80 although this practice is recommended in the guidelines.81 60

Complications Patients with superficial thrombophlebitis are at increased risk of having an associated DVT, although the magnitude of this increased risk is controversial. One study of 44 patients with superficial thrombophlebitis of the lower extremity found the 23% of them had a DVT and recommended that all patients with superficial thrombophlebitis get ultrasounds to look for DVT.82 Another study that looked at 551 patients who had ultrasonography found that 5.6% of them had DVTs, leading the authors to recommend obtaining ultrasounds in patients with superficial thrombophlebitis only if other risk factors, such as immobility, are present.83 A retrospective cohort study of 185 patients with spontaneous superficial venous thrombophlebitis, who were compared with matched controls, found a 6-month incidence of DVT of 2.7% in the patients with superficial thrombophlebitis compared with 0.2% in the control patients, yielding an adjusted OR of 7.1.84 Patients with superficial thrombophlebitis have also been reported to have an increased risk of PE. One report that evaluated 21 patients with superficial thrombophlebitis with perfusion scans of the lung found that seven (33%) of the patients had a high probability for PE, although only one was symptomatic.85 Another study, which included 232 patients with superficial thrombophlebitis in whom an evaluation for PE was performed only if there was a clinical suspicion for PE, found that only 0.9% of patients had PE. Both of the patients with superficial thrombophlebitis and PE had extension of the superficial thrombophlebitis into the deep venous system.86 Diagnosis The diagnosis of superficial thrombophlebitis is suggested by the signs and symptoms previously mentioned. It is important to distinguish superficial thrombophlebitis from cellulitis. If the erythema, warmth, induration, and 61

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other signs of inflammation spread beyond the area of the vein, then cellulitis must be considered. The absence of a palpable cord at the center of the inflammation also suggests cellulitis rather than superficial thrombophlebitis.87 The role of ultrasonography in the diagnosis depends mainly on the possibility of concomitant DVT. Although ultrasonography can confirm a diagnosis of superficial thrombophlebitis suspected on clinical grounds, its most important role is in evaluating patients for the possible presence of DVT. The likelihood of an associated DVT being present in a patient with superficial thrombophlebitis appears to depend on what risk factors are present and on the anatomic location. Superficial thrombophlebitis located above the knee near the saphenofemoral junction presents a greater risk of extension to form a DVT.88 Patients with hypercoagulable risk factors, such as immobility, active malignancy, pregnancy, postsurgical state, oral contraceptive use, hormone replacement therapy, obesity, or protein C or S deficiency or other thrombophilias, are also at elevated risk of having a DVT associated with superficial thrombophlebitis.73,75 All patients with superficial thrombophlebitis above the knee should undergo ultrasound evaluation. Ultrasonography should also be done in patients with hypercoagulable risk factors. Whether patients with superficial thrombophlebitis below the knee and no hypercoagulable risk factors should have an ultrasound examination to look for DVT is unclear. Varicose veins in a patient with superficial thrombophlebitis make it less likely that the patient will have DVT or other complications of superficial thrombophlebitis.89,90 Therefore, patients with superficial thrombophlebitis below the knee, no hypercoagulable risk factors, and varicose veins are less likely to have an associated DVT.91 Some authors recommend that all patients with superficial thrombophlebitis undergo ultrasonography to look for DVT.92 One practical pitfall that must be avoided results from the terminology used in some ultrasound reports. 62

Thrombosis may be reported in the superficial femoral vein, which is, in fact, part of the deep venous system. Thus, a thrombosis detected in the superficial femoral vein is a DVT and should be treated as such.93 A workup for an underlying malignancy or hypercoagulable state should be considered if superficial thrombophlebitis occurs in the upper extremity unrelated to IV therapy or spontaneously in any vein that is not a dilated, tortuous varicosity. HIT may also present as a superficial thrombophlebitis and should be considered if the thrombosis manifests as inflammation or skin necrosis at a heparin injection site, is in an unusual location, is extensive, or is associated with prior heparin administration within the previous 90 days or a 50% decline in the platelet count. Treatment Before clinicians came to appreciate the potential complications of superficial thrombophlebitis, treatment was mainly aimed at mitigating local symptoms. These measures included the use of compression stockings, heat, elevation, and nonsteroidal anti-inflammatory drugs (NSAIDs). Topical and oral diclofenac was found in a prospective trial of patients with infusion-related superficial thrombophlebitis to be superior to placebo at improving symptoms.94,95 A topical liposomal heparin spray was also found to help with local symptoms.96 These treatments, however, are aimed at controlling symptoms and do not represent definitive therapy. One of the larger trials enrolled 562 patients with superficial thrombophlebitis and large varicose veins who did not have a known systemic disorder. This study contained six arms: elastic compression stockings, surgical long saphenous vein ligation, stripping of the affected veins, low-dose subcutaneous (SC) heparin, LMWH, and warfarin. The primary end point was extension of the thrombophlebitis at 3 and 6 months as assessed by ultrasound. At both time points, the incidence of extension of the thrombophlebitis was significantly higher in the compression stocking alone 63

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and saphenous vein ligation groups. There were no significant differences among the other groups.97 Another study enrolled 427 patients with superficial thrombophlebitis of the lower legs (and no DVT on enrollment) who were randomized to receive either 40 mg/day of SC enoxaparin, 1.5 mg/kg/day of SC enoxaparin, daily oral tenoxicam (an NSAID), or placebo. Patients were treated for 8 to 10 days, with the primary outcome being development of a DVT or PE within 12 days of starting the study. The rates of DVT or PE during the first 12 days were 0.9% in the enoxaparin 40-mg group and 1.0% in the enoxaparin 1.5-mg/kg group, which were significantly lower than the 2.1% rate in the tenoxicam group and the 3.6% rate in the placebo group. Thus, this study suggests that, in the short term, enoxaparin (at either dose) is more effective than either placebo or NSAIDs in preventing the development of DVT.98 Data are too limited to make firm recommendations about the best treatment for patients with superficial thrombophlebitis. Some of authors recommend using LMWH at intermediate or prophylactic doses for 1 month to reduce the likelihood of extension of the superficial thrombophlebitis or development of a DVT.75,92,95,99 Whether anticoagulation should be used in all patients with the thrombophlebitis or only in patients with superficial thrombophlebitis above the knee, as some advocate,91 is an issue that remains unsettled.

Thrombosis at Rare Sites Cerebral Venous Thrombosis Cerebral venous thrombosis may consist of thrombosis of the cerebral veins, resulting in venous obstruction, ensuing edema, and potential infarction. Alternatively, cerebral venous thrombosis may occur as thrombosis of the venous sinus, resulting in decreased cerebrospinal fluid absorption, in turn causing intracranial hypertension. (Ventriculomegaly and hydrocephalus do not generally occur.100) Common signs and symptoms include headache, 64

papilledema, hemiparesis, visual loss, diplopia, seizures, confusion or coma, and dysphasia. The most common symptom is headache.101,102 Cerebral venous thrombosis is rare, occurring in 3 to 4 cases per million population.100 Unlike typical strokes, cerebral venous thrombosis often occurs in younger patients and women. In one large multinational series of 624 patients with cerebral venous thrombosis, the mean age was 39 years, and 74.5% of patients were women.102 In most cases, a cause or risk factor for cerebral venous thrombosis can be identified. When the cause of the cerebral venous thrombosis is not apparent, a cause should be aggressively sought, and hypercoagulability testing should be conducted. Common causes and risk factors of cerebral vein thrombosis include genetic or acquired thrombophilia (eg, antiphospholipid antibody syndrome or nephrotic syndrome), pregnancy or puerperium; malignancy; a hematologic condition (eg, polycythemia or anemia); systemic inflammatory disease (eg, systemic lupus erythematosus or inflammatory bowel disease); infections (eg, meningitis); mechanical causes (eg, head injury, jugular vein or catheter occlusion, or neurosurgery); oral contraceptive use; thyroid disease; or dehydration.100,102 In only 12.5% of cases was no cause identified.102 MRI with MR venography is a sensitive imaging modality for diagnosing cerebral venous thrombosis and is the initial test of choice, although it may be less sensitive than cerebral angiography.103 CT is less sensitive than MRI and cannot definitively exclude the diagnosis of cerebral venous thrombosis, especially chronic cases. Cerebral angiography is less commonly used, and its main role is when the diagnosis is suspected but MRI results are negative.100,103–105 The common treatment for patients with cerebral venous thrombosis is anticoagulation to help prevent extension of the thrombus. In the series of 624 patients with cerebral venous thrombosis, 83.3% of them were anticoagulated in the acute phase, about two thirds of whom received IV heparin 65

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and one third of whom received LMWH.102 The largest trial of anticoagulation for cerebral sinus thrombosis randomized 60 patients to either LMWH for 3 weeks followed by warfarin for 10 weeks or to no anticoagulation. There were no new symptomatic cerebral hemorrhages in either group, and there was one GI bleed in the anticoagulation group. Using end points of death or disability at 3 and 12 weeks, the authors concluded that anticoagulation showed a trend toward improved outcomes but did not achieve statistical significance.106 Similarly, a pooled analysis of this trial and one other trial107 concluded that anticoagulation for cerebral sinus thrombosis showed a statistically nonsignificant trend toward benefit.108 An additional benefit to anticoagulation is that it presumably decreases the likelihood of PE, which has been reported in association with cerebral venous thrombosis.100,109 If there is evidence of increased intracranial pressure, then the patient should be treated with mannitol (Osmitrol®) and other treatments for elevated intracranial pressure, and decompressive surgery may be necessary.100 Portal Vein and Mesenteric Venous Thrombosis Portal vein thrombosis is thrombosis of the extrahepatic portion of the portal vein.110 Its overall incidence was 0.055% in a Japanese autopsy study. A more recent autopsy series found a prevalence of 1.0%.111 The most common causes are cirrhosis, primary hepatobiliary cancer (either hepatic carcinoma or biliary malignancy), secondary hepatobiliary malignancies (with pancreatic, gastric, and colorectal carcinomas being the most common), myeloproliferative disorders, and abdominal infections or inflammation.111 About 14% of cases are idiopathic.111,112 The decreased blood flow rate through the liver likely accounts for at least part of the increase in the rate of portal vein thrombosis in cirrhotic patients.113 There has also been a recent focus on the role of thrombophilias in portal vein thrombosis. One series identified 66

a prothrombotic disorder in 28% of patients with portal vein thrombosis; the most common conditions were hyperhomocysteinemia, antiphospholipid syndrome, hormone replacement therapy, factor V Leiden mutation, protein C deficiency, and polycythemia vera.112 Based on a pooled analysis of more than 3,000 patients, G20210A prothrombin mutation was found to confer an OR of 4.48 for portal vein thrombosis; the OR with factor V Leiden was 1.90.114 Therefore, a hypercoagulability evaluation should be undertaken in patients with portal vein thromboses. Common signs and symptoms include abdominal pain, splenomegaly, fever, hemorrhage, ascites, and weight loss.112 Symptoms may not always be present, however. In a study of 701 cirrhotic patients who underwent Doppler ultrasound examination, 11.2% had portal vein thrombosis, only 57% of whom were symptomatic.113 The complications typically seen with portal hypertension include gastric varices, esophageal varices, hemorrhage, and ascites.112 Diagnostically, ultrasonography is the appropriate firstline imaging modality for portal vein thrombosis. Using angiography or surgical correlation as the gold standard, color-flow Doppler ultrasonography was found to have an overall sensitivity and specificity for detection of 89% and 92%, respectively.115 Ultrasonography, however, may be less sensitive in diagnosing chronic, as opposed to acute, portal vein thrombosis. MRI and MR angiography are also sensitive for detecting portal vein thrombosis and should be the next diagnostic test if the patient’s body habitus or other factors cause a failure to visualize the portal vein or the clinician also wants to see more of the surrounding anatomy.116 CT may also be used.117 No randomized, controlled trials help guide treatment of patients with portal vein thrombosis. However, retrospective data suggest that in recent cases (defined by abdominal pain and no evidence of chronic portal hypertension or collateralization), anticoagulation with heparin in 31 patients resulted in 81% of patients achieving at least 67

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partial recanalization of the portal vein compared with the 2 patients who did not receive heparin, both of whom did not have recanalization. Thus, the authors recommend heparin to treat patients with recent portal vein thrombosis.118 Patients with cirrhosis or malignancy were excluded from this study, so it is unclear if these findings also apply to such patients. In another series of 67 patients with portal vein thrombosis, 45% of the patients without cancer and cirrhosis and 67% of the patients with cancer or cirrhosis had at least partial recanalization with heparin vs 15% of patients who did not receive heparin.112 The risk of recurrent thrombotic events, including a substantial number of thromboses of the mesenteric vein, appears to outweigh the risk of bleeding on anticoagulation.119 Most authors recommend anticoagulation for at least 3 to 6 months. If there is an underlying thrombophilia that cannot be remedied, then indefinite anticoagulation should be considered.110,120-123 Thrombolytic therapy has been used to treat patients with portal vein thrombosis,124 but its role remains undefined. In patients with chronic portal vein thrombosis, there is a risk of variceal bleeding (esophageal and gastric), and treatment aimed at reducing this risk is appropriate. Nonselective β-blockers or endoscopic therapy can be considered.120 In a study of 73 patients with portal vein thrombosis (without underlying cirrhosis or malignancy), variceal band ligation was found to be superior to sclerotherapy, achieving quicker elimination of the varices and reducing the rate of recurrent variceal bleeding.125 Mesenteric venous thrombosis shares a number of features with portal vein thrombosis and may coexist with it. In one series of 69 patients with mesenteric venous thrombosis, 39 had mesenteric venous thrombosis in combination with either thrombosis of the portal vein or splenic vein. Patients with isolated mesenteric venous thrombosis were more likely to have underlying hypercoagulable conditions, were harder to diagnose, and were more likely to 68

require surgery than patients who had mesenteric venous thrombosis combined with portal or splenic vein thrombosis.126 Abdominal pain is the primary symptom of acute mesenteric venous thrombosis, and abdominal pain out of proportion to the physical examination should make one suspicious of mesenteric ischemia, which may result from mesenteric thrombosis. Other symptoms include nausea, vomiting, and diarrhea, which may be bloody.127,128 The risk factors for mesenteric venous thrombosis include hypercoagulable conditions, hematologic conditions (eg, polycythemia vera), neoplasms, and abdominal inflammation (either infectious or noninfectious, eg, pancreatitis). Oral contraceptives have also been clearly associated with mesenteric venous thrombosis.128,129 CT is the best initial diagnostic test for mesenteric venous thrombosis.128,130 Laboratory results indicating metabolic acidosis, lactic acidosis, hyperphosphatemia, hyperamylasemia, and leukocytosis are nonspecific and abnormal only after intestinal necrosis has occurred. Therapy for acute mesenteric venous thrombosis consists of anticoagulation with IV heparin and surgery if there is any evidence of peritonitis or intestinal infarction. Patients with mesenteric vein thrombosis warrant a full hypercoagulability workup.127,128 Hepatic Vein Thrombosis (Budd-Chiari Syndrome) Budd-Chiari syndrome is the eponym for obstruction of the hepatic venous outflow. This obstruction may involve the small hepatic veins, the large hepatic veins, the inferior vena cava (IVC), or a combination and may be classified on this anatomic basis.131,132 Little epidemiologic data on Budd-Chiari have been published, but a report from Japan estimated a prevalence of 1 in 2.4 million.133 The most common presenting signs and symptoms are abdominal pain, ascites, and hepatomegaly, and the presence of these three features in a patient should prompt an evaluation for Budd-Chiari syndrome.132 Jaundice, splenomegaly, and lower extremity edema also frequently occur.134–136 69

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Symptoms are common in the acute syndrome, but in subacute or chronic disease the presentation may be more indolent. Underlying hypercoagulable states are major causes of Budd-Chiari syndrome, including factor V Leiden mutation, protein C deficiency, antiphospholipid antibodies, and the C677T (MTHFR) gene mutations. Any patient with Budd-Chiari syndrome should undergo a thorough workup for hypercoagulable states; 28% of patients with the syndrome had more than one risk factor for the disease.137 Latent myeloproliferative disorders are also common in Budd-Chiari syndrome, with one study of 20 patients finding spontaneous erythroid colony formation, signifying latent myeloproliferative disease, in 16 patients, only 2 of whom had evidence of overt disease.138 Other causes and associations with Budd-Chiari syndrome include malignancy, oral contraceptive use, pregnancy, Behçet’s disease, inflammatory bowel disease, and trauma.134,139 Doppler ultrasonography is the first-line test to assess for the syndrome, with a sensitivity of 87.5%.140 Although considered second-line testing because of its higher cost, MRI is also effective and has the advantages of better defining the surrounding anatomy and may assist in distinguishing among acute, subacute, and chronic Budd-Chiari syndrome.132,141 If there is a strong clinical suspicion for BuddChiari syndrome but the ultrasonography and MRI results are negative, then venography may be performed.134 For treatment, anticoagulation with heparin followed by warfarin is appropriate in the absence of contraindications.135 One retrospective series of 120 patients with Budd-Chiari syndrome from 1970 to 1992 found that all patients post-1985 received anticoagulation, and they had better survival outcomes, establishing at least an association.142 Another series comparing patients with Budd-Chiari syndrome treated medically with patients who underwent liver transplantation concluded that medical treatment was a viable option.143 Local thrombolysis may also be considered 70

as adjunctive therapy in patients with acute thromboses and appears to be most beneficial in thromboses that are smaller and not fully occlusive.144 Angioplasty is another option in the case of IVC webs or stenoses and with stenoses that are shorter in length.134,145 In patients with the syndrome in whom the thrombosis is believed to be chronic or when the other therapeutic measures previously mentioned have not been successful, portosystemic shunting may be used.132,135 Some centers have reported good long-term outcomes with portosystemic shunting, with one achieving a 1-year survival rate of 93% and a 5-year survival rate of 74% (without liver transplantation).146 Other centers have had less long-term success with portosystemic shunting and view it mainly as a bridge to liver transplantation.147 Patients with the syndrome in whom liver transplantation may be indicated include those with fulminant hepatic failure or cirrhosis and those in whom portosystemic shunting has been unsuccessful.134 Patients with genetic thrombophilias in whom liver transplantation may be corrective of these thrombophilias are also candidates.135 With liver transplantation in patients with Budd-Chiari syndrome, 3-year graft survival is 80.6%, and the 3-year patient survival is 84.9%. Prior portosystemic shunting does not have an adverse effect on transplant outcomes.134,135,148 Renal Vein Thrombosis Renal vein thrombosis in adults is strongly associated with the nephrotic syndrome,149 a hypercoagulable state with a high incidence of both venous and arterial thromboembolic events.150 In prospective studies, the incidence of renal vein thrombosis in patients with the nephrotic syndrome ranges from 2% to 51.9%.151,152 Among the different causes of the nephrotic syndrome, membranous nephropathy appears to pose the highest risk of renal vein thrombosis, although the risk is elevated in all causes of glomerulonephritis with the nephrotic syndrome.152,152 Other causes of renal vein thrombosis include hypercoagu71

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lable states, such as antiphospholipid antibody syndrome, factor V Leiden mutation, and protein C and S deficiency; oral contraceptives; postpartum state; malignancies, including renal cell carcinoma; acute pancreatitis; acute pyelonephritis; IVC thrombosis; dehydration (mainly in children); trauma; and renal transplantation, especially in the early posttransplant period.153 The clinical presentation of renal vein thrombosis can vary depending on whether it is acute or chronic. Patients with acute disease have symptoms and signs that may include flank pain and tenderness, gross hematuria, a low-grade fever, and deterioration in renal function. Patients with chronic disease may have few symptoms but urinalysis may show microscopic hematuria and an increase in proteinuria.149,153 Renal vein thrombosis may result in thromboembolic events, including PE.154 In one series of 89 patients with nephrotic syndrome, 21% were diagnosed with a PE based on high-probability V/Q scans, and an additional 11% were diagnosed with PE based on pulmonary angiography despite having had V/Q scans that were intermediate or low probability.155 There is an absence of consensus about the diagnostic imaging modality of choice in renal vein thrombosis, although one group contends that CT angiography should be the initial test.156 Renal venography is the gold standard, but it is invasive and rarely used in practice. One methodologically imperfect study evaluating CT found a sensitivity of 92% and a sensitivity of 100%.152,157 However, a downside of CT is that it requires potentially nephrotoxic IV contrast.153 The data on MRI are very limited, but some small case reports suggest that MRI is helpful in diagnosing renal vein thrombosis.158,159 Ultrasonography has the advantage of being noninvasive and not requiring contrast, but it is operator and body habitus dependent and appears to have limited sensitivity and specificity.152,160,161 Treatment consists of anticoagulation with heparin followed by warfarin.156,162 The optimal duration of anticoagu72

lation is unknown, but it should probably be continued as long as the nephrotic syndrome (or other hypercoagulable condition) is present, taking into consideration the bleeding risk.151 Anticoagulation may even lead to improved renal function.149 There is controversy over whether patients with nephrotic syndrome should receive prophylactic anticoagulation, although some authors have advocated its use in patients with membranous nephropathy.162 Thrombolytic therapy has been used to treat patients with renal vein thrombosis, but its use seems most appropriate in patients who have acute renal vein thrombosis, whose clot burden is large, and who have deterioration in renal function.152,163 Septic Thrombophlebitis Septic thrombophlebitis, also called suppurative thrombophlebitis, refers to infection of the venous wall in conjunction with venous thrombosis. It may involve superficial or deep veins.164 Superficial vein septic thrombophlebitis commonly results from IV catheters.74 Septic thrombophlebitis of the deep veins is often a consequence of the spread of an adjacent infection.164As with other endovascular infections, septic thrombophlebitis may result in persistent bacteremia and metastatic infections, including septic emboli. Important differences exist between superficial vein and deep vein septic thrombophlebitis in both high-risk populations and in appropriate treatment. Superficial Vein Septic Thrombophlebitis Superficial vein septic thrombophlebitis may result from loss of skin integrity over the vein, as occurs with IV catheters, allowing for direct inoculation of skin flora.164 Burn patients are at high risk, with one series of 4,636 burn patients finding an incidence of 4.2%. In this series, only 35% of patients with superficial septic thrombophlebitis had localized signs of infection. In most cases, positive blood cultures led to the search for a source, including actively examining prior sites of IV cannulation.165 Therefore, 73

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a high index of suspicion is needed to make the diagnosis. IV drug users are also at elevated risk for superficial vein septic thrombophlebitis.166 Antibiotic therapy is indicated, with the definitive treatment being surgical excision of the involved vein. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause, so any empiric antibiotic regimen should include vancomycin. Adjacent deep veins should be evaluated for thrombosis. If excision of the involved vein defervescence does not occur within 48 hours, then alternative diagnoses need to be considered. The role of anticoagulation is controversial.165,167 Deep Vein Septic Thrombophlebitis Deep vein septic thrombophlebitis may involve a number of different sites, including the internal jugular vein (Lemierre’s syndrome), the pelvic vein, the portal vein (pylephlebitis), and the cavernous sinus.164 Lemierre’s Syndrome This syndrome results from spread of infection from the oropharynx to the internal jugular vein. Presenting symptoms include high fevers, rigors, and neck pain and tenderness over the area of the internal jugular vein. Localized lymphadenopathy may be present, and there usually is an antecedent sore throat. This condition usually strikes otherwise healthy teenagers or young adults. Metastatic infections may occur, especially in the lungs and joints. The causative organism is classically Fusobacterium necrophorum, although it may also be polymicrobial. A CT scan is the appropriate initial test to look for signs of associated internal jugular vein thrombosis and any abscess that may be present. A commonly recommended antibiotic regimen includes penicillin and metronidazole.168,169 However, others have noted the presence of βlactamase–producing F necrophorum, so they recommend treatment with an antibiotic that is β-lactamase–resistant and has anaerobic activity, such as ticarcillin/clavulanate or 74

ampicillin/sulbactam.170 Any abscess that is found should be drained, but surgical excision of the involved internal jugular vein is usually unnecessary unless bacteremia or septic embolization continues while the patient is taking antibiotics. Anticoagulation is generally not used unless retrograde extension of the thrombus into the cavernous sinus occurs.168,169 Septic Pelvic Thrombophlebitis Involving the deep veins of the pelvis, septic pelvic thrombophlebitis should be suspected when women, within the first week either postpartum or postpelvic surgery, have spiking fevers despite taking appropriate antibiotics. Patients may also complain of abdominal or pelvic pain, and there may be GI involvement, such as an ileus. Occasionally, a ropelike mass can be palpated. Some draw a distinction between ovarian vein thrombophlebitis and septic pelvic thrombophlebitis of other deep pelvic veins. Ovarian vein thrombophlebitis is more likely to be accompanied by abdominal pain and to be detectable on imaging. Septic pelvic thrombophlebitis of other deep pelvic veins is less likely to have abdominal pain, less likely to be detectable on imaging, and may happen earlier postpartum.164,171 The incidence is higher in patients after cesarean section (1 in 800) than after vaginal delivery (1 in 9,000).172 CT or MRI of the abdomen may be used to look for evidence of thrombosis, although both of these imaging modalities have limited sensitivity, so they cannot exclude the diagnosis. Adding to the challenge of making this diagnosis is that blood culture results are often negative. Antibiotic treatment is indicated, with commonly recommended antibiotics including ampicillin/sulbactam or a carbapenem.173 The use of heparin is controversial. In the past, the resolution of fevers after a patient had been taking heparin was used to help confirm the diagnosis, although this is not a reliable diagnostic criterion. The one randomized trial of antibiotics alone versus antibiotics plus heparin in women with 75

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puerperal septic pelvic thrombophlebitis found no benefit to the addition of heparin, but the trial only included 14 patients.172 Most, but not all, authors recommend that heparin be given with antibiotics as treatment.164,171,174,175 Portal Vein Septic Thrombophlebitis Often referred to as pylephlebitis, septic thrombophlebitis of the portal vein usually results from infection in a vascular territory that drains into the portal vein. The most common associated infection is diverticulitis, followed by appendicitis and gastric ulcers. One case series highlighted the possibility that patients could have a hypercoagulable disorder, such as malignancy, that lead to a portal vein thrombosis, which then become secondarily infected.176 Patients present with fever, usually accompanied by abdominal pain. Diarrhea and jaundice have also been reported. Patients may present with sepsis, or they are at risk of progressing to sepsis. Bacteremia is common, occurring in 88% of patients in one series. Enteric flora are the common infecting organisms, and polymicrobial infections are typical.177 The optimal imaging modality for diagnosis is not known, but CT, MRI, and ultrasonography have all been used.178 The cornerstone of treatment is antibiotics, with the coverage based on the suspected source. The antibiotics should provide broad enteric coverage, such as with levofloxacin and metronidazole or a carbapenem. The role of anticoagulation is not clearly defined because no prospective data are available to guide recommendations. One retrospective review concluded that patients with portal vein septic thrombophlebitis who have a hypercoagulable state (eg, a neoplasm or clotting factor deficiency) or those who have involvement of the mesenteric vein should probably be anticoagulated, but those with involvement limited to the portal vein and without any hypercoagulable state may not need anticoagulation.179 Others, however, have argued that anticoagulation should be used more narrowly.164 76

Cavernous Sinus Thrombophlebitis Cavernous sinus thrombophlebitis is rare and usually results from spread of an infection of the face, sphenoid sinus, teeth, or palate. The two most common presenting symptoms are headache, which may be unilateral and retroorbital, and fever. Because of the specific cranial nerves that pass through the cavernous sinus and so can be affected, ptosis, proptosis, and ocular muscle paralysis can occur, as can chemosis. Either CT or MRI should be able to show cavernous sinus thrombophlebitis. S aureus is the most common causative organism. Treatment is with antibiotics, which should include either nafcillin or vancomycin, depending on the concern for MRSA, as well as ceftriaxone and metronidazole. High antibiotic doses should be used for central nervous system penetration. The role of anticoagulation is controversial. In two retrospective series, one concluded that early anticoagulation reduced morbidity but not mortality,180 and the other concluded that early anticoagulation may be helpful in cases of unilateral involvement in the absence of cortical venous infarction.181–183

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57. Timsit JF, Farkas JC, Boyer JM, et al: Central vein catheter-related thrombosis in intensive care patients: incidence, risks factors, and relationship with catheter-related sepsis. Chest 1998;114(1):207-213. 58. Haire WD, Lynch TG, Lieberman RP, et al: Utility of duplex ultrasound in the diagnosis of asymptomatic catheter-induced subclavian vein thrombosis. J Ultrasound Med 1991;10(9):493-496. 59. Köksoy C, Kuzu A, Kutlay J, et al: The diagnostic value of colour Doppler ultrasound in central venous catheter related thrombosis. Clin Radiol 1995;50(10):687-689. 60. Verso M, Agnelli G: Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 2003;21(19):3665-3675. 61. Lee AY, Levine MN, Baker RI, et al: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349(2):146-153. 62. Lindhoff-Last E, Nakov R, Misselwitz F, et al: Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight heparin. Br J Haematol 2002;118(4):1137-1142. 63. Warkentin TE, Eikelboom JW: Who is (still) getting HIT? Chest 2007;131(6):1620-1622. 64. Haire WD, Lynch TG, Lieberman RP, et al: Duplex scans before subclavian vein catheterization predict unsuccessful catheter placement. Arch Surg 1992;127(2):229-230. 65. Seigel EL, Jew AC, Delcore R, et al: Thrombolytic therapy for catheter-related thrombosis. Am J Surg 1993;166(6):716-718; discussion 718-719. 66. Couban S, Goodyear M, Burnell M, et al: Randomized placebocontrolled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer. J Clin Oncol 2005;23(18):4063-4069. 67. Karthaus M, Kretzschmar A, Kröning H, et al: Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: final results of a double-blind, placebocontrolled phase III trial. Ann Oncol 2006;17(2):289-296. 68. Chaukiyal P, Nautiyal A, Radhakrishnan S, et al: Thromboprophylaxis in cancer patients with central venous catheters. a systematic review and meta-analysis. Thromb Haemost 2008;99(1):38-43.

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69. Kirkpatrick A, Rathbun S, Whitsett T, et al: Prevention of central venous catheter-associated thrombosis: a meta-analysis. Am J Med 2007;120(10):901.e901-913. 70. Puéchal X, Fiessinger JN: Thromboangiitis obliterans or Buerger’s disease: challenges for the rheumatologist. Rheumatology 2007;46(2):192-199. 71. Del Conde I, Bharwani LD, Dietzen DJ, et al: Microvesicle-associated tissue factor and Trousseau’s syndrome. J Thromb Haemost 2007;5(1):70-74. 72. Schönauer V, Kyrle PA, Weltermann A, et al: Superficial thrombophlebitis and risk for recurrent venous thromboembolism. J Vasc Surg 2003;37(4):834-838. 73. Leon L, Giannoukas AD, Dodd D, et al: Clinical significance of superficial vein thrombosis. Eur J Vasc Endovasc Surg 2005;29 (1):10-17. 74. Luis Rodríguez-Peralto J, Carrillo R, Rosales B, et al: Superficial thrombophlebitis. Semin Cutan Med Surg 2007;26(2): 71-76. 75. Di Nisio M, Wichers IM, Middeldorp S: Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev 2007(2):CD004982. 76. de Godoy JMP, Braile DM: Protein S deficiency in repetitive superficial thrombophlebitis. Clin Appl Thromb Hemost 2003;9(1): 61-62. 77. de Godoy JM, Batigália F, Braile DM: Superficial thrombophlebitis and anticardiolipin antibodies:report of association. Angiology 2001;52(2):127-129. 78. Samlaska CP, James WD: Superficial thrombophlebitis. I. Primary hypercoagulable states. J Am Acad Dermatol 1990;22 (6 Pt 1):975-989. 79. Webster J, Clarke S, Paterson D, et al: Routine care of peripheral intravenous catheters versus clinically indicated replacement: randomised controlled trial. Br Med J 2008;337:a339. 80. Maki DG: Improving the safety of peripheral intravenous catheters. Br Med J 2008;337:a630. 81. O’Grady NP, Alexander M, Dellinger EP, et al: Guidelines for the prevention of intravascular catheter-related infections. Infect Control Hosp Epidemiol 2002;23(12):759-769.

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82. Jorgensen JO, Hanel KC, Morgan AM, et al: The incidence of deep venous thrombosis in patients with superficial thrombophlebitis of the lower limbs. J Vasc Surg 1993;18(1):70-73. 83. Bounameaux H, Reber-Wasem MA: Superficial thrombophlebitis and deep vein thrombosis. a controversial association. Arch Intern Med 1997;157(16):1822-1824. 84. van Weert H, Dolan G, Wichers I, et al: Spontaneous superficial venous thrombophlebitis: does it increase risk for thromboembolism? A historic follow-up study in primary care. J Fam Pract 2006;55(1):52-57. 85. Verlato F, Zucchetta P, Prandoni P, et al: An unexpectedly high rate of pulmonary embolism in patients with superficial thrombophlebitis of the thigh. J Vasc Surg 1999;30(6):1113-1115. 86. Blumenberg RM, Barton E, Gelfand ML, et al: Occult deep venous thrombosis complicating superficial thrombophlebitis. J Vasc Surg 1998;27(2):338-343. 87. Falagas ME, Vergidis PI: Narrative review: diseases that masquerade as infectious cellulitis. Ann Intern Med 4 2005;142(1):47-55. 88. Sullivan V, Denk PM, Sonnad SS, et al: Ligation versus anticoagulation: treatment of above-knee superficial thrombophlebitis not involving the deep venous system. J Am Coll Surg 2001;193(5):556-562. 89. Lutter KS, Kerr TM, Roedersheimer LR, et al: Superficial thrombophlebitis diagnosed by duplex scanning. Surgery 1991;110(1): 42-46. 90. Bergqvist D, Jaroszewski H: Deep vein thrombosis in patients with superficial thrombophlebitis of the leg. Br Med J (Clin Res Ed) 1986;292(6521):658-659. 91. De Maeseneer MG; Thrombosis Guidelines Group of the Belgian on; Thrombosis and Haemostasis; Belgian Working Group on Angiology: Superficial thrombophlebitis of the lower limb: practical recommendations for diagnosis and treatment. Acta Chir Belg 2005;105(2):145-147. 92. Decousus H, Epinat M, Guillot K, et al: Superficial vein thrombosis: risk factors, diagnosis, and treatment. Curr Opin Pulm Med 2003;9(5):393-397. 93. Bundens WP, Bergan JJ, Halasz NA, et al: The superficial femoral vein. A potentially lethal misnomer. JAMA 25 1995;274(16):12961298.

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94. Becherucci A, Bagilet D, Marenghini J, et al: [Effect of topical and oral diclofenac on superficial thrombophlebitis caused by intravenous infusion.] Med Clin (Barc) 2000;114(10):371-373. 95. Buller HR, Agnelli G, Hull RD, et al: Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 suppl):401S-428S. 96. Górski G, Szopinski P, Michalak J, et al: Liposomal heparin spray: a new formula in adjunctive treatment of superficial venous thrombosis. Angiology 2005;56(1):9-17. 97. Belcaro G, Nicolaides AN, Errichi BM, et al: Superficial thrombophlebitis of the legs: a randomized, controlled, follow-up study. Angiology 1999;50(7):523-529. 98. Superficial Thrombophlebitis Treated By Enoxaparin Study Group: A pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal anti-inflammatory agent, and placebo in the treatment of superficial vein thrombosis. Arch Intern Med 2003;163(14):1657-1663. 99. Wichers IM, Di Nisio M, Büller HR, et al: Treatment of superficial vein thrombosis to prevent deep vein thrombosis and pulmonary embolism: a systematic review. Haematologica 2005;90(5):672-677. 100. Stam J: Thrombosis of the cerebral veins and sinuses. N Engl J Med 2005;352(17):1791-1798. 101. Bousser MG, Chiras J, Bories J, et al: Cerebral venous thrombosis: a review of 38 cases. Stroke 1985;16(2):199-213. 102. Ferro JM, Canhão P, Stam J, et al: Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004;35(3):664670. 103. Dormont D, Anxionnat R, Evrard S, et al: MRI in cerebral venous thrombosis. J Neuroradiol 1994;21(2):81-99. 104. Lafitte F, Boukobza M, Guichard JP, et al: MRI and MRA for diagnosis and follow-up of cerebral venous thrombosis (CVT). Clin Radiol 1997;52(9):672-679. 105. Teasdale E: Cerebral venous thrombosis: making the most of imaging. J R Soc Med 2000;93(5):234-237. 106. de Bruijn SF, Stam J: Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999;30(3):484-488.

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107. Einhäupl KM, Villringer A, Meister W, et al: Heparin treatment in sinus venous thrombosis. Lancet 1991;338(8767):597-600. 108. Stam J, de Bruijn S, deVeber G: Anticoagulation for cerebral sinus thrombosis. Stroke. 2003;34(4):1054-1055. 109. Cakmak S, Nighoghossian N, Desestret V, et al: Pulmonary embolism: an unusual complication of cerebral venous thrombosis. Neurology 2005;65(7):1136-1137. 110. Webster GJ, Burroughs AK, Riordan SM: Review article: portal vein thrombosis: new insights into aetiology and management. Aliment Pharmacol Ther 2005;21(1):1-9. 111. Ogren M, Bergqvist D, Björck M, et al: Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies. World J Gastroenterol 2006;12(13):2115-2119. 112. Sogaard KK, Astrup LB, Vilstrup H, et al: Portal vein thrombosis; risk factors, clinical presentation and treatment. BMC Gastroenterol. 2007;7:34. 113. Amitrano L, Guardascione MA, Brancaccio V, et al: Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 2004;40(5):736-741. 114. Dentali F, Galli M, Gianni M, et al: Inherited thrombophilic abnormalities and risk of portal vein thrombosis. a meta-analysis. Thromb Haemost 2008;99(4):675-682. 115. Tessler FN, Gehring BJ, Gomes AS, et al: Diagnosis of portal vein thrombosis: value of color Doppler imaging. AJR Am J Roentgenol 1991;157(2):293-296. 116. Hidajat N, Stobbe H, Griesshaber V, et al: Imaging and radiological interventions of portal vein thrombosis. Acta Radiol 2005;46(4):336-343. 117. Salanitri J: Portal vein thrombosis with unusual hepatic enhancement pattern: diagnosis using 64-slice multidetector computed tomography and 3 Tesla magnetic resonance imaging. Australas Radiol 2007;51(suppl):B292-B295. 118. Condat B, Pessione F, Helene Denninger M, et al: Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy. Hepatology 2000;32(3): 466-470.

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119. Condat B, Pessione F, Hillaire S, et al: Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy. Gastroenterology 2001;120(2):490-497. 120. de Franchis R: Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005;43(1):167-176. 121. Valla DC, Condat B: Portal vein thrombosis in adults: pathophysiology, pathogenesis and management. J Hepatol 2000;32 (5):865-871. 122. Spaander VM, van Buuren HR, Janssen HL: Review article: The management of non-cirrhotic non-malignant portal vein thrombosis and concurrent portal hypertension in adults. Aliment Pharmacol Ther 2007;26(suppl 2):203-209. 123. Condat B, Valla D: Nonmalignant portal vein thrombosis in adults. Nat Clin Pract Gastroenterol Hepatol 2006;3(9):505-515. 124. Blum U, Haag K, Rossle M, et al: Noncavernomatous portal vein thrombosis in hepatic cirrhosis: treatment with transjugular intrahepatic portosystemic shunt and local thrombolysis. Radiology 1995;195(1):153-157. 125. Zargar SA, Javid G, Khan BA, et al: Endoscopic ligation vs. sclerotherapy in adults with extrahepatic portal venous obstruction: a prospective randomized study. Gastrointest Endosc 2005;61(1):58-66. 126. Kumar S, Kamath PS. Acute superior mesenteric venous thrombosis: one disease or two? Am J Gastroenterol 2003;98(6):1299-1304. 127. Hassan HA, Raufman JP: Mesenteric venous thrombosis. South Med J 1999;92(6):558-562. 128. Kumar S, Sarr MG, Kamath PS: Mesenteric venous thrombosis. N Engl J Med 2001;345(23):1683-1688. 129. Hassan HA: Oral contraceptive-induced mesenteric venous thrombosis with resultant intestinal ischemia. J Clin Gastroenterol 1999;29(1):90-95. 130. Vogelzang RL, Gore RM, Anschuetz SL, et al: Thrombosis of the splanchnic veins: CT diagnosis. AJR Am J Roentgenol 1988;150(1):93-96. 131. Ludwig J, Hashimoto E, McGill DB, et al: Classification of hepatic venous outflow obstruction: ambiguous terminology of the Budd-Chiari syndrome. Mayo Clin Proc 1990;65(1): 51-55.

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132. Janssen HLA, Garcia-Pagan J-C, Elias E, et al: Budd-Chiari syndrome: a review by an expert panel. J Hepatol 2003;38(3): 364-371. 133. Okuda H, Yamagata H, Obata H, et al: Epidemiological and clinical features of Budd-Chiari syndrome in Japan. J Hepatol 1995;22(1):1-9. 134. Menon KVN, Shah V, Kamath PS: The Budd-Chiari syndrome. N Engl J Med 2004;350(6):578-585. 135. Senzolo M, Cholongitas EC, Patch D, et al: Update on the classification, assessment of prognosis and therapy of Budd-Chiari syndrome. Nat Clin Pract Gastroenterol Hepatol 2005;2(4): 182-190. 136. Tang TJ, Batts KP, de Groen PC, et al: The prognostic value of histology in the assessment of patients with Budd-Chiari syndrome. J Hepatol 2001;35(3):338-343. 137. Denninger MH, Chait Y, Casadevall N, et al: Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology 2000;31(3):587-591. 138. Valla D, Casadevall N, Lacombe C, et al: Primary myeloproliferative disorder and hepatic vein thrombosis. a prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med 1985;103(3):329-334. 139. Zimmerman MA, Cameron AM, Ghobrial RM: Budd-Chiari syndrome. Clin Liver Dis 2006;10(2):259-273, viii. 140. Bolondi L, Gaiani S, Li Bassi S, et al: Diagnosis of BuddChiari syndrome by pulsed Doppler ultrasound. Gastroenterology 1991;100(5 Pt 1):1324-1331. 141. Noone TC, Semelka RC, Siegelman ES, et al: Budd-Chiari syndrome: spectrum of appearances of acute, subacute, and chronic disease with magnetic resonance imaging. J Magn Reson Imaging 2000;11(1):44-50. 142. Zeitoun G, Escolano S, Hadengue A, et al: Outcome of Budd-Chiari syndrome: a multivariate analysis of factors related to survival including surgical portosystemic shunting. Hepatology 1999;30(1):84-89. 143. Min AD, Atillasoy EO, Schwartz ME, et al: Reassessing the role of medical therapy in the management of hepatic vein thrombosis. Liver Transpl Surg 1997;3(4):423-429.

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144. Sharma S, Texeira A, Texeira P, et al: Pharmacological thrombolysis in Budd Chiari syndrome: a single centre experience and review of the literature. J Hepatol 2004;40(1):172-180. 145. Fisher NC, McCafferty I, Dolapci M, et al: Managing BuddChiari syndrome: a retrospective review of percutaneous hepatic vein angioplasty and surgical shunting. Gut 1999;44(4):568-574. 146. Rössle M, Olschewski M, Siegerstetter V, et al: The Budd-Chiari syndrome: outcome after treatment with the transjugular intrahepatic portosystemic shunt. Surgery 2004;135(4):394-403. 147. Attwell A, Ludkowski M, Nash R, et al: Treatment of BuddChiari syndrome in a liver transplant unit, the role of transjugular intrahepatic porto-systemic shunt and liver transplantation. Aliment Pharmacol Ther 15 2004;20(8):867-873. 148. Segev DL, Nguyen GC, Locke JE, et al: Twenty years of liver transplantation for Budd-Chiari syndrome: a national registry analysis. Liver Transpl 2007;13(9):1285-1294. 149. Llach F, Papper S, Massry SG: The clinical spectrum of renal vein thrombosis: acute and chronic. Am J Med 1980;69(6): 819-827. 150. Mahmoodi BK, ten Kate MK, Waanders F, et al: High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study. Circulation 2008;117(2):224-230. 151. Yudd M, Llach F: Disorders of the renal arteries and Veins. In: Brenner BM, ed. Brenner & Rector’s The Kidney, vol 2, 7th ed. Philadelphia: Saunders; 2004:1584-1599. 152. Singhal R, Brimble KS: Thromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management. Thromb Res 2006;118(3):397-407. 153. Lewis J, Greco B: Atheromatous and thromboembolic renovascular disease. In: Feehally J, Floege J, Johnson RJ, eds. Comprehensive Clinical Nephrology. Philadelphia: Mosby; 2007:741-743. 154. Chugh KS, Malik N, Uberoi HS, et al: Renal vein thrombosis in nephrotic syndrome: a prospective study and review. Postgrad Med J 1981;57(671):566-570. 155. Cherng SC, Huang WS, Wang YF, et al: The role of lung scintigraphy in the diagnosis of nephrotic syndrome with pulmonary embolism. Clin Nucl Med 2000;25(3):167-172.

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156. Asghar M, Ahmed K, Shah SS, et al: Renal vein thrombosis. Eur J Vasc Endovasc Surg 2007;34(2):217-223. 157. Wei LQ, Rong ZK, Gui L, et al: CT diagnosis of renal vein thrombosis in nephrotic syndrome. J Comput Assist Tomogr 1991;15(3):454-457. 158. Tempany CM, Morton RA, Marshall FF: MRI of the renal veins: assessment of nonneoplastic venous thrombosis. J Comput Assist Tomogr 1992;16(6):929-934. 159. Hussein M, Mooij J, Khan H, et al: Renal vein thrombosis, diagnosis and treatment. Nephrol Dial Transplant 1999;14(1): 245-247. 160. Platt JF, Ellis JH, Rubin JM: Intrarenal arterial Doppler sonography in the detection of renal vein thrombosis of the native kidney. AJR Am J Roentgenol 1994;162(6):1367-1370. 161. Khati NJ, Hill MC, Kimmel PL: The role of ultrasound in renal insufficiency: the essentials. Ultrasound Q 2005;21(4):227-244. 162. Sarasin FP, Schifferli JA: Prophylactic oral anticoagulation in nephrotic patients with idiopathic membranous nephropathy. Kidney Int 1994;45(2):578-585. 163. Markowitz GS, Brignol F, Burns ER, et al: Renal vein thrombosis treated with thrombolytic therapy: case report and brief review. Am J Kidney Dis 1995;25(5):801-806. 164. Chirinos JA, Garcia J, Alcaide ML, et al: Septic thrombophlebitis: diagnosis and management. Am J Cardiovasc Drugs 2006;6(1):9-14. 165. Pruitt BA Jr, McManus WF, Kim SH, et al: Diagnosis and treatment of cannula-related intravenous sepsis in burn patients. Ann Surg 1980;191(5):546-554. 166. Baker CC, Petersen SR, Sheldon GF: Septic phlebitis: a neglected disease. Am J Surg 1979;138(1):97-103. 167. Katz SC, Pachter HL, Cushman JG, et al: Superficial septic thrombophlebitis. J Trauma 2005;59(3):750-753. 168. Riordan T, Wilson M: Lemierre’s syndrome: more than a historical curiosa. Postgrad Med J 2004;80(944):328-334. 169. Dool H, Soetekouw R, van Zanten M, et al: Lemierre’s syndrome: three cases and a review. Eur Arch Otorhinolaryngol 2005;262(8):651-654. 170. Golpe R, Marin B, Alonso M: Lemierre’s syndrome (necrobacillosis). Postgrad Med J 1999;75(881):141-144.

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171. Klima DA, Snyder TE: Postpartum ovarian vein thrombosis. Obstet Gynecol 2008;111(2 Pt 1):431-435. 172. Brown CE, Stettler RW, Twickler D, et al: Puerperal septic pelvic thrombophlebitis: incidence and response to heparin therapy. Am J Obstet Gynecol 1999;181(1):143-148. 173. Kominiarek MA, Hibbard JU: Postpartum ovarian vein thrombosis: an update. Obstet Gynecol Surv 2006;61(5):337-342. 174. Falagas ME, Vardakas KZ, Athanasiou S: Intravenous heparin in combination with antibiotics for the treatment of deep vein septic thrombophlebitis: a systematic review. Eur J Pharmacol 2007;557(2-3): 93-98. 175. Garcia J, Aboujaoude R, Apuzzio J, et al: Septic pelvic thrombophlebitis: diagnosis and management. Infect Dis Obstet Gynecol 2006;2006:15614. 176. Singh P, Yadav N, Visvalingam V, et al: Pylephlebitis: diagnosis and management. Am J Gastroenterol 2001;96(4):1312-1313. 177. Plemmons RM, Dooley DP, Longfield RN. Septic thrombophlebitis of the portal vein (pylephlebitis): diagnosis and management in the modern era. Clin Infect Dis 1995;21(5):1114-1120. 178. Balthazar EJ, Gollapudi P: Septic thrombophlebitis of the mesenteric and portal veins: CT imaging. J Comput Assist Tomogr 2000;24(5):755-760. 179. Baril N, Wren S, Radin R, et al: The role of anticoagulation in pylephlebitis. Am J Surg 1996;172(5):449-452; discussion 452-443. 180. Levine SR, Twyman RE, Gilman S. The role of anticoagulation in cavernous sinus thrombosis. Neurology 1988;38(4):517-522. 181. Southwick FS, Richardson EP Jr, Swartz MN: Septic thrombosis of the dural venous sinuses. Medicine (Baltimore) 1986;65(2):82106. 182. Ebright JR, Pace MT, Niazi AF: Septic thrombosis of the cavernous sinuses. Arch Intern Med 2001;161(22):2671-2676. 183. Southwick FS: Septic thrombophlebitis of major dural venous sinuses. Curr Clin Top Infect Dis 1995;15:179-203.

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Chapter 5

Pulmonary Embolism: Epidemiology, Diagnosis, and Treatment Chee M. Chan, Andrew F. Shorr

P

ulmonary embolism (PE) results from occlusion of the pulmonary arterial bed and can lead to acute cardiovascular collapse or acute right heart failure. Expeditious treatment of patients with acute PE is aimed at stabilization of clot or immediate reestablishment of flow to the pulmonary vascular system. The clinical diagnosis of PE remains challenging. Patients with PE often present with nonspecific clinical symptoms, causing physicians to pursue alternative diagnoses before considering PE. However, a high clinical suspicion for PE results in timely diagnostic evaluation and prompt initiation of therapy. The disease’s importance has led to much research and to the development of management guidelines by the American College of Chest Physicians (ACCP).1 Adequate treatment of patients with acute PE significantly reduces mortality and the development of chronic sequelae, such as recurrent PE and chronic thromboembolic pulmonary hypertension (CTEPH). To minimize these risks, one must thoroughly understand the epidemiology of PE, the risk factors for venous thromboembolism (VTE), risk stratification for PE, diagnostic modalities, and therapeutic options. 92

Epidemiology PE was first studied in the1960s in orthopedic patients.2 As part of a larger spectrum of disease, namely VTE, PE is mostly a consequence of deep vein thrombosis (DVT), and management of PE and DVT should, therefore, be considered as a whole (Figure 5-1). Illustrating this relationship, 70% to 80% of PEs are accompanied by DVTs.3-5 Conversely, those without a detectable DVT likely have a thrombus that dislodged and embolized into the pulmonary arterial bed. Similarly, asymptomatic PE is noted in 40% to 50% of newly diagnosed symptomatic proximal DVTs, reinforcing the nexus between PE and DVT. If proximal DVTs are allowed to progress without treatment, nearly half lead to symptomatic PE within 3 months.3,4 The annual incidence of PE is difficult to assess. In the United States, the prevalence of PE among hospitalized patients was 0.4% between 1979 and 1999.6 There are an estimated 600,000 cases annually,3 and the acute case fatality rate ranges from 7% to 11%.7 Data from Olmsted County, Minnesota, indicated an annual incidence of 69 per 100,000 patients.8 Using autopsy data from 79% of all deceased inhabitants from Malmo, Sweden, 18.3% had a PE, and the incidence of PE was estimated to be 20.8 in 10,000 inhabitants per year.9 In Brittany, France, the incidence of PE was lower (6.0 in 10,000).10 An estimated 10% of symptomatic PEs are fatal within 1 hour after onset of symptoms.3,11 Within 2 weeks, another 25% of those with untreated clinically diagnosed PE die.12 Compounding this increased mortality is an accompanying high VTE recurrence rate if diagnosis is initially missed.12,13 More specifically, first symptomatic PEs bestow an increased risk of recurrent PE, and these subsequent clots increase risk of death 2- to 3-fold.14,15 Predisposing Risk Factors Awareness of factors that predispose to PE increases the likelihood of diagnosis because most patients have 93

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one or more predisposing factors.16 Approximately 20% of VTEs occur unprovoked.17 Virchow’s triad describes three fundamental principles that affect development of thromboembolic disease: disturbance in normal blood flow or stasis, injury to the vascular endothelium, and alteration in the constitution of blood or hypercoagulability. Alternatively, risk factors can be divided into those that are not modifiable (permanent) and those that are modifiable (temporary) (Table 5-1).1,18,19 Permanent risk factors include age,20 active malignancy, previous VTE, obesity, certain comorbid conditions (eg, chronic heart failure or respiratory failure),21 and neurologic injury resulting in hemiplegia.22,23 Congenital or acquired thrombophilias, such as protein C, protein S, and antithrombin deficiencies, factor V Leiden, prothrombin gene mutation, or dysfibrinogenemia, also substantially increase risk of thrombotic events. Medical therapy or lifestyle modification may often reduce or modify such risks. Total hip and knee surgery,24 trauma,25,26 spinal cord injury,27,28 and major general surgery impart a particularly high risk for VTE occurrence, which diminishes as time elapses. A sedentary lifestyle or occupation and prolonged immobilization from acute illness or travel also increase the risk for thromboembolism. Early and frequent mobilization of such patients dramatically modifies their risk profile. Central venous lines,29 pregnancy, and the use of oral contraceptives are other modifiable risk factors that must be considered when evaluating a patient for PE.

Pathophysiology The hemodynamic response associated with PE is influenced by the patient’s underlying cardiopulmonary reserve, neurohumoral effects, and degree of pulmonary vascular occlusion. Release of humoral factors, such as serotonin from platelets, thrombin from plasma, and histamine from tissue, have been shown to cause pulmonary vasoconstric94

tion in animals.30,31 However, the role of these factors in humans is not fully defined.32 Acute occlusion of the pulmonary arterial bed may significantly increase pulmonary vascular resistance. Unlike the crucible-shaped, thick-walled left ventricle, the right ventricle is normally a crescent-shaped, thin-walled chamber that wraps around the interventricular septum (Figure 5-2). Its highly compliant thin wall allows the right ventricle to accommodate large volumes of venous return without a significant increase in pressure. In fact, as right-sided filling pressure increases, the stroke work of the heart only minimally increases. However, these same unique properties of the right ventricle make it exquisitely sensitive to increases in afterload. In the absence of prior cardiopulmonary disease, the right ventricle cannot generate mean pulmonary pressures exceeding 40 mm Hg.33 Thus, in individuals with normal baseline cardiac and pulmonary physiology, mean pulmonary pressures will never surpass 40 mm Hg for hemodynamically stable PEs. Significant increases in pulmonary vascular resistance (afterload) cause right ventricular dilatation, hypokinesis, tricuspid regurgitation, and possible right ventricular failure. Right ventricular enlargement may also cause paradoxical movement of the interventricular septum (Figure 5-3).34 Normally bulging into the right ventricle during systole, increased right ventricular pressure relative to left ventricular pressure causes the septum to bulge into the left ventricle during systole.35 These physiologic changes may significantly reduce cardiac output, contributing to hemodynamic instability and eventual shock. If severe, the right ventricle’s inability to match increasing pressure demands may result in cardiac arrest. Furthermore, the right ventricular wall is primarily supplied by the right coronary artery. Reduced cardiac output from right ventricular strain compromises coronary perfusion pressure and further worsens right ventricular function. In combination, these factors may send the right heart into 95

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Figure 5-1: Pulmonary embolisms usually originate from the deep veins of the legs. Propagation of the clot results in thromboemboli traveling through the right heart to the lungs.

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(Reproduced with permission from Tapson VF: Acute pulmonary embolism. N Engl J Med 2008;358:1037-1052.)

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Table 5-1: Predisposing Factors for Venous Thromboembolism Predisposing Factor High-Risk Factors Hip or leg fracture Hip or knee replacement Major general surgery Major trauma Spinal cord injury Paralytic stroke Moderate-Risk Factors Central venous lines Chemotherapy Chronic heart disease Chronic respiratory disease Irritable bowel disease Hormone replacement therapy Malignancy

Not Modifiable (Permanent)

Modifiable (Temporary) √ √ √ √

√ √

√ √ √ √ √ √ √

a vicious cycle of decompensation from which it cannot recover (Figure 5-4).36 For those who survive the initial event, secondary hemodynamic instability may occur within 24 to 48 hours. The cause of this decompensation is unknown, but possible 98

Predisposing Factor

Not Modifiable (Permanent)

Moderate-Risk Factors (continued) Oral contraceptive therapy Postpartum pregnancy Previous VTE Thrombophilia

Modifiable (Temporary)

√ √

5

√ √

Low-Risk Factors Bed rest >3 days

√

Immobility from prolonged sitting

√

Age >60 years

√

Obesity

√

Laparoscopic surgery

√

Antepartum pregnancy

√

Varicose veins

√

VTE=venous thromboembolism. Adapted from Torbicki et al18.

explanations include the presence of recurrent emboli or the body’s inability to maintain systemic compensatory mechanisms after the initial acute PE. Several mechanisms contribute to arterial hypoxemia in patients with acute PE. In normal lungs, the ratio of 99

Figure 5-2: Diagram showing the partial cross section of the right ventricle (RV) and left ventricle (LV). Note the concentric shape of the LV and the thin-walled RV wrapping the interventricular septum. LA=left atrium, RA=right atrium. (Reproduced with permission from Guyton AC: Textbook of Medical Physiology, 2nd ed. Philadelphia: WB Saunders Co; 1981, pp 124.)

ventilation to lung units and blood flow to pulmonary capillaries (V/Q) is well matched and is approximately 1.0. Matched alveolar ventilation and pulmonary capillary perfusion optimizes gas exchange for efficient transfer of oxygen and carbon dioxide across the lungs. Therefore, reduction in alveolar ventilation relative to blood flow to the pulmonary vasculature impairs oxygen transfer; V/Q is then mismatched, with a ratio below 1.0. When alveolar ventilation is absent or when blood bypasses the pulmon100

5

Figure 5-3: The unique right ventricular (RV) shape and its significance. The crescent shape of the RV allows it to accommodate large intraventricular volumes with minimal increase in free wall area. RV overload may cause paradoxical movement of the interventricular septum and decreased left ventricular (LV) filling. (Reproduced with permission from Greyson CR.34)

ary circulation directly entering the systemic circulation, right-to-left shunt occurs, resulting in hypoxemia refractory to oxygen therapy (Figure 5-5). In acute PE, occlusion of the pulmonary vasculature results in redistribution of blood to different lung units. Ventilation to some lung units will be low relative to capillary perfusion, causing a low V/Q and arterial hypoxemia.37 Other contributing factors to hypoxemia include the pres101

102

Pressure load Volume load

Increased RV pressure RV decompensation Ischemia Increased RV wall stress (02 demand) Increased RV volume Decreased right coronary driving pressure Decreased LV diastolic compliance (septal shift)

Systemic hypotension decreased cardiac output

Decreased LV preload

Tricuspid insufficiency

Decreased RV output

Figure 5-4: Multiple factors contribute to right ventricular (RV) dysfunction. If allowed to progress, the RV may enter a vicious cycle of decompensation. LV = l e f t ve n t r i c l e. (Reproduced with permission from Wiedemann HP, Matthay RA: Acute right heart failure. Crit Care Clin 1985;1(3):631-661.)

ence of right-to-left shunting and decreased cardiac output from right ventricular failure. Lack of response to oxygen supplementation in some patients with PE represents the existence of shunting.38 Venous blood bypasses the pulmonary circulation via the heart or lungs; intracardiac shunting through a patent foramen ovale occurs from increased right atrial pressure relative to left atrial pressure. Atelectatic lung or pulmonary hemorrhage may significantly reduce V/Q matching or even cause intrapulmonary shunting. Finally, increased extraction of oxygen in tissues because of low cardiac output reduces the partial pressure of oxygen in venous blood. Together, these factors significantly reduce oxygen content and delivery to vital organs. Alternatively, redistribution of blood to other lung units increases ventilation relative to perfusion. Dead space arises when there is total obstruction of blood flow in the presence of ventilated lung units. Increased dead space impairs efficient carbon dioxide elimination. The increase in carbon dioxide levels stimulates medullary chemoreceptors38 to increase minute ventilation and often results in respiratory alkalosis.

Classification and Risk Stratification PE is classified into three categories: massive, submassive, and nonmassive. This classification pertains to the level of hemodynamic stability and risk of mortality as opposed to the amount of clot burden or distribution of intrapulmonary emboli.18 Those with massive PE have hemodynamic instability translating into a higher risk of immediate death. Short-term mortality is greater than 15%17,39 and requires immediate aggressive diagnostic and therapeutic intervention. At 3 months, mortality is greater than 50%, but fortunately, fewer than 5% of all PEs present in this life-threatening fashion.17 Submassive PE refers to the presence of right ventricular dysfunction without hemodynamic compromise. Usually 103

5

104

O2 = 150 mm Hg CO2 = 0

B O2 = 40 CO2 = 45

O2=40

A

C

O2 = 100 CO2 = 40

O2 = 150 CO2 = 0

CO2 = 45 0

∞

Normal Diminution

Augmentation

V/Q

V/Q

Figure 5-5: Schematic of the ventilation/perfusion (V/Q) relationship. A. Normal lung ventilation is well matched with capillary perfusion (V/Q=1.0). B. When ventilation is absent despite adequate perfusion, shunting occurs (V/Q=0). C. Ventilated lung units that are not perfused produce dead space (V/Q = ∞). (Reproduced with permission from West JB: Respiratory Physiology: The Essentials, 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2000, p 52.)

diagnosed using echocardiography, right ventricular dysfunction is defined as right ventricular enlargement combined with loss of inspiratory collapse of the inferior vena cava (IVC) or presence of pulmonary artery hypertension without left ventricular failure or mitral valve disease.40 About 40% to 50% of all PEs present with right ventricular dysfunction; the 3-month mortality rate is estimated at 20%.17 Hemodynamically stable PEs without right ventricular strain are nonmassive; the immediate 2-week mortality is approximately 10% and increases to about 15% at 3 months.17 Proper classification and aggressive diagnosis of massive and submassive PEs are imperative to management. The poorer prognosis of massive PE requires specific lifesaving therapy. Careful monitoring of patients with right ventricular dysfunction can catch early hemodynamic decompensation from right ventricular failure and trigger more aggressive therapies.

Diagnosis Vague clinical symptoms require physicians to maintain vigilance in considering PE in the appropriate clinical setting. The availability of clinical prediction rules helps determine whether diagnosis of PE should be pursued. In the face of high clinical suspicion, many modalities exist to assist in diagnosis. Surrogate markers are often used in combination to rule out PE or as early markers for right ventricular dysfunction. Clinical Presentation Evaluating the likelihood of PE (eg, pretest probability) is integral to the interpretation of diagnostic tests. More than 90% of patients present with one or more of the following: dyspnea, pleuritic chest pain, and syncope (Table 5-2).41 Classically, dyspnea is abrupt in onset but may be slowly progressive over the course of days or weeks. In about 30% of cases, dyspnea is the only presenting symptom,42 and 105

5

PE is considered when further workup for other causes of dyspnea remains inconclusive. Pleuritic chest pain is caused by irritation of the pleura by distal emboli, inducing pulmonary infarction; actually a form of alveolar hemorrhage, hemoptysis is a rare accompanying symptom.43 Syncope is an ominous sign that may indicate reduced hemodynamic reserve. Most likely a consequence of increasing dead space and hypoxemia, tachypnea is the most common clinical sign of PE. Tachycardia and cyanosis are also manifestations of decreased oxygen content and cardiac output. Chest radiographs are usually abnormal (Table 5-3). Atelectasis, pleural effusions, and pleural-based opacities are the most common chest radiography findings.44,45 Similar to the clinical signs and symptoms, radiographic findings are usually nonspecific, and the initial chest radiographs are predominantly used to exclude other potential causes for hypoxemia and dyspnea rather than as confirmatory testing. D-dimer D-dimer is a fibrin degradation product that is elevated in acute thrombosis. Active coagulation and fibrinolysis produce D-dimer, and normal levels are therefore useful in excluding PE or DVT with a high negative predictive value (NPV).46,47 However, elevated D-dimer levels have also been found in patients with cancer, infection, necrosis, trauma, and other inflammatory states and therefore cannot be used to confirm the diagnosis of PE48,49; the positive predictive value (PPV) is low (Figure 5-6). Several assays are available for measuring D-dimer levels.48,49 Enzyme-linked immunosorbent assay (ELISA) is highly sensitive (>95%), but its specificity is only 40%. Sensitivity for both the quantitative latex-derived assays and whole blood agglutination assay ranges from 85% to 90%. In low or moderate pretest probability, a low D-dimer (<500 μg/L) yields a 3-month thromboembolic risk of less than 1%.50-53 Thus, in the emergency department, a low Ddimer together with a low or moderate pretest probability 106

Table 5-2: Prevalence of Signs and Symptoms in Patients With Suspected Pulmonary Embolism Pulmonary Embolism Confirmed (n=219) (%)

Pulmonary Embolism Excluded (n=546) (%)

Dyspnea

80

59

Chest pain (pleuritic)

52

43

Chest pain (substernal)

12

8

Cough

20

25

Hemoptysis

11

7

Syncope

19

11

Tachypnea (≥20 breaths/min)

70

68

Tachycardia (>100 beats/min)

26

23

Signs of DVT

15

10

Cyanosis

11

9

Symptoms

5

Signs

DVT=deep vein thrombosis. Reproduced with permission from Torbicki et al.18

107

Table 5-3: Chest Radiograph Findings in Pulmonary Embolism Pulmonary Embolism (n=117) (%)

No Pulmonary Embolism (n=247) (%)

Atelectasis or parenchymal abnormality

68

48

Pleural effusion

48

31

Pleural based opacity

35

21

Elevated diaphragm

24

19

Decreased pulmonary vascularity

21

12

Prominent central pulmonary artery

15

11

Cardiomegaly

12

11

Westermark’s sign

7

2

Pulmonary edema

4

13

Reproduced with permission from Stein et al.44

for PE can preclude further diagnostic workup because the likelihood for PE is extremely low.52,54 But, the broad differential diagnosis associated with high D-dimer levels makes it useless in determining the presence of PE. When clinical suspicion for PE is high, imaging studies should be pursued irrespective of the D-dimer level.55 Clinical Prediction Rules The importance of pretest probability in diagnosing PE has been demonstrated in several large studies. In the 108

PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) study,56 patients were classified into one of three categories: low, moderate, and high clinical probability for PE. The posttest probability of PE using ventilation/perfusion scintigraphy (V/Q scan) varied considerably, depending on the pretest clinical probability. However, clinical judgment is often inaccurate and cannot be taught. Several clinical prediction rules have been developed to assist with pretest probability. The most frequently used scoring system is the Wells score (Table 5-4). The clinical probability for PE can be divided into one of three categories (low, moderate, high) or one of two categories (PE likely and PE unlikely). The rate of PE after 3-month follow-up in the low clinical probability group was 3.4%; it was 27.8% for moderate probability and 78.4% for high clinical probability.57 When combined with a negative D-dimer, validation of the Wells score demonstrated that the rate of PE was 2.7% (95% confidence interval [CI], 0.3% to 9.0%) if the score was less than 2% or 2.2% (CI, 1.0% to 4.0%) if the score is less than or equal to 4.58 Variables used to calculate the score are simple and easily accessible. Use of this scoring system is therefore helpful in determining the pretest probability for PE. The Geneva score is another prediction tool (Table 5-5). Similar to the Wells score, it is easy to apply.59 Ventilation/Perfusion Scintigraphy V/Q scintigraphy is a safe, well-established modality for diagnosing PE. The perfusion portion requires injection of technetium into the vasculature. Occlusion of the pulmonary arteries prevents technetium particles from entering the capillary bed. An accompanying ventilation scan using an inhaled tracer determines the presence or absence of a matched V/Q defect. In general, PE is diagnosed in the presence of a V/Q mismatch when ventilation is normal but perfusion is diminished or absent. The V/Q scan is therefore most diagnostic in patients without underlying cardiopulmonary disease. 109

5

110 Suspect PE

Clinical low or moderate

Clinical high

D-dimer rapid ELISA negative

D-dimer rapid ELISA positive

No treatment

Further tests

Further tests

Figure 5-6: D-dimer enzyme-linked immunosorbent assay (ELISA) pathway. A negative D-dimer safely rules out pulmonary embolism (PE) when clinical suspicion is low or moderate. High clinical suspicion or a positive D-dimer warrants further testing. (Reproduced with permission from Stein PD, et al.55)

Abnormalities in ventilation by lung parenchymal disease make it difficult to assess if perfusion defects are a consequence of clot or hypoxic pulmonary vasoconstriction. Normal lung perfusion essentially rules out acute PE, rendering it safe to withhold anticoagulation therapy. In the presence of a low clinical suspicion for PE, the negative predictive value (NPV) of a low-probability or normal V/Q scan is 96%.56 Additionally, the positive predictive value (PPV) of having a high-probability V/Q scan and high pretest clinical probability for PE ranges from 88% to 96%.56,60-62 Therefore, when both clinical judgment and imaging results correlate, V/Q scanning is very useful for the diagnosis of PE. However, when clinical suspicion contradicts V/Q imaging results or the V/Q results are nondiagnostic, further diagnostic testing should be pursued if alternative diagnoses are absent. Computed Tomography With improving technology, computed tomography (CT) is rapidly becoming the diagnostic test of choice for PE. Invention of the multidetector CT scanner has dramatically improved image quality and is relatively safe. Additionally, in light of nonspecific symptoms, visualization of the lung parenchyma may suggest alternative diagnoses when adequately visualized central, segmental, and subsegmental vessels show absence of PE. In the PIOPED II trial,63 824 patients with suspected PE underwent CT pulmonary angiography (CTPA) with a multidetector CT scan. The sensitivity and specificity of this modality were 83% (CI, 76% to 92%) and 96% (CI, 93% to 97%), respectively. The PPV was 86% (CI, 79% to 90%), and the NPV was 95% (CI, 92% to 96%). Similar to the V/Q scan, the pretest clinical probability for PE substantially changed the PPV and NPV of this test. When the index of suspicion was high or intermediate in the presence of a positive CTPA result, PPV increased to 96% (CI, 78% to 99%) and 92% (CI, 84% to 96%), respectively. Among those with 111

5

Table 5-4: Clinical Prediction Tool for Pulmonary Embolism: Wells Score Variable Predisposing Factors Previous DVT or PE Recent surgery or immobilization Cancer Symptoms Hemoptysis Clinical Signs Heart rate (>100 bpm) Clinical signs of DVT

Points +1.5 +1.5 +1 +1 +1.5 +3

Clinical Judgment Alternative diagnosis less likely than PE

+3

Clinical Probability (Three Levels) Low Intermediate High

Total 0-1 2-6 ≥7

Clinical Probability (Two Levels) PE unlikely PE likely

0-4 >4

DVT=deep vein thrombosis, PE=pulmonary embolism. Reproduced with permission from Torbicki A, et al.18 Data obtained from Wells et al.57

112

Table 5-5: Clinical Prediction Tool for Pulmonary Embolism: Revised Geneva Score Variable Predisposing Factors Age >65 years Previous DVT or PE Surgery or fracture within 1 mo Active malignancy

Points

Symptoms Unilateral lower limb pain Hemoptysis Clinical Signs Heart rate 75-94 bpm ≥95 bpm Pain on lower limb deep vein at palpation or unilateral edema Clinical Probability Low Intermediate High

+1 +3 +2 +2

5

+3 +2

+3 +5 +4

Total 0-3 4-10 ≥11

DVT=deep vein thrombosis; PE=pulmonary embolism. Reproduced with permission from Torbicki et al.18 Data obtained from Le Gal et al.59

113

low clinical suspicion and a negative CTPA result, the NPV was 96% (CI, 92% to 98%). However, when the clinical suspicion was low and the CTPA result was positive, the PPV decreased to 58%, and further diagnostic testing for confirmation may be warranted (Figure 5-7). CTPA may exclude PE when clinical probability is low or moderate, with or without D-dimer levels. In a study in which 756 consecutive emergency department patients were suspected of PE,64 442 patients with negative CTPA results and 232 with D-dimers below 500 μg/L were discharged without anticoagulation therapy. At 3-month follow-up, only 1.7% (CI, 0.7% to 3.9%) of the patients developed thromboembolism, although none were in the Ddimer alone category. In the Christopher study,50 the Wells score was used to determine the likelihood of PE. If PE was unlikely and the D-dimer result was negative, further testing was not pursued. Otherwise, CTPA was performed. The 3-month follow-up for 3,505 patients enrolled with suspected PEs showed a 0.5% incidence (CI, 0.2% to 1.1%) for VTE in those who had low D-dimer levels and 1.3% (CI, 0.7% to 2.0%) for those with a negative CTPA result. In a third similar study of 1,819 consecutive outpatients,65 the 3-month thromboembolic risk for those with low D-dimer and negative results was only 0.3% (CI, 0.1% to 1.1%). Therefore, these data suggest that a negative multidetector CT is sufficient to exclude patients for PE when the clinical suspicion is not high (Figure 5-8). However, when the presenting signs and symptoms strongly suggest PE, further diagnostic testing should be considered despite a negative CTPA result (Figure 5-9). In a recent large, randomized, controlled trial,66 CTPA diagnosed more patients with PE than V/Q scanning. The pretest probability for PE was determined using the Wells score and D-dimer testing. Of 701 patients randomized to the CTPA group, 19.2% were diagnosed with PE compared with 14.2% in the V/Q scan group. Because half of the V/Q scans were nondiagnostic, 7.0% were diagnosed with VTE 114

Low-probability clinical assessment Positive D-dimer rapid ELISA CT angiography or CT angiography CT venography

CT angiogram negative (NPV 96%) CT angiography/CT venography negative (NPV 97%)

No treatment

115

Figure 5-7: Low-probability clinical assessment. Negative computed tomography pulmonary angiography (CTPA) safely rules out pulmonary embolism (PE) when the clinical probability is low. CT=computed tomography, ELISA=enzymelinked immunosorbent a s s ay, M R I = m a g n e t i c resonance imaging, NPV= negative predictive value, PPV=positive predictive value. (Reproduced with permission from Stein PD, et al.55)

CT angiogram positive (PPV 58%) CT angiography/CT venography positive (PPV 57%)

Segmental (PPV 68%) Subsegmental (PPV 25%)

Options: • Repeat CT angiography or CT angiography/CT venogram if poor quality • If CT angiography only, ultrasonography or MRI venography • Pulmonary scintigraphy • Digital subtraction angiography • Serial ultrasonography

Main or lobar PE (PPV 97%)

Treat

5

using other diagnostic modalities. At 3-month follow-up, only 0.4% of patients in the CTPA group developed symptomatic VTE compared with 1.0% in the V/Q scanning group (95% CI, –1.6% to 0.3%; P=0.29). Therefore, these modalities are both safe and effective in excluding PE because failure to diagnose PE using either CTPA or V/Q scan were quite low. Those with indeterminate V/Q scans required further testing without the added benefit of evaluating the lung parenchyma. As such, CT scanning is becoming the preferred diagnostic tool. More PEs are diagnosed with CTPA than with V/Q scanning. Improvements in CT visualization of peripheral vessels have probably contributed to this increase. However, this also means that more patients are being subjected to the risks of anticoagulation therapy who would not have received them otherwise. Further investigation is required to confirm these findings and to determine the clinical significance of these PEs. The potential for contrast nephropathy must always be considered before obtaining a CTPA. Patients with chronic renal insufficiency and diabetes mellitus are at particular risk. Although the incidence for renal failure requiring hemodialysis is low, laboratory-defined contrast nephropathy (increase in creatinine >0.5 mg/dL or >25% within 7 days) occurs in 4% to 12% of cases.67 The increased cost and length of stay associated with this complication require careful consideration and prevention in those at risk.68 Pulmonary Angiography Pulmonary angiography is the gold standard for the diagnosis of PE, providing direct visualization of thrombi as small as 1 to 2 mm in the subsegmental arteries.69 However, it is invasive, requiring skilled physicians to both perform the test and accurately interpret the data. Injection of contrast dye can also induce contrast nephropathy in those with acute or chronic renal insufficiency. Although contrast nephropathy may also occur with CTPA, its quick, noninvasive nature and similar diagnostic yield have reduced the need to use pul116

Moderate-probability clinical assessment Positive D-dimer rapid ELISA CT angiography or CT angiography/CT venography CT angiography negative (NPV 89%) CT angiography/CT venography negative, (NPV 92%)

CT angiography positive (PPV 92%) CT angiography/CT venography positive, (PPV 90%)

No treatment

Treat

Figure 5-8: Moderate-probability clinical assessment. Patients in this group should be treated according to their computed tomography pulmonary angiography (CTPA) results with close follow-up. CT=computed tomography, MRI=magnetic resonance imaging, NPV=negative predictive value, PPV=positive predictive value. (Reproduced with permission from Stein PD, et al.55)

Options if CT angiography only, ultrasonography or MRI venography

117

5

118 High-probability clinical assessment

CT angiography or CT angiography CT venography

CT angiogram negative (NPV 60%) CT angiogram/CT venography negative, (NPV 82%)

CT angiography positive (PPV 96%) CT angiography/CT venography positive, (PPV 96%)

Options: • Repeat CT angiography or CT angiography/CT venography if poor quality • If CT angiography only, ultrasonography or MRI venography • Pulmonary scintigraphy • Digital subtraction angiography • Serial ultrasonography

Treat

Figure 5-9: High probability clinical assessment. Fur ther testing should be considered when computed tomography pulmonary angiography (CTPA) is negative when clinical suspicion is high. CT=computed tomography, MRI=magnetic resonance imaging, NPV=negative predictive value, PPV=positive predictive value. (Reproduced with permission from Stein PD, et al.55)

monary angiography for definitive diagnosis. The inability to appreciate the lung parenchyma for alternative diagnoses is another limiting factor. However, when other modalities are nondiagnostic, pulmonary angiography remains the definitive test of choice. Unfortunately, because of its invasive nature, the mortality rate for pulmonary angiography is 0.2% (95% CI, 0% to 0.3%), which usually occurs in those with hemodynamic compromise or acute respiratory failure.70 Right Ventricular Dysfunction With a full arsenal of readily available diagnostic tools, risk stratifying of patients with right ventricular dysfunction can be performed. Electrocardiography, a bedside tool, suggests right ventricular strain when there is new onset inversion of T waves in leads V1-V4, a QR pattern in lead V1, the classic S1Q3T3, or partial or complete right bundle branch block. In a prospective multivariate analysis,71 508 patients with acute massive or submassive PE were evaluated for the presence of electrocardiographic abnormalities. There findings were associated with an abnormal echocardiogram in 78% and an increased risk of death (odds ratio [OR], 2.56; CI, 1.49 to 4.57; P < 0.001). Thus, an echocardiogram may be used to screen hemodynamically stable PE patients for right ventricular dysfunction. Cardiac biomarkers can help with risk stratification. Kucher and Goldhaber72 demonstrated elevated cardiac troponin I and T levels in 11% to 50% of patients with acute PE. Echocardiographically detected right ventricular dysfunction correlates with cardiac troponin elevation, but normal levels rule out right ventricular dysfunction with an NPV of 93% to 100%. However, the PPV is only 12% to 44%.73 Similar to ECG findings, elevated troponin I levels (>0.5 ng/mL) are associated with increased allcause mortality (OR 3.5; 95% CI, 1.0 to 11.9).74 Although an elevated troponin level alone does not reliably predict adverse outcomes from acute PE, it can reliably predict those without right ventricular dysfunction. 119

5

Brain natriuretic peptide (BNP) and N-terminal fragment BNP (NT-proBNP) are released when cardiomyocytes are stretched from volume overload. NT-proBNP is another cardiac biomarker used to risk stratify patients with acute PE. Kostrubiec et al75 examined the prognostic value of both troponin T and NT-proBNP in 100 normotensive patients admitted with PE. They found that those with NT-proBNP levels below 600 pg/mL had no deaths or serious complications during 40-day follow-up. Those with NT-proBNP levels above 600 pg/mL but troponin T below 0.07 ng/mL had an intermediate risk of fatal outcome (3.7% for acute PE), and patients with NT-proBNP and troponin T elevations had a PE-related death rate of 33%. Cardiac markers are helpful in screening patients for right ventricular dysfunction, but echocardiography is still required for diagnosis. Echocardiogram findings of right ventricular dysfunction include right ventricular enlargement and hypokinesis, leftward septal shift, and evidence of pulmonary hypertension. Abnormal cardiac biomarkers (NT-proBNP >1000 μg/mL) and echocardiographic findings consistent with right ventricular strain are associated with a 12-fold increase in hospital death or complications (P=0.002). Likewise, the risk of adverse outcomes was increased 10-fold in patients with elevated troponin T and right ventricular dysfunction (P=0.004).76 Patients with acute PE should be risk stratified for right ventricular dysfunction. Normal cardiac enzymes and BNP levels can safely rule out right ventricular strain in hemodynamically stable patients. However, elevation of one or the other alludes to right heart strain and warrants echocardiography for definitive diagnosis.

Treatment For those who survive their initial PE, the goals of treatment include stabilization of the clot or immediate revascularization of occluded pulmonary vessels (Figure 5-10). With treatment, serial angiography and lung scanning 120

demonstrate minimal resolution of clot after 2 hours of treatment, about 10% resolution in 24 hours, 40% in 7 days, and 50% after 2 to 4 weeks. Eventually, there will be complete resolution in two thirds of cases; the remaining patients will have partial resolution.4 CTEPH occurs in about 5% of patients despite the use of anticoagulants.77,78 Nonmassive Pulmonary Embolism In patients with nonmassive PE, the objectives of anticoagulant therapy are to prevent propagation and recurrence of the clot. High mortality associated with untreated PE requires immediate anticoagulant therapy when the pretest probability is high and there are no contraindications to anticoagulation, even in patients awaiting definitive diagnostic confirmation. Generallly, treatment is tolerated well, with a low mortality rate. Therefore, immediate parenteral administration with an anticoagulant approved by the Food and Drug Administration, such as intravenous unfractionated heparin (UFH), subcutaneous low-molecular-weight heparins (LMWH), or a pentasaccharide, fondaparinux (Arixtra®), is imperative.1 UFH, an antithrombin inhibitor, has been used to treat patients with PE since the 1960s, when it was proven to decrease mortality compared with placebo.12 As a weightbased medication, an initial bolus of UFH should be given at 80 U/kg followed by an infusion at a rate of 18 U/kg/hr.79 Subsequent doses should be adjusted based on activated partial thromboplastin time (aPTT) levels to maintain a goal between 1.5 to 2.5 times control, checking aPTT levels every 4 to 6 hours until the target therapeutic dose has been reached.80 Thereafter, levels can be checked once a day to ensure adequate dosage. UFH is ideal for patients at increased risk of bleeding or those with severe renal impairment (creatinine clearance <30 mL/min). UFH heparin has a short half-life, can be stopped quickly, and can be reversed with protamine if significant bleeding occurs. 121

5

Otherwise, LMWH has rapidly become the anticoagulant of choice. LMWH is a polysaccharide formed by depolarization of UFH. LMWH is as safe and effective as UFH and does not require monitoring. Compilation of 12 studies into a meta-analysis (N=1,951) found that LMWH is at least as efficacious as UFH.81 Occurrence of symptomatic PE after treatment was only 1.7% with LMWH compared with 2.3% with UFH (OR, 0.72; CI, 0.35 to 1.48; P=NS). Additionally, the safety of LMWH is comparable to that of UFH, as evidenced by the low rate of all-cause mortality: 1.4% vs 1.2% after treatment (OR, 1.20; CI, 0.59 to 2.45; P=NS) and 4.7% vs 6.1% after 3 months (OR, 0.77; CI, 0.52 to 1.15; P=NS), respectively, and similarly low bleeding risk 1.4% for LMWH compared with only 2.3% in the UFH group (OR, 0.67; CI, 0.36 to 1.27; P=NS). One must exercise caution when using LMWH in patients with severe renal impairment.82 Dose adjustment is required when creatinine clearance is below 30 mL/min. Normal renal function precludes the need for anti-Xa levels but should be considered when renal function is impaired. The ideal time to check anti-Xa levels is 4 hours after administration of the morning dose. The target range is 0.6 to 1.0 IU/mL for twice-daily dosing and 1.0 to 2.0 IU/mL for once-daily dosing.83 In addition to bleeding, heparin-induced thrombocytopenia (HIT) is another potential complication of UFH or LMWH. HIT is an immune-mediated process in which antibodies of the immunoglobulin G class react with heparin–platelet factor 4 complexes to activate platelets.84-86 This thrombogenic condition causes arterial or venous thrombi formation in 20% to 50% of cases.87,88 The incidence of HIT is quite low (1% to 3% for UFH and about 1% for LMWH),89 but its potentially catastrophic sequelae require platelet monitoring during treatment with UFH or LMWH. Fondaparinux is a synthetic selective factor Xa inhibitor given subcutaneously. Its long half-life (17 to 21 hr) allows 122

Diagnosed PE

Hemodynamically stable

No ECG changes, BNP, and troponin

Hemodynamically unstable

5

ECG changes or BNP or troponin

Echocardiography

No RV dysfunction

RV dysfunction Monitor for hemodynamic status

Vital signs remain stable

Anticoagulation alone

Hemodynamic decompensation

Consider thrombolysis, thrombectomy, or embolectomy

Figure 5-10: Risk stratification algorithm for acute pulmonary embolism. BNP=brain natriuretic peptide, ECG=electrocardiogram, PE=pulmonary embolism, RV=right ventricle.

123

for once-daily administration. In the Matisse study, which included 2,213 PE patients,90 weight-adjusted, fixed-dose fondaparinux was associated with similar rates of recurrent VTE (3.8% vs 5.0%), major bleeding (2.0% vs 2.4%), and death (5.2% vs 4.4%) at 3 months as UFH. This medication is therefore as safe and effective as UFH for the treatment of patients with PE. Its use is contraindicated in patients with creatinine clearance below 30 mL/min given its long half-life. To date, there are no proven cases of HIT, and platelet count monitoring is therefore unnecessary when administering fondaparinux. Treatment with parenteral anticoagulants should be continued for 5 days while the patient is transitioning to oral vitamin K antagonists (VKAs). Five to 7 days of UFH is as effective as 10 to 14 days if alternative long-term therapy is adequate.91 If warfarin is the VKA of choice, parenteral treatment should be stopped when the International Normalized Ratio (INR) is between 2.0 and 3.0 for at least 2 consecutive days. After parenteral therapy has been initiated, starting VKAs the same day as initial anticoagulation is preferred.92 When given alone, VKAs confer a 3-fold increased risk for recurrent VTE93 from drug-induced protein C and S deficiency.94 Thus, VKAs should only be prescribed in combination with other anticoagulants. In general, the duration of treatment for PE with transient risk factors, such as recent surgery, trauma, medical illness, or pregnancy, is 3 months. Shorter durations increase the risk for VTE recurrence,95 and longer durations do not lower the rate of recurrence.96,97 Unprovoked PE is associated with higher rates of recurrence, and continued treatment with VKAs or LMWH should be reassessed at the end of 3 months.98 Those with persistent risk factors, such as thrombophilia, antiphospholipid syndrome, or one or more prior VTE, should be considered for longer, if not indefinite, therapy.18 In these patients, the risk of bleeding must be carefully balanced with the risk of recurrent VTE. Certainly, indefinite treatment is recommended 124

for patients with a malignancy and a second unprovoked PE or DVT. Therefore, in hemodynamically stable PE without evidence of right ventricular dysfunction, multiple agents are available for treatment. The most recent guidelines from the ACCP recommends initial therapy with UFH, LMWH, or fondaparinux for at least 5 days until the INR is 2.0 or above for at least 24 hours using VKAs.1 Patients with nonmassive PEs can be admitted to the general medical floor with low rates of complications. Submassive Pulmonary Embolism Patients with submassive PE have a higher mortality rate and increased likelihood for decompensation, requiring closer monitoring. When possible, the utmost priority should be given to administering anticoagulant therapy while awaiting definitive testing. In a study in which 256 patients with submassive PE40 without risk of bleeding were randomized to UFH alone or UFH plus thrombolytic therapy with alteplase (Activase®), the thrombolytic group had lower rates of clinical deterioration. Escalation of treatment with rescue thrombolytic therapy was more frequent in the heparin-alone group (24.6%) than in the alteplase group (10.2%; P=0.004). The decision to use rescue thrombolytic therapy was influenced by unblinding of subjects, which has led to much criticism of this study. Despite later administration of alteplase in the heparinalone group, the overall mortality (3.4% vs 2.2%; P=0.71) and bleeding risk (0.8 vs 3.6%; P=0.29) between the two groups were similar. Thrombolytic therapy for submassive PE remains controversial. Anticoagulant therapy for submassive PE should include UFH with frequent reassessment for thrombolytic therapy. In the face of clinical deterioration and lack of bleeding risk, thrombolytic therapy should be administered immediately. UFH can be held or administered concurrently with thrombolytics.1 Those with 125

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clinical improvement can be transitioned to LMWH, fondaparinux, or VKAs when the need for thrombolytic therapy is eliminated. LMWH and fondaparinux have not been studied in hemodynamically unstable patients and should therefore be avoided for impending circulatory collapse. Additionally, the longer half-lives of these agents can significantly potentiate bleeding in conjunction with thrombolytic therapy. Massive Pulmonary Embolism Excessive risk for mortality in this population requires aggressive management. Respiratory failure should be supported with mechanical ventilation, and hypotension may require pressor therapy. The risk of death is very high in patients with sustained hypotension and circulatory shock. Quick resolution of hypotension requires immediate revascularization of pulmonary vessels. Therefore, unless contraindicated, patients with massive PE should be treated with thrombolytic therapy. Data for thrombolytics are limited. Agents with similar efficacies include streptokinase, urokinase, and recombinant tissue-type plasminogen activator (rtPA).99-102 Streptokinase is an inexpensive and effective fibrinolytic produced from β-hemolytic streptococcus. Production of humanbased fibrinolytics (urokinase, tissue plasminogen activator [tPA]) has reduced the use of streptokinase because the fibrinolytics are less allergenic. Only one trial containing 8 patients with massive PEs exists.103 Randomization to streptokinase resulted in survival (N=8) compared with 100% mortality in the heparin-only group. Thrombolytic therapy exerts a beneficial effect on hemodynamic parameters. In an early study (N=30), streptokinase increased the cardiac index by 80% while decreasing pulmonary arterial pressure by 40%.104 Serial angiography revealed that tPA relieved vascular obstruction by 12% in contrast to no relief with heparin. Recombinant tPA also reduced the mean pulmonary ar126

terial pressure by 30% and increased the cardiac index by 15% at the end of a 2-hr infusion period.105 Further evidence of hemodynamic parameter improvement with tPA includes reduction in mean right ventricular enddiastolic area evaluated by echocardiography after 3 hr of infusion.106 Pooled data, including 11 studies and 748 patients,107 contrasting thrombolytic therapy with UFH for the treatment of PE of differing severity showed a trend toward reduction in recurrent PE (2.7% vs 4.3%; OR, 0.67; CI, 0.33 to 1.37) and all-cause mortality (4.3% vs 5.9%; OR, 0.70; CI, 0.37 to 1.30). The risk of bleeding did not increase significantly (9.1% vs 6.1%; OR, 1.42; CI, 0.81 to 2.46). This benefit became more prominent for hemodynamically unstable PE. In a subset of five trials totaling 254 patients, there was a significant reduction in mortality with thrombolytic therapy (6.2% vs 12.7%; OR, 0.47; CI, 0.20 to 1.10) but a marked increase in major bleeding (21.9% vs 11.9%; OR 1.98; CI, 1.00 to 3.92). Therefore, thrombolytic therapy can potentially benefit those with life-threatening PE. But a significant risk of bleeding requires physicians to carefully weigh risk and the potential hemodynamic benefits of these medications. Definitive trials confirming the mortality advantage with these agents are lacking. Recommendations for their use are based on extrapolated data and consensus statements. The American College of Physicians and the American Academy of Family Physicians have put forth guidelines for the acute management of PE (Figure 5-11). Alternative Treatment When the risk for bleeding is too excessive for thrombolytic or anticoagulant therapy or when thrombolytic therapy has been ineffective in hemodynamic stabilization for massive PE, percutaneous catheter embolectomy or surgical pulmonary embolectomy may be considered. Case reports suggest that percutaneous techniques may be lifesaving.109-112 127

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PE Treatment Plan IVC Filter

Anticoagulation Risk Stratify

2-Day Hospital LMWH

5- to 10- Day UFH or LMWH

Lysis

Embolectomy

Figure 5-11: The American College of Physicians and the American Academy of Family Physicians guidelines for the acute management of PE. Adapted from Snow V, et al.108

After placement of a pulmonary artery catheter, local mechanical fragmentation of thrombus is performed using a rotating basket catheter, pigtail rotational catheter, or other macerating device. If the bleeding risk is acceptable, local administration of thrombolytics may be combined with mechanical intervention. The goal of thrombus extraction is to reduce pulmonary artery pressure, alleviate right ventricular dilatation and dysfunction, and increase cardiac output. Risks of this procedure include bleeding and infection at the puncture site, rupture of the pulmonary artery, cardiac tamponade, contrast reaction, and death. Surgical embolectomy with cardiopulmonary bypass is another treatment option for acute massive PE.113-115 Additional indications for this procedure include a right atrial thrombus, impending paradoxical arterial thromboembolism, or closure of a patent foramen ovale. Incision into the pulmonary arterial trunk permits removal of clot from both pulmonary arteries under direct visualization. Outcomes are better in patients without cardiogenic shock, with mortality rates between 6% and 8%.112,113 128

Inferior Vena Cava Filters In patients who are hemodynamically stable but have an unacceptably high risk of bleeding, the placement of IVC filter should be considered. There are currently no randomized controlled trials evaluating use of IVC filters for acute PE. To date, only one randomized controlled trial exists in which 400 patients with DVT were randomized to IVC filter plus anticoagulation or anticoagulation alone.116 The rate of PE was statistically significantly lower in the IVC filter group within the first 2 weeks of placement (1.1% vs 4.8%; OR, 0.22; P=0.03), but this benefit disappeared during 2-year follow-up. On the contrary, an IVC filter was associated with higher rates of DVT at 2 years than those who received only anticoagulation (20.8% vs 11.6%; OR, 1.87; P=0.02). Placement of removal IVC filters is becoming more popular. Ideally, retrieval of these filters should occur within 2 weeks of implantation. However, more often than not, these filters are left permanently in place; they have a 10% complication rate (ie, migration, device thrombosis).117 IVC filter placement is therefore not routinely recommended at this time.

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99. Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. JAMA 1974;229(12):1606-1613. 100. Meyer G, Sors H, Charbonnier B, et al: Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. The European Cooperative Study Group for Pulmonary Embolism. J Am Coll Cardiol 1992;19(2):239-245. 101. Goldhaber SZ, Kessler CM, Heit J, et al: Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988;2(8606):293-298. 102. Meneveau N, Schiele F, Vuillemenot A, et al: Streptokinase vs alteplase in massive pulmonary embolism. A randomized trial assessing right heart haemodynamics and pulmonary vascular obstruction. Eur Heart J 1997;18(7):1141-1148. 103. Jerjes-Sanchez C, Ramírez-Rivera A, de Lourdes García M, et al: Streptokinase and heparin versus heparin alone in massive pulmonary embolism: A randomized controlled trial. J Thromb Thrombolysis 1995;2(3):227-229. 104. Tibbutt DA, Davies JA, Anderson JA, et al: Comparison by controlled clinical trial of streptokinase and heparin in treatment of lifethreatening pulmonary embolism. Br Med J 1974;1(5904):343-347. 105. Dalla-Volta S, Palla A, Santolicandro A, et al: PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol 1992;20(3):520-526. 106. Goldhaber SZ, Haire WD, Feldstein ML, et al: Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993;341(8844):507-511. 107. Wan S, Quinlan DJ, Agnelli G, et al: Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a metaanalysis of the randomized controlled trials. Circulation 2004;110(6): 744-749. 108. Snow, V, Qaseem A, Barry P, et al: Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2007;146:204-210.

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109. de Gregorio M, Gimeno M, Alfonso R, et al: [Mechanical fragmentation and intrapulmonary fibrinolysis in the treatment of massive pulmonary embolism hemodynamic repercussions]. Arch Bronconeumol 2001;37(2):58-64. 110. Fava M, Loyola S, Flores P, et al: Mechanical fragmentation and pharmacologic thrombolysis in massive pulmonary embolism. J Vasc Interv Radiol 1997;8(2):261-266. 111. Schmitz-Rode T, Janssens U, Duda SH, et al: Massive pulmonary embolism: percutaneous emergency treatment by pigtail rotation catheter. J Am Coll Cardiol 2000;36(2):375-380. 112. Schmitz-Rode T, Janssens U, Schild HH, et al: Fragmentation of massive pulmonary embolism using a pigtail rotation catheter. Chest 1998;114(5):1427-1436. 113. Leacche M, Unic D, Goldhaber SZ, et al: Modern surgical treatment of massive pulmonary embolism: results in 47 consecutive patients after rapid diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg 2005;129(5):1018-1023. 114. Meneveau N, Séronde MF, Blonde MC, et al: Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest 2006;129(4):1043-1050. 115. Sukhija R, Aronow WS, Lee J, et al: Association of right ventricular dysfunction with in-hospital mortality in patients with acute pulmonary embolism and reduction in mortality in patients with right ventricular dysfunction by pulmonary embolectomy. Am J Cardiol 2005;95(5):695-696. 116. Decousus H, Leizorovicz A, Parent F, et al: A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med 1998;338(7):409-415. 117. Karmy-Jones R, Jurkovich GJ, Velmahos GC, et al: Practice patterns and outcomes of retrievable vena cava filters in trauma patients: an AAST multicenter study. J Trauma 2007;62(1):17-24; discussion 24-25.

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Chapter 6

Perioperative Concerns: Orthopedics, General Surgery, Surgical Oncology, and Obstetrics Franklin Michota Jr

T

he perioperative setting provides unique challenges in the use of anticoagulant medications. Not only does the patient undergo physiologic stress that may alter pharmacokinetics, but the nature of surgery itself also increases the risk for hemorrhage. Although communication between the surgical team and the hospitalist is always important for successful patient management, the use of anticoagulant medication in surgery patients demands even greater multidisciplinary contact and mutual understanding of the patient care plan. Each patient group discussed in this chapter is known to be at high risk for the development of thromboses and often requires the use of anticoagulant medication.

Orthopedics Patients undergoing major orthopedic surgery, which includes total hip arthroplasty (THR), total knee arthroplasty (TKR), and hip fracture surgery (HFS), represent a group that has a particularly high risk for venous thromboembolism (VTE). Routine pharmacologic thromboprophylaxis has been the standard of care in these patients for more than 2 decades.1 The choice of anticoagulant is important because differences in efficacy are found among the 140

anticoagulant choices. In addition, the timing, dose, and duration of anticoagulant used have important implications in the orthopedic surgery population. Choice of Anticoagulant The most recent guidelines from the American College of Chest Physicians (ACCP) for the prevention of VTE recommend the use of low-molecular-weight heparin (LMWH), fondaparinux (Arixtra®), or adjusted-dose vitamin K antagonists (VKAs) in patients undergoing THR or TKR.1 For patients undergoing HFS, unfractionated heparin (UFH) is added to these choices and for patients undergoing hip replacement surgery desirudin is added to these choices (Table 6-1). UFH is not an acceptable choice in THR or TKR patients because its efficacy is limited. Meta-analysis data show that LMWH is more efficacious than adjusted-dose VKA in preventing overall VTE.2 Aspirin and other antiplatelet medications are explicitly not recommended by the ACCP for the prevention of VTE in any patient group. However, the American Academy of Orthopedic Surgeons (AAOS) continues to support VTE prophylaxis with aspirin as a reasonable option.3 Aspirin and other antiplatelet drugs are effective at reducing major thrombotic vascular events in patients who are at risk for or who have established atherosclerotic disease. Evidence suggests that antiplatelet agents also provide some protection against VTE.4 However, much of the evidence citing a benefit for the use of antiplatelet drugs as VTE thromboprophylaxis is based on methodologically limited studies, and much more effective choices are readily available. The use of aspirin is associated with a small but significant increased risk of major bleeding, especially when it is combined with other antithrombotic agents.5 Neuraxial Anesthesia/Analgesia Systemic reviews of neuraxial blockade (spinal or epidural anesthesia and continuous epidural analgesia) have dem141

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Table 6-1: Recommended Anticoagulant Prophylaxis for Major Orthopedic Surgery Type of Surgery

Agent

Hip arthroplasty

Enoxaparin Fondaparinux Desirudin Adjusted-dose VKA

Knee arthroplasty

Enoxaparin Fondaparinux Adjusted-dose VKA

Hip fracture surgery

Enoxaparin Fondaparinux Adjusted-dose VKA Unfractionated heparin

b.i.d.=twice a day, INR=International Normalized Ratio, VKA=vitamin K antagonist

onstrated a significant reduction in cardiac and pulmonary morbidity and in bleeding compared with general anesthesia or with narcotic-based systemic analgesia.6 Furthermore, pain control and patient satisfaction are both improved with these techniques.7 Neuraxial anesthesia/analgesia is commonly used in patients undergoing orthopedic surgery. The risk of spinal or epidural hematoma, which is a rare but potentially devastating complication of neuraxial blockade, may be increased with the concomitant use of anticoagulant medication.8 Bleeding into the enclosed space of the spinal canal may produce spinal cord ischemia and paraplegia. Risk factors that have been associated with the develop142

Dosage

Duration (d)

40 mg/d

10-35

2.5 mg/d

10-35

15 mg SC b.i.d

9-12

Target INR, 2.0–3.0

10-35

30 mg b.i.d.

10-35

2.5 mg/d

10-35

Target INR, 2.0–3.0

10-35

40 mg/d

10-35

2.5 mg/d

10-35

Target INR, 2.0–3.0

10-35

5000 U b.i.d.

10-35

6

ment of spinal hematomas after neuraxial blockade are shown in Table 6-2. With appropriate caution, neuraxial anesthesia with or without epidural analgesia may be used in conjunction with prophylactic doses of UFH, LMWH, or desirudin.1,9 Generally, neuraxial anesthesia should be avoided in patients with significant impairment of hemostasis by antithrombotic drugs at the time of the anticipated epidural or spinal procedure (Table 6-3). Continuous epidural analgesia should be avoided altogether or used for less than 48 hours in patients receiving adjusted-dose VKA. If thromboprophylaxis with a VKA is used at the same time as epidural analgesia, the catheter 143

Table 6-2: Risk Factors for Spinal Hematoma in Neuraxial Blockade • Known systemic bleeding disorder • Hemorrhagic or traumatic tap • Indwelling epidural catheters • Additional doses of LMWH (ie, b.i.d. dosing) • Concomitant use of medications that may impair hemostasis • Communication gap between providers b.i.d.=twice a day, LMWH=low-molecular-weight heparin

should be removed while the International Normalized Ratio (INR) is below 1.5.10 Postoperative fondaparinux appears to be safe in patients who have received a spinal anesthetic (‘one-shot’ spinal anesthetic), but it is not known if postoperative continuous epidural analgesia is safe in the presence of this anticoagulant.8 The long half-life of fondaparinux (ie, 17 to 21 hr) and its renal mode of elimination raise concerns about the potential for accumulation of the drug, especially in elderly patients. Nonsteroidal anti-inflammatory agents and aspirin do not appear to increase the risk of spinal hematoma when no additional antithrombotic agents are used concurrently.1 Timing of Anticoagulant Initiation The timing of thromboprophylaxis in major orthopedic surgery should include a discussion of preoperative vs postoperative initiation as well as how early after surgery anticoagulant thromboprophylaxis should begin.11 Because thromboses may develop during the operation itself, it 144

Table 6-3: Dose Timing for Anticoagulant Prophylaxis in Neuraxial Blockade Once-Daily LMWH • Administer the first dose 6-24 hr after the procedure • Administer the second dose no sooner than 24 hr after the first and only in the presence of adequate hemostasis • Indwelling catheters may be safely maintained – Catheters should not be removed a minimum of 10-12 hr after the last LMWH dose, with the subsequent dose given a minimum of 2 hr after catheter removal

6

Twice-Daily LMWH • Administer the first dose no sooner than 24 hr after the procedure and only in the presence of adequate hemostasis • Indwelling catheters should be removed before the initiation of pharmacologic prophylaxis • The first dose should be given a minimum of 2 hr after catheter removal Twice-Daily Direct Thrombin Inhibitor • Administer the first dose of desirudin 5 to 15 min prior to surgery, but after induction of regional-block anesthesia • Removal of the catheter should be performed when the anticoagulant effect of desirudin is low

LMWH=low-molecular-weight heparin

145

has been common practice to start thromboprophylaxis before surgery. Adjusted-dose VKA has a delayed onset of action, so the initial dose should be routinely administered the evening before surgery. Even with this approach, a target INR is usually not reached until the third postoperative day.12 However, LMWH has a rapid onset of action, and preoperative dosing has shown greater efficacy in preventing VTE.1 Unfortunately, randomized trials have also shown higher rates of major bleeding with LMWH preoperative prophylaxis compared with postoperative prophylaxis. Systemic literature reviews have concluded that LMWH thromboprophylaxis given postoperatively provides protection comparable to preoperative initiation.13 In addition, postoperative initiation of anticoagulant thromboprophylaxis does not interfere with decisions about the use of neuraxial anesthetic techniques, it facilitates same day admission, and it does not contribute to intraoperative bleeding. Postoperative administration of LMWH thromboprophylaxis close to surgery (ie, 6 to 8 hours postoperatively) has been shown to enhance its efficacy as well as its potential to cause bleeding. Similarly, studies using fondaparinux also support the concept that dosing close to orthopedic surgery enhances efficacy of the drug.14 For fondaparinux, the incidence of major bleeding was significantly higher in patients who received a first dose within 6 hours of skin closure compared with waiting more than 6 hours.15 For most patients, the initial dose of LMWH or fondaparinux should be delayed for 12 to 24 hours after surgery and until primary hemostasis has been demonstrated based on examination of the surgical site. Randomized trials of desirudin administered preoperatively in total hip replacement have shown greater efficacy versus LMWH and UFH without increased bleeding complications. Desirudin is the only available SC direct thrombin inhibitor and may offer an advantage in this setting owing to its relatively short half-life of 2 hours. In clinical trials, desirudin was initiated within 30 minutes before the 146

start of surgery, but after the induction of regional-block anesthesia, if that was used. Current recommendations for use are to initiate desirudin 5 to 15 minutes prior to the start of surgery, but after induction of regional-block anesthesia, if used (Table 6-3). The first postoperative dose of desirudin should be administered approximately 12 hours after the first dose of desirudin was administered preoperatively, or approximately 12 hours after the start of surgery. Duration of Anticoagulant Use In orthopedic surgery patients, most symptomatic VTEs occur after hospital discharge, and the risk continues to be higher than expected for at least 2 months after surgery.16 VTE is the most common cause of readmission to the hospital after THR.17 VTE thromboprophylaxis is routinely administered to patients who have undergone major orthopedic surgery, yet it is frequently stopped at the time of hospital discharge.18 Multiple randomized trials1 have evaluated the efficacy of extending VTE prophylaxis out of the hospital for up to 35 days after surgery; these trials confirm the overall benefit of this approach in THR, TKR, and HFS patients while using LMWH, fondaparinux, or adjusted-dose VKA. The greatest benefit for extended prophylaxis appears to be in patients who have undergone THR or HFS. In addition, studies19 have examined the cost implications of longer vs shorter duration of VTE thromboprophylaxis after THR. Based on somewhat different assumptions and methods, most investigators have concluded that prolonged thromboprophylaxis is either cost saving or more costly but a good value in consideration of net benefits. The most important factor driving these results is the cost savings provided by thromboprophylaxis (because of reduced medical costs for prevented VTE) relative to the cost of thromboprophylaxis. Current ACCP recommendations support at least 10 days and up to 35 days of thromboprophylaxis in patients undergoing THR, TKR, or HFS. 147

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General Surgery The risk for thromboses in general surgical patients is uncertain because studies without thromboprophylaxis are no longer performed. Factors that tend to reduce the risk of VTE in patients include improvements in general perioperative care, more rapid mobilization, and greater use of neuraxial anesthesia and thromboprophylaxis. However, more extensive surgery in older and sicker patients and shorter hospital lengths of stay (leading to shorter durations of thromboprophylaxis) may heighten the risk of VTE in general surgery patients. Along with individual patient factors, the type of surgery is the primary determinant of the risk for deep vein thrombosis (DVT). Anticoagulant thromboprophylaxis is recommended in all high- to very-high-risk general surgery patients and some moderate-risk patients (Table 6-4). The options that have clearly been shown to reduce VTE, including pulmonary embolism (PE), are UFH and LMWH.1 The clinical advantages of LMWH over UFH include its once-daily administration and its lower risk of heparin-induced thrombocytopenia (HIT). Fondaparinux appears to be as effective and safe as LMWH.20 Laparoscopic Surgery Considerable uncertainty is related to the risk of VTE after laparoscopic procedures, and the use of thromboprophylaxis is controversial. Surgical trauma generally occurs less often with laparoscopic than with open abdominal surgery, but activation of the coagulation system occurs similar to or only slightly less often with laparoscopic procedures. Laparoscopic operations may be associated with longer surgical times than comparable open procedures. Both pneumoperitoneum and the reverse Trendelenburg position reduce venous return from the legs, creating venous stasis. Patients undergoing laparoscopic surgery may have shorter hospital stays, but they may not mobilize more rapidly at home than those who have had open procedures. Based on the available evidence, the observed rate of VTE after 148

laparoscopic procedures appears to be low.1,21 As such, anticoagulant thromboprophylaxis should be reserved for laparoscopic surgery patients who have additional VTE risk factors (Table 6-4). Bariatric Surgery Over the past decade, the rate of bariatric procedures has increased dramatically.22 The most frequently performed bariatric surgical procedure is the Roux-en-Y gastric bypass, followed by gastric banding, vertical-banded gastroplasty, and biliopancreatic diversion.23 These operations may be performed either as open or laparoscopic procedures, the latter of which generally has a shorter hospital length of stay. An increasing proportion of laparoscopic gastric bypasses are now performed entirely as outpatient procedures. The reported incidence of VTE after bariatric surgery varies widely because of the differences in study samples, use of thromboprophylaxis, and outcome measures used. Furthermore, the optimal anticoagulant regimen, dosage, timing, and duration of thromboprophylaxis in bariatric surgery patients are unknown. Only one randomized trial has been published to date, and it used a LMWH not available in the US (ie, nadroparin).24 A nonrandomized study reported greater efficacy with escalated doses of LMWH combined with mechanical prophylaxis (40 mg of enoxaparin [Lovenox®] every 12 hr vs 30 mg of enoxaparin every 12 hr).25 Pharmacologic data demonstrate a strong negative correlation between body weight and anti-Xa activity after injection of a prophylactic dose of LMWH.26 Because of this, higher doses of LMWH or UFH than are traditionally used for VTE thromboprophylaxis in normal-weight individuals are recommended for morbidly obese patients. The ACCP advises that thromboprophylaxis recommendations for higher risk general surgery patients be used to guide decision making in patients undergoing bariatric surgery. For patients undergoing this type of surgery who have acute VTE and need therapeutic weight-adjusted 149

6

Table 6-4:

Risk Categories and Recommended Prophylaxis in General Surgery Patients

Risk Category

Descriptor

Low

Minor same-day procedures Laparoscopic procedures in patients aged 40 or younger with no additional VTE risk factors

Moderate

Gynecologic surgeries in patients aged 40-60 without additional VTE risk factors Laparoscopic procedures in patients with one additional VTE risk factor

High

General, colorectal, urologic surgeries Gynecologic surgeries in patients aged older than 60 or with multiple risk factors

Very high

Major orthopedic surgery, spinal cord injury, trauma

GCS=graduated compression stockings, IPC=intermittent pneumatic compression, LMWH=low-molecular-weight heparin, t.i.d.=three times a day, UFH=unfractionated heparin, VKA=vitamin K antagonist, VTE=venous thromboembolism

anticoagulation, it is important that the actual body weight be used when dosing UFH, LMWH, or fondaparinux (Table 6-5). There is a paucity of clinical trial data in using unmonitored LMWH or fondaparinux therapy in patients 150

Prophylaxis Recommended Aggressive mobilization

GCS, IPC, LMWH, UFH

6

LMWH, UFH t.i.d. with or without IPC, fondaparinux

LMWH, fondaparinux, adjusted-dose VKA

who weigh more than 120 kg. Fondaparinux is dosed by weight tertiles, and it is unclear whether the highest dose is uniformly adequate across the spectrum of morbidly obese individuals above this threshold weight. Regard151

Table 6-5: Weight-Adjusted Dosing for Therapeutic Anticoagulation Agent

Dosage

UFH

80 U/kg IV bolus; 18 U/kg/hr infusion Monitor aPTT

Enoxaparin

1.5 mg/kg/d; 1 mg/kg q 12 hr

Tinzaparin

175 IU/kg/d

Dalteparin

200 IU/kg/d; 100 IU/kg q 12 hr

Fondaparinux

5 mg for patients <50 kg: 7.5 mg for patients 50-100 kg; 10 mg for patients >100 kg

aPTT=activated partial thromboplastin time, IV=intravenous

ing LMWH, there is a valid concern that morbidly obese patients may actually receive too high a LMWH dose if their actual body weights are used because the volume of distribution is not linearly associated with weight at such extreme boundaries. For this reason, anti-Xa monitoring is recommended when LMWH is dosed by weight in patients who exceed 120 kg. A protocol for this approach is shown in Table 6-6.

Surgical Oncology Patients with cancer have at least a 6-fold increased risk of VTE compared with patients without cancer.27 Cancer patients undergoing surgery have at least twice the risk of postoperative DVT and more than 3 times the risk of fatal PE than do patients without cancer who undergo 152

Table 6-6: Therapeutic Anticoagulation With Low-Molecular-Weight Heparin for Morbidly Obese Patients • Dose actual body weight with LMWH (enoxaparin, tinzaparin, dalteparin) • Check anti-Xa activity 2-3 hr after the third dose of LMWH (target, 0.3-1.2 IU/mL) – If anti-Xa is in the target range, continue LMWH at the current dose – If anti-Xa is <0.3 IU/mL, increase the dose by 25% and recheck anti-Xa – If anti-Xa is >1.2 IU/mL, decrease the dose by 25% and recheck anti-Xa LMWH=low-molecular-weight heparin

similar procedures.28 Strong evidence suggests that UFH effectively reduces the risk of symptomatic and fatal VTE after cancer surgery.1,29 LMWH is at least as efficacious as UFH in these patients.30,31 In cancer surgery, the dose of UFH is important; thrice-daily administration is more efficacious than twice-daily dosing.1 Generally, surgical oncology patients should be considered very high risk and should receive anticoagulant prophylaxis, namely, UFH (dosed 3 times daily), LMWH, or fondaparinux. Clinical trials have addressed the use of extended thromboprophylaxis with LMWH beyond the period of hospitalization after oncologic surgery.32,33 These studies confirm a significant reduction in asymptomatic VTE by venography. The ACCP recommends that extended anticoagulant thromboprophylaxis (ie, 28 to 35 days) be considered for patients who have had major cancer surgery. 153

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Anticoagulants for Central Venous Catheters The presence of a central venous catheter (CVC) in cancer patients predisposes them to upper extremity VTE. This may result in arm swelling and discomfort, PE, a predisposition to catheter-related sepsis, and the need to replace the catheter. Peripherally inserted CVCs appear to be associated with a greater risk of thrombosis than subclavian vein or internal jugular vein catheters.34 If the CVC tip is placed in the upper superior vena cava or more peripherally, the DVT risk is higher than when the catheter tip is located at or just above the right atrium.35 Eight randomized trials have evaluated anticoagulant thromboprophylaxis in the prevention of catheter-associated VTE.1 In summary, none of the strategies used (fixed low-dose VKA, adjusted-dose VKA, LMWH, IV UFH) significantly reduced the rate of catheter-associated thrombosis. As a result, routine anticoagulant thromboprophylaxis to prevent catheter-associated VTE is not recommended.

Obstetrics Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of VTE, for the prevention and treatment of systemic embolism in patients with mechanical heart valves, and in combination with aspirin for the prevention of recurrent pregnancy loss in women with antiphospholipid antibodies.36 The use of anticoagulant therapy during pregnancy is challenging because of the potential for fetal and maternal complications. Anticoagulant Effects on the Fetus VKAs cross the placenta and have the potential to cause fetal wastage, bleeding in the fetus, and teratogenicity.37 Embryopathy typically occurs after in utero exposure to VKAs during the first trimester of pregnancy.38 Given their potential for deleterious effects on fetuses, VKAs should only be used during pregnancy when the potential benefits for the mother justify the potential risks to the fetus. Al154

though UFH and LMWH are as effective as VKAs in the management of VTE, VKAs may be more effective than these agents in patients with mechanical prosthetic valves. Therefore, after discussing the risks and benefits with the patient, it is reasonable to use VKAs in pregnant women with high-risk valves. UFH does not cross the placenta, so it does not have the potential to cause fetal bleeding or teratogenicity, although bleeding at the uteroplacental junction is possible.39 Several studies strongly suggest that UFH therapy is safe for fetuses and should be used as necessary for maternal indications.36 As determined by measurement of anti-Xa activity in fetal blood, LMWH also does not cross the placenta.40 There is no evidence of teratogenicity or risk of fetal bleeding.41 Therefore, LMWH is a safe anticoagulant choice for fetuses. Available evidence suggests that low-dose aspirin during the second and third trimesters is safe for fetuses, so clinicians should use this agent as necessary for maternal indications.42 Although the safety of aspirin ingestion during the first trimester remains uncertain, there is no clear evidence of harm to fetuses and, if fetal anomalies are caused by early aspirin exposure, they are very rare. Although no placental passage of fondaparinux was demonstrated in an in vitro human cotyledon model, anti-factor Xa activity at approximately one tenth the concentration of maternal plasma was found in the umbilical cord plasma in newborns of five mothers treated with fondaparinux.43 Clinicians should avoid the use of fondaparinux during pregnancy whenever possible and reserve its use for pregnant women with HIT or a history of HIT who cannot receive danaparoid (Orgaran®). Teratology studies with desirudin have been performed in rats at subcutaneous doses in a range of 1 to 15 mg/kg/ day (about 0.3 to 4 times the recommended human dose based on body surface area) and in rabbits at IV doses in a range of 0.6 to 6 mg/kg/day (about 0.3 to 3 times the recommended human dose based on body surface area) 155

6

Table 6-7: Therapeutic Anticoagulation With Low-Molecular-Weight Heparin in Pregnant Patients • Dose actual body weight with LMWH (enoxaparin, tinzaparin, dalteparin) • Check anti-Xa activity every 1-3 mo at 4-6 hr after the LMWH dose – Target, 0.6-1.0 IU/mL for q 12 hr dosing – Target, 0.8-1.2 IU/mL for daily dosing • Discontinue 24-36 hr before elective induction of labor • If spontaneous labor occurs during full anticoagulation, neuraxial anesthesia should not be used LMWH=low-molecular-weight heparin

and have revealed desirudin to be teratogenic. Observed teratogenic findings included omphalocele, asymmetric and fused sternebrae, edema, shortened hind limbs, etc, in rats, and spina bifida, malrotated hind limb, hydrocephaly, gastroschisis, etc, in rabbits. There are no adequate and well-controlled studies in pregnant women. Desirudin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Breast-feeding For a drug to pose a risk to breast-fed infants, not only must it be transferred and excreted into breast milk, it must also be absorbed from the infant’s gut. Drugs that are poorly absorbed orally are unlikely to affect neonates. Two convincing reports44,45 demonstrated that VKAs are not detected 156

in breast milk and do not induce an anticoagulant effect in breast-fed infants. Therefore, the use of VKAs in women who require postpartum anticoagulant therapy is safe. UFH does not pass into breast milk and can be safely given to nursing mothers.46 LMWH may be excreted into breast milk in small amounts,47 but given the very low bioavailability of orally ingested heparin, there is unlikely to be any clinically relevant effect on nursing infants. Anticoagulants and Pregnancy Maternal complications of anticoagulant therapy are similar to those seen in nonpregnant patients and include bleeding (for all anticoagulants), as well as HIT, heparin-associated osteoporosis, and pain at injection sites for heparin-related compounds. During pregnancy, the activated partial thromboplastin time (aPTT) response to UFH is often attenuated, likely because of increased levels of heparin-binding proteins, factor VIII, and fibrinogen.48 This causes a ‘blunting’ of the aPTT response relative to the heparin level and a resultant increased requirement for UFH. Consequently, the use of an aPTT range that corresponds to therapeutic heparin levels in nonpregnant patients might result in higher dosing and heparin levels in pregnant women than in nonpregnant women. It is not clear that this translates into a higher rate of bleeding. Long-term treatment with UFH has been reported to cause osteoporosis in laboratory animals and humans.49 In animal studies, UFH causes a dose-dependent loss of cancellous bone through decreasing rates of bone formation and increased bone resorption. Animal models demonstrating that heparin is sequestered in the bone for extended periods also suggest that heparin-induced osteoporosis may not be rapidly reversible. Several lines of evidence suggest that LMWHs are associated with a lower risk of osteoporosis than UFH.50 For pregnant patients, LMWH is recommended for the prevention and treatment of VTE because of its better bioavailability, longer plasma half157

6

life, more predictable dose response, and improved safety profile with respect to osteoporosis and thrombocytopenia compared with UFH.36 Unlike UFH, LMWH does not require frequent aPTT monitoring, but its requirements may alter as pregnancy progresses because its volume of distribution changes and the glomerular filtration rate increases in the second trimester.51 Thus, some monitoring of anti-Xa activity is recommended during pregnancy. Table 6-7 provides a treatment protocol for pregnant patients. Cesarean Section Although cesarean section is likely a risk factor for VTE, the risk for symptomatic events attributable to it appears modest and is similar to that seen in low-risk surgical patients for whom no routine thromboprophylaxis other than mobilization is recommended.1 The presence of additional risk factors may increase the risk of VTE associated with cesarean section. When cesarean section is performed emergently, the risk of VTE is approximately double that of an elective procedure.52 Quantification of risk when multiple factors are combined is not clearly established. The addition of multiple other risk factors (increased age, prior VTE, obesity, thrombophilia, lower limb paralysis, immobilization, extended surgery such as hysterectomy, preeclampsia, and comorbid conditions such as heart failure) is likely to place the patient at moderate to high risk for VTE. Thus, a thrombosis risk assessment should be performed in all women undergoing cesarean section to determine the need for thromboprophylaxis. In patients without additional thrombosis risk factors undergoing cesarean section, anticoagulant thromboprophylaxis is not recommended, and early mobilization should be encouraged. In the presence of moderate risk, either pharmacologic or nonpharmacologic strategies for prevention may be used.36 If the risk is high, then pharmacologic strategies should be added to mechanical prophylaxis. It should be noted that two thirds of DVT in 158

pregnancy occur antepartum, with these events distributed relatively equally in all three trimesters.53 In contrast, 50% of all pregnancy-related PE occurs in the 4 to 6 weeks after delivery.54,55 For selected patients with risk factors that persist beyond delivery, extended prophylaxis (≤4 to 6 weeks after delivery) should be considered.36 Each patient group discussed in this chapter is known to be at high risk for the development of thromboses and often requires the use of anticoagulant medication. Using the approaches discussed will result in best patient outcomes.

References 1. Geerts WH, Bergqvist D, Pineo GF, et al: Prevention of venous thromboembolism: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th ed). Chest 2008;133(suppl 6):381S-453S. 2. Mismetti P, Laporte S, Zufferey P, et al: Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta-analysis. J Thromb Haemost 2004;2:1058-1070. 3. American Academy of Orthopaedic Surgeons. Clinical Guideline on Prevention of Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty 2007. Available at: http://www.aaos. org/Research/guidelines/PE_guideline.pdf. Accessed November 17, 2008. 4. Collaborative overview of randomized trials of antiplatelet therapy: III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists’ Collaboration. Br Med J 1994;308:235-246. 5. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) Trial. Lancet 2000;355:1295-1302. 6. Block BM, Liu SS, Rowlingson AJ, et al: Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA 2003;290: 2455-2463. 7. Wu CL, Cohen SR, Richman JM, et al: Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opiods: a meta-analysis. Anesthesiology 2005;103:1079-1088.

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8. Horlocker TT, Wedel DJ, Benzon H, et al: Regional anesthesia in the anticoagulated patient: defining the risks (the Second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003;28:172-197. 9. Douketis JD, Dentali F: Managing anticoagulant and antiplatelet drugs in patients who are receiving neuraxial anesthesia and epidural analgesia: a practical guide for clinicians. Tech Reg Anesth Pain Manage 2006;10:46-55. 10. Parvizi J, Viscusi ER, Frank HG, et al: Can epidural anesthesia and warfarin be coadministered? Clin Orthop Relat Res 2007; 456:133-137. 11. Raskob GE, Hirsh J: Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest 2003;124(6 suppl):379S-385S. 12. Asnis PD, Gardner MJ, Ranawat A, et al: The effectiveness of warfarin dosing from a nomogram compared with house staff dosing. J Arthroplasty 2007;22:213-218. 13. Strebel N, Prins M, Agnelli G, et al: Preoperative or postoperative start of prophylaxis for venous thromboembolism with lowmolecular-weight heparin in elective hip surgery? Arch Intern Med 2002;162:1451-1456. 14. Turpie AG, Bauer KA, Eriksson BI, et al: Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:1833-1840. 15. Turpie A. Bauer K, Eriksson B, et al: Efficacy and safety of fondaparinux in major orthopedic surgery according to the timing of its first administration. Thromb Haemost 2003;90:364-366. 16. Douketis JD, Eikelboom JW, Quinlan DJ, et al: Short-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes. Arch Intern Med 2002;162:1465-1471. 17. Seagroatt V, Tan HS, Goldacre M: Elective total hip replacement: incidence, emergency readmission rate, and postoperative mortality. Br Med J 1991;303:1431-1435. 18. Kearon C: Duration of venous thromboembolism prophylaxis after surgery. Chest 2003;124(suppl 6):386S-392S.

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19. Skedgel C, Goeree R, Pleasance S, et al: The cost-effectiveness of extended-duration antithrombotic prophylaxis after total hip arthroplasty. J Bone Joint Surg Am 2007;89:819-828. 20. Agnelli G, Bergqvist D, Cohen AT, et al: Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005;92:1212-1220. 21. Querleu D, Leblanc E, Cartron G, et al: Audit of preoperative and early complications of laparoscopic lymph node dissection in 1000 gynecologic cancer patients. Am J Obstet Gynecol 2006;195:12871292. 22. Steinbrook R: Surgery for severe obesity. N Engl J Med 2004;350:1075-1079. 23. DeMaria EJ: Bariatric surgery for morbid obesity. N Engl J Med 2007;356:2176-2183. 24. Kalfarentzos F, Stavropoulou F, Yarmenitis S, et al: Prophylaxis of venous thromboembolism using two different doses of lowmolecular-weight heparin (nadroparin) in bariatric surgery: a prospective randomized trial. Obes Surg 2001;11:670-676. 25. Scholten DJ, Hoedema RM, Scholten SE: A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg 2002;12:19-24. 26. Frederiksen SG, Hedenbro JL, Norgren L: Enoxaparin effect depends on body-weight and current doses may be inadequate in obese patients. Br J Surg 2003;90:547-548. 27. Blom JW, Doggen CJ, Osanto S, et al: Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715-722. 28. Clarke-Pearson DL, Coleman RE, Synan IS, et al: Venous thromboembolism prophylaxis in gynecologic oncology: a prospective, controlled trial of low-dose heparin. Am J Obstet Gynecol 1983;145:606-613. 29. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial. Lancet 1975;2: 45-51. 30. ENOXACAN Study Group: Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blinded randomized

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multicentre trial with venographic assessment. Br J Surg 1997;84: 1099-1103. 31. McLeod RD, Geerts WH, Sniderman KW, et al: Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery: results of the Canadian colorectal DVT prophylaxis trial: a randomized, double-blind trial. Ann Surg 2001;233:438-444. 32. Bergqvist D, Agnell G, Cohen AT, et al: Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002;346:975-980. 33. Rasmussen MS, Jorgensen LN, Wille-Jorgensen P, et al: Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost 2006; 4:2384-2390. 34. Cheong K, Perry D, Karapetis C, et al: High rate of complications associated with peripherally inserted central venous catheters in patients with solid tumors. Intern Med J 2004;34:234-238. 35. Tesselaar ME, Ouwerkerk J, Nooy MA, et al: Risk factors for catheter-related thrombosis in cancer patients. Eur J Cancer 2004;40: 2253-2259. 36. Bates SM, Greer IA, Pabinger I, et al: Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008;133:844S-886S. 37. Ginsberg JS, Hirsh J, Turner DC, et al: Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost 1989:61: 197-203. 38. Hall JG, Paul RM, Wilson KM: Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980;68:122-140. 39. Flessa HC, Kapstrom AB, Glueck HI, et al: Placental transport of heparin. Am J Obstet Gynecol 1965;93:570-573. 40. Forestier F, Daffos F, Capella-Pavlovsky M: Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound. Thromb Res 1984;34:557-560. 41. Forestier F, Daffos F, Rainant M, et al: Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy. Thromb Haemost 1987;57:234.

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42. Coomarasamy A, Honest H, Papaioannou S, et al: Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Obstet Gynecol 2003;101:1319-1332. 43. Dempfle CE: Minor transplacental passage of fondaparinux in vivo. N Engl J Med 2004;350:1914-1915. 44. Orme ML, Lewis PJ, de Swiet M, et al: May mothers given warfarin breast-feed their infants? Br Med J 1977;1:1564-1565. 45. McKenna R, Cole ER, Vasan U: Is warfarin sodium contraindicated in the lactating mother? J Pediatr 1983;103:325-327. 46. O’Reilly R: Anticoagulant, antithrombotic and thrombolytic drugs. In: Gillman AG, et al, eds. The Pharmacologic Basis of Therapeutics, 6th ed. New York: Macmillan, 1980, p 1347. 47. Richter C, Sitzmann J, Lang P, et al: Excretion of low molecular weight heparin in human milk. Br J Clin Pharmacol 2001;52: 708-710. 48. Chunilal SD, Young E, Johnston MA, et al: The aPTT response of pregnant plasma to unfractionated heparin. Thromb Haemost 2000;87:92-97. 49. Muir J, Andrew M, Hirsh J, et al: Histomorphometric analysis of the effect of standard heparin on trabecular bone in vivo. Blood 1996;88:1314-1320. 50. Carlin AJ, Farquharson RG, Quenby SM, et al: Prospective observational study of bone mineral density during pregnancy: low molecular-weight heparin versus control. Hum Reprod 2004;19: 1211-1214. 51. Barbour LA, Oja JL, Schultz LK: A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004;191:1024-1029. 52. Macklon NS, Greer IA: Venous thromboembolic disease in obstetrics and gynecology: the Scottish experience. Scott Med J 1996;41:83-86. 53. Ray JG, Chan WS: Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and leg of presentation. Obstet Gynecol Surg 1999;54:265-271. 54. Gherman RB, Goodwin TM, Leung B, et al: Incidence clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999;94:730-734.

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55. Simpson El, Lawrenson RA, Nightingale AL, et al: Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. Br J Obstet Gynaecol 2001;108:56-60.

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Chapter 7

Cardiovascular and Antithrombotic Management: Acute Coronary Syndromes, Arrhythmias, and Cerebrovascular Diseases

7

Jason C. Robin, Dan J. Fintel

T

he various applications of anticoagulation in cardiovascular disease are broad and concern primary and secondary prevention of angina and infarction, atrial fibrillation and flutter, and stroke and transient ischemic attack; percutaneous and surgical revascularization; artificial valve replacement; and precautions for impaired ventricular function. Several methods of anticoagulation may be used in each of these indications, including thrombin antagonists, vitamin K antagonists, and thrombolytics. In addition, antiplatelet therapy is often used to supplement the anticoagulants or at times may be considered a reasonable replacement. This chapter primarily focuses on the roles of anticoagulation, antiplatelet, and thrombolytic therapy in the management of patients with acute coronary syndromes (ACS), atrial arrhythmias, and cerebrovascular disease (CVD). Every hospitalist should be knowledgable about these agents and trained in their indications and handling. 165

Acute Coronary Syndromes ACS is an umbrella term used to cover any group of clinical symptoms compatible with acute myocardial ischemia. Acute myocardial ischemia is caused by insufficient blood supply to the heart muscle that typically results from coronary artery disease (CAD). ACS thus covers the spectrum of clinical conditions ranging from unstable angina (UA) to non–ST-segment elevation myocardial infarction (NSTEMI) to ST-segment elevation myocardial infarction (STEMI). These life-threatening disorders are a major cause of emergency medical care and hospitalization in the US. UA and NSTEMI are common manifestations of CAD. The diagnosis is made with a history, physical examination, electrocardiography, and cardiac biomarkers. With respect to anticoagulation and antiplatelet therapy in ACS, it is best to differentiate UA and NSTEMI from STEMI. Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction Antiplatelet therapy is the cornerstone of therapy for UA/NSTEMI. The potential biochemical targets for antiplatelet therapy are to decrease the formation of thromboxane A2 through acetylation of cyclooxygenase 1 (aspirin), inhibit the P2Y12 component of the adenosine diphosphate receptor pathway of platelet activation (thienopyridines such as clopidogrel), and directly inhibit platelet aggregation (glycoprotein [GP] IIb/IIIa inhibitors).1 The disruption of platelet activation and aggregation is essential therapy, especially in high-risk populations (Figure 7-1). Aspirin The antiplatelet effect of aspirin lasts for the lifetime of the platelet, approximately 7 to 10 days. To rapidly achieve therapeutic levels, the patient should chew the tablet to promote rapid buccal absorption. Several trials have demonstrated a clear benefit of aspirin in the UA/NSTEMI, with a 50% reduction of death or myocardial infarction (MI). 166

This benefit is seen on the first day of treatment and should, therefore, be the primary therapy for these patients.2,3 In addition, there does not appear to be a dose response in efficacy to aspirin.2 Thus, for safety purposes, after an initial loading dose of 162 to 325 mg, a dose of 81 mg appears sufficient. Absolute contraindications for aspirin therapy include aspirin allergy, active bleeding, and a known platelet disorder. In patients with an aspirin allergy, clopidogrel should be administered. Clopidogrel Clopidogrel (Plavix®) is a thienopyridine derivative that avoids the hematologic complications (ie, neutropenia and thrombotic thrombocytopenic purpura) associated with its thienopyridine predecessor, ticlopidine. The addition of clopidogrel to aspirin in patients with UA/NSTEMI was studied in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial.4 The population was randomized to aspirin, heparin, standard therapy, and clopidogrel (a 300-mg loading dose followed by 75 mg/day) vs aspirin, heparin, standard therapy, and placebo. The combination of clopidogrel plus aspirin conferred a 20% reduction in cardiovascular death, MI, or stroke compared with aspirin alone. The benefit was seen as early as 24 hours and extended to 1 year (Figure 7-2). Therefore, initiating clopidogrel as soon as possible on admission for UA/NSTEMI is a reasonable treatment strategy. The caveat to this approach is the increased risk of major bleeding if the patient undergoes coronary artery bypass graft (CABG) surgery within 5 days of clopidogrel administration. Therefore, an alternative strategy is to delay clopidogrel treatment until after coronary angiography and administer the drug ‘on the table’ if percutaneous coronary intervention (PCI) is planned or shortly thereafter if the patient is not going to be treated with revascularization. Therefore, the early treatment strategy reduces early ischemic events at the cost of a 3.5% absolute increase in major bleeding in the 10% of patients 167

7

168

who undergo CABG. Interestingly, patients who are pretreated with clopidogrel and undergo CABG benefit from a 3.5% reduction in cardiovascular death, MI, and stroke.4 In patients with UA/NSTEMI, the initial dose of clopidogrel should be 300 to 600 mg followed by 75 mg/day. The higher loading dose may achieve a steady state of platelet inhibition after 1 to 2 hours compared with the lower dose, which achieves effective platelet inhibition after 4 to 6 hours. In a study of 254 patients undergoing PCI, pretreatment with the higher dose led to a significantly lower rate of cardiovascular events.5 Regarding duration of treatment, the CURE trial showed that clopidogrel therapy provided benefit for up to 1 year in patients with UA/NSTEMI. Another factor to consider is whether the patient receives a drug-eluting stent (DES) or a bare metal stent (BMS). In those who have a DES placed, it is imperative that the patient have uninterrupted clopidogrel therapy (in addition to aspirin) for at least 1 year and perhaps longer. This recommendation is based on recent data indicating that the incidence of stent thrombosis, a catastrophic complication of PCI, may occur many months after stent deployment. When clopidogrel must be held for a surgical procedure, a short-acting GP IIb/IIIa inhibitor has been used with success in some patients.6 For BMS placement, the clinician may temporarily withhold clopidogrel after 4 weeks of treatment for invasive procedures but should resume clopidogrel as soon as it is safe to do so, given the recommendation for at least 1 year of combined oral antiplatelet therapy after admission for NSTEMI. Figure 7-1: (facing page) Platelet and coagulation inhibition. ADP=adenosine diphosphate; AT III=antithrombin III, LMWH= low-molecular-weight heparin, PAF=platelet-activating factor, TxA2=thromboxane A2, Xa=factor Xa, X=factor X, IIb=factor IIB. (Adapted from INTEGRILIN® Web site. Available at http:// www.integrilin.com/popups/platelet2.html. Accessed January 13, 2009.)

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7

0.98 0.96

Clopidogrel

0.94

Placebo

0.92

Proportion event free

1.00

0 to 30 days

0.90

RR: 0.79 (0.67-0.92) P = 0.003 0

1

2

3

4

6,026 5,993

5,990 5,965

Weeks No. at risk Clopidogrel Placebo

6,259 6,303

6,145 6,159

6,070 6,048

Figure 7-2: Impact of clopidogrel compared with placebo in cardiovascular death, myocardial infarction, or stroke within

Glycoprotein IIb/IIIa Inhibitors The GP IIb/IIIa inhibitors prevent the final common pathway of platelet aggregation, the fibrogen-mediated cross-linkage of activated platelets (Figure 7-1). Three agents are available for UA/NSTEMI, eptifibatide (Integrilin®), tirofiban (Aggrastat®), and abciximab (ReoPro®). The latter is only approved for patients undergoing PCI. The receptor blocking activity and the bleeding risks 170

0.96

0.98

Clopidogrel

0.94

Placebo

7

0.92

Proportion event free

1.00

31 days to 12 months

0.90

RR: 0.82 (0.70-0.95) P = 0.009 1

4

6

8

10

12

4,004 3,929

3,180 3,159

2,418 2,388

Months No. at Risk Clopidogrel 5,891 Placebo 5,954

5,481 5,390

4,742 4,639

first 30 days and from 30 days to 12 months. RR=relative risk. (Adapted from Yusuf S, et al: Circulation 2003;107:966-972.)

subside approximately 4 hours after the discontinuation of eptifibatide and tirofiban. However, based on the pharmacodynamics, there is no way to reverse bleeding with platelet transfusion. Abciximab allows for the return of most platelet function approximately 12 hours after discontinuation, although the antiplatelet effects may be reversed with platelet transfusion. 171

Several trials have examined GP IIb/IIIa inhibition in patients with UA/NSTEMI. Overall, the benefit is an approximately 9% reduction in death or MI at 30 days.7 However, the benefit appears greatest when used in high-risk patients, such as those with ST segment changes or diabetes and in those with elevated troponin level (Figure 7-3). Regarding the timing of GP IIb/IIIa inhibition, infusion either at the time of presentation or during PCI is acceptable. Observational studies have found a 10% lower mortality for patients treated earlier, but a recent randomized trial evaluating the two strategies failed to demonstrate a difference in recurrent ischemic events and noted a higher rate of bleeding with administration upon presentation.8,9 Major complications of GP IIb/IIIa inhibition are major hemorrhage (2.4% vs 1.4% for placebo; P <0.0001) and thrombocytopenia (<0.5% of patients).6 So a reasonable strategy is early administration in high-risk patients, especially those with elevated cardiac biomarkers, and those in whom cardiac catheterization and PCI are planned. Heparin Anticoagulation, traditionally with unfractionated heparin (UFH), has been shown to provide a 33% reduction in death and MI when added to aspirin compared with aspirin alone.10 It works by inactivating thrombin and activated factor X (factor Xa) through an antithrombin-dependent mechanism (Figure 7-1). Frequent monitoring of the anticoagulant response using activated partial thromboplastin time (aPTT) with a goal of 50 to 70 seconds is recommended. Guidelines recommend a 60-U/kg bolus and 12-U/kg/hr infusion with monitoring of the aPTT every 6 hours until in the target range and every 12 hours thereafter. A standard nomogram for heparin titration is a useful reference (Table 7-1).1 Common adverse effects include bleeding and heparin-induced thrombocytopenia (HIT), which is more common with longer durations of infusion. 172

Placebo group Abciximab group

Cumulative rate of primary end point, %

20

Troponin >0.03 µg/L Log-rank P =0.02

15 10

Troponin >0.03 µg/L Log-rank P =0.98

5

Figure 7-3: Kaplan-Meier analysis of cumulative incidence of death, myocardial infarction, or urgent target vessel revascularization for both treatment groups in the subsets with and without elevated troponin levels (>0.03 μg/L). (Adapted from Kastrati et al, JAMA 2006;295:1531-1538.)

0 0

5

10

15

20

25

30

Days after randomization

173

No. at risk Troponin >0.03 µg/L Placebo 536 Abciximab 513

445 453

441 453

439 450

439 447

438 447

438 446

Troponin ≤0.03 µg/L Placebo 474 Abciximab 499

455 480

454 477

452 477

452 477

452 476

452 476

7

Table 7-1: Standardized Nomogram for Titration of Heparin Activated Partial Thromboplastin Time (sec)

Change

<35

70 U/kg bolus

+3

35-49

35 U/kg bolus

+2

50-70

0

0

71-90

0

–2

>100

Hold infusion for 30 min

–3

Intravenous Infusion (U/kg/hr)

Initial dose: 60 U/kg bolus and an infusion of 12 U/kg/hr. The activated partial thromboplastin time should be checked and infusion adjusted at 6, 12, and 24 hr after initiation of heparin, daily thereafter, and 4-6 hr after any adjustment in dose.

Low-Molecular-Weight Heparin Low-molecular-weight heparin (LMWH) also inhibits the action and generation of thrombin. Potential advantages of LMWH include its greater anti-factor Xa activity (Figure 7-1), more predictable anticoagulation by binding less avidly to plasma proteins, lower rates of thrombocytopenia and HIT compared with UFH, and the luxury of not having to monitor the level of anticoagulation. However, LMHW is more affected by renal insufficiency, so its dose should be reduced in patients with a creatinine clearance below 30 mL/min. Also, unlike UFH, protamine is less effective in reversing its anticoagulant effect. A meta-analysis evaluating six randomized, controlled trials compared enoxaparin (Lovenox®) with UFH in the 174

treatment of patients with ACS. Of the 22,000 patients identified, there was no significant difference in death at 30 days for enoxaparin vs UFH (3.0% vs 3.0%; odds ratio [OR], 1.00; 95% confidence interval [CI], 0.85 to 1.17). However, a statistically significant reduction in the combined end point of death or nonfatal MI at 30 days was observed for enoxaparin vs UFH in the overall trial populations (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83 to 0.99; number needed to treat, 107). In addition, no significant difference was found in blood transfusion (OR, 1.01; 95% CI, 0.89 to 1.14) or major bleeding (OR, 1.04; 95% CI, 0.83 to 1.30) at 7 days after randomization. The standard dose of enoxaparin is 1 mg/kg subcutaneously (SC) every 12 hours. Based on these data, the American Heart Association (AHA) and American College of Cardiology (ACC) made a class IIa recommendation that enoxaparin is preferred over UFH for UA/NSTEMI.11 Fondaparinux Fondaparinux (Arixtra ®) is a synthetic pentasaccharide and an indirect Xa inhibitor that requires antithrombin for its action. In the OASIS-5 (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes) trial,12 once-daily fondaparinux (2.5 mg) was compared with standard-dose enoxaparin in more than 20,000 patients. The rates of death, MI, and refractory ischemia were similar in the two groups throughout the first 9 days. However, the rate of major bleeding was 50% lower in the fondaparinux arm (2.2% vs 4.1%; P <0.001). By 30 days, the mortality was significantly lower in the fondaparinux arm (2.9% vs 3.5%; P <0.02). However, in the subset undergoing PCI, fondaparinux was associated with a 3-fold increase in catheter-related thrombi. This was somewhat minimized with supplemental UFH at the time of catheterization. Therefore, more data on fondaparinux are still needed, especially in patients who will undergo PCI. 12 175

7

Direct Thrombin Inhibitors These agents have several potential advantages over indirect thrombin inhibitors such as UFH and LMWH because they do not require antithrombin, inhibit clot-bound thrombin, provide stable anticoagulation, and do not cause thrombocytopenia. Direct thrombin inhibitors include lepirudin (Refludan®), bivalirudin (Angiomax®), desirudin (Iprivask®), and argatroban. Desirudin is approved for DVT prophylaxis and lepirudin and argatroban are approved for anticoagulation in patients with HIT and associated thromboembolic disease. Bivalirudin has been studied in UA/NTEMI patients in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial,13 which randomized patients to UFH and enoxaparin plus a GP IIb/IIIa inhibitor (group 1), bivalirudin plus a GP IIb/IIIa inhibitor (group 2), or bivalirudin alone (group 3). All patients were managed with an early invasive strategy. The primary end points were death, MI, unplanned revascularization for ischemia, and major bleeding at 30 days. Groups 1 and 2 had similar efficacies and rates of bleeding. Group 3, when compared with group 1, had no difference in efficacy end points but had a significantly lower rate of bleeding (3.0% vs 5.7%; P <0.001).13 Thus, the substitution of bivalirudin as an anticoagulant in patients receiving GP IIb/IIIa inhibitors did not change efficacy or safety outcomes, but the strategy of bivalirudin alone was associated with less bleeding than the combination of UFH and enoxaparin plus a GP IIb/IIIa inhibitor.1

ST-Segment Elevation Myocardial Infarction The pathophysiology of STEMI is different from that of NSTEMI. With STEMI, rupture of an unstable plaque occurs, leading to the formation of intracoronary thrombus and resulting in complete occlusion of the coronary artery. The key to short- and long-term survival in these patients is early revascularization (Figure 7-4).1 The primary methods of emergent revascularization are thrombolysis and angioplasty with stent placement. If the patient presents 176

less than 3 hours from the onset of symptoms and there will be no delay in an invasive strategy, either strategy is acceptable. Thrombolysis is the preferred strategy if the patient presents less than 3 hours from symptom onset but there will be more than a 90-minute delay from doorto-balloon time (eg, an unavailable local catheterization laboratory with surgical backup). An invasive strategy is preferred when a patient presents to a center with a skilled PCI laboratory with surgical backup and the doorto-balloon time will be less than 90 minutes, there are bleeding contraindications to thrombolysis, the diagnosis of STEMI is in doubt, or the symptom onset was more than 3 hours ago.14 The following recommendations for antiplatelet, anticoagulation, and thrombolytic therapy are mainly targeted to hospitalists and emergency department physicians who do not have access to PCI laboratories. When a laboratory is available and an invasive strategy is used, the interventional cardiologist typically determines the management. Aspirin As in the case of UA/NSTEMI, 162 to 325 mg of chewable aspirin should be given upon the patient’s arrival to the emergency department. Regardless of the symptom onset to time of presentation, aspirin consistently provides a 20% to 25% reduction in mortality.1 Therefore, under almost all circumstances, aspirin therapy should be given. In patients with an aspirin allergy, clopidogrel should be administered. Clopidogrel Based on the results of the COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) and CLARITYTIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy– Thrombolysis in Myocardial Infarction) trial, the 2007 AHA/ACC guidelines state that it is reasonable to give clopidogrel to all STEMI patients, regardless of the mecha177

7

178 Mortality reduction, %

100

Shifts in potential outcomes with different treatment strategies A to B No Benefit A to C Benefit B to C Benefit D to B Harm D to C Harm

D

80 60

C 40 20

Extent of myocardial salvage

B

A

0 0

4

8

12

16

20

24

Time from symptom onset to reperfusion therapy, hr Critical time-dependent period Goal: myocardial salvage

Time-independent period Goal: open infarct-related artery

Figure 7-4: Relationship among the duration of symptoms of acute myocardial infarction before reperfusion therapy, mortality reduction, and extent of myocardial salvage. (Adapted from Gersh BJ, et al, JAMA 2005;293:979-986.)

nism of revascularization. If a patient is younger than 75 years old, a 300-mg loading dose should be administered followed by 75 mg/day. In a patient older than 75 years old, the loading dose can be withheld.1 In the setting of PCI, loading doses up to 600 mg have been studied and have shown benefit. Thrombolytic Therapy When the method of revascularization is “lytic” therapy, the goal for door-to-needle time is less than 30 minutes. Contraindications must be considered (Table 7-2).14 The survival benefit appears to be greatest when the drug is given less than 2 hours after symptom onset.15 The approved therapies differ in administration, propensity for allergic reaction, efficacy, and cost. The tissue plasminogen activator (tPA) molecule has been modified to create the third-generation lytics alteplase (Activase®), reteplase (Retavase®), and TNK-tPA (Tenecteplase®) (Table 7-3).1 With respect to the agent of choice, the physician must weigh the mortality risk as well as the risk of intracranial hemorrhage (ICH). In patients presenting within the first 4 hours of symptom onset, a fast-acting lytic therapy is necessary because time is muscle (Figure 7-4).1 In this situation, a high-intensity regimen such as a tPA is the preferred treatment, except for patients in whom the risk of death is low or the risk of ICH is high. In these situations, streptokinase and the tPA agents are nearly equivalent choices. In patients presenting well after the onset of symptoms, the speed of reperfusion is of lesser importance, and either streptokinase or a tPA agent is reasonable, given the difference in cost. In patients with an increased risk of ICH, streptokinase may be preferable. In patients presenting more than 12 hours after symptom onset, lytic therapy does not appear to improve survival. In addition, in those older than 65 years, lytic therapy given after 12 hours has the propensity to cause cardiac rupture. For these patients, especially if chest pain is ongoing, a more reasonable strategy is PCI. 179

7

Table 7-2: Contraindications and Cautions for Fibrinolytic Use in Non–ST-Segment Elevation Myocardial Infarction Absolute Contraindications • Any prior intracranial hemorrhage • Known structural cerebral vascular lesion (eg, AVM) • Known malignant intracranial neoplasm (primary or metastatic) • Ischemic stroke within 3 mo except acute ischemic stroke within 3 hr • Suspected aortic dissection • Active bleeding or bleeding diathesis (excluding menses) • Significant closed head or facial trauma within 3 mo

AVM=arteriovenous malformation; CPR=cardiopulmonary resuscitation; INR=International Normalized Ratio.

Heparin The evidence favoring the use of UFH in conjunction with a lytic agent is still not conclusive. However, there may be a mortality benefit and a lower likelihood of left ventricular thrombus formation. Therefore, the current recommendations suggest the use of heparin for 48 hours 180

Relative Contraindications • History of chronic severe poorly controlled hypertension • Severe uncontrolled hypertension on presentation (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg) • History of ischemic stroke more than 3 mo ago, dementia, or known intracranial pathology not covered in contraindications

7

• Traumatic or prolonged (>10 min) CPR or major surgery (<3 wk) • Recent (within 2-4 wk) internal bleeding • Noncompressible vascular punctures • For streptokinase or anistreplase: Prior exposure (>5 d ago) or prior allergic reaction to these agents • Pregnancy • Active peptic ulcer • Current use of anticoagulants (the higher the INR, the higher the risk of bleeding)

after thrombolysis and maintenance of an aPTT target of approximately two times that of control.14 Low-Molecular-Weight Heparin As stated earlier, the potential advantages of LMWH are its greater anti-factor Xa activity, more predictable 181

anticoagulation by binding less avidly to plasma proteins, lower rates of thrombocytopenia and HIT compared with UFH, and the luxury of not having to monitor the level of anticoagulation. However, renal insufficiency must be considered, and the dose should be reduced in patients with a creatinine clearance below 30 mL/min. Compared with UFH, the rate of early reperfusion (90 min) of the infarctrelated artery is not improved with LMWH. However, reocclusion, reinfarction, and recurrent ischemic events appear to be reduced. The dosing strategy used in the ExTRACTTIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction) trial was adjusted according to age and renal function. For patients younger than 75 years old, enoxaparin was given as a 30-mg IV bolus followed 15 minutes later by a 1-mg/kg SC injection every 12 hours for the duration of the hospitalization. For patients older than 75 years, the bolus was eliminated, and the SC dose was given as 0.75 mg/kg every 12 hours. For those with a creatinine clearance below 30-mL/min, the dose was given as 1 mg/kg every 24 hours. Major bleeding did occur more often in the enoxaparin group, but the composite end point of death, nonfatal reinfarction, or nonfatal ICH occurred in 12.2% of patients given UFH and 10.1% of those given enoxaparin (P <0.001).16 Therefore, LMWH is probably superior to UFH for STEMI and is preferred to support thrombolysis. In patients with HIT, the use of bivalirudin may be considered in conjunction with streptokinase.17 In patients scheduled for emergent CABG, the preferred antithrombin therapy is UFH. For an overview of antiplatelet, anticoagulation, and thrombolytic therapy in the setting of ACS, see Figure 7-5.1

Arrhythmias The atrial arrhythmias, particularly atrial fibrillation and flutter, are commonly seen in the hospital. From the Framingham data, the lifetime risk of developing either of these 182

arrhythmias is greater than 25%.18 They may be the reason for admission or may arise in the setting of another concurrent illness, often noncardiac. The concern with this diagnosis is the future risk of systemic emboli, often occuring in the left atrium or the appendage as a result of circulatory stasis. Thus, a challenging question is when to anticoagulate and how do it. The following section examines this question and provides evidence and consensus-based recommendations. For all practical purposes, atrial fibrillation (AF) and atrial flutter are considered similar with respect to the future risk of systemic emboli and will herein in be considered as one entity, AF. The following section breaks down anticoagulation and AF into the acute management phase, the chronic management phase, and a reasonable strategy to use when anticoagulation must be held for invasive procedures. Acute Management, New Onset A person with AF diagnosed for the first time should first be hemodynamically stabilized with rate-lowering agents such as calcium channel blockers, β-blockers, or digoxin. In addition, reversible causes should be investigated and treated. If the patient is clinically unstable, emergent electrical cardioversion is the treatment of choice. After emergent cardioversion (electrical or chemical), anticoagulation with UFH or LMWH should be initiated in conjunction with warfarin. The heparin-based agent can be discontinued when the patient’s International Normalized Ratio (INR) is greater than or equal to 2.0. It is reasonable to overlap heparin with warfarin for 2 additional days after the INR is at the goal level. The duration of warfarin therapy depends on various clinical factors (see Arrhythmias, Chronic Management). In patients who are stabilized with rate-lowering agents but remain in AF, restoration of normal sinus rhythm may still be desired by the patient and the physician. In these instances, the question is whether or not the patient has been in AF for more than 48 hours. If so, he or she should 183

7

Table 7-3: Comparison of Approved Fibrinolytic Agents Dose Bolus administration

1.5 MU in 30-60 min No

≤100 mg in 90 min (based on weight) No

Antigenic

Yes

No

Allergic reactions (hypotension most common)

Yes

No

Marked

Mild

~50

~75

TIMI grade 3 flow (%)

32

54

Cost per dose (US $)

568

2,750

Systemic fibrinogen depletion 90-min patency rates (%)

TIMI=Thrombolysis in myocardial infarction.

begin anticoagulation and return for an elective cardioversion after 3 consecutive weeks of therapeutic INR (2.0 to 3.0). An alternative strategy is to obtain a transesophageal echocardiogram to assess for intracardiac thrombus. If thrombus is present, cardioversion should be delayed until at least 3 consecutive weeks of therapeutic INR have been obtained. If no thrombus is present, it is reasonable to pursue elective cardioversion during the index hospitaliza184

10 U x 2 (30 min apart) each over 2 min Yes

30-50 mg based on weight Yes

No

No

No

No

Moderate

Minimal

7

~75

~75

60

63

2,750

2,750 for 50 mg

tion. In either case, the patient should be anticoagulated with warfarin for an additional 4 weeks after reversion to normal sinus rhythm (Figure 7-6). Again, the duration of warfarin therapy depends on various clinical factors. For those who have been in AF for less than 48 hours, it is reasonable to proceed directly to cardioversion. In a patent with no clinical risk factors for an embolic event, it is unclear whether subsequent anticoagulation for the next 4 185

Chewable aspirin: 325 mg*

Clopidogrel: 300-600 mg** NSTEMI/UA GP Ilb/Illa inhibitor if high-risk features and PCI is planned*** ACS

LMWH 1 mg/kg SC q 12 hr†

STEMI/New LBBB/Posterior wall MI

Cardiac catheterization lab available and time from door to balloon <90 min

Cardiac catheterization lab unavailable

Figure 7-5: The role of antiplatelet, anticoagulation, and thrombolytic therapy in acute coronary syndromes. *In case of allergy, give clopidogrel. **If there is a high likelihood of coronary artery bypass graft (CABG) surgery, administering clopidogrel can be considered after the angiogram has been examined. ***Can be administered just before percutaneous coronary intervention (PCI) (IA); can be given with aspirin and heparin if high-risk features are present when an invasive strategy is not planned (IIA); can be given to patients receiving heparin, aspirin, and clopidogrel when PCI is planned (IIA). Dosing for normal renal function: Abciximab: 0.25-mg/kg bolus followed by 0.125 mg/kg/min for 12 to 24 hr; eptifibatide: 180μg/kg bolus followed by 2 μg/kg/min for 72 hr; tirofiban: 0.4 μg/kg/min for 30 min followed by 0.1 μg/kg/min for 72 hr. † Low-molecular-weight heparin (LMWH) is preferable over unfractionated heparin (UFH) unless CABG is planned within 24 hours (IIA). In

186

Aspirin: 81 mg/d indefinitely Clopidogrel: 75 mg/d for minimum of 1 year3 Continue until time of PCI (and 12-18 hr after) or for up to 72 hr if managed conservatively Continue until time of PCI or for up to 72 hr if managed conservatively Chewable aspirin: 325 mg*

Send directly for PCI with subsequent management dictated by cardiologist

7

Chewable aspirin: 325 mg* Streptokinase or tPA agent based ‡

Consider rescue PCI if no resolution of ST elevation or clinical deteriorations

LMWH 30 mg IV followed by 1 mg/kg SC for duration of hospitalization∆

patients managed invasively, UFH is still reasonable. Once-daily dosing should be used in those with creatinine clearance <30. Fondaparinux should be considered in patients being managed without PCI; for those with heparin-induced thrombocytopenia (HIT), direct thrombin inhibitors or bivalirudin in conjunction with glycoprotein (GP) IIb/IIIa should be considered. ‡ The agent used should be based on the timing of symptoms and concern of intracranial hemorrhage (ICH) (see text): Streptokinase: 1.5 MU over 30 to 60 min; alteplase: ≤100 mg in 90 min (weight based); reteplase: 10 U x 2 (30 min apart) each over 2 min; TNK-tPA: 30-50 mg (weight based). ∆ The dose should be modified for those younger than 75 years old with renal insufficiency (see text). If CABG is scheduled, UFH should be used. In the setting of HIT, bivalirudin should be used. LBBB=left bundle branch block; NSTEMI=non-ST-segment elevation myocardial infarction; SC=subcutaneous; tPA=tissue plasminogen activator; UA=unstable angina.

187

weeks is beneficial. If a patient does indeed have risk factors that put him or her at risk, long-term anticoagulation should be seriously considered.19 Chronic Management Many studies have examined the risk of stroke in patients with AF. Patients with AF and mitral stenosis (valvular AF), have up to a 6% incidence of embolism annually; however, these patients should be anticoagulated unless they have significant comorbidities that would increase the risk of a life-threatening bleed. In those with nonvalvular AF, risk factors that predict stroke are previous stroke or transient ischemic attack (TIA) (relative risk [RR], 2.5), diabetes (RR, 1.7), hypertension (RR, 1.6), and increasing age (RR, 1.4 for each decade). Any of these risk factors gives an annual risk of stroke of 4% if left untreated. Patients whose only stroke risk factor is heart failure or coronary disease have stroke rates that are 3 times higher than those without risk factors. Patients younger than 65 years who have normal echocardiograms and none of the risk factors have an annual risk of 1%. These patients are often referred to as those with “lone atrial fibrillation.”1 Based on these risk factors, a set of criteria known as the CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke) score has been created (Figure 7-7).20 This system uses these risk factors in the decision-making process and helps physicians determine how aggressively they should anticoagulate patients with AF. The main therapeutic options include warfarin, with a goal INR of 2.0 to 3.0, or full-dose aspirin. These treatment strategies have been evaluated in a meta-analysis (Table 7-4). Based on these data, patients with CHADS2 scores of 0 to 1 are considered low risk and can be treated with full-dose aspirin. Those with scores of 2 to 3 are at moderate risk of a stroke, and unless contraindicated, they should probably be prescribed chronic warfarin therapy. A caveat to this is that a patient with a prior stroke or TIA should be consid188

ered high risk even if his or her overall score is less than 3. This alone puts a patient at a 12% to 15% risk for another embolic event. A score of greater than 4 puts the patient at high risk; chronic warfarin therapy should not be withheld in these patients. Overall, the CHADS2 score provides a useful model in helping clinicians decide which patients should have chronic warfarin therapy. The ACC/AHA also have recommendations for preventing thromboembolism in AF that can be useful (Table 7-5).21 Withholding Anticoagulation for Invasive Procedures During temporary interruption of warfarin therapy, the risk of stroke and other thromboembolic events can be interpolated from the data in high-, moderate- and low-risk patients with chronic AF. But, the ACC/AHA guidelines state: In patients with AF who do not have mechanical prosthetic heart valves, interrupting anticoagulation for up to 1 wk before a surgical or diagnostic procedure that carries a risk of bleeding without substituting heparin is reasonable. This may overly simplify the management of patients with chronic AF who require warfarin cessation. However, only two studies involving 20 patients have investigated the perioperative clinical course of such patients. Consequently, there are inadequate data to provide reliable risk estimates for perioperative thromboembolism in patients with chronic AF. However, a reasonable classification scheme that stratifies patients with chronic AF according to their thromboembolic risk and provides a suggested anticoagulation management strategy for each risk category can be found in Table 7-6.22 In patients at moderate to high risk for an embolic event, bridging therapy with UFH or enoxaparin should be considered. When deciding at which point to begin bridging therapy after surgery, a discussion with the surgeon is mandatory. 189

7

Atrial fibrillation Acute rate control

Reversion strategy

Duration <48 hr

Long-term rate control

Duration >48 hr

no TOE

TOE

No thrombus

Atrial thrombus

≥3 wk anticoagulation

Cardioversion Cardioversion

≥4 wk anticoagulation Figure 7-6: Management of new-onset atrial fibrillation. TOE=transesophageal echocardiography.

Cerebrovascular Diseases Each year, more than 700,000 Americans have strokes, and more than 150,000 die, making CVD the country’s third leading cause of death. More than 25% of survivors older than 65 years are still disabled 6 months later. Although many of the risk factors for CVD overlap with those of 190

Adjusted stroke rate* per 100 patient-years

20 18 16 14 12 10 8 6 4 2 0 0

1

2

3 4 CHADS2 score

5

6

7

Figure 7-7: Adjusted stroke rate stratified by CHADS2 score in patients with nonvalvular atrial fibrillation not taking warfarin.

cardiac disease, it is critical to recognize that this disease represents a variety of conditions, can reflect a diverse set of pathophysiologic processes, and specific therapeutic interventions for it may confer levels of benefit and risk that differ from other forms of vascular disease.1 The following discussion focuses on therapeutic interventions for acute ischemic stroke and for stroke prevention. Acute Ischemic Stroke As with ACS, time is tissue in the treatment of patients with acute stroke. A variety of conditions, such as migraines, meningitis, and demyelinating processes, may cause symptoms and signs that can be mistaken for those of a stroke. Therefore, in the period immediately after the onset of ischemic symptoms, the evaluation is aimed at determining whether the patient is an appropriate candidate for reperfusion therapy. 191

Table 7-4: Summary of Meta-Analysis for Antithrombotic Therapy in Chronic Atrial Fibrillation Treatment Comparison

Relative Risk Reduction (%) (95% Confidence Interval)

Adjusted-dose oral anticoagulation vs no antithrombotic therapy

68 (50-79)

Adjusted vs no antithrombotic therapy

21 (0-38)

Adjusted-dose oral anticoagulation vs aspirin

52 (37-63)

Recombinant Tissue-Type Plasminogen Activator Intravenous (IV) recombinant tissue-type plasminogen activator (rtPA) is the only specific treatment for acute ischemic stroke that has received approval from the Food and Drug Administration. Treatment is aimed at lysis of a clot occluding a cerebral artery. On the basis of a pivotal National Institutes of Health–sponsored randomized clinical trial,23 treatment of appropriate patients is associated with a 13% absolute increase in the proportion of patients free of disability 3 months later. Benefits are similar for patients with small, penetrating artery distribution ischemic stroke and for those with occlusion of larger intracranial arteries. Although treatment is also associated with an increase in the risk of hemorrhage (6.4% risk of symptomatic ICH with treatment vs 0.6% with placebo; 2.9% risk of fatal hemorrhage vs 0.3% with placebo), the overall benefit includes these adverse events.23 The drug must be given within 3 hours of the onset of symptoms, 192

which means that the patient must generally arrive at a properly equipped hospital within 2 hours of symptom onset to have the necessary evaluations (including a brain computed tomography scan to exclude hemorrhage or other conditions). To use the drug safely, a strict protocol needs to be closely followed, and patients need to be carefully selected (Table 7-7).23 Heparin The indications for acute anticoagulation of patients with ischemic stroke are quite limited. The AHA/American Academy of Neurology guidelines specifically indicate that emergent anticoagulation as well as the initiation of anticoagulant therapy within 24 hours of treatment with IV-administered rtPA is not recommended, nor is urgent anticoagulation for treatment of moderate to severe stroke because of a high risk of intracranial bleeding complications.24 Patients with AF-associated stroke benefit from long-term anticoagulation unless contraindicated because of a high bleeding risk. The risk of early recurrence in patients with stroke related to AF is generally low (~0.3% to 0.5% per day for the first 2 weeks), so the timing of the initiation of anticoagulation needs to be balanced against the risk of bleeding. Patients with large strokes or uncontrolled hypertension are generally at highest risk of spontaneous hemorrhagic transformation.1 The use of anticoagulants in patients with stroke related to endocarditis is problematic. Systemic embolization occurs in up to 50% of patients, with up to 65% of emboli affecting the central nervous system. No benefit for anticoagulation in patients with native valve endocarditis has been demonstrated, and it is generally not recommended for at least the first 2 weeks of antibiotic therapy in patients with stroke related to Staphylococcus aureus prosthetic valve endocarditis.25 Anticoagulation is generally avoided because of the concern that subclinical mycotic aneurysms, which have the propensity to rupture, may be present. 193

7

194

Table 7-5: American College of Cardiology/American Heart Association Recommendations for Preventing Thromboembolism in Atrial Fibrillation Level of Evidence

Class

Indication

Class I (indicated)

Antithrombotic therapy is recommended to prevent thromboembolism for all patients with AF except those with lone AF or contraindications.

A

The antithrombotic agent should be selected based on the absolute risks of stroke and bleeding and the relative risk and benefit for a given patient.

A

For patients without mechanical heart valves at high risk for stroke, chronic oral anticoagulant therapy should be instituted with a VKA in a dose adjusted to achieve the target intensity INR of 2.0 to 3.0 unless contraindicated. Factors associated with the highest risk for stroke in patients with AF are prior thromboembolism (stroke, TIA, or systemic embolism) and rheumatic mitral stenosis.

A

Anticoagulation with a VKA is recommended for patients with more than one moderate risk factor (age ≥75 yr, hypertension, HF, impaired LV systolic function [EF ≤35% or fractional shortening <25%], and diabetes mellitus).

A

Class IIa (strong supportive evidence)

The INR should be determined at least weekly during initiation of therapy and monthly when anticoagulation is stable.

A

Aspirin (81-325 mg/d) is an alternative to VKAs in low-risk patients and in those with contraindications to oral anticoagulation.

A

For patients with AF and mechanical heart valves, the target INR should be based on the type of prosthesis, maintaining an INR of at least 2.5.

B

Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF.

C

Antithrombotic therapy with aspirin or a VKA is reasonable to prevent thromboembolism in patients with nonvalvular AF and only a single validated risk factor (age ≥75 yr, especially female patients; hypertension; HF; impaired LV function; or diabetes mellitus) based on an assessment of the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences.

A

195

Antithrombotic therapy with aspirin or a VKA is reasonable to prevent B thromboembolism in patients with nonvalvular AF who have one or more less well-validated risk factors (age, 65-74 yr; female gender; CAD). The choice of agent should be based on the risk of bleeding complications, ability to sustain adjusted chronic anticoagulation safely, and patient preferences. (continued on next page)

7

196

Table 7-5: American College of Cardiology/American Heart Association Recommendations for Preventing Thromboembolism in Atrial Fibrillation (continued) Class

Class IIb (weak supportive evidence)

Indication

Level of Evidence

Antithrombotic therapy can be reasonably selected using the same criteria irrespective of the pattern (ie, paroxysmal, persistent, or permanent) of AF.

B

In patients with AF who do not have mechanical prosthetic heart valves, interrupting anticoagulation for up to 1 wk before surgical and diagnostic procedures that carry a risk of bleeding without substituting heparin is reasonable.

C

The need for anticoagulation should be reevaluated at regular intervals.

C

A lower INR target of 2.0 (range, 1.6–2.5) may be considered for prevention of ischemic stroke and systemic embolism in patients 75 yr and older who are at increased risk of bleeding but without frank contraindications to oral anticoagulant therapy, as well as in other patients with moderate risk factors for thromboembolism who are unable to safely tolerate anticoagulation at the standard intensity of INR 2.0–3.0.

C

In high-risk patients, during interruption of oral anticoagulant therapy for longer than 1 wk for surgical procedures, UFH may be administered or LMWH given by SC injection.

C

After PCI or revascularization surgery in patients with AF, low-dose aspirin (<100 mg/d), clopidogrel (75 mg/d), or both may be given concurrently with anticoagulation to prevent myocardial ischemic events.

C

In patients undergoing PCI, anticoagulation may be interrupted to prevent bleeding at the site of peripheral arterial puncture, but the VKA should be resumed as soon as possible after the procedure and the dose adjusted to achieve an INR in the therapeutic range. Aspirin may be given temporarily during the hiatus, but the maintenance regimen should then consist of the combination of clopidogrel (75 mg/d) plus warfarin (INR, 2.0–3.0). Clopidogrel should be given for a minimum of 1 mo after implantation of a BMS or at least 12 mo for a DES, after which warfarin may be continued as monotherapy in the absence of a subsequent coronary event. When warfarin is given in combination with clopidogrel or low-dose aspirin, the dose intensity must be carefully regulated.

C

197

(continued on next page) 7

198

Table 7-5: American College of Cardiology/American Heart Association Recommendations for Preventing Thromboembolism in Atrial Fibrillation Class

Class III (not indicated)

Indication

Level of Evidence

In AF patients younger than 60 yr without heart disease or risk factors for thromboembolism (lone AF), the risk of thromboembolism is low without treatment, and the effectiveness of aspirin for primary prevention of stroke relative to the risk of bleeding has not been established.

C

In patients with AF who sustain ischemic stroke or systemic embolism during treatment with low-intensity anticoagulation (INR, 2.0–3.0), increasing the intensity of anticoagulation to a target INR of 3.0 to 3.5 may be a more reasonable approach than adding an antiplatelet agent.

C

Long-term anticoagulation with a VKA is not recommended for primary prevention of stroke in younger patients (<60 yr) without heart disease (lone AF) or any risk factors for thromboembolism.

C

AF=atrial fibrillation; BMS=bare metal stent; CAD=coronary artery disease; DES=drug-eluting stent; EF=ejection fraction; HF=heart failure; INR=International Normalized Ratio; LMWH=low-molecularweight heparin; LV=left ventricular; PCI=percutaneous coronary intervention; SC=subcutaneous; TIA=transient ischemic attack; UFH=unfractionated heparin; VKA=vitamin K antagonist.

Table 7-6: Perioperative Anticoagulant Management in Patients With Chronic Atrial Fibrillation Thrombolism Risk Category

Patient Characteristics

Suggested Anticoagulant Management

High risk

Recent (within 1 wk) stroke or TIA; rheumatic mitral valvular heart disease

Bridging anticoagulant therapy is strongly recommended

Moderate risk

Chronic AF and 2 more risk factors*

Bridging anticoagulant therapy should be considered

Low risk

Chronic AF and less than 2 stroke risk factors*

Bridging anticoagulant therapy is optional

*Stroke risk factors include left ventricular dysfunction, hypertension, diabetes, remote stroke or transient ischemic attack (TIA), and age greater than 75 years. AF=atrial fibrillation.

199

7

Aspirin There may be benefit from treatment with full-dose aspirin if it is begun within 48 hours of acute ischemic stroke. (Antiplatelet drugs are prohibited for the first 24 hours in patients treated with IV rtPA.) A combined analysis of two relevant trials24 found that treatment with aspirin (160 to 325 mg/day) was associated with a small but statistically significant reduction of 9 (±3) fewer deaths or nonfatal strokes per 1,000 treated patients. No data have shown a benefit of any other platelet antiaggregant, given either alone or in combination, in the setting of acute ischemic stroke.24 Stroke Prevention: Primary Prophylaxis Approximately 70% of strokes are first cardiovascular events, making primary prevention of paramount importance. When considering primary prophylaxis, platelet inhibition and anticoagulation have their roles and the use of either must be considered in the context of the patient’s global risk for cardiovascular events and stroke. Aspirin The benefit of aspirin for primary prophylaxis outweighs its associated risk of bleeding complications among persons with a 10-year risk of coronary events of 6% to 10%, but there is no evidence of a reduction in stroke risk even in these patients (predominantly men), and aspirin is not recommended for this purpose.26 Although the Women’s Health Study found no reduction in its primary end point (nonfatal MI, nonfatal stroke, or cardiovascular death) with aspirin (100 mg on alternate days), there was a 17% reduction in the risk of stroke, although with an increase in the risk of bleeding.27 This benefit was primarily in women at increased stroke risk because of other risk factors such as hypertension and diabetes. As a result, aspirin may be considered in women whose risk of stroke is sufficiently high to outweigh the associated bleeding risk.1 There is 200

no evidence of benefit in reducing the risk of a first stroke with any other platelet inhibitor. Warfarin Another situation to consider is the management of patients with mechanical heart valves. The risks of thrombosis and thromboembolism are greater with any mechanical valve in the mitral rather than in the aortic position, and higher doses of warfarin are generally recommended for patients with mitral prostheses. However, patients with any mechanical prosthesis, regardless of its design or site of placement, require long-term anticoagulation and aspirin administration for embolic prophylaxis, which is typically greatest in the first postoperative year. Without anticoagulants and aspirin, the incidence of thromboembolism is 3-fold to 6-fold higher than when proper doses of these medications are administered. Rarely, thrombosis of the mechanical valve occurs, which can be fatal, but when nonfatal, it interferes with prosthetic valve function.1 For the ACC/AHA guidelines on goal INR in the setting of mechanical heart valves, see Table 7-8.28 A difficult scenario arises when a patient with a mechanical valve becomes pregnant or when a patient requires temporary cessation of warfarin before an invasive procedure. In the latter case, the patient should have warfarin held and have the INR checked regularly. After the INR is below the target value, UFH should be given during the perioperative state with a goal aPTT of two times the upper limit of normal. Warfarin should be resumed after surgery along with UFH, which can be stopped after a therapeutic INR has been achieved. Because the period of not being protected is relatively short, there is a minimal risk of thrombosis or embolism. Pregnancy is more complicated because there is no perfect anticoagulation strategy, and each modality is associated with some hazard for the mother, the fetus, or both. Before any approach is adopted, it is crucial to explain the risks to the patient. 201

7

Table 7-7: Characteristics of Patients With Ischemic Stroke Who Could Be Treated With Recombinant Tissue-Type Plasminogen Activator • Diagnosis of ischemic stroke causing measurable neurologic deficit • Neurologic signs should not be clearing spontaneously • Neurologic signs should not be minor and isolated • Caution should be exercised in treating a patient with major deficits • Symptoms of stroke should not be suggestive of SAH • Onset of symptoms <3 hr before beginning treatment • No head trauma or prior stroke in the previous 3 mo • No MI in the previous 3 mo • No GI or urinary tract hemorrhage in the previous 21 d • No major surgery in the previous 14 d • No arterial puncture at a noncompressible site in the previous 7 d • No history of previous ICH • Blood pressure not elevated (systolic >185 mm Hg or diastolic >110 mm Hg)

The hypercoagulable state of pregnancy makes the risk of valve thrombosis and thromboembolism significant. Heparin One option for pregnant patients is UFH, which has the advantages of not crossing the placenta and not causing developmental abnormalities in fetuses. However, labora202

• No evidence of active bleeding or acute trauma (fracture) on examination • Not taking an oral anticoagulant, or if anticoagulant is being taken, INR <1.7 • If receiving heparin in the previous 48 hr, the aPTT must be in the normal range • Platelet count >100,000 mm3 • Blood glucose concentration >50 mg/dL (2.7 mmol/L) • No seizure with postictal residual neurologic impairments • CT does not show a multilobar infarction (hypodensity in one third of the cerebral hemisphere) • The patient or family understand the potential risks and benefits of treatment aPTT=activated partial thromboplastin time; CT=computed tomography; GI=gastrointestinal; ICH=intracranial hemorrhage; INR=International Normalized Ratio; MI=myocardial infarction; SAH=subarachnoid hemorrhage.

tory control of aPTT is difficult. The aPTT ratio should be maintained at a level of at least two times the upper limit of normal. UFH has been used SC and IV and is often begun in the first trimester as soon as pregnancy is diagnosed to minimize fetal exposure to warfarin at the critical time of fetal embryogenesis. It is usually continued until week 13 or 14 of pregnancy when fetal embryogenesis is almost com203

7

plete, and then warfarin may be substituted. Our practice is to continue heparin throughout pregnancy to avoid any fetal exposure to warfarin, but UFH has been shown to be a poor anticoagulant in pregnancy. One large retrospective European study comparing different anticoagulation strategies has shown that most maternal complications, including valve thrombosis, stroke, and death, occur while mothers are taking heparin.29 Most complications occur with mechanical mitral tilting disc prostheses. One meta-analysis showed that using heparin early in the first trimester virtually eliminates the risk of fetal embryopathy but at the expense of maternal valve thrombosis, which occurred with a frequency of 9%.30 Low-Molecular-Weight Heparin The American College of Chest Physicians has suggested that LMWH may be used with the anticoagulant effect carefully monitored by measuring the anti-Xa level. It is recommended that it be administered SC every 12 hours and then the dose adjusted so that a 4-hour postinjection anti-Xa level is maintained at approximately 1.0 to 1.2 U/ mL, perhaps measured weekly.31 The addition of 75 to 162 mg/day of low-dose aspirin has also been recommended. Although more convenient than UFH, retrospective studies have also indicated treatment failure with valve thrombosis in approximately 10% of patients. This may have been secondary to fixed dosing without dosage modification based on anti-Xa levels. Unfortunately, no large prospective series and no evidence-based data are available to support which levels of anti-Xa activity should be maintained. UFH can be substituted peridelivery because it can be started and stopped abruptly.1 Stroke Prevention: Secondary Prophylaxis Prevention of recurrent events is also critical because 15% of stroke survivors have a second stroke within 1 year, and 30% do so within 5 years. The period soon after the stroke is typically associated with the highest rate of recur204

Table 7-8: Recommendations on Anticoagulation Levels After Heart Valve Replacement Valve AHA/ACC Position Recommendations Mechanical Valves* First generation: Starr Edwards, Bjork Shiley standard

2.5-3.5

Second generation: St. Jude, Medtronic Hall, BS Monostrut, Carbomedics

Aortic

2.0-3.0

Mitral

2.5-3.5

Bioprostheses in Sinus Rhythm

Aortic Mitral

Aspirin: 80-100 mg Aspirin: 80-100 mg

7

No anticoagulation after 3 mo Bioprostheses in Atrial Fibrillation

Aortic Mitral

2.0-3.0 2.5-3.5

*Aspirin (81 mg/d) is recommended for all patients with prosthetic valves. ACC=American College of Cardiology; AHA=American Heart Association. Adapted from Society for Cardiothoracic Surgery in Great Britain and Ireland Web site. Available at: http://www.scts.org/ doc/5167. Accessed November 24, 2008.

205

rence. In addition, the risk of ischemic stroke after a TIA is as high as 10.5% over 90 days, with the highest risk over the first week.1 Therefore, secondary prevention is crucial. Different treatment strategies have been studied. Aspirin and Dipyridamole Aspirin (the lowest effective dose compared with placebo is 50 mg/day) lowers by approximately 18% the risk of recurrent stroke in persons with a noncardioembolic ischemic stroke. Sustained-release dipyridamole (Persantine ®) (200 mg twice daily) is as efficacious as aspirin in reducing the risk of recurrent stroke caused by focal brain or retinal ischemia, with a further significant reduction (~37%) when the two drugs are combined. The recently completed PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) study demonstrated equivalent efficacy outcomes with clopidogrel and the combination of aspirin and dipyridamole but a lower rate of bleeding and side effects with clopidogrel. Aspirin with sustained-release dipyridamole is available in the US in a fixed-dose combination (25 mg of aspirin plus 200 mg of dipyridamole) that is given twice daily.32

References 1. Libby P, Bonow RO, Mann DL, et al: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders, 2007. 2. Théroux P, Ouimet H, McCans J, et al: Aspirin, heparin or both to treat unstable angina. N Engl J Med 1988;319:1105-1111. 3. Risk of Myocardial Infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet 1990;336:827-830. 4. Fox KA, Mehta SR, Peters R, et al: Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST elevation acute coronary syndrome (CURE) Trial. Circulation 2004;110:1202-1208. 5. Patti G, Colonna G, Pasceri V, et al: Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial

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infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005;111:2099-2106. 6. Broad L, Lee T, Conroy M, et al: Successful management of patients with a drug-eluting coronary stent presenting for elective, non-cardiac surgery. Br J Anaesth 2007;98(1):19-22. 7. Boersma E, Harrington RA, Moliterno DJ, et al: Platelet IIb/IIIa inhibition in acute coronary syndromes: a meta-analysis of all major randomized clinical trials. Lancet 2002;359:189-198. 8. Peterson ED, Pollack CV, Roe MT, et al: Early use of glycoprotein IIb/IIIa inhibitors in non-ST-elevation acute myocardial infarction: Observations from the National Registry of Myocardial Infarction 4. J Am Coll Cardiol 2003;42:45-53. 9. Stone GW, McLaurin BT, Cox DA, et al: ACUITY: Timing of glycoprotein IIb/IIIa inhibition for patients with acute coronary syndromes. JAMA 2007;297:591-602. 10. Eikelboon JW, Anand SS, Malmberg K, et al: Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 2000;355:1936-1942. 11. Petersen JL, Mahaffey KW, Hasselblad V, et al: Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a systematic overview. JAMA 2004;292:89-96. 12. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators; Yusuf S, Mehta SR, Chrolavicius S, et al: Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354:1464-1476. 13. Stone GW, McLaurin BT, Cox DA, et al: Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-2216. 14. Antman EM, Anbe DT, Armstrong PW, et al: ACC/AHA guideline for the management of patients with STEMI: a report of the ACC/AHA 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. 15. Boersma E, Maas AC, Deckers JW, et al: Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771-775.

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16. Antman EM, Morrow DA, McCabe CH, et al: Enoxaparin versus heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477-1488. 17. 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;358:1855-1863. 18. Lloyd-Jones DM, Wang TJ, Leip EP, et al: Lifetime risk for development of atrial fibrillation: the Framingham heart study. Circulation 2004;110:1042-1046. 19. Ninio DM: Contemporary management of atrial fibrillation. Aust Prescrib 2000;23:100-102. 20. Wang TJ, Massaro JM, Levy D, et al: A risk score for predicting stroke or death in individuals with new onset atrial fibrillation in the community: The Framingham Heart Study. JAMA 2003;290:1049-1056. 21. Go AS: Efficacy of anticoagulation for stroke prevention and risk stratification in atrial fibrillation: translating trials into clinical practice. Am J Manag Care 2004;10(suppl 3):S58-S65. 22. Douketis JD: Perioperative anticoagulation management in patients who are receiving oral anticoagulant therapy: a practical guide for clinicians. Thromb Res 2002;108:3-13. 23. Adams H, Adams R, Del Zoppo G, et al: Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update. A scientific statement from the stroke Council of the American Heart Association/American Stroke Association. Stroke 2005;36:916-923. 24. Coull BM, Williams LS, Goldstein LB, et al: Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association. Neurology 2002;59:13-22. 25. Baddour LM, Wilson WR, Bayer AS, et al: Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. Circulation 2005;111:e394-434. 26. Goldstein LB, Adams R, Alberts MJ, et al: Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council. Stroke 2006;37:1583-1633.

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27. Ridker PM, Cook NR, Lee I-M, et al: A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-1304. 28. Society for Cardiothoracic Surgery in Great Britain and Ireland: Available at http://www.scts.org. 29. Sbarouni E, Oakley CM: Outcome of pregnancy in women with valve prostheses. Br Heart J 1994;71:196-201. 30. Chan WS, Anand S, Ginsberg JS: Anticoagulation of pregnant women with mechanical heart valves: A systematic review of the literature. Arch Intern Med 2000;160:191-196. 31. Bates SM, Greer IA, Hirsh J, et al: Use of antithrombotic agents during pregnancy. the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 suppl):627S-644S. 32. Sacco RL, Adams R, Albers G, et al: Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. A statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke. Stroke 2006;37:577-617.

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Chapter 8

Heparin-Induced Thrombocytopenia Geno J. Merli, Alpesh N. Amin, Steven B. Deitelzweig

H

eparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction that is a strong risk factor for venous and arterial thrombosis.1,2 Early identification and treatment of HIT may prevent more serious complications such as venous thromboembolism, limb gangrene, and skin necrosis. Both arterial and venous thrombosis may arise from a single episode of HIT. Routine assessment of platelet counts is necessary with unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) therapy because a decreased platelet level is usually the only indication of HIT. Treatment with a direct thrombin inhibitor (DTI), such as lepirudin, argatroban, or bivalirudin, is an effective strategy in reversing the thrombin generation associated with HIT and reducing its complications.

Background Heparin is a widely used anticoagulant drug for the prevention and treatment of venous and arterial thromboembolic diseases. Thrombocytopenia, a frequently occurring complication of heparin therapy, may occur in two distinct types. The more common type I (sometimes called heparin-associated thrombocytopenia), occurs in 10% to 20% of patients receiving heparin1 and is a nonimmunogenic response to 210

therapy.3 This mild thrombocytopenia is not progressive and is not associated with bleeding or thrombosis. No special treatment is required; the platelet count is usually above 100 x 109/L and gradually increases to pretreatment levels within a few days, even if heparin therapy is not discontinued. The less frequent but more severe form of HIT, type II, is an immune response caused by the idiopathic presence of drug-related antibodies. It occurs in 1% to 3% of patients exposed to UFH and in up to 0.8% of patients receiving LMWH.3-5 Although the main risk of thrombocytopenia is bleeding, with HIT there is a paradoxical primary risk for thrombosis. HIT may lead to a systemic thrombotic response that may span both venous and arterial vascular beds, although venous events are 4 times more common.6,7 The most frequent complications are deep vein thrombosis (DVT) and pulmonary embolism (PE).6 In rare cases, patients with HIT may develop life-threatening thromboses such as thromboembolic occlusions of peripheral limb arteries, acute myocardial infarction, and stroke. Other possible complications include warfarin-induced skin necrosis, acute systemic reactions, and transient global amnesia.7 Pathophysiology The central concept of HIT is formation of heparin-dependent IgG that activates platelets by way of their FcyIIa receptors (Figure 8-1). IgG and IgM class antibodies are not pathogenic because they cannot activate platelets by way of Fcy (IgG) receptors.8 The target antigen is a complex between heparin and platelet factor 4 (PF4), a tetrameric member of the CXC subfamily of chemokines.9,10 HIT antibodies recognize conformationally altered sites on PF4 resulting from its binding to heparin or because of close approximation of PF4 tetramers by heparin charge neutralization.9,10 LMWH is less likely to trigger antibodies and HIT than UFH, particularly in women receiving surgical prophylaxis.11,12 The pentasaccharide anticoagulant fondaparinux (Arixtra®), although similarly immunogenic 211

8

Figure 8-1: The process of HIT. PF4= platelet factor 4; PMN=polymorphonuclear.

as LMWH, does not form well the antigens on PF4, suggesting that it has even lower risk for causing HIT.13 Factors leading to thrombosis in HIT include the platelet activating nature of HIT antibodies, including formation of procoagulant and platelet-derived microparticles, as well 212

as “pancellular” activation (endothelium, monocytes) and neutralization of the anticoagulant effect of heparin by PF4 released from activated platelets14 Given the severe sequelae associated with HIT, its immediate recognition and treatment are critical. Typical presentation begins 5 or more days after therapy (the minimum period required for pathogenic antibodies to reach clinically significant levels) but may manifest much sooner if the patient has had previous exposure to heparin.7,15,16 Incidence of Heparin-Induced Thrombocytopenia Patients who have had recent major surgery represent one of the highest risk groups for development of HIT (Table 8-1). HIT is more prevalent in patients receiving antithrombotic prophylaxis after peripheral vascular, coronary artery bypass graft, and orthopedic surgery.26 The thrombotic complications are consistent with the baseline thrombotic risks that are more prevalent in each respective surgical population (ie, lower extremity DVT after hip or knee arthroplasty). A lower incidence of HIT is seen in medical patients and general surgery patients receiving prophylactic doses of UFH or LMWH. Medical and obstetric patients treated with prophylactic doses of LMWH have the lowest risk.24 However, because HIT is an immunologic reaction, it can potentially develop from exposure to any dose of heparin. Incidental exposure through heparin-coated catheters and heparin flushes to maintain an intravenous (IV) line can also provide an independent stimulus for HIT.17,25 In a study of 12 patients, Laster et al25 found that the thrombocytopenia resulting from heparin-coated catheters continued as long as the catheters were in place, regardless of whether other sources of the drug were discontinued. Thrombosis and skin necrosis that occur during heparin therapy should also raise strong suspicion for HIT. Warfarin treatment in patients with active HIT may cause DVT to progress to venous limb gangrene and may induce skin necrosis.27 213

8

Table 8-1: Incidence of Heparin-Induced Thrombocytopenia According to Population at Risk and Recommendations for Monitoring Clinical Population at Risk

Therapy

Risk

Heparin (new or remote [>100 d] exposure)

High

Patients undergoing orthopedic surgery1,7

Intermediate

Adults undergoing surgery7 Children undergoing cardiac surgery17

Intermediate

General medical patients8,11 Patients with neurologic conditions18 Patients undergoing PCI for ACS19

Low to rare

Patients undergoing acute hemodialysis20 General pediatric patients17 Pregnant women21 Patients undergoing chronic hemodialysis22

214

Incidence of Platelet Factor 4– Incidence of Heparin Heparin-Induced Platelet Count Antibodies* (%) Thrombocytopenia Monitoring 14

3-5

25-50

1-2

At baseline and at least every other day from days 4-14 of heparin therapy or until heparin is discontinued†‡

8 8-20

0.8-3.0

0-2.3

0-0.1

Not essential†

continued on next page 215

Table 8-1: Incidence of Heparin-Induced Thrombocytopenia According to Population at Risk and Recommendations for Monitoring (continued) Therapy

Risk

LMWH (new or remote [>100 d] exposure)

Intermediate

Rare

Clinical Population at Risk Medical patients8,9 Patients with neurologic conditions Patients undergoing surgical or orthopedic procedures7 Pregnant women23 General pediatric patients17

Heparin or LMWH (exposure within 100 d)

All clinical populations10

*Rates of seropositivity were determined by antigen or serologic enzyme-linked immunosorbent assays. † Recommendations for monitoring platelets are those of the American College of Chest Physicians.24

Clinical Manifestations and Diagnosis In HIT, the relative decrease in platelet counts is key to diagnosis. Clinical criteria include a decrease in platelet count of 50% or above or to levels below 100 x 109/L; current use of heparin; and a new thrombotic or thromboembolic event.5,18 While thrombocytopenia caused by drugs 216

Incidence of Platelet Factor 4– Incidence of Heparin Heparin-Induced Platelet Count Antibodies* (%) Thrombocytopenia Monitoring 2-8

0-0.9

At baseline and every 2-4 days after days 4-14 of LMWH therapy or until LMWH is discontinued‡

0-0.1

Routine monitoring not recommended‡

8 At baseline, within 24 hr and every other day from days 4-14 until heparin is discontinued†‡ ‡

Recommendations for monitoring platelets are those of the British Committee for Standards in Haematology.25 ACS=acute coronary syndromes; HIT=heparin-induced thrombocytopenia; LMWH=low-molecular-weight heparin.

other than heparin commonly presents with bleeding, HIT is recognized as a markedly thrombotic syndrome with bleeding complications occurring less frequently. Between 30% and 75% of patients develop thrombosis, which is counterintuitive to a decrease in platelet count, illustrates a normal distribution of thrombotic events based on platelet count 217

nadir, and emphasizes the presence of thrombosis across the clinical spectrum of the syndrome (Figure 8-2).5,7,18 The most common complications of HIT are presented in Table 8-2.28 Approximately 50% of patients presenting with isolated thrombocytopenia eventually experience a thrombotic event, and approximately 20% of these patients experience venous thrombosis, with DVT and PE identified as the most common events. While previous retrospective studies often focused on specific patient populations at high risk for arterial thrombosis, a 14-year study of patients with HIT conducted by Warkentin and Kelton18 found that the syndrome is mainly associated with venous thrombosis. Life-threatening venous thrombosis, especially PE, is an important presentation of HIT and may be consistent with the fact that many patients with HIT receive heparin prophylaxis because of their high baseline risk for thrombotic events.18 Several clinical syndromes are caused by HIT but do not present with classic symptoms. These include acute systemic reactions after an IV bolus, disseminated intravascular coagulation, and warfarin-associated venous limb gangrene or skin necrosis. Recent reports also suggest that HIT could explain approximately 5% of cases of acute adrenal failure caused by bilateral adrenal hemorrhagic infarction.7,29,30

Laboratory Diagnosis of HIT The diagnosis of HIT is based primarily on clinical grounds. Laboratory finding of the heparin antibodies is useful to corroborate the diagnosis and to monitor its presence in cases in which there is a clinical need to rechallenge a specific patient with heparin or heparin products (ie, onpump open heart surgery).15 Serologic or functional assays are used to document the presence of heparin-dependent antibodies. The most widely used assays for the diagnosis of HIT are the PF4–heparin enzyme-linked immunosorbent assay (ELISA) and the C-serotonin release assay (SRA). 218

Number of patients with HIT

40

Median platelet count nadir=59 x 109/L

No HIT-associated thrombosis HIT-associated thrombosis

Standard definition of thrombocytopenia

30

20

10

0 5

10

20

30

50

70

100

150

200

219

Platelet count nadir (x 109/L)

300

500

1,000

Figure 8-2: Platelet counts in patients w i t h H I T. Fr o m Warkentin, 7 used with permission.

8

Table 8-2: Thrombotic Complications of Heparin-Induced Thrombocytopenia Venous

Arterial

DVT PE Cerebral dural sinus thrombosis Adrenal hemorrhagic infarction

Aortic occlusion Acute thrombotic stroke MI Thrombosis in the upper and lower limbs Mesenteric, renal, and spinal arteries

DVT=deep vein thrombosis; MI=myocardial infarction; PE=pulmonary embolism. Adapted from Menajovsky.28

The PF4-dependent enzyme immunoassays use PF4heparin or PF4–polyvinyl sulfonate as targets. These assays detect all IgG, IgM, and IgA antibodies. They have a high sensitivity (>97%) and a lower specificity (74%–80%), meaning that these antibodies can be found in patients without HIT.6,7,29 Thus, the positive predictive value of the immunoassay can be low (10% to 93%) depending on the population, but the negative predictive value is high (>95%).29,30 The specificity of these immunoassays would be markedly improved if only the IgG antibodies were measured. The functional assays measure platelet activation and detect heparin-dependent antibodies capable of binding to and activating the Fc receptors on platelets. The sensitivity of aggregation testing is greater than 90%, and the specificity ranges from 77% to 100%.24,29 An assay measuring the 220

14 C serotonin release from activated platelets has high sensitivity (88% to 100%) and specificity (89% to 100%).6,24,29 Because of the variability in responsiveness among platelet donors to PF4–heparin antibodies, the positive predictive value of functional assays tends to be higher (89% to 100%) with a negative predictive value of 81%.29 Table 8-3 lists the main differences between the two commonly used with regard to clinical applicability.31-34 As is true for every diagnostic or screening test, it is important to establish the clinical pretest probability to help decide which test needs to be ordered as well as how to interpret the results. By estimating the pretest probability and knowing the likelihood ratios, the clinician can quantify the reliability of either a positive or a negative test result. Although yet to be validated, the 4 T’s (thrombocytopenia, timing, thrombosis, and the absence of other explanations) clinical scoring system has been proposed by Warkentin.30 Clinicians can use the guidelines in Table 8-4 to calculate the pretest probability of having the disease.35 Assuming a linear correlation between the individual score obtained from Table 8-4 and the pretest probability (expressed in percentage) and knowing the likelihood ratios calculated in Table 8-3, the clinician can estimate the post-test probability of either a positive or a negative test result in Table 8-5.28,36,37 Practically speaking, for a patient with very low (<10%) or high (>60%) pretest probability for HIT, a negative or positive, respectively, PF4–heparin ELISA test result should suffice to either rule in or rule out the diagnosis.28 In the moderate-risk groups, the SRA should be the test of choice; however, in no circumstances does it help to rule out the disease.

Current Management Strategies Current management of patients with HIT begins with the immediate discontinuation of all sources of heparin or LMWH (Table 8-6), including heparin flushes as well as heparin-coated catheters. The goal of management of 221

8

Table 8-3: Clinical Differences Between Platelet Factor 4–Heparin Enzyme-Linked Immunosorbent Assay and 14 C-Serotonin Release Assay2 Assay PF4–heparin ELISA SRA

Readily Available

Labor Intensity

Yes

+

No

++++

ELISA=enzyme-linked immunosorbent assay; LR=likelihood ratio; PF4=platelet factor 4; SRA=serotonin release assay. *A positive result is the sensitivity divided by 1 minus the specificity. †

A negative result is 1 minus the sensitivity divided by the specificity.

Adapted from Amiral et al,31 Arepally et al,32 Chong et al,33 and Pauker et al.34

HIT is to diminish the thrombotic risk by reducing platelet activation and thrombin generation. Treatment of patients with HIT requires anticoagulation with one of two classes of anticoagulant agents, DTIs or heparinoids. This latter class is not available for use in the US. Three DTIs—lepirudin, argatroban, and bivalirudin—are available for treating patients with HIT. These agents directly bind and inactivate thrombin without the need for antithrombin III binding as is required with heparin and LMWH. Lepirudin ( Refludan®) is a recombinant analogue of hirudin, a leech protein. It is cleared renally, which requires a dosing adjustment for creatinine clearance. Three observational studies6,38,39 examined lepirudin in 403 patients and 120 historical controls. In an analysis of these studies,15 the rate of the combined outcome of death, 222

Sensitivity

Specificity

LR(+)

LR(−)†

≥90%

80%

4.5

0.13

≥90%

98%

4.5

0.1

8

amputation, and thrombosis at 35 days was lower in those receiving lepirudin than in control subjects (20.3% vs 43%; P <0.001). Separate analyses of these outcomes revealed significant differences in the rate of new thrombotic events but not in rates of death or amputation; however, the studies were underpowered for these end points. Bleeding rates were significantly higher among control subjects (5.8%), and bleeding was the cause of death in 1.2% of treated patients.15 These observations have led to a change in the dosing recommendations for older patients in whom subclinical renal insufficiency may impair drug clearance.15,38,40 Antibodies to lepirudin develop in about 30% of patients after initial exposure and in about 70% of patients after repeated exposure.15 Because fatal anaphylaxis has been reported after sensitization to lepirudin,27 patients should not be treated with this agent more than once. 223

Table 8-4: The 4 T’s Scoring System: Estimating the Pretest Probability of HIT The Ts Thrombocytopenia

Point 2 >50% decrease to nadir 20,000/mm3

Timing of platelet count decrease, thrombosis, or other sequelae (firstday exposure of heparin course=day 0*)

Day 5-10 onset or <1 d (with heparin exposure within 5-30 d)

Thrombosis (including adrenal infarction) or other sequelae (skin lesions)

Proven new thrombosis or skin necrosis (at injection or after IV heparin bolus anaphylactoid No explanation for platelet decrease is evident

OTher cause for thrombocytopenia

Total score (pretest probability): High, 6-8 points; intermediate, 4-5 points; low, 0-3 points. *The first day of immunizing heparin exposure is considered day 0, and the day the platelet count begins to decrease is considered the day of onset of thrombocytopenia. It generally takes 1 to 3 more days until an arbitrary threshold that defines thrombocytopenia is passed. Usually, heparin administration at or near surgery is the most immunizing situation. Adapted from Warkentin.35

224

Point 1 30% to 50% decrease

Point 0 <30%

Nadir 10,000-19,000 mm3 Consistent with day 510 decrease but not clear (missing platelet counts) or <1 d (heparin exposure within past 31-100 d) or platelet counts decrease after day 10 Progressive or recurrent thrombosis, erythematous skin lesions (at injection sites), or suspected thrombosis (not proven) Possible other cause is evident

Nadir <10,000 mm3 Platelet count decreases <4 d without recent heparin exposure

None

8

Definite other cause is present

225

Table 8-5: Posttest Probability: Enzyme-Linked Immunosorbent Assay and 14C-Serotonin Release Assay Pretest Probability, 4 T’s score (%)

Posttest Probability,† Positive ELISA (%)

0 (0%)

0

1 (10%)

33

2 (20%)

53

3 (30%)

66

4 (40%)

75

5 (50%)

82

6 (60%)

87

7 (70%)

91

8 (80%)

95

*Pretest probability=likelihood of having HIT before test results. †

Posttest probability=likelihood of having HIT after test results.

ELISA=enzyme-linked immunosorbent assay; HIT=heparininduced thrombocytopenia. Adapted from Fagan36 and Jaeschke et al.37

Argatroban is a synthetic compound that binds reversibly to the catalytic site of thrombin. It is hepatically cleared and should not be used in patients with impaired liver function. Argatroban was investigated in two prospective multicenter studies involving a total of 722 patients with HIT.14,28 The combined outcome of death, amputation, and thrombosis 226

Posttest Probability, Negative ELISA (%)

Posttest Posttest Probability, Probability, Positive SRA (%) Negative SRA (%)

0

0

0

1.4

83

1

3

92

2.5

5

95

4

8

97

6

12

98

9

16

98.5

13

23

99

19

34

99.5

29

8

at 37 days was significantly lower among those receiving argatroban (34% to 35%) than among control subjects (43%).14,28 As with lepirudin, the benefit was seen largely in the reduction of new thromboembolic complications (10% to 14% among those receiving argatroban vs 25% among control subjects; P=0.05) but was not seen regard227

Table 8-6: Direct Thrombin Inhibitors Agent

Clearance

Lepirudin

Renal

Argatroban

Hepatic

Bivalirudin

80% enzymatic 20% renal

ACT=activated clotting time; aPTT=activated partial thromboplastin time.

ing death or amputation.14,28 The rates of serious bleeding did not differ significantly between the two groups.14,28 Antibodies to argatroban have not been reported. In patients with renal insufficiency, argatroban is a recommended therapeutic choice. Bivalirudin (Angiomax®) is a synthetic thrombin inhibitor approved for percutaneous coronary intervention (PCI) in patients who have or are at risk for HIT. In a report of a prospective, open-label, single-arm study on the use of PCI in patients with HIT, Mahaffey et al39 found that bivalirudin 228

Dosing

Monitoring

Bolus: 0.4 mg/kg

aPTT 2 hr after starting infusion; then 2 hr after every dose, adjust to the target therapeutic aPTT of the hospital laboratory

Infusion: 0.15 mg/kg/hr Maximum bolus: 44 mg Maximum infusion: 16.5 mg/kg/hr Infusion: 2 µg/kg/min Maximum infusion: 10 µg/kg/min

Bolus: 0.75 mg/kg Infusion: 1.75 mg/kg/hr

aPTT 2 hr after starting infusion; then 2 hr after every dose, adjust to the target therapeutic aPTT of the hospital laboratory ACT 5 min after completing IV bolus

Low-dose infusion: 0.2 µg/kg/hr

demonstrated safety and efficacy in patients enrolled at 24 centers in the US and Germany. Patients were divided into two groups and given bivalirudin 5 min or more before PCI. The high-dose group received the drug as a 1-mg/kg bolus followed by a 2.5-mg/kg/hr infusion for 4 hr; the low-dose group was given a 0.75-mg/kg bolus followed by a 1.75-mg/kg/hr infusion for 4 hr. There was a 98% rate of procedural success and a 96% rate of clinical success, and no patients had significant thrombocytopenia after treatment. Only one major bleeding event was reported; 229

8

Cumulative frequency of thrombosis (%)

100 90 80 70

52.8%

60 50 40 30 20 10 0 0 2

4 6

8 10 12 14 16 18 20 22 24 26 28 30

Days after isolated HIT recognized

Figure 8-3: Difference in thrombosis rates in patients with HIT. From Warkentin TE, Kelton JG,14 used with permission.

this occurred in a patient receiving high-dose therapy who underwent elective bypass surgery. After initiation of DTI therapy, warfarin should not be introduced until the platelet count has recovered above 150,000/mm3. The dose of warfarin should be 5 mg and overlapped with the selected DTI for at least 5 days and until the INR is therapeutic (2.0–3.0) for at least 48 hours. This recommendation is based on case reports of warfarin-induced venous gangrene in the limbs and skin necrosis occurring during short periods of overlap therapy.24 Argatroban management during this bridge period requires the use of a conversion table provided in the manufacturer’s guidelines for adjusting the INR. The duration of therapy with warfarin depends on the presence of thrombosis with HIT or isolated HIT without thrombosis. In this latter group, the literature supports at least 90 days of therapy becasuse the disappearance of PF4–heparin antibodies is a median of 85 days.41 230

However, cessation of heparin therapy alone is insufficient to reverse the process of HIT. Platelet activation and the coagulation cascade may continue because heparin cessation also eliminates the classic heparin-, antithrombinmediated inhibition of coagulation. Indeed, the incidence of HIT-related complications remains high, particularly in the first week after stopping heparin.24 Figure 8-3 demonstrates the lack of difference in thrombosis rates in a population of patients presenting with isolated thrombocytopenia.18 Although half of the patients were treated with heparin cessation alone and half were treated with heparin cessation combined with warfarin, cumulative thrombosis rates remained at 52.8%.18 Additional pharmacologic therapies must be used in these patients because of the lack of efficacy of heparin cessation alone and the prevalence of underlying thrombosis in patients diagnosed with HIT.7 Conservative treatment of isolated HIT has been associated with a high rate of subsequent thrombosis; patients presenting with HIT should be treated with early, aggressive therapy.5,18 Srinivasan and coworkers42 caution, however, that adequate systemic coagulation with a thrombin inhibitor is essential before administering warfarin in any thrombotic process and recommend initiation of therapy at a low dosage (≤5 mg/day) in warfarin-naïve patients with HIT.43

On the Horizon Another DTI, desirudin (Iprivask®), administered subcutaneous without monitoring, has been available since March 2010 in the US for the prevention of venous thromboembolism in hip replacement surgery. Recently, a prospective, randomized, open-label, exploratory study compared the clinical and economic utility of subcutaneous desirudin versus argatroban in patients with confirmed HIT with and without thrombosis.44 The primary efficacy end point was the composite of new or propagation of clot, amputation, or death. Other end points included major and minor 231

8

bleeding, platelet count recovery, and pharmacoeconomics of treatment. Eight patients were randomized to fixed-dose desirudin (15 mg or 30 mg) every 12 hr and eight patients were randomized to activated partial thromobplastin time (aPTT) adjusted IV argatroban. One argatroban patient (1/8 —12.5%) had propagation of existing clot. Neither of the two groups had amputation or death. Two patients had three major bleeds (3/8 —37.5%) in the agatroban cohort while there were none in the desirudin group. Each of the two groups had one minor bleeding event (1/8 —12.5%). The average medication cost per course of treatment was $1,688 for desirudin and $8,250 for argatroban. Although the results of this study are limited by the small sample size and open-label design, it seems that desirudin appears to be a feasible and cost-effective alternative to argatroban in suspected and confirmed HIT, but further study is warranted, most likely in a registry model. Currently, an oral DTI, dabigatran (Pradaxa®), has undergone randomized, prospective trials in venous thromboembolism prophylaxis for orthopedic joint replacement surgery, treatment of acute deep vein thrombosis and pulmonary embolism and prevention of stroke in atrial fibrillation. Dabigatran etexilate is the prodrug of dabigatran, a potent, nonpeptide, small molecule that specifically and reversibly inhibits both free and clot-bound thrombin by binding to the active site of the thrombin molecule.45 Dabigatran has a time-to-maximum-plasma concentration of 1.5 hr, is renally excreted, is not affected by the CYP450 system, has no dietary interactions, and does not require monitoring. Dabigatran has been approved by the FDA for the treatment of nonvalvular atrial fibrillation. We await studies using this new agent in HIT patients with or without thrombosis.45

References 1. Arepally GM, Ortel TL: Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 2006;355(8):809-817.

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2. Warkentin TE: Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003;121(4):532-555. 3. Warkentin TE, Greinacher A, Koster A, et al; American College of Chest Physicians: Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th ed). Chest 2008;133(suppl): 340S-380S. 4. Walenga JM, Jeske WP, Prechel MM, et al: Decreased prevalence of heparin-induced thrombocytopenia with low-molecularweight heparin and related drugs. Semin Thromb Hemost 2004;30 (suppl 1):69-80. 5. Warkentin TE, Chong BH, Greinacher A: Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998;79: 1-7. 6. Lewis BE, Wallis DE, Leya F, et al; Argatroban-915 Investigators: Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003;163:1849-1856. 7. Warkentin TE: Clinical presentation of heparin-induced thrombocytopenia. Semin Hematol 1998;35(suppl 5):9-16; discussion 35-36. 8. Kelton JG, Sheridan D, Santos A, et al: Heparin-induced thrombocytopenia: laboratory studies. Blood 1988;72(3):925-930. 9. Suh JS, Aster RH, Visentin GP: Antibodies from patients with heparin-induced thrombocytopenia/thrombosis recognize different epitopes on heparin: platelet factor 4. Blood 1998;91(3):916-922. 10. Greinacher A, Gapinadhan M, Günther JU, et al: Close approximation of two platelet factor 4 tetramers by charge neurtralization forms the antigens recognized by HIT antibodies. Aterioscler Thromb Vasc Biol 2006;26(10):2386-2393. 11. Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin. N Engl J Med 1995;332(20):1330-1335. 12. Warkentin TE, Roberts RS, Hirsh J, et al: An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med 2003;163(20):2518-2524. 13. Warkentin TE, Cook RJ, Marder VJ, et al: Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005;106(12):3791-3796.

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14. Warkentin TE: An overview of the heparin-induced thrombocytopenia syndrome. Semin Thromb Hemost 2004;30(3):273-283. 15. DeEugenio DL, Ruggiero NJ, Thomson LJ, et al: Early-onset heparin-induced thrombocytopenia after a 165-day heparin-free interval: case report and review of the literature. Pharmacotherapy 2005;25:615-619. 16. Lubenow N, Kempf R, Eichner A, et al: Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 2002;122:37-42. 17. Spinler SA, Dager WE: Overview of heparin-induced thrombocytopenia. Am J Health Syst Pharm 2003;60(suppl 5):S5-S11. 18. Warkentin TE, Kelton JG: A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996;101:502-507. 19. Warkentin TE, Sheppard JA, Moore JC, et al: Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need? J Lab Clin Med 2005;146:341-346. 20. Warkentin TE, Sheppard JA, Horsewood P, et al: Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000;96:1703-1708. 21. Pouplard C, Amiral J, Borg JY, et al: Decision analysis for use of platelet aggregation test, carbon 14 serotonin release assay, and heparin platelet factor 4 enzyme linked immunosorbent assay for diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1999;111:700-706. 22. Verma AK, Levine M, Shalansky SJ, et al: Frequency of heparininduced thrombocytopenia in critical care patients. Pharmacotherapy 2003;23:745-753. 23. Warkentin TE, Greinacher A: Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126(suppl 3):311S-337S. 24. Dager WE, White RH: Pharmacotherapy of heparin-induced thrombocytopenia. Expert Opin Pharmacother 2003;4:919-940. 25. Laster JL, Nichols WK, Silver D: Thrombocytopenia associated with heparin-coated catheters in patients with heparin-associated antiplatelet antibodies. Arch Intern Med 1989;149:2285-2287. 26. Lindhoff-Last E, Wenning B, Stein M, et al: Risk factors and long-term follow-up of patients with the immune type of heparin-

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induced thrombocytopenia. Clin Appl Thromb Hemost 2002;8: 347-352. 27. Warkentin TE, Elavathil LJ, Hayward CP, et al: The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997;127:804-812. 28. Menajovsky LB: Heparin-induced thrombocytopenia: clinical manifestations and management strategies. Am J Med 2005;118(suppl 8A):21S-30S. 29. Gupta AK, Kovacs MJ, Sauder DN: Heparin-induced thrombocytopenia. Ann Pharmacother 1998;32:55-59. 30. Warkentin TE: Heparin-induced thrombocytopenia. Curr Hematol Rep 2002;1:63-72. 31. Amiral J, Bridey F, Wolf M, et al: Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost 1995;73:21-28. 32. Arepally G, Reynolds C, Tomaski A, et al: Comparison of PF4/heparin ELISA assay with the 14C-serotonin release assay in the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1995;104:648-665. 33. Chong BH, Burgess J, Ismai F: The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 1995;69:344-350. 34. Pauker SG, Kopelman RI: Interpreting hoofbeats: can Bayes help clear the haze? N Engl J Med 1992;327:1009-1013. 35. Warkentin TE: Heparin-induced thrombocytopenia: diagnosis and management. Circulation 2004;110:e454-458. 36. Fagan TJ: Nomogram for Bayes theorem [letter]. N Engl J Med 1975;293:257. 37. Jaeschke R, Guyatt G, Sackett D: Users’ guides to the medical literature. III How to use an article about a diagnostic test. What are the results and will they help me in caring for my patients? The Evidence-Based Medicine Working Group. JAMA 1994;271: 703-707. 38. Lewis BE, Wallis DE, Berkowitz SD, et al: Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001;103:1838-1843. 39. Mahaffey KW, Lewis BE, Wildermann NM, et al: ATBAT Investigators: The anticoagulant therapy with bivalirudin to assist in the

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performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol 2003;15:611-616. 40. Lubenow N, Eichler P, Lietz T, et al: Lepirudin in patients with heparin induced thrombocytopenia: results of the third prospective (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost 2005;3:2428-2436. 41. Warkentin TE, Kelton JG: Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286-1292. 42. Srinivasan AF, Rice L, Bartholomew JR, et al: Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparininduced thrombocytopenia. Arch Intern Med 2004;164:66-70. 43. Boyce SW, Bandyk DF, Rice L: PREVENT-HIT: A randomized, comparative trial of desirudin vs argatroban in suspected HIT. Poster presentation from the Hemophilia & Thrombosis Research Society/ NASCOLA Scientific Symposium, April 15-17, 2010, Chicago, Illinois. Available at: http://www.htrs.org/Assets/PDFs/2010_ HTRS%20POSTER_PRESENTATIONS.pdf. Accessed July 1, 2010. 44. Boyce SW, Bandy KDF, Bartholomew JR, et al: A randomized, open-label pilot study comparing desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis: PREVENT-HIT Study. Am J Ther 2010, November e-publication. 45. van Ryn J, Stangier J, Haertter S, et al: Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor—Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010. ePub doi:10.1160/TH09-11-0758.

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Chapter 9

Anticoagulants in Pediatrics Thomas W. Young

W

ith continued advances in the care of the sickest pediatric patients, there has been an increase in the number of children placed at risk for thrombotic disease.1 Premature newborns, pediatric cancer patients, and children with complex congenital heart disease are just a few of the populations with improved survival that are at risk for thrombotic complications. Indwelling central venous catheters combined with prolonged hospitalizations, developmental and acquired alterations in the hemostatic system, the use of toxic medications, and anatomic substrates for clot formation increase the risk for thrombotic disease in pediatric patients. Unfortunately, thrombotic complications often go unrecognized in pediatric patients. Lack of awareness by medical caregivers is often to blame. However, the small size of these patients (with more difficult venous and arterial access), the inability of very young and developmentally delayed children to report symptoms, and the frequent need for sedation to obtain diagnostic testing make diagnosis difficult. Because the pediatrics literature is frequently limited to case reports and uncontrolled studies, therapeutic decisions must often be made based on data extrapolated from adult studies. The maturation of the hemostatic system and the pharmacokinetics of anticoagulant medications evolve as pediatric patients grow, resulting in an ever-changing epidemiology of thrombotic 237

9

disease and response to therapy as neonates mature into children and then into young adults. Despite these difficulties, it is important that appropriate efforts be made to prevent, recognize, and treat thromboembolic disease in children. Postthrombotic syndrome is increasingly recognized as a late complication of deep vein thrombosis (DVT) in children, and aggressive thrombolytic therapy has been shown to decrease the risk.2,3 Venous thromboembolic disease in the central nervous system (cerebral sinus), liver, kidney, and gut may lead to chronic neurologic, hepatic, renal, and intestinal dysfunction, respectively.4 Pulmonary emboli, sometimes chronic in nature, may negatively affect the long-term survival in patients with complex heart disease.5 Arterial thromboembolic disease may acutely threaten organ or limb viability. Fortunately, a slowly growing body of research is now focused on the pediatric population. For example, the American College of Chest Physicians (ACCP) publishes frequently updated evidence-based guidelines for antithrombotic therapy in neonates and children.6 Services such as 1-800-NO-CLOTS, a free consultation service for clinicians managing pediatric thrombotic disease, also provide support.7 Consultation with a pediatric hematologist is strongly recommended when caring for these challenging patients. It is beyond the scope of this chapter to discuss recommendations for specific clinical situations, which often differ between very young and older children. These kinds of recommendations can be found in the current ACCP guidelines. Instead, this chapter focuses on commonly used anticoagulants and alternative therapies.

Heparin Unfractionated heparin (UFH) is frequently used in pediatric inpatients. As experience with low-molecularweight heparin (LMWH) grows, the use of UFH in the outpatient setting is increasing as well. 238

Unfractionated Heparin UFH is used commonly in pediatrics, both to prevent thrombus formation and to treat already present thromboembolic disease.8 In the past, therapy was directed by the activated partial thromboplastin time (aPTT). However, a growing body of research now suggests that this approach is not appropriate in the pediatric population. Monitoring Recommended aPTT ranges are based on adult plasma values. The baseline aPTT is higher in children (especially newborns), so using an adult aPTT treatment goal represents a lower ‘relative’ increase in children. Also, the correlation between the aPTT and anti-factor Xa (anti-FXa) levels varies with age, and therapeutic anti-FXa levels have been found to be frequently associated with an aPTT greater than 180 seconds.9,10 This may lead to undercoagulation if the aPTT is used solely to guide therapy. However, there is limited experience with using the anti-FXa level to guide management, and the most widely published protocols for adjusting the continuous infusion are based on the aPTT (Table 9-1). The goal level of heparin for the treatment of thrombi corresponds to an aPTT between 60 and 85 seconds or an anti-FXa between 0.35 and 0.70 U/mL.11 Dosing Infants have higher dosing requirements than older children to reach the same aPTT. Dosing guidelines reflect this (Table 9-1).12 Before heparin is started, the aPTT should be obtained to confirm normal pretreatment values and again 4 hours after starting therapy or after any change in dose (Table 9-2). Adverse Effects The most common adverse event is bleeding. The true risk is unknown, but a recent prospective cohort study showed a 24% incidence of major bleeding in critically ill 239

9

Table 9-1: Dosing of Unfractionated Heparin Age

Bolus Dose* (U/kg)

Maintenance Dose (U/kg/hr)

<1 year

75

28

>1 year

75

20

Teenagers

75-5000

18

*Given IV over 10 min

children treated with therapeutic doses of UFH.14 Simply stopping the UFH infusion is usually sufficient because its half-life is short (~90 min). When needed, protamine may be used to reverse heparin quickly (Table 9-3). Patients with fish allergies, those who are taking protamine-containing insulin, and those with a history of previous protamine exposure are at increased risk for hypersensitivity reactions. The infusion rate should not exceed 5 mg/min in these patients. Additionally, osteoporosis is rare in the pediatric population but is a potential concern if chronic heparin therapy is needed.15 Although heparin-induced thrombocytopenia (HIT) is relatively uncommon in pediatrics, many cases probably go unrecognized because of other potential causes of thrombocytopenia found frequently in sick children, including sepsis and recent cardiopulmonary bypass (CPB).16 The diagnosis of HIT should be suspected with any unexpected decrease in platelet count greater than 50% in a patient exposed to heparin, even if the exposure is small (including heparin flushes of central lines). The platelet decrease is typically noted between 5 and 10 days after the start of heparin exposure, but it can be almost immediate in patients with a history of heparin exposure. 240

Table 9-2: Protocol for Adjustment of Unfractionated Heparin in Pediatric Patients13 aPTT (sec)

UFH Bolus (U/kg)

Time to Infusion Time to Hold UFH Rate Repeat (min) Change (%) aPTT (hr)

<50

50

0

+10

4

50-59

0

0

+10

4

60-85

0

0

0

Next day

86-95

0

0

-10

4

96-120

0

30

-10

4

>120

0

60

-15

4

aPTT=activated partial thromboplastin time, UFH=unfractionated heparin

9 Thrombosis is a significant potential complication, and the presence of a thrombus should raise the suspicion of HIT. False-positive results for HIT with the platelet factor 4 antibody enzyme-linked immunosorbent assay are common, especially in patients who have had CPB, so a functional washed platelet is preferable. If suspected, all heparin should be stopped. Alternative anticoagulants are suggested in these patients (discussed later in this chapter) because simple discontinuation of heparin may be inadequate to prevent thrombus formation.17 A thorough search for thrombus is warranted. Areas of preexisting disease (including surgical anastomoses) and central venous lines are common sites of thrombus localization. Venous gangrene may be precipitated by warfarin therapy in patients with HIT. Warfarin should not be started until the platelet count has normalized, and 241

Table 9-3: Protamine Reversal of Heparin Time Since Last Heparin Dose (min)

Protamine Dose (mg) per 100 U of UFH*

<30

1.0

30-60

0.50–0.75

60-120

0.375–0.500

>120

0.250–0.375

*Maximum dose, 50 mg UFH=unfractionated heparin

therapy with an alternative anticoagulant should overlap warfarin therapy for at least 5 days. Low-Molecular-Weight Heparin Despite a paucity of clinical data in pediatric patients, subcutaneous LMWH is used with increasing frequency because of several real and potential benefits compared with UFH and warfarin. Ease of administration (no intravenous [IV] access is needed) and the need for less frequent blood draws to monitor response are obvious benefits. HIT and osteoporosis are less likely. Outpatient therapy is also feasible, although patient (and parental) compliance with twice-daily injections may be an issue. Although several forms of LMWH exist, the vast majority of the experience in children is with enoxaparin (Lovenox®). Monitoring The therapeutic range is based on the anti-FA level and is derived from adult data. The therapeutic dose of LMWH corresponds to an anti-FA level of 0.5 to 1.0 U/mL drawn 4 to 6 hours after a subcutaneous (SC) injection. The prophylactic dose corresponds to a range of 0.1 to 0.3 U/mL. 242

Table 9-4: Initial Dosing for Enoxaparin Low-Molecular-Weight Heparin Age (mo)

Therapeutic Dose (mg/kg q 12 hr)

Prophylactic Dose (mg/kg q 12 hr)

<2

1.5

0.75

>2

1

0.5

Dosing As with UFH, dosing requirements are higher in neonates (Table 9-4).18 Twice-daily dosing is recommended, although a recent study19 suggests efficacy of daily dosing at 1.5 mg/kg in children with DVT after the initial 1 to 2 weeks of standard therapy. Although a consistent level of absorption has not been proven in pediatric patients, some clinicians give the LMWH through an indwelling SC catheter that can be replaced weekly, minimizing needlesticks for the patient. However, local bleeding may occur in neonates with limited subcutaneous tissue using this approach.20 Although a considerable variation in individual dose requirement exists, the algorithm (Table 9-5) has been used to titrate dosing. Adverse Events The incidence of major bleeding was 4.8% in a recent cohort study of children treated with therapeutic LMWH.22 Minor bleeding is treated with direct pressure and, if needed, discontinuation of LMWH. Protamine may be given at a dose of 1 mg for every 1 mg of LMWH given within the previous 8 hours. A lower dose of 0.5 mg for every 1 mg of LMWH given may be used if the last dose of LMWH was given within 8 and 12 hours or if repeat protamine is required. Protamine is not generally needed if the last dose was more than 12 hours ago. 243

9

Table 9-5: Dosage Titration for Enoxaparin Low-Molecular-Weight Heparin21 Anti-FA level (U/mL)

Dose Titration (%)

Time to Repeat Anti-FA Level

<0.35

+25

4 hr after next dose

0.35-0.49

+10

4 hr after next dose

0.5-1.0

0

Next day; if stable, repeat in 1 week and then monthly

1.1-1.5

-20

Before next dose

1.6-2.0

Hold dose for 3 hr; then -30

Before next dose; then 4 hr after next dose

>2

Hold all doses until level is <0.5; then -40

Before next dose; then q 12 hr until level is <0.5

HIT and osteoporosis are thought to be less common with LMWH, although only limited data are available to support this belief.

Alternative Thrombin Inhibitors There is some limited experience in pediatrics with the use of argatroban and lepirudin as alternative anticoagulation in HIT patients. There is even less experience with danaparoid and bivalirudin. Dosing is, by and large, extrapolated from adult data, although there is some emerging experience with argatroban in critically ill children. 244

Argatroban A recently completed trial examined the use of argatroban in pediatrics.23 A goal aPTT 1.5 to 3.0 times the baseline value was used for continuous infusion. Serious bleeding and the need for blood transfusion were more frequent in younger patients (<8 years of age), especially those younger than 6 months of age. Argatroban is hepatically cleared, so a lower dose is recommended in the presence of liver dysfunction (Table 9-6). The aPTT is followed and dose adjustments are made. A wide range of dose requirements has been reported (0.1 to 12.0 µg/kg/min), but the recent trial suggests that most pediatric patients do not require more than 5 µg/kg/min.24 A bolus dose of 250 µg/kg may be used from cardiac catheterization and other procedures requiring shortduration anticoagulation. The activated clotting time is used to ensure efficacy. Warfarin Warfarin, a vitamin K antagonist, is often used in patients who require long-term anticoagulation. It is orally administered and given daily. The half-life is long and variable (~40 hours in adults), so a more immediate anticoagulant such as UFH or LMWH is usually started while awaiting the results of therapeutic warfarin levels. Several other factors significantly complicate warfarin therapy in children. Vitamin K levels may be altered significantly by diet, and patients must be counseled about this. Breast milk has low concentrations of vitamin K, making these infants quite susceptible to toxicity. Infant formula is supplemented with vitamin K, causing the opposite problem. Multiple medications, including many anticonvulsants and antibiotics, may alter warfarin metabolism and affect levels of vitamin K, which could alter the INR. Warfarin is not readily available as a liquid. Although it dissolves well in water or can be crushed and sprinkled on food, the long-term stability of warfarin solution is in doubt, and 245

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Table 9-6: Suggested Initial Argatroban Dosing for Goal Activated Partial Thromboplastin Time 1.5 to 3.0 Times Baseline Hepatic Function

Argatroban Initial Dose (µg/kg/min)

Normal

1.0

Reduced

0.2

giving doses other than those available in tablet form is problematic. Because of all of these issues, along with the need for very frequent blood monitoring, warfarin is often avoided in young infants. Monitoring Warfarin therapy is guided by the International Normalized Ratio (INR). For most indications, a target INR of 2.5 (or a range of 2 to 3) is used. A lower range (1.5 to 2.0) may be acceptable in thrombus prophylaxis, and higher target levels are sometimes desired for patients at severe risk for thrombosis. An INR is generally drawn daily when starting therapy. After a therapeutic INR is obtained on a stable warfarin dose, blood draws can be spaced. Unlike in adults, only a small percentage of children can be safely followed monthly, with some requiring weekly INR checks.25 Growth, changes in diet, intercurrent illness, and new medications (often short courses of antibiotics, which may be prescribed by physicians who are not involved in the patient’s anticoagulation) may all alter levels, so the frequency of monitoring must be individualized.26 Point-of-care (POC) testing is convenient for families because it provides rapid INR results at home or in the laboratory, where the capillary-derived blood sample may 246

be much easier to obtain than the venous sample needed for a standard INR. However, concerns exist about the accuracy and reproducibility of some of these test results.27 POC monitoring is also significantly more expensive. However, as further validation occurs, POC testing will likely become more prevalent. Dosing Warfarin is frequently ‘loaded’ over a 4-day period using daily dosing. The dosing regimen shown in Tables 9-7 and 9-8 aims for a target INR of 2 to 3. If the baseline INR is higher than normal (>1.3), lower doses are frequently used. Likewise, a lower initial dosage (0.1 mg/kg/day) may be appropriate in patients with underlying hepatic dysfunction, malnutrition, heart failure, or ‘Fontan’ cardiac physiology. As with many of the other anticoagulants, infants appear to require more warfarin (0.33 mg/kg/day on average) than teenagers (0.09 mg/kg/day).28 Adverse Effects Bleeding is the major adverse effect. The true incidence of major bleeding is low, with two recent studies reporting a bleeding rate of less than 1% per patient-year,29,30 but care must be taken to avoid trauma. Because of its long half-life, warfarin must be withheld for several days before invasive procedures are performed to allow for normalization of the INR. Anticoagulation with UFH or LMWH may be necessary during this time and while reapproaching the target INR after warfarin therapy has been restarted in patients at high risk for thrombosis. Immediate reversal in the face of severe bleeding or if emergent surgery is needed is usually accomplished with 10 to 15 mL/kg of fresh-frozen plasma (FFP), although recombinant factor VIIa may also be used. Vitamin K may also be given, although it takes several hours to reach its full effect. A dose of 30 µg/kg may be used in smaller children.31 In older children, 0.5 to 5.0 mg may be given, with 247

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Table 9-7: Protocol for Initiating Warfarin Oral Anticoagulation in Pediatric Patients Day of Warfarin Initiation

INR

Action

1

1.0-1.3 (normal)

Dose 0.2 mg/kg daily PO (maximum dose, 10 mg)

2-4

1.1-1.3

Repeat initial loading dose

1.4-1.9

Administer 50% of initial loading dose

2.0-3.0

Administer 50% of initial loading dose

3.1-3.5

Administer 25% of initial loading dose

>3.5

Hold until INR <3.5; then restart at 50% of previous dose

INR=international normalized ratio Adapted from Michelson et al.13

smaller doses used when bleeding is less severe or if further anticoagulation with warfarin is likely. The preferred route is subcutaneous, although IV and intramuscular administration are also possible. Another important potential adverse effect is warfarin embryopathy. Women of childbearing age must be counseled about the risks of fetal exposure to warfarin. Although controversy surrounds the true risk to fetuses, especially at lower maternal warfarin doses (<5 mg/day), avoidance of pregnancy while taking warfarin is certainly preferable.32 248

Table 9-8: Protocol for Maintenance of Warfarin Oral Anticoagulation (After Day 4)13 INR 1.1–1.4

Action Increase dose by 20%

1.5–1.9

Increase dose by 10%

2–3

No change

3.1–3.5

Decrease dose by 10%

>3.5

Hold warfarin, check INR daily, and restart at a 20% decreased dose after INR <3.5

INR=international normalized ratio Adapted from Michelson et al.13

9

Antiplatelet Agents Aspirin Aspirin is by far the most commonly used antiplatelet medication in pediatrics. Its affordability, daily (or even every other day) oral dosing schedule, lack of the need for monitoring, and favorable side effect profile compared with other antithrombotic agents make it quite attractive, although its role is likely limited to prophylaxis rather than treatment of active thromboembolic disease. Monitoring Most clinicians do not regularly monitor aspirin therapy. Salicylate levels may be checked to assess compliance with therapy or to evaluate for toxicity in overdose, but levels do not mirror platelet inhibition. A platelet function analyzer may be used to assess platelet inhibition if needed. 249

Dosing Aspirin is given in a dosage of 3 to 5 mg/kg/day for inhibition of platelet aggregation. The dose is usually rounded to a convenient amount (eg, to allow a half of a 81-mg aspirin). Much higher doses are used in patients with Kawasaki’s disease (80 to 100 mg/kg/day divided 4 times a day) during the acute inflammatory stage of the disease. The dose is then decreased to a standard antiplatelet dose. Adverse Effects Adverse effects are uncommon. Bleeding is rare with regular antiplatelet doses in the absence of additional anticoagulant therapy. Stomach upset, gastritis, and, rarely, gastric ulcers are potential adverse effects. Reye’s syndrome is rare and is associated with doses far exceeding the usual antiplatelet dose.33,34 It still seems reasonable to hold aspirin if possible during varicella or influenza infection, although the risk of thrombosis must be weighed against the tiny risk of Reye’s syndrome. Aspirin resistance has been widely studied in adult patients. The pediatric experience is limited, and the true incidence in children is not known (2.3% in one recent study).35 Correlation between assays is poor, and the true relevance of positive assay results is in doubt. Monitoring for aspirin resistance is not standard in pediatric patients, although thrombus formation while on aspirin might raise suspicion. Clopidogrel Clopidogrel (Plavix®) is used with increasing frequency as an antiplatelet agent in pediatrics despite limited supportive data. It is often used in conjunction with aspirin, and its antiplatelet effects appear to be additive. It is given in a daily oral dose. Monitoring Laboratory monitoring of clopidogrel levels or its antiplatelet effects is not routinely performed, although regular evaluation of hepatic and renal function is recommended. 250

Dosing Well-substantiated pediatric dosing for clopidogrel does not exist. Frequently, a dosage of 1 mg/kg/day given orally is used. A liquid preparation can be compounded, facilitating therapy in younger patients. A recent study in patients 2 years of age or younger with congenital heart disease at risk for thrombosis suggested that a lower dose of 0.2 mg/kg/day resulted in a level of platelet inhibition similar to that seen in adults taking standard dosages.36 Adverse Effects Although the primary concern is bleeding, the risk of significant hemorrhage (along with hepatic and renal dysfunction) with clopidogrel therapy appears to be quite low. As additional studies are completed, the true risk will become better defined. Other Antiplatelet Agents Dipyridamole and ticlopidine have limited roles in pediatrics, especially with the emerging clopidogrel experience.

Thrombolytic Agents Despite a significant cost disadvantage compared with streptokinase and urokinase, tissue plasminogen activator (tPA) has become the primary pediatric thrombolytic agent because of a decreased risk of allergic reactions and experimental evidence of increased efficacy.37 Significant physiologic differences in pediatric patients (especially in neonates) affect their response to tPA. In particular, low plasminogen levels may reduce effectiveness. Supplementation with plasminogen in the form of FFP may increase the thrombolytic effect and is routinely used at many centers, although supportive data are not available.38,39 Because of the significant risk of bleeding complications, thrombolytic therapy is usually reserved for life-threatening venous thromboembolism and life- or organ- (including limb-) threatening arterial thromboem251

9

bolism. Low doses may be administered to restore central venous catheter patency. Regarding contraindications for thrombolytic therapy in pediatrics, clinicians must weigh the risks of tPA-associated bleeding against the continued risk of thromboembolism. Contraindications include major surgery or hemorrhage within 10 days, invasive procedures within 3 days, seizures within 2 days, prematurity (<32 weeks), sepsis, active bleeding, significant thrombocytopenia, fibrinogen levels below 100 mg/dL, severe untreated hypertension, and a severe asphyxia event within 1 week.40 Thrombus resolution is linked indirectly to the age of the thrombus. Older thrombi are less likely to respond. This may explain why arterial thromboembolism, which tends to present more acutely, appears more susceptible to tPA therapy than venous disease. A recent study41 using a representative tPA protocol noted an 81% arterial thrombus complete resolution rate compared with 0% for venous thrombi, although other studies have reported much better venous thrombus resolution rates. Some advocate catheter-directed thrombolytic therapy as superior to systemic IV administration, allowing lower doses (with a lower bleeding risk) with increased response. But, no definitive evidence supports this theory. It is reasonable to administer tPA via the affected catheter if the thrombus is related to a central venous line. Monitoring The fibrinogen level, platelet count, aPTT, and prothrombin time may be checked before initiation of therapy because significant abnormalities may increase the bleeding risk with thrombolytic therapy. Vitamin K, FFP, or platelets may then be given as necessary. The affect of concurrent heparin therapy on the aPTT must be taken into effect. Ddimers and fibrin degradation products should increase in the face of effective thrombolytic therapy. If they do not, a dose increase may be necessary. 252

Dosing The optimal tPA doing regimen is not known because protocols are derived from case series (Table 9-9). Systemic tPA therapy for pediatric patients should be used at a dosage of 0.1 to 0.6 mg/kg/hr for 6 hours. This may be repeated after 12 to 24 hours.13 In a recent study41 using a fixed tPA infusion of 0.5 mg/kg/hr for 6 hours, investigators gave 10 mL/kg of FFP before institution of tPA along with concurrent low-dose UFH at 10 U/kg/hr. UFH at a therapeutic dose is resumed after completion of tPA infusion. Adverse Effects Given the significant differences in dosing protocols among various case series, patient populations, and the definition of significant bleeding, it is not surprising that the reported incidence of serious bleeding with systemic thrombolytic therapy has varied significantly (0% to 56%). Minor bleeding is common. Intracranial hemorrhage is uncommon except in premature infants, a population already susceptible to this complication.42 Bleeding is usually treated with direct pressure in minor cases and discontinuation of tPA along with cryoprecipitate in more severe cases.

Nonpharmacologic Therapy Surgical and Catheter-Directed Thrombectomy No specific guidelines have been established for the use of surgical thrombectomy in pediatrics. Because of the high risk of vessel damage associated with these procedures in small children, surgical intervention is uncommon and is usually reserved for specific acute indications. Surgical thrombectomy has most often been used in patients with congenital heart disease who have cardiac surgery–associated thrombi (eg, thrombosed systemic to pulmonary artery shunts, prosthetic valve thromboses, intracardiac clots). 253

9

Table 9-9: Local Tissue Plasminogen Activator Dosing in Pediatrics With an Occluded Central Venous Line Weight (kg)

Single-Lumen CVL

<10

0.5 mg diluted with normal saline to a sufficient volume to fill the catheter

>10

1 mg/mL Concentration: Use a sufficient amount to fill the catheter up to a maximum of 2 mg

CVL=central venous line Adapted from Michelson et al.13

The pediatric experience with percutaneous transcatheter thrombectomy is limited to case reports and small case series. Mechanical fragmentation of the thrombus using wires and catheters, sometimes associated with catheterdirected local thrombolytic therapy, has been done with success, as has thrombus extraction using a basket device.43 More recently, successful hydrodynamic fragmentation and aspiration of thrombi using a specialized catheter has been reported.44 Most of these interventions have been in children with complex cyanotic congenital heart disease with worsening cyanosis. Early consultation with an experienced pediatric interventional radiologist or cardiologist is recommended. Inferior Vena Cava Filters Inferior vena cava filters are used infrequently in pediatric patients.45 The usual indication is lower extremity 254

Double-Lumen CVL

Subcutaneous Port

The same as for a single lumen, but treat 1 lumen at a time

0.5 mg diluted with normal saline to 3 mL

The same as for single lumen, but treat 1 lumen at a time

2 mg diluted with normal saline to 3 mL

DVT in the presence of a contraindication to anticoagulation, for recurrent DVT despite therapy, or as prophylaxis in very-high-risk patients. A retrievable filter is often used, especially if the long-term risk of recurrent thrombus is low.46 Epithelialization may begin as early as 12 days after insertion, so the device should be removed as soon as possible or repositioned at regular intervals if prolonged therapy is necessary. A recent report47 describes the use of retrievable filters in children as young as 2 years of age.

References 1. Hoppe C, Matsunaga A: Pediatric thrombosis. Pediatr Clin North Am 2002;49:1257-1283. 2. Goldenberg NA, Durham JD, Knapp-Clevenger R, et al: A thrombolytic regimen for high risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children. Blood 2007;110(1):45-53.

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3. Kuhle S, Koloshuk B, Marzinotto, et al: A cross-sectional study evaluating post-thrombotic syndrome in children. Thromb Res 2003;111(4-5):227-233. 4. Goldenberg NA: Long-term outcomes of venous thrombosis in children. Curr Opin Hematol 2005;12:370-376. 5. Varma C, Warr MR, Hendler AL, et al: Prevalence of “silent” pulmonary emboli in adults after the Fontan operation. J Am Coll Cardiol 2003;18:2252-2258. 6. Monagle P, Chalmers E, Chan A, et al: Antithrombotic therapy in neonates and children. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008 (suppl 6);113:887S-968S. 7. Kuhle S, Massicotte P, Chan A, et al: Systemic thromboembolism in children. Data from the 1-800-NO-CLOTS Consultation Service. Thromb Haemost 2004;92:722-728. 8. Newall F, Barnes C, Ignjatovic V, et al: Heparin-induced thrombocytopenia in children. J Paediatr Child Health 2003;39: 289-292. 9. Ignjatovic V, Furmedge J, Newall F, et al: Age-related differences in heparin response. Thromb Res 2006;118(6):741-745. 10. Ignjatovic V, Summerhayes R, Than J, et al: Therapeutic range for unfractionated heparin therapy: age-related differences in response in children. J Thromb Haemost 2006;4:2280-2283. 11. Hirsh J: Heparin. N Engl J Med 1991;324:1565-1574. 12. Andrew M, Marzinotto V, Massicotte P, et al: Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res 1994;35:78-83. 13. Michelson AD, Bovill E, Andrew M: Antithrombotic therapy in children. Chest 1995;108(4 suppl):506S-522S. 14. Kuhle S, Eulmesekian P, Kavanagh B: A clinically significant incidence of bleeding in critically ill children receiving therapeutic doses of unfractionated heparin: a prospective cohort study. Haematologica 2007;92(2):244-247. 15. Sackler JP, Liu L: Heparin-induced osteoporosis. Br J Radiol 1973;46:548-550. 16. Schmugge M, Risch L, Huber A, et al: Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients. Pediatrics 2002;109:E10.

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17. Boshkov L, Kirby A, Shen I, et al: Recognition and management of heparin-induced thrombocytopenia in pediatric cardiopulmonary bypass patients. Ann Thorac Surg 2006;81(suppl): 2355S-2359S. 18. Massicotte P, Adams M, Marzinotto V, et al: Low-molecular weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Pediatr 1996;128:313-318. 19. Schobess R, Düring C, Bidlingmaier C, et al: Long-term safety and efficacy data on childhood venous thrombosis treated with a low molecular weight heparin: an open-label pilot study of oncedaily versus twice-daily enoxaparin administration. Haematologica 2006;91:1701-1704. 20. Dix D, Andrew M, Marzinotto V, et al: The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000;136:439-445. 21. Monagle P, Michelson AD, Bovill E, et al: Antithrombotic therapy in children. Chest 2001;119(suppl 1):344S-370S. 22. Revel-Vilk S, Sharathkumar A, Massicotte P, et al: Natural history of arterial and venous thrombosis in children treated with low molecular weight heparin: a longitudinal study by ultrasound. J Thromb Haemost 2004;2:42-46. 23. Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin. ClinicalTrials.gov identifier: NCT00039858. Completed October 10, 2008. 24. Hursting MJ, Dubb J, Verme-Gibboney CN: Argatroban anticoagulation in pediatric patients: a literature analysis. J Pediatr Hematol Oncol 2006; 28(1):4-10. 25. Andrew M, Marzinotto V, Brooker L, et al: Oral anticoagulation therapy in pediatric patients: a prospective study. Thromb Haemost 1994;71(3):265-269. 26. Bonduel MM: Oral anticoagulation therapy in children. Thromb Res 2006;118:85-94. 27. Williams VK, Griffiths AB: Acceptability of CoaguChek S and CoaguChek XS generated international normalized ratios against a laboratory standard in a paediatric setting. Pathology 2007;39(6): 575-579. 28. Streif W, Andrew M, Marzinotto V, et al: Analysis of warfarin therapy in pediatric patients: a prospective cohort study on 319 patients. Blood 1999;94:3007-3014.

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29. Marzinotto V, Monagle P, Chan A, et al: Capillary whole blood monitoring of oral anticoagulants in children in outpatient clinics and the home setting. Pediatr Cardiol 2000;21:347-352. 30. Newall F, Campbell J, Savoia H, et al: Incidence of major bleeding in a large paediatric cohort of patients requiring warfarin therapy [abstract]. J Thromb Haemost 2005;3(suppl 1). 31. Bolton-Maggs P, Brook L: The use of vitamin K for reversal of over-warfarinization in children. Br J Haematol 2002;118:924. 32. Vitale M, De Feo M, De Santo LS, et al: Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33:1637-1641. 33. Young RS, Torretti D, Williams RH, et al: Reye’s syndrome associated with long-term aspirin therapy. JAMA 1984;251:754-756. 34. Wei CM, Chin HL, Lee PI, et al: Reye’s syndrome developing in an infant on treatment of Kawasaki syndrome. J Paediatr Child Health 2005;41:303-304. 35. Yee DL, Dinu BR, Sun CW, et al: Low prevalence and assay discordance of “aspirin resistance” in children. Pediatr Blood Cancer 2008;51(1):86-92. 36. Li JS, Yow E, Berezny KY, et al: Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the platelet inhibition in children on clopidogrel (PICOLO) trial. Circulation 2008;117:553-559. 37. Gupta AA, Leaker M, Andrew M, et al: Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children. J Pediatr 2001;139:682-688. 38. Andrew M, Brooker L, Leaker M, et al: Fibrin clot lysis by thrombolytic agents is impaired in newborns due to a low plasminogen concentration. Thromb Haemost 1992;68:325-330. 39. Traivaree C, Brandao L, Chan A, et al: The efficacy and safety of fresh frozen plasma (FFP) and systemic tissue plasminogen activator for treatment of intravascular thrombosis in infants. J Thromb Haemost 2007;5(suppl 2):415. 40. Manco-Johnson MJ, Grabowski EF, Hellgreen M, et al: Recommendations for tPA thrombolysis in children. On behalf of the Scientific Subcommittee on Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International

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Society of Thrombosis and Haemostasis. Thromb Haemost 2002;88: 157-158. 41. Newall F, Browne M, Savoia H, et al: Assessing the outcomes of systemic tissue plasminogen activator for the management of venous and arterial thrombosis in pediatrics. J Pediatr Hematol Oncol 2007;29(4):269-273. 42. Zenz W, Arlt F, Sodia S, et al: Intracerebral hemorrhage during fibrinolytic therapy in children: a review of the literature of the last thirty years. Semin Thromb Hemost 1997;23:321-332. 43. Robinson A, Fellows KE, Bridges ND, et al: Effectiveness of pharmacomechanical thrombolysis in infants and children. Am J Cardiol 2001;87:496-498. 44. Menon SC, Hagler DJ, Cetta F, et al: Rheolytic mechanical thrombectomy for pulmonary artery thrombus in children with complex cyanotic congenital heart disease. Catheter Cardiovasc Interv 2008;71(2):237-243. 45. Cook A, Shackford S, Osler T, et al: Use of vena cava filters in pediatric trauma patients: data from the National Trauma Data Bank. J Trauma 2005;59(5):1114-1120. 46. Raffini L, Cahill AM, Hellinger J, et al: A prospective observational study of IVC filters in pediatric patients. Pediatr Blood Cancer 2008;51(4):517-520. 47. Chaudry G, Padua HM, Alomari A: The use of inferior vena cava filters in young children. J Vasc Interv Radiol 2008;19:1103-1106.

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9

Chapter 10

Anticoagulation and National Patient Safety Goals Debbie Simonson, Parmis Khatibi, Steven B. Deitelzweig, Alpesh N. Amin

C

onsidered the nation’s predominant standard-setting and accrediting body in health care, The Joint Commission evaluates and accredits nearly 15,000 health-care organizations and programs in the United States.1 The Joint Commission also established the National Patient Safety Goals to promote targeted improvements in patient safety. The goals highlight problem areas in health care. National Patient Safety Goal 3E is to reduce the likelihood of patient harm associated with anticoagulation. Anticoagulants have been classified as high-alert medications by the Institute of Safe Medical Practice because they are associated with a heightened risk of significant patient harm when used in error. Supratherapeutic levels may lead to bleeding complications, and subtherapeutic levels may lead to thromboembolic complications in patients with atrial fibrillation or deep vein thrombosis (DVT). Anticoagulants are estimated to be the cause of 5.1% of all adverse drug events requiring emergency care.2 The Joint Commission’s rationale for requiring the anticoagulation safety goal is that anticoagulation is a highrisk treatment that commonly leads to adverse drug events because of the complexity of dosing these medications, monitoring their effects, and ensuring patient compliance 260

with outpatient therapy. The use of standardized practices that include patient involvement may reduce the risk of adverse drug events associated with the use of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), warfarin, and other anticoagulants (Table 10-1). The Joint Commission’s national patient safety goal requires that warfarin, heparin, and LMWHs be used with established monitoring procedures and that the therapy be individualized to each patient. It would be wise to follow similar monitoring procedures for new DVT prophylaxis agents, such as desirudin.

Warfarin Therapy Warfarin (Coumadin®) is taken to inhibit vitamin K, which is essential for effective production of clotting factors II, VII, IX, and X as well as for anticoagulant proteins C and S. Warfarin takes 4 to 7 days to reach its optimum effect, but protein C has a very short half-life. Therefore, protein C is depleted quickly. Because protein C is an anticoagulant, a rapid depletion may lead to a transient hypercoagulable state in the first 1 to 2 days of therapy. The use of loading doses may actually potentiate this state. Table 10-2 provides the half-lives for factors II, VII, IX, and X as well as protein 10 C and S. These half-life data explain why it takes from 4 to 7 days to reach optimal effect. Warfarin is monitored by the prothrombin time (PT) and International Normalized Ratio (INR). If the INR rapidly increases during the first 2 to 3 days of warfarin therapy, it is a reflection of a reduction of the shorter half-life factors VII and IX. Factor II has a 50-hour half-life (Table 10-2). Table 10-3 provides recommended target INR values for different disease states. Monitoring A baseline INR is required for all patients starting on warfarin therapy. The safety goal requires that a current INR be available to monitor and adjust therapy and then 261

Table 10-1: The Joint Commission’s National Patient Safety Goals1 1. The organization implements a defined anticoagulation program to individualize the care provided to each patient receiving anticoagulant therapy. 2. To reduce compounding and labeling errors, the organization uses only oral unit-dose products and premixed infusions when these products are available. 3. When pharmacy services are provided by the organization, warfarin is dispensed for each patient in accordance with established monitoring procedures. 4. The organization uses approved protocols for the initiation and maintenance of anticoagulation therapy appropriate to the medication used, to the condition being treated, and to the potential for drug interactions. 5. For patients being started on warfarin, a baseline International Normalized Ratio (INR) is available, and for all patients receiving warfarin therapy a current INR is available and is used to monitor and adjust therapy. 6. When dietary services are provided by the organization, the service is notified of all patients receiving warfarin and responds according to its established food-drug interaction program. 7. When heparin is administered intravenously and continuously, the organization uses programmable infusion pumps. 8. The organization has a policy for conducting the baseline and ongoing laboratory tests required for patients receiving heparin or low-molecularweight heparin therapy. (continued on next page) 262

Table 10-1: The Joint Commission’s National Patient Safety Goals (continued) 9. The organization provides education regarding anticoagulation therapy to prescribers, staff, patients, and families. 10. Patient and family education includes the importance of follow-up monitoring, compliance issues, dietary restrictions, and the potential for adverse drug reactions and interactions. 11. The organization evaluates anticoagulation safety practices.

a daily INR should be obtained while the patient is in the hospital. Dosing Numerous nomograms are available for the initiation of warfarin therapy and for dosage adjustments for maintenance therapy. A general guideline is to start with a 5-mg dose. 10

Table 10-2: Vitamin K–Dependent Clotting Factors Name

Function

Half–Life (hr)

Protein C

Anticoagulant

8

Protein S

Anticoagulant

30

Factor VII

Procoagulant

7

Factor IX

Procoagulant

24

Factor X

Procoagulant

36

Factor II

Procoagulant

50 263

Table 10-3: Therapeutic Recommendations for Warfarin Disease DVT or PE

INR Range 2-3

Atrial fibrillation

2-3

MI

2-3

Mechanical heart valves

2.5-3.5

DVT=deep vein thrombosis, INR=International Normalized Ratio, MI=myocardial infarction, PE=pulmonary embolism

Several studies have confirmed that a 5-mg initiation achieves therapeutic anticoagulation as rapidly as a 10-mg initiation but with a lower frequency of supratherapeutic INRs.3,4 Elderly and debilitated patients often require lower daily doses of warfarin. Shepherd et al5 found that the rate of clotting factor synthesis is lower in older patients, leading to a reduction in warfarin dosing requirements. A number of factors influence the sensitivity to warfarin (Tables 10-4 and 10-5). Many nomograms recommend initiating warfarin at 2.5 mg in these patients. Example Dosing Nomograms for Initiation of Warfarin Therapy This is a guideline for initiation of warfarin. Clinical judgment should always be used when making decisions for individual patients. • The INR should be checked daily. • The 10-mg initiation nomogram should only be used in relatively young and healthy patients who are likely to be insensitive to warfarin and in patients 264

Table 10-4: Factors That Influence Sensitivity to Warfarin • • • • • • • • •

Age >75 years Clinical CHF Diarrhea Drug interactions (eg, concurrent drugs that inhibit warfarin metabolism) Elevated baseline INR Fever Hyperthyroidism Malignancy Malnutrition or NPO >3 d

CHF=congestive heart failure, INR=International Normalized Ratio, NPO=nothing by mouth

Table 10-5: Disease States That May Affect a Patient’s Response to Oral Anticoagulants Well Inadequate Response Documented Study CHF Febrile illnesses Hepatic dysfunction Hyperthyroidism Hypothyroidism

+ + + + +

√ √ √ √ √

CHF=congestive heart failure

265

10

Table 10-6: 5-mg and 10-mg Warfarin Nomograms 5-mg Warfarin Nomogram Day 1

INR

Dose 5 mg

2

<1.5 1.5-1.9 2.0-2.5 >2.5

5 mg 2.5 mg 1.0-2.5 mg 0

3

<1.5 1.5-1.9 2.0-2.5 2.5-3.0 >3

5-10 mg 2.5-5.0 mg 0-2.5 mg 0-2.5 mg 0

4

<1.5 1.5-1.9 2-3 >3

10 mg 5.0-7.5 mg 0-5 mg 0

5

<1.5 1.5-1.9 2-3 >3

10 mg 7.5-10.0 mg 0-5 mg 0

6

<1.5 1.5-1.9 2-3 >3

7.5-12.5 mg 5-10 mg 0-7.5 mg 0

INR=International Normalized Ratio Adapted from Harrison et al.3

266

10-mg Warfarin Nomogram Day 1

INR

Dose 10 mg

2

<1.5 1.5-1.9 2.0-2.5 >2.5

7.5-10.0 mg 2.5 mg 1.0-2.5 mg 0

3

<1.5 1.5-1.9 2.0-2.5 2.5-3.0 >3

5-10 mg 2.5-5.0 mg 0-2.5 mg 0-2.5 mg 0

4

<1.5 1.5-1.9 2-3 >3

10 mg 5.0-7.5 mg 0-5 mg 0

5

<1.5 1.5-1.9 2-3 >3

10 mg 7.5-10.0 mg 0-5 mg 0

6

<1.5 1.5-1.9 2-3 >3

7.5-12.5 mg 5-10 mg 0-7.5 mg 0

10

267

Table 10-7: Criteria for Establishing a Drug or Food Interaction With Warfarin Level of Evidence

Criteria Required

1. Highly probable

A, B, and C plus one or more of D to G A and B plus one or more of C to G A plus one or more of B to G

2. Probable 3. Possible 4. Doubtful

Any combination of B to G or A alone

A. Was the timing pharmacologically plausible? B. Did results from the INR, PT, or thrombotest support the contention? C. Were other potential factors affecting warfarin pharmacokinetics or pharmacodynamics ruled out? D. Was there other objective evidence (eg, warfarin blood levels)? E. Was a dose–response relation shown for the interacting drug? F. Was the patient rechallenged and, if so, did a similar response occur? G. Did the same thing happen on previous exposure to the drug?

INR=international normalized ratio, PT=prothrombin time Adapted from Wells et al6

268

taking current medications known to induce warfarin metabolism. • A starting dose of 2.5 mg should be considered for patients with any of the following risk factors: age older than 70 years, weight below 50 kg, uncompensated congestive heart failure, liver failure, recent history of bleeding, recent surgery, hematocrit below 30, increased PT on admission, taking an interacting drug, nutritionally depleted (nothing by mouth >3 days), and a history of falls. • Loading doses of warfarin are not recommended (Table 10-6). Interactions When patients are taking warfarin with other medications, it is prudent to identify and monitor them for possible drug–drug interactions. Wells et al6 evaluated the quality of studies about food and drug interactions with warfarin. They evaluated each article and assigned a level of evidence. Tables 10-7 to 10-10 are based on their findings.

Unfractionated Heparin Therapy Heparin, a highly sulfated glycosaminoglycan, is widely used as in injectable anticoagulant. Heparin binds to the 10 enzyme inhibitor antithrombin (AT), causing a conformational change that results in its activation. The heparin–AT complex inactivates thrombin (factor IIA); activated clotting factors Xa, IXa, and XIIa; and the tissue factor VIIa complex. By inactivating thrombin or attenuating its generation, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of platelets and factors V, VIII, and XI (Table 10-11).7-9 Monitoring The effects of heparin are measured in the laboratory by the activated partial thromboplastin time (aPTT). Different laboratories use reagents with varying sensitivities to the effects of UFH. Therapeutic anticoagulation requires 269

Table 10-8: Level 1 Evidence of Drug and Food Interactions With Warfarin*

Interaction

Antibiotics

Cardiac Drugs

Potentiation

Cotrimoxazole (8), erythromycin (8), fluconazole (6), isoniazid (1), metronidazole (8), miconazole (6)

Amiodarone (28), clofibrate (8), propafenone (8), propranolol (12), sulfinpyrazone† (13)

Inhibition

Griseofulvin† (2), nafcillin (1), rifampin (31)

Cholestyramine (27),

No effect

Enoxacin (5)

Atenolol (6), bumetanide (10), felodipine (2), metoprolol (6), moricizine (1),

*

AntiInflammatory Drugs Phenylbutazone† (14), piroxicam† (1),

Diflunisal (5), ketorolac (10), naproxen (5),

Numbers in parentheses are numbers of patients, volunteers, or both. Supporting level 1 evidence from patients and volunteers

†

270

Central Nervous System Drugs

Gastrointestinal Drugs

Alcohol (with liver disease)† (1)

Cimetidine‡ (50), omeprazole (19)

Barbiturates (12), carbamazepine (3), chloridiazepoxide (1)

Sucralfate (1),

Alcohol (15), fluoxetine (3), nitrazepam (3),

Antacids (6), famotidine (8), nizatidine (7), psyllium (6), ranitidine§ (4)

Miscellaneous Drugs

Foods and enteral feeds with high vitamin K content (5), large amounts of avocado (2)

10

‡

In a small number of volunteers, an inhibitory drug interaction occurred. § Level 2 evidence of potentiation in patients Adapted from Wells et al.6

271

Table 10-9: Drug and Food Interactions With Warfarin by Level of Supporting Evidence and Type of Interaction Level of Evidence

Potentiation

1

Alcohol (if concomitant liver disease), amiodarone, cimetidine*, clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid (600 mg/d), metronidazole, miconazole, omeprazole, phenylbutazone*, piroxicam, propafenone, propranolol, sulfinpyrazone*

2

Acetaminophen, anabolic steroids, aspirin, chloral hydrate, ciprofloxacin, dextropropoxyphene, disulfiram, itraconazole, quinidine, simvastatin, tamoxifen, tetracycline, influenza vaccine

3

Disopyramide, 5-fluorouracil, iphosphamide, lovastatin, metolazone, nalidixic acid, norfloxacin, ofloxacin, topical salicylates, sulindac, tolmetin

4

Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole

*Supporting level 1 evidence from patients and volunteers Adapted from Eighth ACCP Consensus Conference on Antithrombotic Therapy,14 Menon et al,10 Wells et al.6

272

Inhibition

No Effect

Barbiturates, carbamazepine, chloridiazepoxide, cholestyramine, griseofulvin*, nafcillin, rifampin, sucralfate, foods and enteral feeds with high vitamin K content, large amounts of avocado

Alcohol, antacids, atenolol, bumetanide, diflunisal, enoxacin, famotidine, felodipine, fluoxetine, ketorolac, metoprolol, moricizine, naproxen, nitrazepam, nizatidine, psyllium, ranitidine*

Dicloxacillin, phenytoin

Ibuprofen, ketoconazole, ketoprofen

10

Azathioprine, cyclosporine, etretinate, trazodone

Diltiazem, tobacco, vancomycin

273

Table 10-10: Contraindications to Warfarin Absolute Contraindications

Relative Contraindications

• Presence of a severe or active bleeding diathesis

• Uncontrolled hypertension (systolic >180 mm Hg; diastolic >100 mm Hg)

• Noncompliance

• Severe liver disease

• First trimester of pregnancy

• Recent surgery involving the nervous system, spine, or eye

heparin concentrations of 0.2 to 0.4 U/mL; in most laboratories, this corresponds to aPTT values that are 1.5 to 2.5 times the control values. The anti-Xa heparin assay is an alternative to the aPTT for UFH monitoring. The assay is used for monitoring UFH in the presence of baseline prolongation of the aPTT caused by lupus anticoagulant, factor deficiencies, and the suspicion of heparin resistance.11,12 Baseline laboratory studies should include a complete blood count (CBC) to assess hemoglobin, hematocrit, and platelet count. PT and partial thromboplastin time (PTT) should be drawn before heparin initiation. A stool guaiac should also be done if possible.13 Dosing Numerous nomograms are available for the initiation of heparin therapy and for dose adjustments. Heparin dosing is based on body weight. A general guideline is to start with a loading dose of 80 U/kg intravenous (IV) push followed by an initial maintenance dosage of 18 U/kg/hr if using aPTT to monitor the results for venous thromboembolism (VTE). For patients with acute coronary syndromes (ACS), a loading dose of 60 U/kg followed by a maintenance infusion 274

Table 10-11: Clinical Use of Heparin Condition Prophylaxis of VTE Treatment of VTE

ACS

Recommended Heparin Regimen 5000 U SC q 8 hr or q 12 hr or adjusted low-dose heparin IV: • 80-U/kg bolus and 18-U/kg/hr infusion • 5000-U bolus and at least 32,000U/24-hr infusion SC • 5000-U bolus followed by 250 U/kg b.i.d. • 333 U/kg bolus followed by 250 U/ kg b.i.d. Unstable angina and STEMI: • 60-70 U/kg (maximum, 5000 U) IV bolus followed by 12-15 U/kg/hr IV infusion (maximum, 1000 U/hr) STEMI administered in conjunction with fibrinolytic agents: • 60 U/kg (maximum, 4000 U) IV bolus followed by 12 U/kg/hr (maximum, 1000 U/kg/hr)

ACS=acute coronary syndrome, b.i.d.=twice a day, IV=intravenous, SC=subcutaneous, STEMI=ST-segment elevation myocardial infarction, VTE=venous thromboembolism Adapted from Eighth ACCP Consensus Conference on Antithrombotic Therapy.14

rate of 12 U/kg/hour should be used. If therapeutic aPTT is not achieved after 6 hr of initiation, then the patient can be rebolused or the rate of infusion should be adjusted.14–16 275

10

Table 10-12: Factors That Influence Dose Reductions of Heparin Reasons to Consider Omission or Reduction of the Loading Dose

Reasons to Consider Reduction in the Maintenance Dose

• Recent major surgery within 7 d

• Recent major surgery within 7 d

• Recent minor surgical incisions (eg, tracheostomy, cutdown) • Recent femoral catheterization • Definable factors that predispose the patient to major bleeding complication

• Recent history of GI bleeding • Oral anticoagulant therapy before admission • Decrease in platelet count • Severe liver or renal disease

GI=gastrointestinal

Loading doses are not recommended for patients with cerebrovascular accidents or transient ischemic attacks or for patients who have been taking warfarin before admission and have a baseline INR of 1.4 or above. Dose requirements of heparin may be reduced in certain patients (Table 10-12). Example Dosing Nomograms for Initiation of Heparin Therapy This is a guideline for initiation of heparin. Clinical judgment should always be used when making decisions for individual patients. 276

• The aPTT should be obtained every 6 hours after infusion initiation and after each heparin dosage adjustment until the target range is attained with two consecutive samples. • After two consecutive aPTTs are within the target range, the aPTT should be obtained daily thereafter. • A CBC with platelets should be obtained every day for 2 days and then every other day while the patient is on heparin infusion. • When a gastrointestinal bleed is suspected while the patient is taking heparin, guaiac stools should be obtained. • The patient should be inspected daily for bleeding. The nomograms shown in Tables 10-13 and 10-14 are examples of heparin infusion therapy using either aPTT or anti-Xa levels. Limitations of Heparin Besides bleeding complications, heparin has pharmacokinetic limitations, ie, it impairs bone formation and enhances bone resorption by binding to osteoblasts. This may lead to osteoporosis in susceptible persons. Heparin may also bind to platelet factor 4 (PF4), causing platelet activation. These activated platelets are removed from the circulation, which causes heparin- 10 induced thrombocytopenia (HIT). Heparin also has inhibitory activity toward aldosterone and manifests mildly increased serum potassium.11,17

Low-Molecular-Weight Heparins LMWHs were developed for their potential advantages over heparin, such as their superior pharmacokinetic properties and reduced antifactor IIa activity relative to antifactor Xa activity. Compared with UFH, LMWHs have fewer side effects, particularly heparin-induced osteopenia and HIT. In contrast to UFH, the LMWHs appear not to be inactivated by PF4. After subcutaneous injection, LMWHs exhibit less plasma protein binding and hence greater bioavailability than UFH. 277

Table 10-13: Heparin Nomogram Using Activated Partial Thromboplastin Time Levels18,19 aPTT (sec)

Bolus or Hold

<40 40-44 45-49 50-80 (therapeutic range)

Rebolus — — —

81-90 91-100 >100

— Hold for 30 min Hold for 60 min

aPTT=activated partial thromboplastin time

Table 10-14: Heparin Nomogram Using Anti-Xa Levels18,19 6-hr Anti-Xa Level

Action

<0.2

Bolus of 30 U/kg

0.2-0.3

Bolus of 15 U/kg

0.31-0.60 (therapeutic range)

—

0.61-0.70

—

0.71-0.9

—

>0.9

Hold infusion for 1 hr

278

Rate Adjustment (U/hr) +200 +200 +100 —

-100 -200 -300

Repeat aPTT (After Dose Adjustment) 6 hr 6 hr 6 hr q 6 hr until 2 consecutive aPTTs are in this range; then every morning 6 hr 6 hr 6 hr

10 Rate Change

Repeat Anti-Xa Level

↑ By 3 U/kg/hr

6 hr after rate change

↑ By 2 U/kg/hr

6 hr after rate change

—

Next morning laboratory study results

↓ By 1 U/kg/hr

6 hr after rate change

↓ By 2 U/kg/hr

6 hr after rate change

↓ By 4 U/kg/hr

6 hr after rate restart

279

Bleeding is the major adverse effect of LMWH. It commonly appears at the sites of trauma. The most feared complication is epidural bleeding and spinal hematoma after insertion or removal of an epidural catheter inserted to provide perioperative anesthesia.20 Three LMWHs are on the market in the US, and all have a black box warning for the risk of epidural or spinal hematoma in patients in whom neuraxial anesthesia is used. Epidural and spinal hematoma may lead to long-term or permanent paralysis. The benefits versus the risks should be considered before using neuraxial interventions in patients who are scheduled to be anticoagulated. Dalteparin (Fragmin®)21–23 Food and Drug Administration (FDA)-Approved Indications • Prophylaxis of ischemic complications and in combination with aspirin, in patients with unstable angina and non-Q-wave myocardial infarction (MI) • Extended treatment of symptomatic VTE and to reduce the recurrence of VTE in patients with cancer • Prophylaxis of DVT, which may lead to pulmonary embolism (PE), for: – Hip replacement surgery – Abdominal surgery – Medical patients with restricted mobility (Table 10-15) Contraindications Thrombocytopenia associated with positive in vitro test results for antiplatelet antibody in the presence of dalteparin has occurred. Patients undergoing regional anesthesia should not receive dalteparin for unstable angina or non–Q-wave MI because of an increased risk of bleeding associated with the dosage of dalteparin recommended for unstable angina and non–Q-wave MI. 280

Table 10-15: Dosages of Dalteparin for Patients With Restricted Mobility Indication

Dalteparin Dosage

Hip replacement surgery (prophylaxis)

2500 IU SC given 2 hr before surgery followed by 2500 IU SC the evening after surgery and at least 6 hr after the first dose; then 5000 IU SC q 24 hr or 5000 IU SC q 24 hr started the evening before surgery or 2500 IU SC started 4-8 hr after surgery; then 5000 IU SC q 24 hr

Abdominal surgery (prophylaxis)

2500 IU SC started 1-2 hr before surgery, then q 24 hr Patients with malignancy: 5000 IU SC the evening before surgery; then 5000 IU SC q 24 hr or 2500 IU SC 1-2 hr before surgery, then 2500 IU 12 hr after surgery followed by 5000 IU SC q 24 hr 100 IU/kg SC q 12 hr or 200 IU/kg SC q 12 hr 120 IU/kg SC q 12 hr

DVT treatment (with or without PE) Unstable angina or non–Q-wave MI Medical prophylaxis

5000 IU SC daily for 12-14 d

DVT=deep vein thrombosis, MI=myocardial infarction, PE=pulmonary embolism, SC=subcutaneous

281

10

Monitoring Periodic CBCs, including platelet counts and stool occult blood tests, should be done. Monitoring of PT and PTT is not necessary. Tinzaparin (Innohep®)24-26 FDA-Approved Indication • Tinzaparin has been FDA approved for the treatment of acute symptomatic DVT with or without PE in combination with warfarin in hospitalized patients. Dosing For treatment of established DVT, a daily dose of 175 IU/kg should be given subcutaneously (SC) as soon as possible after diagnosis and continued for at least 6 days until oral anticoagulation with warfarin has been achieved. Contraindications Patients with HIT or a history of HIT should not be administered tinzaparin. Patients with known hypersensitivity to sulfites, benzyl alcohol, or pork products should not be treated with tinzaparin. Monitoring Periodic CBCs, including platelet counts and stool occult blood tests, should be done. Monitoring of PT and PTT is not necessary. Enoxaparin (Lovenox®)27 FDA-Approved Indications • Prophylaxis of DVT – Abdominal surgery – Hip replacement surgery – Knee replacement surgery – Medical patients with severely restricted mobility during acute illness 282

• Inpatient treatment of acute DVT with or without PE • Outpatient treatment of acute DVT without PE • Prophylaxis of ischemic complications of unstable angina and non–Q-wave MI • Treatment of acute ST-segment elevation myocardial infarction (STEMI) managed medically or with subsequent percutaneous coronary intervention (PCI) (Table 10-16) When enoxaparin is administered in conjunction with a thrombolytic (fibrin specific or nonfibrin specific), enoxaparin should be given between 15 min before and 30 min after the start of fibrinolytic therapy. All patients should receive aspirin as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. For patients managed with PCI, if the previous enoxaparin SC administration was given less than 8 hr before balloon inflation, no additional dosing is needed. If the previous enoxaparin SC administration was given more than 8 hr before balloon inflation, an IV bolus of 0.3 mg/kg of enoxaparin should be administered. Renal Impairment 10 No dosage adjustment is recommended in patients with moderate (creatinine clearance, 30 to 50 mL/min) and mild (creatinine clearance, 50 to 80 mL/min) renal impairment. However, a dosage adjustment is recommended for patients with severe (creatinine clearance, <30 mL/min) renal impairment (Table 10-17). Contraindications • Active bleeding • Thrombocytopenia associated with a positive in vitro test result for antiplatelet antibody in the presence of enoxaparin • Known hypersensitivity to enoxaparin, heparin or pork products, or benzyl alcohol 283

Table 10-16: Dosages of Enoxaparin Indication

Standard Regimen

DVT prophylaxis in abdominal surgery

40 mg SC daily with the initial dose given 2 hr before surgery 30 mg SC q 12 hr

DVT prophylaxis in knee replacement surgery DVT prophylaxis in hip replacement surgery DVT prophylaxis in medical patients Inpatient treatment of acute DVT with or without pulmonary embolism Outpatient treatment of acute DVT without PE Unstable angina and non–Q-wave MI Acute STEMI in patients <75 years of age

Acute STEMI in patients 75 years of age and older

30 mg SC q 12 hr or 40 mg SC daily 40 mg SC daily 1 mg/kg SC q 12 hr or 1.5 mg/kg SC daily (with warfarin) 1 mg/kg SC q 12 hr (with warfarin) 1 mg/kg SC q 12 hr (with aspirin) 30 mg single IV bolus plus a 1-mg/kg SC dose followed by 1 mg/kg SC q 12 hr with aspirin (maximum, 100 mg for first 2 doses followed by 1-mg/kg dosing for remaining doses) 0.75 mg/kg SC q 12 hr (no bolus)

*Do not use as intramuscular injection. †For SC use, do not mix with other injections or infusions. DVT=deep vein thrombosis, IV=intravenous, MI=myocardial infarction, PE=pulmonary embolism, SC=subcutaneous, STEMI=ST-segment elevation myocardial infarction Adapted from Sanofi Aventis: Lovenox (enoxaparin) package insert.27

284

Table 10-17: Dosage Regimens for Patients With Severe Renal Impairment* Indication

Dosage Regimen

Prophylaxis in abdominal surgery Prophylaxis in hip or knee replacement surgery

30 mg SC once daily

Prophylaxis in medical patients during acute illness

30 mg SC once daily

Inpatient treatment of acute DVT with or without PE when administered in conjunction with warfarin sodium

1 mg/kg SC once daily

Outpatient treatment of acute DVT without PE when administered in conjunction with warfarin sodium

1 mg/kg SC once daily

Prophylaxis of ischemic complications of unstable angina and non–Q-wave MI when concurrently administered with aspirin

1 mg/kg SC once daily

Treatment of acute STEMI in patient younger than 75 years of age

30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC once daily

30 mg SC once daily

(continued on next page) *Creatinine clearance <30 mL/min

285

10

Table 10-17: Dosage Regimens for Patients With Severe Renal Impairment* (continued) Indication Treatment of acute STEMI in geriatric patients 75 years of age and older

Dosage Regimen 1 mg/kg SC once daily (no initial bolus)

*Creatinine clearance <30 mL/min DVT=deep vein thrombosis, IV=intravenous, MI=myocardial infarction, PE=pulmonary embolism, SC=subcutaneous, STEMI=ST-segment elevation myocardial infarction Adapted from Sanofi Aventis: Lovenox (enoxaparin) package insert.27

Monitoring Periodic CBCs, including platelet counts and stool occult blood tests, should be done. Monitoring of PT and PTT is not necessary. Desirudin (Iprivask®) FDA-Approved Indications • Desirudin is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing elective hip replacement surgery. Dosing For DVT prophylaxis, desirudin should be administered 15 mg SC twice daily. In the setting of heparin-induced thrombocytopenia, the doses studied have been 15 mg SC b.i.d. (without thrombosis) and 30 mg SC b.i.d. (with thrombosis). No dose adjustments are necessary based on patient weight. 286

Contraindications Desirudin is contraindicated in patients with known hypersensitivity to natural or recombinant hirudins, and in patients with active bleeding and/or irreversible coagulation disorders. Renal Impairment No dosage adjustment is recommended in patients with moderate (creatinine clearance, 30 to 60 mL/min) and mild (creatinine clearance, 60 to 90 mL/min) renal impairment. However, a dosage adjustment is recommended for patients with severe (creatinine clearance, <30 mL/min) renal impairment of 7.5 mg SC q.d. Monitoring No monitoring is recommended except for patients with severe renal insufficiency. Monitoring of desirudin’s anticoagulant effect is done by aPTT, which has a linear relationship to dose. For DVT prophylaxis, peak (2 hr) aPTT should be 1.5–2 times baseline.

References 1. The Joint Commission: 2008 National Patient Safety Goals. The Joint Commission Web site. Available at: http://www. jointcommission.org/NR/rdonlyres/82B717D8-B16A-4442AD00-CE3188C2F00A/0/08_HAP_NPSGs_Master.pdf. Accessed November 7, 2008. 2. Budnitz DS, Pollock DA, Weidenback KN, et al: National surveillance of emergency department visits for outpatient adverse drug events. JAMA 2006;296(15):1858-1866. 3. Harrison L, Johnston M, Massicotte MP, et al: Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997;126:133-136. 4. Crowther MA, Ginsberg JB, Kearon C, et al: A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med 1999;159:46-48. 5. Shepherd AM, Hewick DS, Morland TA, et al: Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977;4:315-320.

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6. Wells PS, Holbrook AM, Crowther NR, et al: Interactions of warfarin with drugs and food. Ann Intern Med 1994;121:676-683. 7. Lane DA, Denton J, Flynn AM, et al: Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4. Biochem J 1984;218:725-732. 8. Lindalh U, Thunberg L, Bäckström G, et al: Extension and structural variability of the antithrombin-binding sequence in heparin. J Biol Chem 1984;259:12368-12376. 9. Nesheim ME: Simple rate law that describes the kinetics of the heparin-catalyzed reaction between antithrombin III and thrombin. J Biol Chem 1984;258:14708-14717. 10. Menon V, Berkowitz SD, Antman EM, et al: New heparin dosing for patients with acute coronary syndromes. Am J Med 2001;110: 641-650. 11. Baker BA, Adelman MD, Smith PA, et al: Inability of the activated partial thromboplastin time to predict heparin levels. Arch Intern Med 1997;157:2475-2479. 12. Bates SM, Weitz JI, Johnston M, et al: Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med 2001;161:385-391. 13. Brandt JT, Triplett DA:. Laboratory monitoring of heparin: effect of reagents and instruments on the activated partial thromboplastin time. Am J Clin Pathol 1981;76(suppl 4):530-537. 14. Eighth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2008;133(suppl):454S-545S. 15. Schaefer DC, Hufnagle J, Williams L: Rapid heparin anticoagulation: use of a weight-based nomogram. Am Fam Phys 1996; 54(8):2517-2521. 16. Kearon C, Ginsberg JS, Julian JA, et al: Comparison of fixeddose weight-adjusted unfractionated heparin and low-molecularweight heparin for acute treatment of venous thromboembolism. JAMA 2006;296:935-942. 17. Levine MN, Hirsh J, Gent M, et al: A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994;154:49-56. 18. Cruickshank MK, Levine MN, Hirsh J, et al: A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991;151:333-337.

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19. Raschke RA, Gollihare B, Peirce JC: The effectiveness of implementing the weight-based heparin nomogram as a practice guideline. Arch Intern Med 1996;156:1645-1649. 20. Morabia A: Heparin doses and major bleedings. Lancet 1986; 1:1278-1279. 21. Pharmacia & Upjohn: Fragmin (dalteparin) package insert. Kalamazoo, MI; May 1999. 22. Kim MH, Decena BF, Bruckman D, et al: Use patterns of lowmolecular weight heparin. Am Heart J 2003;145:665-669. 23. Hirsh J, Bauer K, Donati MB, et al: Parenteral anticoagulants. Chest 2008;133:141S-159S. 24. Hunt D: Low molecular weight heparins in clinical practice. South Med J 1998;91:2-10. 25. Bhandari M, Hirsh J, Weitz JI, et al: The effects of standard and low molecular weight heparin on bone nodule formation in vitro. Thromb Haemost 1998;80:413-417. 26. Dupont Pharma: Innohep (tinzaparin) package insert. Wilmington, DE; July 2000. 27. Sanofi Aventis: Lovenox (enoxaparin) package insert. Bridgewater, NJ; May 2007.

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289

Chapter 11

Anticoagulation in Cancer Patients Gregory C. Connolly, Alok A. Khorana

Cancer-Associated Thrombosis: An Overview The association between malignancy and thrombosis has been known for years.1 Most thromboses in cancer patients occur in the form of venous thromboembolism (VTE) with events such as deep vein thrombosis (DVT) and pulmonary embolism (PE). However, high rates of arterial thrombotic events, such as myocardial infarction and stroke, have also been reported in cancer patients.2 There are many theories to explain the complex mechanisms underlying this association (reviewed in Varki3). Some have proposed that the production of procoagulants by tumor cells, particularly tissue factor (TF), is partly responsible for the hypercoagulable state of malignancy. Also likely involved are prothrombotic oncogene-mediated processes; treatment-mediated vascular injury by surgery, radiation, and chemotherapy; and mechanical obstruction of flow by tumors. Patients with cancer have a 2- to 7-fold increased risk of developing thrombosis compared with individuals without cancer.4-6 The reported incidence of VTE in studies of pooled cancer patients is between 1.6% and 8%,2,5,7-10 but rates are significantly higher in some subgroups of the cancer population. In two large population-based studies looking 290

at cohorts with a first lifetime presentation of VTE, cancer patients accounted for 12% and 22% of the total population.4,6 The problem of cancer-associated VTE is likely even larger than these epidemiologic studies suggest because in autopsy studies of cancer patients the rate of VTE can be as high as 50%.11,12 VTE in hospitalized cancer patients has been well studied. In a large retrospective study of more than 1 million hospitalized cancer patients from 1995 to 2003, DVT occurred in 3.4% per admission and PE in 1.1%, with VTE rates approaching 4.6% in 2002 to 2003 (Figure 11-1).13 This represented an increase of 28% over the duration of study, with an even higher rate of increase of 47% in hospitalized cancer patients on chemotherapy. Similarly, two earlier studies reported lower overall rates of VTE (0.6% and 2%).5,14 However, rates of VTE in the study by Stein et al5 increased steadily over time and were as high as 4% in the late 1990s. This trend is likely driven by an increased rate of cancerassociated VTE, improved diagnostic procedures (particularly the sensitivity of multidetector computed tomography [CT] technology), and the increased thrombogenicity of newer cancer regimens. The occurrence of VTE has important implications for patients with malignancy. Several studies have demonstrated that the presence of VTE is an independent predictor of 11 worse survival in patients with cancer.15,16 VTE was the second leading cause of death in one study of cancer patients receiving outpatient chemotherapy, behind only progression of malignancy as a cause of death.15 In hospitalized cancer patients, mortality rates were significantly higher in cancer patients with VTE recorded during the same hospital admission compared with patients without VTE (16.3% vs 6.3%; P <0.0001). In-hospital mortality rates were particularly high in patients with PE (24.8% vs 6.5% in those without PE; P <0.0001). Cancer patients with VTE also experience higher rates of VTE recurrence and bleeding complications and tend to present with more extensive and more symptomatic clots 291

Rate of VTE (%)

292 VTE—patients on chemotherapy VTE—all patients

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

DVT—all patients PE—all patients

1995

1996

1997

1998

1999

2000

2001

2002

2003

Figure 11-1: Increase in the rate of venous thromboembolism (VTE) over time in hospitalized cancer patients, particularly in those on chemotherapy. DVT=deep vein thrombosis. Adapted from Khorana et al.13

compared with patients without cancer.17,18 Also, significant costs and health care resource utilization issues are related to cancer-associated VTE.19 Thus, the development of VTE in hospitalized cancer patients has important consequences for patients, providers, and health systems.

Screening for Cancer in Patients With Idiopathic Venous Thromboembolism A high percentage of patients with unprovoked venous thrombosis are subsequently found to have malignancy, further supporting the association between cancer and thrombosis. Many cohort studies have suggested that the incidence of cancer among patients with unprovoked VTE is 3-fold higher than the incidence among patients with provoked VTE.20 It has been proposed that by diagnosing previously undetected cancer in patients with new idiopathic thrombosis, we may permit treatment of malignancy at earlier stages. A recent meta-analysis of more than 30 trials summarized the results of studies looking at extensive cancer screening in patients with newly diagnosed unprovoked VTE.21 The authors found that 6% of these patients have cancer at time of VTE diagnosis and another 10% will be diagnosed with cancer in the subsequent 12 months. Limited cancer screening consisting of a careful medical history and review of age-appropriate screening tests, physical examination, 11 routine laboratory blood work, and chest radiography performed within several weeks of the incident VTE detected 49% of cancers. These and more extensive cancer screening measures such as: ultrasonography or CT of the abdomen and pelvis; measurement of tumor markers (PSA, CEA, CA-125); and in some cases, other invasive studies such as colonoscopy and sputum cytology—detected 70% of cancers. This difference was statistically significant, but the impact of extensive screening on either morbidity or mortality could not be assessed.21 The authors suggest that the cost of increased patient anxiety, expenditures, and other complications of invasive studies must be weighed against 293

the potential benefit of detecting cancer at an earlier and potentially more treatable stage.

Risk Factors and Biomarkers for Venous Thromboembolism in Cancer Patients Many risk factors for cancer-associated thrombosis have been identified (Table 11-1). These include patient-associated factors such as age, obesity, and medical comorbidities; cancer-associated factors such as site and stage of cancer; and treatment-associated factors. In addition, several biomarkers associated with an increased risk of cancer-associated thrombosis have been identified. The site of cancer has consistently been one of the most important factors in determining a cancer patient’s risk of developing VTE. In several studies of hospitalized cancer patients with different types of malignancies, the rate of VTE is consistently highest in patients with cancers of the pancreas, stomach, brain, kidney, uterus, lung, and ovary.2,5,7,9,10,13,14 Patients with advanced stages of cancer have at least a 2-fold increased risk of thrombosis compared with those with localized cancer.2,10,22 The risk of VTE in cancer patients is also considerably higher in the first 6 months after diagnosis.9 Multiple patient-related factors have been shown to be important in predicting a cancer patient’s risk of developing VTE. In a large retrospective study, multivariate analysis identified older age; black race; female gender; and multiple medical comorbidities, such as pulmonary disease, renal disease, and infection, as significant risk factors for the development of VTE.13 Obese patients without cancer have up to a 4-fold increased risk of developing thrombosis compared with nonobese patients without cancer,23-27 and obesity has been shown to be a significant risk factor for VTE in cancer patients as well.28,29 Indeed, a body mass index of 35 kg/m2 or above was identified as one of five variables in a recently developed risk model for predicting chemotherapy-associated thrombosis in ambulatory cancer patients.30 294

Table 11-1: Selected Risk Factors for Cancer-Associated Thrombosis Patient-Associated Risk Factors Age Race Gender Medical comorbidities Obesity History of thrombosis Immobility Cancer-Associated Risk Factors Site of cancer Cancer stage Cancer histology Time after initial diagnosis Treatment-Associated Risk Factors Chemotherapy Surgery Indwelling catheters Hormonal therapy Radiation Transfusions Erythropoiesis-stimulating agents Antiangiogenic agents (thalidomide, lenalidomide) Biomarkers Platelet count ≥350,000/mm3 Leukocyte count >11,000/mm3 Hemoglobin <10 g/dL Tissue factor (antigen expression, circulating antigen or activity level) Soluble P-selectin D-dimer C-reactive protein

11

295

Chemotherapy is one of the most important factors in VTE risk stratification of cancer patients. Large population-based studies in groups of pooled cancer patients have demonstrated a 2- to 6-fold increased risk in cancer patients receiving chemotherapy compared with those not receiving chemotherapy.6,7 Chemotherapy treatment is associated with increased rates of VTE in hospitalized cancer patients as well.2,13 Antiangiogenic agents, such as thalidomide, lenalidomide, and bevacizumab, used in the treatment of myeloma and other cancers, are associated with a particularly increased risk of VTE, with rates as high as 75% reported in some studies.31-34 Several biomarkers have been identified that may help identify cancer patients at highest risk for developing VTE. Elevated platelet count, elevated leukocyte count, and low hemoglobin levels are recognized risk factors for cancer-associated thrombosis.8 TF, a transmembrane glycoprotein present on subendothelial tissue, platelets, and leukocytes, is a key component in initiation of coagulation and may play a role in cancer-associated thrombosis.35,36 In patients with pancreatic cancer, VTE is 4 times more common in patients with a high level of TF expression in their tumors,37 with similar associations reported in ovarian cancer.38 Elevated or increasing levels of circulating TF have been associated with VTE in patients with pancreatic cancer.37 Other proteins and inflammatory markers, such as C-reactive protein, P-selectin, and D-dimer, have been associated with increased risk of VTE in cancer patients and may play a role in risk stratification.39-42 However, the significance of biomarkers in predicting hospital-acquired VTE is unknown. Which of these factors are most important in risk stratifying cancer patients for development of VTE? Risk assessment models for DVT in specific high-risk populations have been developed and are used clinically.43-47 Recently, a risk assessment model for ambulatory cancer patients incorporating five easily obtained clinical variables was 296

Table 11-2: Predictive Model for ChemotherapyAssociated Venous Thromboembolism Patient Characteristic • Site of cancer – Very high risk (stomach, pancreas) – High risk (lung, lymphoma, gynecologic, bladder, testicular)

Risk Score 2 1

• Prechemotherapy platelet count ≥35,0000/mm3 • Hemoglobin level <10 g/dL or use of red blood cell growth factors

1

• Prechemotherapy leukocyte count >11,000/mm3

1

• Body mass index ≥35 kg/m2

1

1

Adapted from Khorana et al.30

published (Table 11-2).30 Rates of VTE in the development and validation cohorts, respectively, were 0.8% and 0.3% in the low-risk category (score, 0), 1.8% and 2% in the inter- 11 mediate-risk category (score, 1 to 2), and 7.1% and 6.7% in the high-risk category (score ≥3) over a median period of 2.5 months (C-statistic, 0.7 for both cohorts). The applicability of this model to hospitalized patients or in the postdischarge setting is an area for future research.

Prevention of Venous Thromboembolism in Hospitalized Cancer Patients Prevention of VTE in cancer patients could significantly affect their morbidity, mortality, and use of health-care resources. Many large, randomized studies have demonstrated the benefits of using prophylactic low-molecular-weight 297

heparin (LMWH) in cancer patients undergoing surgery48-51 and are discussed elsewhere in this book. Recommendations for prophylaxis in hospitalized nonsurgical cancer patients are derived from studies in general medical patients because no cancer-specific studies have been conducted. Three large, randomized, double-blinded, placebo-controlled trials in acutely ill medical patients have demonstrated reduced rates of VTE with the use of prophylactic LMWH or fondaparinux (Arixtra®) (Table 11-3).52-56 These studies reported an absolute risk reduction of 2% to 10% in the incidence of VTE over a 3-month follow-up period, and one study even reported a significant improvement in 1-month mortality rate. Cancer patients represented a percentage of the patients in these studies. The MEDENOX (Prophylaxis in Medical Patients with Enoxaparin) study, published in 1999, was the first of these studies. More than 1,100 acutely ill hospitalized medical patients were randomized to receive 40 mg of subcutaneous (SC) enoxaparin (Lovenox®), 20 mg of enoxaparin SC, or placebo for 6 to 14 days with assessment for DVT by bilateral venography during the initial 14-day period and subsequent 3-month follow-up. Fifteen percent of the study population had a previous or current diagnosis of cancer. The 40-mg treatment group had a significantly lower incidence of VTE (5.5% vs 14.9%; P <0.001) and a trend toward reduced mortality that was not significant. The treatment group also had a higher incidence of hemorrhage, which was not statistically significant (17.4% vs 14.3%). Subgroup analysis of the MEDENOX study demonstrated a relative risk of 0.5 in cancer patients with prophylaxis, which was not statistically significant because of the small sample size.57 The PREVENT (Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial) used a similar design to demonstrate the efficacy of dalteparin (Fragmin®) in VTE prophylaxis.54 In this trial, 3,700 patients were randomized to receive 5000 U of SC dalteparin or placebo with compression ultrasonography between days 298

Table 11-3: Selected Studies of Prophylaxis of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Study

Regimen

MEDENOX Enoxaparin 40 mg/d SC

Patients (n)

Cancer Patients (%)

579

12

VTE (%, Placebo vs Drug)

Reference

14.9 vs 5.5; P< 0.001 Samama et al53

PREVENT

Dalteparin 5000 U/d SC

3706

5

4.9 vs 2.7; P=0.002

Leizorovicz et al54

ARTEMIS

Fondaparinux 2.5 mg/d SC

849

15

10.5 vs 5.6; P=0.03

Cohen et al55

299

ARTEMIS=Arixtra for Thromboembolism Prevention in Medical Indications Study, MEDENOX=Prophylaxis in Medical Patients with Enoxaparin, PREVENT=Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial, RRR=relative risk reduction, SC=subcutaneous, VTE=venous thromboembolism.

11

21 to 24 and subsequent 3-month follow-up. There was significantly less VTE in the treatment group (4.9% vs 2.7%; P=0.0015). There was again a trend toward increased risk of bleeding events in the LMWH group, but this was not found to be statistically significant (0.49% vs 0.16%; P=0.15). No difference in mortality was observed. Approximately 5% of the patients in this trial had cancer. The most recent of these three trials is ARTEMIS (Arixtra for Thromboembolism Prevention in Medical Indications Study), which assessed the efficacy of fondaparinux, a factor Xa inhibitor.55 Almost 850 patients were randomized to receive either 2.5 mg of SC fondaparinux or placebo. There was a significant reduction in the incidence of VTE over a 3-month follow-up period (10.6% vs 5.6%; P=0.029), with no difference in bleeding events. This is the only one of the three studies to report a significant reduction in 3-month mortality in the treatment group (3.3% vs 6.0%; P=0.06). Approximately 15% of the patients had cancer. Prophylactic doses of SC unfractionated heparin (UFH) are also effective at preventing VTE in hospitalized medical patients. A meta-analysis incorporating 16 trials and almost 20,000 medical patients showed that UFH was as effective as LMWH in preventing VTE but may be associated with increased risk of bleeding.56 Nonpharmacologic strategies for VTE prophylaxis, such as the use of graduated compression stockings or pneumatic compression devices, have proven to be effective in the postoperative period58,59 but have not been formally studied in medical patients. Results from the EXCLAIM (Extended Clinical Prophylaxis in Acutely Ill Medical Patients) study suggest that an extended duration of prophylaxis may be beneficial in medical patients.60 Acutely ill hospitalized medical patients were randomized to receive either 40 mg of SC enoxaparin or placebo for 28 days after an initial 10-day course of prophylactic enoxaparin. There was a significant reduction in the incidence of VTE (2.8% vs 4.9%; P=0.0011) in the group receiving extended prophylaxis. An extended period 300

of prophylaxis may be particularly important for cancer patients given that the major risk factor for VTE in this population persists after discharge from the hospital. Full details regarding the cancer subgroup of this study await publication.61 Based on extrapolation from the available data in medically ill patients, recently released clinical practice guidelines from the American Society of Clinical Oncology (ASCO), American College of Chest Physicians (ACCP), and National Comprehensive Cancer Network (NCCN) unanimously support the use of thromboprophylaxis in hospitalized oncology patients.62-64 A recent large multinational epidemiologic study of more than 68,000 patients looking at the use of prophylactic anticoagulation in hospitalized surgical and medical patients highlights the need for more stringent adherence to these guidelines.65 In this study, only 58% of surgical patients and 39% of medical patients at risk for VTE received appropriate prophylaxis during hospitalization according to the ACCP guidelines. Adherence rates were generally higher in the US than in many other countries, where nearly 60% of at-risk medical patients received prophylaxis. Additionally, compliance rates with prophylaxis was considerably better in this study than in earlier studies, suggesting increasing acceptability of thromboprophylaxis.66-68 However, there continues to be a need for further education about the negative 11 impact and prevention of VTE in hospitalized patients.

Ambulatory Cancer Patients Most cancer patients receive treatment in the outpatient setting, where the utility of thromboprophylaxis is less clear and the question of how to manage thromboprophylaxis on hospital discharge is an important one. Multiple recent studies have investigated the potential benefit of various anticoagulant agents in ambulatory cancer patients. Most of these studies have not demonstrated a significant benefit with prophylaxis.69-73 Current ASCO guidelines support the use of thromboprophylaxis only in ambulatory patients receiving 301

thalidomide and related agents because of the high rate of treatment-associated VTE in these patients and because of studies demonstrating reduced rates of VTE with the use of VTE prophylaxis.33,62 Prophylaxis studies targeting various high-risk subgroups of the ambulatory population based on a previously described risk model are ongoing.

Treatment of Venous Thromboembolism in Cancer Patients Based on the results of several randomized trials and meta-analyses, LMWH products should be used in the initial treatment of VTE in cancer patients.74-77 These studies have demonstrated reduced rates of recurrent VTE, reduced bleeding complications, and even significant improvement in mortality in patients treated initially with LMWH instead of UFH. Fondaparinux is also an acceptable agent to use in the initial treatment.78 Warfarin is the standard anticoagulant for long-term treatment and prevention of VTE after the initial treatment period for most patients; however, LMWHs offer several advantages in cancer patients. A retrospective study of more than 800 patients being treated with standard oral anticoagulation demonstrated significantly higher rates of recurrent VTE (20% vs 6%) and major bleeding (12% vs 5%) in patients with cancer compared with those without cancer.17 These findings could not be explained by suboptimal anticoagulation. Another prospective study of almost 750 patients demonstrated significantly increased risk bleeding and a very strong trend toward increased risk of recurrent VTE in cancer patients on oral anticoagulation compared with noncancer patients.79 Of note, the increased bleeding events were not associated with supratherapeutic anticoagulation. In this study, cancer patients spent more than double the amount of time at higher-than-intended anticoagulation levels compared with those without cancer. LMWHs have been proven to be more efficacious in long-term treatment of VTE in cancer patients as well. The 302

CLOT (Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism) trial randomized 676 cancer patients with VTE to receive initial dalteparin followed by 6 months of either dalteparin or warfarin with target International Normalized Ratio of 2.5 (Figure 11-2).80 Fifteen percent of patients treated with warfarin developed recurrent VTE compared with 7.9% of patients treated with dalteparin (0.48, 95% confidence interval [CI] 0.30 to 0.77). This translates into an absolute risk reduction of 7.8% or a number needed to treat of 12 to prevent one recurrent VTE. This landmark trial established the superiority of LMWH for long-term anticoagulation in cancer patients. Other smaller studies with tinzaparin (Innohep®) and enoxaparin support the role of LMWH in the treatment of cancer-associated VTE (Table 11-4).61,81-83 Clinical practice guidelines issued by ASCO, ACCP, and NCCN all recommend long-term anticoagulation with LMWH for cancer patients with VTE as the preferred approach.62,64,84 The optimal duration of anticoagulation in cancer patients with VTE is unknown. Theoretically, many patients with active cancer have a persistent risk for thrombosis, so extended anticoagulation beyond the standard 6 months should be considered, especially for those with cancer or 11 those receiving anticancer treatments. Thereafter, the riskbenefit ratio should be weighed periodically, and an individualized decision regarding the duration of anticoagulation is recommended.64,84 Filters should be used conservatively and only temporarily in situations with a serious contraindication to anticoagulation. The PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) study is the only reported randomized trial to assess the potential late complications of recurrent DVT or PE with the use of vena cava filters.85 In this prospective, randomized, controlled trial of 200 patients (including 56 with cancer) on antico303

304 Probability of Recurrent VTE (%)

25

P = 0.002

20

Oral anticoagulant

15

10

Dalteparin 5 0 0

30

60

90

120

150

180

Days After Randomization No. at Risk Dalteparin Oral anticoagulant

336 336

301 280

264 242

235 221

227 200

210 194

164 154

210

Figure 11-2: Prolonged treatment with dalteparin reduces recurrent venous thromboembolism (VTE) in patients with cancer and established VTE. Adapted from Lee et al.80

Table 11-4: Regimens for Long-Term Treatment of Venous Thromboembolism in Patients With Cancer Drug

Regimen

Study

Dalteparin

200 U/kg SC once daily for 1 month then 150 U/kg SC once daily

CLOT study87

Enoxaparin

1.5 mg/kg SC once CANTHANOX82,83 daily and ONCENOX studies83

Tinzaparin

175 U/kg SC once daily

Warfarin

Adjust dose to achieve an INR of 2 to 3

LITE study81

CANTHANOX=Cancer-associated therapies: New Considerations in the treatment and prevention of recurrent venous thromboembolism, CLOT=Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism, INR=International Normalized Ratio, LITE=Trial of the Effect of Low-Molecular-Weight Heparin (LMWH) Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (DVT), ONCENOX=Multifactorial etiology of cancer associated venous thrombosis: Results from the baseline profiling of cancer patients recruited in a study for the secondary prevention of venous thrombosis with a low molecular weight heparin, SC=subcutaneous

305

11

agulation, those who received a filter had short-term protection from PE but experienced significantly more recurrent DVT and filter-site thrombosis compared with those who did not have filters placed (20.8% vs 11.6%; odds ratio [OR] 1.87; 95% CI 1.10 to 1.38). Retrospective studies have noted a 32% to 40% incidence of recurrent DVT in cancer patients who receive vena cava filters.19,86 The ASCO guidelines recommend insertion of a vena cava filter only for patients with contraindications to anticoagulant therapy and in patients with recurrent VTE despite adequate long-term therapy with LMWH.62

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Chapter 12

Brave New World: Antithrombotics on the Horizon Charles E. Mahan, Alex C. Spyropoulos, Erica A. Baca, Alpesh N. Amin, Steven B. Deitelzweig

V

enous thromboembolism (VTE) and arterial thromboembolism (ATE) continue to be major causes of morbidity and mortality globally. ATE is the most common cause of myocardial infarction (MI), limb gangrene, and ischemic stroke.1 In the United States, approximately 865,000 acute MIs are estimated to occur annually, with an 18% and 35% recurrence rate within 6 years for men and women, respectively.2 ATEs consist of platelet aggregates bound by small amounts of fibrin. Because ATEs are platelet rich, strategies to inhibit ATE formation have primarily focused on drugs that block platelet function. Another strategy is developing anticoagulants for preventing cardioembolic events in patients with mechanical valves or atrial fibrillation.1 VTE is comprised of pulmonary embolism (PE) and deep vein thrombosis (DVT) and remains the most preventable cause of hospital death within the US,3 with an incidence of 1 to 2 per 1,000 people.4 VTE represents 1 in 10 hospital deaths, and postthrombotic syndrome and pulmonary hypertension occur in 10% of DVT and 5% of PE patients, respectively.5 It is estimated that between 60,0006 and 300,0007 deaths occur annually in the US from fatal PE, as many as 200,000 in US hospitals.7 314

Because of the high incidence of ATE and VTE, the search continues for antithrombotic agents that can help to both prevent and treat these diseases. Several limitations of available antithrombotic drugs exist and continue to drive the need for research into novel agents. Recent antithrombotic management of VTE has gone through major developments. For example, indirect inhibitors, such as low-molecular-weight heparin (LMWH) and the pentasaccharide fondaparinux (Arixtra®), represent improvements over traditional drugs such as unfractionated heparin (UFH) for acute treatment of VTE with more targeted approaches, predictable pharmacokinetic profiles, and a lack of need for monitoring. Vitamin K antagonists (VKAs; eg, warfarin) have inherent limitations such as multiple food and drug interactions and a frequent need for monitoring, but with the removal of the oral direct thrombin inhibitor (DTI) ximelagatran from the world market because of safety concerns, the VKAs remain the only oral anticoagulants approved for long-term secondary thromboprophylaxis in VTE. (The safety concerns with ximelagatran were thrombin rebound and liver enzyme elevation.) Newer anticoagulant drugs include oral DTIs (dabigatran), oral direct factor Xa inhibitors (PRT 054021, rivaroxaban, apixaban, YM-150, and DU-176b), parenteral pentasaccharides (idraparinux and SSR-126517-E), and tissue factor VIIa (TF–FVIIa) complex inhibitors (NAPc2). These 12 newer agents are tailor-made to target specific procoagulant complexes. Therefore, many of the anticoagulants being researched have the potential to expand the antithrombotic therapy for both acute and long-term treatment of VTE. Sought-after advantages of the new anticoagulants are the possibility of having nonmonitored parenteral and oral anticoagulants with a wide therapeutic window and a predictable anticoagulant response and new antiplatelets and fibrinolytics that demonstrate improved efficacy or reduced bleeding. 315

Studies in New Agents for Arterial Thromboembolism: Antiplatelets Antiplatelet agents that are in advanced stages of development primarily target adenosine diphosphate (ADP), thromboxane A2, or thrombin receptors on the platelet surface (Figure 12-1). Of the ADP receptor antagonists, most specifically target P2Y12. The thrombin receptor antagonists primarily target protease activated receptor-1 (PAR-1). Adenosine Diphosphate Receptor Antagonists ADP receptor antagonists in late testing include cangrelor and AZD6140, while prasugrel has recently been approved for use within the US by the FDA. Drug labeling of prasugrel required a black box warning in patients over 75 years old, under 60 kg, transient ischemic attack and stroke patients, and other specific serious contraindications.8 Cangrelor Cangrelor is an adenosine triphosphate (ATP) analog and a direct competitive inhibitor of P2Y12.9 A two-part, randomized phase II trial evaluated cangrelor in patients undergoing percutaneous coronary intervention (PCI).10 Primary end points were composite adverse cardiac events at 1 month, including death, MI, unplanned repeat coronary intervention, and minor and major bleeding within 1 week. In the first part, patients were randomized to an 18- to 24hour infusion of cangrelor at 1, 2, or 4 g/kg/min vs placebo. Both the cangrelor and placebo groups received aspirin plus heparin. During the second part, patients received either cangrelor at 4 g/kg/min or abciximab before PCI. At 1 month, there was no significant difference in adverse cardiac events between the cangrelor (7.6%) or abciximab (5.3%) groups. Similarly, major and minor bleeding at 1 week were not statistically different between the cangrelor (13%) and placebo (8%) groups in part 1 or in part 2 for the cangrelor (7%) and abciximab (10%) groups. 316

One of the possible advantages of cangrelor is that it does not require hepatic conversion to an active metabolite. However, both prasugrel and clopidogrel do require this conversion. Because of this difference, intravenous (IV) cangrelor more rapidly inhibits ADP-induced platelet aggregation. Prasugrel and clopidogrel have much slower onsets of action. Cangrelor’s half-life is typically less than 5 min, and platelet function recovers within 1 hour after discontinuation of the drug.9,11 Because phase II trials appear safe and efficacious, cangrelor is undergoing phase III testing in PCI patients. Prasugrel Prasugrel is a thienopyridine analog that is rapidly absorbed after oral administration.12 It is then hydrolyzed by esterases to an inactive metabolite that is then further metabolized by the hepatic cytochrome P450 (CYP) enzyme system to the active metabolite R-138727. The CYP3A and CYP2B6 enzymes are the main systems involved with converting prasugrel to its active metabolite. Conversion of prasugrel to R-138727 occurs by single-step oxidation in the liver.12 Compared with clopidogrel (Plavix®), activation of prasugrel is more efficient because after clopidogrel is absorbed, esterases convert clopidogrel into an inactive metabolite, making less available for activation. This may be a possible advantage of prasugrel. Prasugrel irreversibly inhibits the P2Y12 receptor on the 12 platelet in the same fashion as clopidogrel and ticlopidine (Ticlid®). Similar to clopidogrel, R-138727 binds covalently to P2Y12.12 Compared with clopidogrel, prasugrel appears to be a more potent and effective inhibitor of ADPinduced platelet aggregation.12,13 Although prasugrel has a more rapid onset of action than clopidogrel, both drugs are irreversible inhibitors of the P2Y12 receptor on the platelet. Thus, both prasugrel and clopidogrel have a moderate duration of approximately 1 week and delayed offset of action.14 317

318

New Antiplatelet Drugs

ADP Receptor Antagonists

Parenteral

Oral

Cangrelor

Prasugrel AZD6140

A

Thromboxane A2 Receptor Antagonists

S18886

PAR-1 Antagonists

E5555

SCH-530348

Thromboxane A2 Receptor Antagonists PAR-1 Antagonists

ADP Receptor Antagonists

TXA2

PAR-1 ADP

Platelet

B 319

Figure 12-1: New antiplatelet drugs. ADP=adenosine diphosphate; PAR-1=protease activated receptor-1.

12

Initial information suggests that prasugrel may be significantly less affected by human genetic polymorphisms in CYP enzymes, specifically CYP2C9 and CYP2C19.13 Although CYP3A4 is involved with prasugrel, it appears that prasugrel is more inert to this system than clopidogrel. This may be partly because clopidogrel is activated by the CYP system through multiple oxidative steps, but only a single oxidative step is required for prasugrel. CYP3A4 genetic polymorphisms are hypothesized to be one of the reasons clopidogrel “resistance” occurs in certain patients.14-16 The phase II study in prasugrel, the JUMBO TIMI-26 (Joint Utilization of Medications to Block Platelets Optimally Thrombolysis in Myocardial Infarction) trial, evaluated prasugrel vs clopidogrel and measured a combined end point of death, MI, stroke, clinical target vessel thrombosis, and recurrent MI requiring hospital readmission at 1 month.17 The safety outcome was combined major and minor bleeding at 30 days. Dosing in the prasugrel arm was an initial loading dose of 40, 60 or 60 mg followed by 7.5, 10, or 15 mg once daily. Clopidogrel dosing was an initial loading dose of 300 mg followed by a maintenance dose of 75 mg once daily. The study was designed to compare the safety profile of the two drugs. Although there was a trend in improved efficacy of the combined end point with prasugrel (7.2%) vs clopidogrel (9.4%), the difference was not statistically significant. Combined major and minor bleeding occurred in 1.7% of patients given prasugrel and in 1.2% of clopidogrel patients, and the difference was not statistically significant. The phase III trial of prasugrel, the TRITON–TIMI-38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition) trial, again compared prasugrel with clopidogrel for 6 to 15 months and a composite efficacy end point of cardiovascular death, nonfatal stroke, and nonfatal MI, with the safety end point being major bleeding. Dosing in the prasugrel arm was an initial 320

loading dose of 60 mg followed by 10 mg once daily as the maintenance dose. Similar to the JUMBO TIMI-26, dosing with clopidogrel was an initial loading dose of 300 mg loading dose followed by 75 mg once daily as the maintenance dose. Approximately 13,000 moderateto high-risk ACS, elective PCI patients were enrolled in the study.18 Prasugrel demonstrated significantly superior efficacy, with the composite end point occurring in 9.9% of patients receiving prasugrel vs 12.1% of those given clopidogrel (P <0.001). Prasugrel was also significantly superior to clopidogrel for nonfatal MI and urgent target vessel revascularizations at 7.4% vs 9.7% (P <0.001) and 1.1% vs 2.4% (P <0.001), respectively. Unfortunately with prasugrel vs clopidogrel, fatal bleeding (0.4% vs 0.1%, P <0.002), major bleeding (2.4% vs 1.8%, P <0.03), and life-threatening bleeding (1.4% and 0.9%, P <0.01) occurred statistically significantly more frequently. Later subgroup, post hoc analysis found that pre-enrollment patients with the risk factors of weight less than 60 kg, age 75 years or older, and a history of stroke or transient ischemic attack exhibited a higher risk of bleeding. Additional dose-finding or specific population studies may be beneficial in determining if the risk–benefit tradeoff of prasugrel will be worthwhile. AZD6140 AZD6140 is the first oral, reversible, direct competi- 12 tive inhibitor of the P2Y12 platelet receptor. It is an ATP analog that is metabolized to adenosine and demonstrates rapid inhibition of ADP-induced platelet aggregation.19 The drug’s half-life is approximately 12 hours and thus requires twice-daily administration.20 An advantage of AZD6140, similar to cangrelor, is that it does not require hepatic conversion to an active metabolite and therefore does not require a loading dose because of its rapid onset of action. 321

In initial trials, AZD6140 produced more rapid and more potent inhibition of ADP-induced platelet aggregation than clopidogrel in atherosclerosis patients also treated with aspirin. AZD6140 was dosed at 100 mg twice daily, 200 mg twice daily, or 400 mg once daily.21 The DISPERSE 2 (Dose Confirmation Study Assessing Antiplatelet Effects of AZD6140 vs Clopidogrel in non–ST segment-elevation MI) study was a randomized, double-blind trial comparing the efficacy, safety, and tolerability of AZD6140 plus aspirin with clopidogrel plus aspirin. The primary end point was a combination of major and minor bleeding. Additional goals were to assess the individual and composite incidence of MI (including silent MI), death, stroke, severe recurrent ischemia, and the incidence of recurrent ischemia between the arms. A total of 1,018 patients were screened, and 990 patients with non–ST-segment elevation acute coronary syndromes (ACS) were randomized into the study from 132 international sites.21 AZD6140 dosing was 90 mg twice daily or 180 mg twice daily vs clopidogrel 75 mg once daily. For patients undergoing PCI within 48 hours after randomization, an additional dose of clopidogrel 300 mg could be administered at the discretion of the physician. Placebo was blindly administered in the AZD6140 arm if the physician requested the additional dose. Half of the patients randomized to AZD6140 were given a loading dose of 270 mg, and the other half did not receive a loading dose and only received the maintenance dose. The primary end point of bleeding occurred in 9.8% of patients given either dose of AZD6140 and in 8.1% of the clopidogrel patients. Adverse events associated with AZD6140 included chest pain, bradycardia, rash, syncope, dizziness, insomnia, headache, hyperuricemia, nausea, dyspepsia, hypotension, and dyspnea. Dyspnea occurred more frequently in the AZD6140 groups at 6% vs 2% in the clopidogrel groups. Because AZD6140 is metabolized to adenosine, researchers have hypothesized that adenosine may contribute to brady322

cardia as well as dyspnea. Other potential explanations for dyspnea include subclinical thrombotic thrombocytopenia purpura or fluid retention,22 although the investigators noted that there were no reported signs of fluid retention, congestive heart failure (CHF), or bronchospasm, challenging this hypothesis. The results of this study showed no difference in major bleeding and an increase in minor bleeding at higher doses and demonstrated encouraging results on the secondary end point of MI, demonstrating a trend of better efficacy at 5.6% of the clopidogrel patients, 3.8% of the AZD6140 90-mg patients, and 2.5% of the AZD6140 180-mg patients. However, insufficient numbers of clinical events limited demonstration of statistical significance. Large, ongoing phase III trials of AZD6140 will likely draw better conclusions of efficacy and safety. Thromboxane A2 Receptor Antagonists S18886 is an orally active, selective inhibitor of the thromboxane A2 receptor on platelets that is being studied for the secondary prevention of thrombotic events in cardiovascular disease. Its half-life is approximately 6 to10 hours, with peak levels occurring between 30 min and 2 hours after administration. The drug demonstrates strong dose–response inhibition of platelet aggregation, with maximum inhibition obtained with drug levels above 10 ng/mL, usually within 1 hour of administration. This serum 12 concentration is typically achieved with doses between 10 and 30 mg. The effect is maintained for at least 12 hours. No attributable adverse events occurred.23 In another study, 10 mg of S18886 was administered as a one-time dose to 12 patients with coronary artery disease who also received aspirin. The results demonstrated improved forearm blood flow after acetylcholine infusion in the S18886 arm compared with the placebo arm of eight patients who received aspirin only.24 Phase II studies of S18886 are occurring in patients for secondary prevention of stroke. 323

Protease Activated Receptor-1 Antagonists PARs are a family of G-protein–coupled receptors on platelets. Human platelets express PAR-1 and PAR-4 but not PAR-2 or PAR-3. The PARs are activated by proteolytic cleavage. Both PAR-1 and PAR-4 can be activated by thrombin to induce platelet secretion and aggregation.25 Thrombin-mediated platelet aggregation is thought to be a key feature in the formation of arterial thrombosis.26 Activation of either PAR-1 or PAR-4 may cause platelet aggregation independently of each other. However, PAR-1 and PAR-4 act synergistically to affect platelet activation. The affinity of the receptors for thrombin is quite disparate, with PAR-1 demonstrating a 40-fold higher affinity for thrombin than that of PAR-4.25 PAR-1 is therefore activated by relatively low concentrations of thrombin; PAR-4 activation requires significantly higher thrombin concentrations. For these reasons, PAR-1 has been identified as the major thrombin receptor on human platelets and the optimal target of PAR-1 and PAR-4. In addition, PAR-1 has been identified on smooth muscle cells, endothelial cells, fibroblasts, and cardiac myocytes.25 Because of this, it is hypothesized that thrombin-mediated activation of PAR-1 not only inhibits the formation of arterial thrombosis but may also have an effect on other processes on the cells with which thrombin is involved. One of the areas that is thought to possibly be affected is restenosis.1 E5555 and SCH-530348 are two PAR-A antagonists that are in phase II testing. E5555 E5555, a reversible PAR-1 antagonist, binds to PAR-1 with high affinity and blocks thrombin and thrombin receptor agonist peptide (TRAP)–induced platelet aggregation. Maximal platelet inhibition is achieved within 5 hours of dosing. E5555 is rapidly absorbed and demonstrates high oral bioavailability. The antiplatelet effects of E5555 persist for about 1 week. Thus far in healthy volunteers, the drug 324

does not prolong bleeding times. E5555 is undergoing phase II testing in ACS patients. SCH-530348 SCH-530348 is a synthetic analog of himbacine, which is a tetracyclic piperidine alkaloid27-29 originally isolated from the bark of Australian magnolia trees.30,31 Because himbacine expresses strong antimuscarinic activity, it was synthesized in the hopes of helping to address Alzheimer’s disease.32 SCH-530348 is a potent and specific inhibitor of PAR-1.33 The drug has excellent oral bioavailability and a long half-life and produces dose-dependent inhibition of thrombin- or TRAP-induced platelet aggregation. It does not appear to have an effect on platelet aggregation in response to other agonists. SCH-530348 inhibits TRAPinduced platelet aggregation for up to 1 month thus far in healthy volunteers, and does not prolong bleeding times. The phase II trial of SCH-530348 studied patients scheduled for coronary angiography and possible PCI. Patients were randomized to SCH-530348 or placebo in addition to aspirin, clopidogrel, and an anticoagulant, specifically bivalirudin or heparin. In the SCH-530348 arm, loading doses of 10, 20, or 40 mg were given followed by 0.5, 1.0, or 2.5 mg once daily for 60 days as a maintenance dose. The primary efficacy end point was death and major adverse cardiovascular events, and the primary safety outcome was a combination of TIMI (Thrombolysis in Myocardial 12 Infarction) major and minor bleeding. Approximately 1,000 patients entered the study, and 573 patients underwent PCI. Major and minor bleeding occurred in 3.3% of the placebo arm and 2.8% of the SCH-530348 arm. Major bleeding occurred in 1.3% and 0.7% of the same respective groups. The combination of death, major adverse coronary events, and stroke occurred in 8.6% of patients randomized to placebo and in 6.2% of those given SCH-530348. The primary efficacy end point of death and major adverse cardiovascular events occurred in 8.6% and 5.9% of the 325

placebo and SCH-530348 groups, respectively. The phase II testing results are encouraging because bleeding does not appear to be increased with SCH-530348, but efficacy trends have been noted. Phase III trials are underway in a wide range of ACS patients.

Studies in New Agents For acute VTE treatment, limitations of UFH include a less-than-predictable anticoagulant response with the need for frequent monitoring; a relatively narrow therapeutic window; and the potential for severe toxicity, especially heparin-induced thrombocytopenia (HIT), in up to 1% to 5% of patients depending on the patient group.34,35 In the past 15 years, the use of indirect inhibitors such as LMWH has greatly improved the acute management of patients with VTE. More recently, the synthetically derived pentasaccharide fondaparinux was introduced to give further options for the acute treatment and prevention of VTE. More predictable pharmacokinetic and pharmacodynamic characteristics, a more targeted approach to procoagulant complex inhibition, and improved safety and efficacy profiles have enabled complete outpatient treatment of VTE in selected patients with once- or twice-daily dosing. In the vast majority of these patients treated on an outpatient basis, a major advantage of LMWHs and fondaparinux is that there is no need for anticoagulant monitoring. Other parenteral drugs, the DTIs lepirudin and argatroban, have found only limited use in acute VTE treatment. These two agents are primarily used in patients with thrombosis associated with HIT or suspected HIT and sometimes in cardiothoracic surgery patients with recent suspected or confirmed HIT. Lepirudin and argatroban have been limited because of high drug acquisition costs and the need for frequent monitoring. Optimal long-term treatment of VTE is defined by the limitations of VKAs. Until recently, with the approval of rivaroxaban in some European countries and Canada, VKAs 326

have been the only oral anticoagulants approved for use. Warfarin is still the only oral anticoagulant approved in the US. The limitations of VKAs include a slow onset of action and the need for bridging anticoagulation with a parenteral drug in the acute setting at times. In addition, VKAs have genetic variations in metabolism, multiple food and drug interactions, and a narrow therapeutic window, requiring frequent coagulation monitoring and dose adjustment. Although infrequent, toxicities with VKAs include hypersensitivity reactions and purple-toe and blue-toe syndromes. These reactions may require the use of alternative anticoagulants for secondary thromboprophylaxis.36 Furthermore, VKAs are contraindicated or cannot be tolerated by some patient subgroups. For example, VKA use in pregnant patients is associated with a risk of teratogenicity,37 and it is associated with higher risks of recurrent thromboembolism and major bleeding in patients with active cancer.38,39 In both of these patient groups, emerging data support the use of long-term LMWH,40-42 with the only primary limitation being the necessity of parenteral use and somewhat painful injections. More recent understanding of molecular mechanisms of coagulation and thrombosis have led to the development of newer antithrombotic drugs for potential use in VTE treatment. Many of these drugs are orally active, synthetically derived, and tailor-made to target specific procoagulant complexes.43 These drugs can broadly be categorized as: 12 • Drugs that inhibit thrombin activity • Drugs that interfere with the initiation of coagulation (ie, TF–FVIIa complex inhibitors) • Drugs that propagate coagulation, specifically indirect and direct inhibitors of activated factor X (FXa) or IX (FIXa) Inhibitors of Thrombin Activity Thrombin is the key serine protease in hemostasis, with mechanisms of action that affect platelet activation, 327

coagulation, fibrinolysis, and vascular cell biology. One of thrombin’s primary roles is to help with the formation of fibrin and activate FXIII, which cross-links fibrin. Thrombin is essential for feedback activation of other coagulation factors, including FV, FVIII, and FIX, and also has a role in platelet activation and subsequent aggregation.44 Thrombin also acts as an anticoagulant by binding to thrombomodulin. This process converts protein C to its active form, which inactivates FVa and FVIIIa. Therefore, thrombin downregulates fibrinolysis. Because thrombin has such a pivotal role in the coagulation cascade, thrombin inhibitors are an important drug class in anticoagulant therapy. So far in studies, theories that thrombin inhibitors may be more effective than FXa inhibitors in ATE because thrombin is also critical in platelet activation and that thrombin inhibitors may be less effective in VTE have not been demonstrated. Indirect Thrombin Inhibitors SNAC–Heparin The sodium N-[8(2-hydroxybenzoyl) amino] caprylate (SNAC) molecule itself does not possess pharmacologic activity. Because the heparin molecule is poorly absorbed orally, various methods were researched to deliver heparin orally. It was discovered that combination with the SNAC macromolecule with heparin enabled oral delivery of the large, negatively charged heparin molecule. In phase I testing, SNAC–heparin appeared to be well tolerated, and nausea was the only significant adverse event reported.45 In the SNAC–heparin phase III trial, more than 2,000 hip replacement patients were randomized to either low- or high-dose SNAC–heparin for 30 days vs 10 days of the LMWH enoxaparin 30 mg subcutaneously (SC) every 12 hours.46 Patient compliance was poor in 22.1% and 31.4% of the patients in the low-dose and high-dose SNAC–heparin regimens, respectively, and this result was a key contributor to the drug not attaining proof of principle 328

for VTE prevention as an indirect FIIa/Xa inhibitor. This agent is no longer being investigated. Direct Thrombin Inhibitors Five parenteral DTIs—lepirudin (Refludan®), desirudin (Iprivask®), bivalirudin (Angiomax®), argatroban, and melagatran—have emerged. The first four are approved for clinical use. Desirudin is the only subcutaneous DTI and the only DTI approved for DVT prophylaxis, specifically for hip surgery. In addition, two parenteral DTIs, flovagatran and pegmusirudin, have recently completed phase II testing.1 Lepirudin is a naturally occurring bivalent DTI that is approved in patients with HIT associated with thromboembolic complications. Argatroban is the prototype noncovalent, reversible, small molecule DTI indicated for thromboprophylaxis or treatment of HIT. Melagatran is the active form of the oral, prodrug, small-molecule DTI ximelagatran. Limitations of these agents include parenteral use, the need for frequent monitoring, a high acquisition cost, and limited indications. DTI development has been driven by the increasing recognition of HIT as a potentially serious life- and limbthreatening complication.1,47 In addition, because heparin– antithrombin inhibition of thrombin produces only weak inhibition of cell surface– or clot-bound thrombin, bound thrombin is active and can be released during fibrinolysis.48 Therefore, nonantithrombin-based thrombin inhibitors that 12 have improved safety profiles over UFH and the ability to inhibit surface- or clot-bound thrombin and predictable dose–responses may present clinical advantages. Oral formulations of these drugs would also represent a major advantage. The DTIs are ideal drugs for the treatment of patients with HIT because of the generation of large amounts of thrombin associated with this condition. Lastly, a theoretical concern of DTIs has been the inhibition of the anticoagulant properties of thrombin, namely, inhibition of the thrombin-, thrombomodulin-mediated negative 329

feedback mechanism of the protein C system, with the possibility of rebound hypercoagulability.49 Flovagatran Flovagatran, formerly termed TGN 255, shows predictable and dose-dependent pharmacokinetics after IV injection. It is being studied as an alternative to heparin during hemodialysis in patients with end-stage renal disease (ESRD) who have antibodies to the heparin–platelet factor 4 (PF4) complex.1 Pegmusirudin Pegmusirudin is a chemically modified hirudin derivative.50 Compared with hirudin, which has a half-life of 1 hour after IV injection, pegmusirudin has a half-life of approximately 12 hours when administered as an IV bolus to patients with normal renal function. The half-life is prolonged in patients with renal insufficiency because of renal clearance. Pegmusirudin has completed phase II trials in patients with ESRD receiving chronic hemodialysis for the reduction of vascular graft occlusion events. Pegmusirudin provides anticoagulation during and between dialysis sessions.1 Selective Oral Direct Thrombin Inhibitors Ximelagatran Ximelagatran represented the first of a new class of orally active, small-molecule DTIs to reach late-stage development. It was administered twice daily and did not require anticoagulant monitoring or dose adjustment.1 Ximelagatran was studied extensively in a large phase III program for VTE prevention and treatment and was found to be either superior or equivalent to warfarin in efficacy.5156 But, long-term data with ximelagatran revealed liver enzyme elevations of approximately 6%, with one death occurring because of hepatorenal failure and two deaths 330

occurring from hepatic failure in patients taking ximelagatran.1 The Food and Drug Administration (FDA) did not approve the agent in the US, and in 2006 it was withdrawn from the market because of concerns of severe liver toxicity with long-term use. Dabigatran Dabigatran etexilate is a double prodrug. It is another orally active, small-molecule DTI that has reached latestage clinical development. It is rapidly absorbed from the gastrointestinal (GI) tract and then converted to the active form BIBR 953. It is excreted renally, primarily unchanged at approximately 80% to 85%. It has limited oral bioavailability of 4% to 6%.1,57 Dabigatran has linear characteristics between concentration and global coagulation parameters, including thrombin clotting time, International Normalized Ratio (INR), and ecarin clotting time. It also has a Ki of 4.5 ± 0.2 nM; a peak plasma concentration that occurs 2 hours after administration; and a half-life of approximately 8 hours after single-dose administration, increasing to around 14 to 17 hours after multiple-dose administration.1,58 Because of its long half-life, it may be able to be administered as a once-daily drug. In multicenter, parallel-group, double-blind study for VTE prevention in 1,949 patients undergoing total hip or knee replacement,59 patients were randomized to receive 50, 150, or 225 mg of dabigatran twice daily or 300 mg dabigatran once daily initiated 1 to 4 hours after surgery. 12 The comparator was 40 mg once daily of enoxaparin initiated 12 hours before surgery. A statistically significant, dose-dependent decrease in DVT occurred with increasing doses of dabigatran (P >0.001). Specifically, DVT was significantly lower in patients receiving 150 mg of dabigatran twice daily (odds ratio [OR], 0.47; P=0.0007), 300 mg once daily (OR, 0.61; P=0.02), and 225 mg twice daily (OR, 0.47; P=0.0007) compared with the enoxaparin arm. Major bleeding was lower with 50 mg of dabigatran twice 331

daily (0.3 vs 2.0%; P=0.047) compared with enoxaparin but increased at higher doses, with trends almost reaching statistical significance in those receiving 300 mg of dabigatran once daily (4.7%; P=0.051). The incidence of elevated alanine aminotransferase above three times the upper limit of normal was lower in the dabigatran groups (1.5% to 3.1%) than in the enoxaparin group (7.4%). No cases of clinically relevant thrombocytopenia occurred. Dabigatran started in the early postoperative period appeared to be safe and effective across a wide range of doses. Severe hepatic abnormalities in this study were much lower than those observed with ximelagatran. Another phase II trial in atrial fibrillation patients compared a 3-month course of dabigatran at 50, 150, and 300 mg twice daily with warfarin at a target INR of 2.0 to 3.0. Patients were also randomized to 81 mg or 325 mg of aspirin or placebo in a factorial design.60 Recruitment into the high-dose dabigatran and aspirin arm was stopped early because of an increased number of GI bleeds noted in that arm, although this effect was not observed in other arms. Only two of the 105 patients in the low-dose dabigatran group experienced a thromboembolic event; therefore, 361 of 432 patients continued open-label treatment for at least 16 months at 50, 100, or 300 mg twice daily or 150 or 300 mg once daily. The 50-mg twice daily and 150-mg daily doses were discontinued early because of annual stroke rates of 8.4% and 8.1%, respectively. The 300-mg daily dose had an annual stroke rate of 9.5%, but the rates were lower with the other doses. Elevations in alanine aminotransferase above three times the upper limit occurred in 2% of dabigatran patients and 1% of warfarin patients. Extrapolating from these results, the Randomized Evaluation of Long Term Anticoagulant Therapy (RELY) trial is an ongoing phase III trial comparing twice-daily dabigatran (110 or 150 mg) with warfarin for stroke prevention in approximately 18,000 patients with nonvalvular atrial fibrillation. 332

Dabigatran has also recently undergone phase III evaluation in the RE-MODEL, RE-NOVATE, and REMOBILIZE trials comparing dabigatran with enoxaparin in orthopedic patients.61,63 In the first two trials, safety and efficacy were not statistically different. However, in the REMOBILIZE trial, which looked at patients who had undergone knee replacement surgeries, dabigatran was inferior to enoxaparin in efficacy, with similar safety. Although the RE-MOBILIZE trial also occurred in knees as well, enoxaparin dosing was 40 mg daily; in the RE-MODEL trial, the higher regimen of 30 mg of enoxaparin twice daily was used. Therefore, it is postulated that the dosage differences in enoxaparin may have led to dabigatran’s inferiority in the RE-MOBILIZE trial. Dabigatran is also undergoing phase III testing for the treatment of VTE. TGN-167 TGN-167 (TRI-50c-04) is another oral thrombin inhibitor for the treatment of thrombosis. A controlled-release formulation of TGN-167 is also being developed for longterm treatment of thrombosis. The compound has minimal effect on activated partial thromboplastin time (aPTT) while producing a marked increase in thrombin clotting time. A double-blind, phase I, dose-escalation study with 20 volunteers demonstrated that the drug is well tolerated.64 No significant adverse events were reported. All of the subjects dosed with 600 mg of TGN-167 achieved in vitro effective 12 anticoagulant activity. Phase II studies are planned. Tissue Factor VIIa Complex Inhibitors The TF–FVIIa complex, as part of the extrinsic system of the coagulation cascade, is considered to be the essential system for the initiation of coagulation. In orthopedic surgery and in specific subsets of cancer patients, exposure of TF in the venous system may be responsible for the higher risk of developing VTE in these patient groups.65,66 Therefore, pharmacologic inhibition of the TF–FVIIa 333

complex may be an important target.67 TF function may be blocked by active site-inhibited FVIIa, by small molecules or antibodies that block the TF–FVIIa complex function, by antibodies that prevent the binding of FVIIa to TF, and by molecules that inhibit the active site of FVIIa in the TF–FVIIa complex after first binding to FXa.68,69 Furthermore, TF pathway inhibitor (TFPI), which is a naturally occurring inhibitor, forms a neutralizing complex with TF–FVIIa and FXa.67 For this reason, TFPI may be an attractive anticoagulant either by exogenous administration of recombinant TFPI (rTFPI) or by causing upregulation. Nematode Anticoagulant Proteins Nematode anticoagulant proteins (NAPs) are derived from the canine hookworm Ancylostoma caninum and have been targeted as antithrombotic drugs because of their inhibition of the TF–FVIIa complex.1,70 NAPc2 is an 85-amino acid polypeptide, and recombinant NAPc2 is expressed in yeast. NAPc2 binds to a noncatalytic site on FXa or FX.71 Inhibition of the TF–FVIIa complex with NAPc2 is achieved either through binding to FXa alone or in combination with a protein exosite, which is the case for NAPc2. Because NAPc2 binds with such high affinity, the half-life is approximately 50 hours after SC administration, which allows for every-48-hour dosing.72 In the pilot phase I/II trial, NAPc2 was tested for VTE prophylaxis in 293 patients undergoing total knee replacement surgery. Five regimens of NAPc2 were tested with a every-48-hour dosing scheme given on the day of surgery (day 1), day 3, day 5, and an optional dose on day 7. The most successful regimen was 3 μg/kg of NAPc2 administered within 1 hour after surgery. It was associated with an overall DVT rate of 12.2%, a proximal DVT rate of 1.3%, and a major bleeding rate of 2.3%.73 Additional phase II testing is occurring in unstable angina, NSTEMI, and in PCI patients. One study of addition of NAPc2 to usual antithrombotic therapy in approximately 334

200 ACS patients reduced prothrombin fragment 1.2 in a dose-dependent fashion while not increasing bleeding.74 A second phase II trial used NAPc2 in patients undergoing elective PCI in doses ranging from 3.5 to 10.0 μg/kg. Similarly, prothrombin fragment 1.2 was suppressed.75 Phase III studies are planned with an ongoing trial evaluating NAPc2 as a substitute for heparin in PCI patients. Other Tissue Factor VIIa Complex Inhibitors Data exist on the anticoagulant effect of TFPI in animals76 and the possibility that TFPI release may have a role in secondary anticoagulant mechanisms of LMWH in humans.77 A recombinant form of TFPI, tifacogin, has been researched in patients with sepsis. It is administered by IV infusion, has a half-life of minutes, and is excreted by the liver. A phase II trial compared tifacogin with placebo for 4 days at doses of 25 or 50 μg/kg/hr, and major bleeding and 28-day mortality were assessed.78 A 20% relative risk reduction occurred in 28-day mortality, and a nonsignificant trend in major bleeding occurred with tifacogin (9% vs 6%). A phase III trial compared tifacogin with placebo in more than 1,700 patients with severe sepsis.79 Rates of major bleeding were significantly higher with tifacogin at 34.2% compared with placebo at 33.9%; efficacy was not significantly improved. A phase III trial in patients with severe community-acquired pneumonia is comparing tifacogin at two doses with placebo. 12 Inhibitors of Coagulation Propagation Coagulation propagation may be inhibited by agents that target FIXa or FXa or by agents that inactivate FVIIIa or FVa, which are the cofactors for FIXa and FXa, respectively. It is therefore widely accepted that FXa has a central role in clot formation as part of the prothrombinase complex with FVa, given that FXa is generated by both the extrinsic and intrinsic pathways of coagulation as they converge into the final common pathway. Moreover, one molecule of FXa 335

can exponentially generate 138 molecules of thrombin per minute within the prothrombinase complex. Therefore, FXa inhibitors may have theoretical advantages over thrombin inhibitors by preventing the activation of coagulation amplification mechanisms as well as thrombin generation in both fibrin-rich venous thrombosis as well as platelet-rich arterial thrombosis. Obviously, this makes FXa a prime target for anticoagulant drug design. In animal models, however, selective FXa inhibition has been less potent than direct thrombin inhibition in arterial and venous models of thrombosis, with a greater prolongation of global clotting times. This information has refuted the concept that FXa is more effective than direct thrombin activity in controlling thrombin formation.80 The theoretical possibility exists that selective upstream inhibition of FXa may result in a safer bleeding profile because in the absence of thrombin activity inhibition, small amounts of thrombin would escape neutralization and thereby facilitate hemostasis. FXa inhibitors include both direct (ie, antithrombinindependent) and indirect (ie, antithrombin-mediated) selective inhibitors. FIXa inhibitors, FVIIIa and FVa inhibitors, and inhibitors of activated protein C or soluble thrombomodulin represent additional possible targets of coagulation propagation by affecting the prothrombinase complex or other routes of coagulation. Indirect Factor Xa Inhibitors Fondaparinux (Arixtra®) and idraparinux are synthetic pentasaccharides and are selective indirect FXa inhibitors. Fondaparinux was the prototype agent in this class. Both agents exert their action by high-affinity binding and activation of antithrombin, which subsequently inhibits free FXa. Fondaparinux has the antithrombin-binding pentasaccharide sequence found in UFH and LMWH and selectively binds to and induces a conformational change in antithrombin. In a catalytic manner, this increases the 336

anti-FXa activity of antithrombin approximately 300-fold. Fondaparinux has a predictable anticoagulant response and a linear pharmacokinetic profile. It has a half-life of approximately 17 to 21 hours and greater than 95% bioavailability after SC or IV injection, allowing for nonmonitored once-daily SC dosing. Its half-life is prolonged with worsening renal impairment. An advantage that has been borne out in clinical practice is that fondaparinux does not bind to PF4, and only one case report to date of fondaparinux-induced thrombocytopenia has occurred.81 Fondaparinux is approved for acute treatment of DVT and PE based on the recently completed MATISSE (Mondial Assessment of Thromboembolism Treatment Initiated by Synthetic Pentasaccharide with Symptomatic Endpoints) studies in VTE.82,83 In addition, in the US, fondaparinux is approved for VTE prophylaxis in hip replacement, knee replacement, hip fracture surgery, and abdominal surgery. Although it is approved in other countries for medical prophylaxis of VTE, the FDA did not approve this use in the US. Phase III testing has also been completed in patients with NSTEMI and ST-segment elevation MI (STEMI),84,85 although the FDA has not yet given approval for use for this indication. Use of fondaparinux indicates that FXa inhibitors are as effective as previously approved drugs with established antithrombin activity for the prevention and treatment of VTE. The agent also represents the first of a new class 12 of antithrombotic drug designed specifically to inhibit a single procoagulant complex (ie, target) in the coagulation cascade. Ongoing studies in Europe are assessing whether fondaparinux is effective as an alternate anticoagulant in HIT patients. Idraparinux Idraparinux sodium is a second-generation pentasaccharide that is a hypermethylated derivative of fondaparinux. Its extended half-life allows for once-weekly administra337

tion.86 Idraparinux’s advantages are similar to fondaparinux and include 100% bioavailability after parenteral administration, linear pharmacokinetics, a predictable anticoagulant response with no need for monitoring, lack of induction of platelet aggregation, lack of PF4 effects, and no evidence of induction of thrombocytopenia. Similar to fondaparinux, however, a major disadvantage has been the lack of an antidote. However, biotinylated idraparinux (discussed later) does have an antidote. In a phase IIa study of VTE treatment, idraparinux was superior to warfarin in reducing symptomatic VTE and death without increased bleeding.87 In a phase II dosefinding study, 2.5 mg weekly of idraparinux was chosen because higher rates of bleeding occurred with doses higher than 2.5 mg.88 The phase III trials (the Van Gogh DVT and PE treatment studies) compared the efficacy and safety of idraparinux with heparin or fondaparinux and doseadjusted warfarin (target INR, 2.0 to 3.0) in both acute and long-term treatment of DVT and PE. But this study did not meet the noninferiority criterion.89 The Van Gogh Extension study90 revealed that major bleeding occurred in 3.7% of the idraparinux group, including three fatal intracranial bleeds, compared with no major bleeds in placebo group. Based on these results, it is unlikely that idraparinux will be pursued further. Attention was then shifted to biotinylated idraparinux (discussed below). SSR-126517-E This synthetic pentasaccharide, which is a biotinylated form of idraparinux, has antithrombotic properties resulting from antithrombin mediation of FXa activity. SSR-126517-E is identical to idraparinux with the exception of a biotin moiety that is covalently bound to the pentasaccharide structure. This difference in structure allows for the anti-FXa activity to be neutralized rapidly in vivo by a specific protein called avidin. Avidin is a large tetrameric protein derived from egg 338

whites. IV avidin binds biotin with high affinity to form a 1:1 complex that is then cleared through the kidneys.1 In vitro studies reveal that SSR-126517-E shows high-affinity binding (dissociation rate constant [Kd], <1 nanomolar to human antithrombin with a concentration-dependent inhibition of FXa. It does not demonstrate direct thrombin inhibition and does not inhibit platelet aggregation. Furthermore, it does not cross-react with antibodies from sera of patients with HIT. Phase I studies with SSR-126517-E demonstrated that the median time to reach the maximum concentration was 4 hours, with an absolute bioavailability of 100% and a half-life of around 80 hours. The overall pharmacokinetic and pharmacodynamic profiles are similar to idraparinux, and can also be administered once weekly. Administration of avidin in patients with SSR-126517-E has revealed a rapid decrease of anti-FXa activity with no serious adverse events. SSR-126517-E is undergoing phase III studies for both treatment of DVT and PE using UFH/LMWH followed by dose-adjusted warfarin as comparators. Patients are given at least 5 days of UFH/LMWH before being randomized to a VKA or SSR-126517-E. Sanofi-aventis has discontinued development of this drug as well because they did not believe the drug brought significant advances to patient care in atrial fibrillation.91 Other Pentasaccharides and Oligosaccharides Additional once-weekly pentasaccharides and third- 12 generation oligosaccharides with additional thrombinbinding capacities are being studied. One such agent is SR-123781, a synthetic hexadecasaccharide that catalyzes the inhibition of both FXa and thrombin, similar to heparin. In addition, SR-123781, unlike heparin, appears to be capable of inhibiting fibrin-bound thrombin.92 HIT is unlikely to occur because SR-123781 does not bind PF4. It is administered SC and is primarily excreted by the kidneys intact. SR-123781 is in phase II evaluation for prophylaxis in patients undergoing knee arthroplasty.1 339

Selective Direct Factor Xa Inhibitors Direct FXa inhibitors may possess advantages such as the absence of intermediary molecules that may potentially result in inconsistent anticoagulation. The first in the class to complete phase II trials, DX-9065 is a small, parenteral, reversible, synthesized, selective direct FXa inhibitor that was originally studied in arterial thrombosis.93,94 Efforts to produce orally available selective FXa inhibitors for VTE are underway. Otamixaban Otamixaban, is a selective direct FXa inhibitor administered IV with a half-life of 2 to 3 hours.1 The phase II compared otamixaban with heparin in patients undergoing nonurgent PCI. Otamixaban was shown to significantly reduce levels of prothrombin fragment 1 + 2 without any difference in major bleeding.95 PRT 054021 PRT 054021 is an oral direct FXa inhibitor with a Ki of 0.12 nM. It has a half-life of 19 hours and an oral bioavailability of 47%. The phase II trial compared PRT 054021 with enoxaparin for postoperative thromboprophylaxis in patients undergoing knee arthroplasty. DVT occurred in 20% and nonfatal PE in 15% of patients receiving 15 or 40 mg of oral PRT 054021 and in 10% of patients receiving enoxaparin.96 There were no major bleeds in the 171 patients receiving PRT 054021 compared with one bleed in the 43 patients receiving enoxaparin. Razaxaban Razaxaban represents the first of a new class of synthetically derived, small-molecule, oral direct FXa inhibitors that does not require monitoring. In phase II trials, razaxaban was studied for DVT prevention in patients undergoing total knee replacement.97 Razaxaban at 25, 50, 75, or 100 mg twice daily initiated 8 hours after surgery was 340

compared with enoxaparin 30 mg twice daily initiated 12 to 24 hours after surgery. DVT was the primary end point and occurred in 8.6% of the low-dose razaxaban and 15.9% of the enoxaparin patients. Major bleeding occurred in 0.7% of the low-dose razaxaban and in no patients in the enoxaparin arm. The arms with the three higher doses of razaxaban were stopped early because of increased rates of major bleeding. The drug was discontinued in 2005. Apixaban Apixaban, or DPC-AG0023, is a variant of razaxaban and another orally active, small-molecule, direct FXa inhibitor. Apixaban is a highly potent inhibitor of human FXa, with a Ki of 0.08 ± 0.01 nM, with approximately 87% bound to serum proteins.98 It has high oral absorption and bioavailability, linear pharmacokinetics with maximal plasma concentration (Cmax) achieved within 3 hours, and an effective half-life of 9 hours for twice-daily and 14 hours for once-daily administration.58,99 Food has no effect on absorption. Thus far, no CYP interactions have been noted. Apixaban produces a predictable anticoagulant effect and has only modest effects on INR and aPTT, with effects on a third experimental coagulation marker, the modified prothrombin time (PT), under investigation. Phase I testing revealed a prolongation of the bleeding time, with only mild bleeding. No evidence of high elevation (ie, five or more times the upper limit of normal) of transaminases, 12 including alanine transaminase and aspartate transaminase, occurred. A phase II trial in more than 1,200 patients undergoing total knee replacement compared apixaban with enoxaparin or warfarin.100 Apixaban was administered in total daily doses of 5, 10, or 20 mg given as once- or twice-daily regimens. The primary end point was all-cause mortality and total VTE. Apixaban was superior at all doses to enoxaparin and warfarin. At 10- and 20-mg daily doses, twice-daily dosing efficacy appeared better than once-daily 341

dosing. Total bleeding was less frequent with apixaban 2.5 mg twice daily or 5 mg every day, but at higher doses more bleeding occurred than with enoxaparin or warfarin. Extrapolating from these results, a dosage of 2.5 mg twice daily was chosen for phase III study. Phase III trials will compare this dosing with enoxaparin in two knee replacement surgery trials and in one trial in hip replacement surgery. This dose is also being evaluated in medical patients for VTE prophylaxis. Additional phase II trials are occurring for acute VTE treatment, for secondary prevention in ACS patients, and in cancer patients for VTE prophylaxis. ADVANCE-1, a phase III VTE prevention study in patients undergoing total knee replacement, compared 2.5 mg twice daily of apixaban with 30 mg twice daily of enoxaparin. Primary efficacy outcome, a composite of DVT, PE, and death by any cause, was 9.0% with apixaban and 8.9% with enoxaparin but did not meet the prespecified noninferiority criteria, resulting in an inability to demonstrate noninferiority to enoxaparin. Major bleeding was lower in the apixaban group but was not statistically significant.101 Rivaroxaban Rivaroxaban, an oxazolidin derivative, is a selective, small-molecule, oral direct FXa inhibitor for the prevention and treatment of thrombosis. Preclinical studies showed a consistent and potent antithrombotic effect because of its inhibition of FXa. The agent did not demonstrate inhibition of thrombin or other proteins in the coagulation pathway or direct inhibition of platelet aggregation. Endogenously generated FXa was inhibited with an IC50 value of 1 nM.102 The antithrombotic effect was demonstrated in different thrombosis models, depending on models and species, with 0.6 to 10 mg/kg of oral rivaroxaban. The bioavailability was 60% to 86% in dogs and approximately 80% in humans. During phase I studies, rivaroxaban was well tolerated and rapidly absorbed (Cmax was reached after 30 min).102 Elimina342

tion occurred with terminal half-lives of 4.86 to 9.15 hours. Dose-dependent prolongation of PT, aPTT, and HepTest occurred, with no influence on bleeding time. In men and women older than 60 years of age, the mean area under the curve (AUC) and Cmax values tended to be approximately 20% higher. No QTc prolongation was observed, and with the exception of strong CYP3A4 inhibitors, no drug interactions or induction of major CYP isoforms were noted. Four large, dose-ranging studies with rivaroxaban, were completed. The open-label phase IIa study used mandatory venography and confirmed proof of principle of rivaroxaban for this indication.103 Overall, the four studies explored a wide, 12-fold dosage range of 2.5 to 30 mg twice daily and 5 to 40 mg/day for VTE prevention in major orthopedic surgery.104-107 A series of four RECORD (Regulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE) trials involved more than 12,500 patients undergoing total knee and hip replacement and evaluated rivaroxaban compared with enoxaparin for prevention of VTE. The RECORD1 trial compared 10 mg/day of rivaroxaban given after surgery with 40 mg/day of given the evening before surgery in patients undergoing total hip arthroplasty.108 The primary efficacy outcome, which was DVT, nonfatal PE, or death from any cause up to 36 days, occurred in 1.1% of patients in the rivaroxaban treatment group and in 3.7% of patients in the enoxaparin treatment group. The 12 drugs had similar safety profiles regarding major bleeding. There were significantly fewer major VTE events in the rivaroxaban group (0.2%) compared with the enoxaparin group (2.0%). The RECORD2 trial compared extended-duration rivaroxaban (10 mg/day for 31 to 39 days beginning 6 to 8 hours after wound closure) with short-term enoxaparin (40 mg/day beginning 12 hours before surgery and continuing for 10 to 14 days) after total hip arthroplasty.109 The primary efficacy outcome, which was composite of DVT, nonfatal 343

PE, and all-cause mortality up to days 30 to 42, occurred in 2.0% of patients in the rivaroxaban group and in 9.3% of patients in the enoxaparin group. The incidence of major bleeding was similar between the two treatment groups. Major VTE occurred in significantly fewer patients in the rivaroxaban group (0.6%) compared with the enoxaparin treatment group (5.1%). The RECORD-3 trial compared 10 mg/day of rivaroxaban started 6 to 8 hours after surgery with 40 mg/day of enoxaparin started the evening before surgery in more than 2,500 patients undergoing knee replacement surgery.100,110 The primary efficacy end point, a composite of DVT, nonfatal PE, and all-cause mortality, occurred in 9.6% and 18.9% of rivaroxaban and enoxaparin patients, respectively. This was a 49% (P <0.001) statistically significant relative risk reduction with rivaroxaban. Major VTE was also significantly reduced, but bleeding was not significantly different in the groups. The RECORD4 trial compared 10 mg/day of rivaroxaban administered 6 to 8 hours after surgery with 30 mg twice daily of enoxaparin administered 12 to 24 hours after surgery.110,111 The primary efficacy end point was met in 6.9% patients in the rivaroxaban group and in 10.1% in the enoxaparin group, which corresponded to a 31% relative risk reduction over enoxaparin (P=0.012) Major VTE occurred less often in the rivaroxaban group but did not reach statistical significance. The incidence of major bleeding was higher in the rivaroxaban group, but was not statistically significant compared with enoxaparin. Approximately 1,200 patients have been evaluated in phase II dose-finding studies. The first, was a randomized, multicenter, double-blind, parallel-group study assessing the dose–response relationship of a once-daily dose of rivaroxaban at 20, 30, and 40 mg compared with UFH/LMWH followed by dose-adjusted warfarin (target INR, 2.5) in the treatment of patients with acute symptomatic DVT for a 12-week period.112 344

The other study was another phase II study that compared regimens of rivaroxaban at 10, 20, and 30 mg twice daily and 40 mg daily with dose-adjusted VKA for the same indication. Results from both studies revealed no significant dose–response relationship with rivaroxaban for the primary efficacy end point of major bleeding in addition to no significant effects on liver enzymes.112,113 The efficacy was similar to traditional UFH/LMWH VKA therapy, and rates in all arms were low for major bleeding.114 YM-150 YM-150 is an oral selective FXa inhibitor for DVT prevention. The compound has a Ki of 31 nM and reveals an immediate antithrombotic effect after oral administration, with a dose-dependent response and prolongation of PT. No significant drug–food interactions have been noted. A phase II dose-escalation study in patients undergoing elective primary hip replacement surgery used YM-150 at 3, 10, 30, or 60 mg PO once daily and demonstrated a statistically significant dose–response for efficacy. The drug was administered 6 to 10 hours after surgery for 7 to 10 days and was compared with 40 mg/day of SC enoxaparin initiated 12 hours before surgery.115 No major bleeding occurred and no dose-response trend for clinically relevant nonmajor bleeding was noted. The median incidence of VTE ranged from 52% with YM-150 at 3 mg to 19% with YM-150 at 60 mg. In general, the drug seemed to be safe 12 and well tolerated. A second phase II trial is underway in patients undergoing elective hip arthroplasty. DU-176b DU-176b, is an oral FXa inhibitor for the treatment of thrombotic disorders. It inhibits FXa and has a Ki of 0.56 nM.116 In mouse models, preclinical data demonstrated potent antithrombotic effects in both antithrombin-positive and antithrombin-deficient mice.117 In rat models, DU176b at 0.05 to 1.25 mg/kg/hr resulted in prevention of 345

both arterial and venous thromboses. In addition, the drug also stimulated a 3- to 4-fold increase in TFPI in human vascular endothelial cells. Phase II studies began in the US and Europe. LY-517717 LY-517717 is an indol-6-yl-carbonyl derivative with oral bioavailability between 25% and 82% and a plasma half-life of about 25 hours. The agent is a 1,000-fold more selective FXa inhibitor than other serine proteases, with a Ki of between 5 and 7 nM. In an atrioventricular shunt model in rats, the compound had a median effective dose of 5 to 10 mg/kg PO, and absorption in dogs suggested a low potential for bleeding issues. LY-517717 was found to be well tolerated and suitable for once-daily administration in phase I testing. A phase II, noninferiority, dose-escalation study for DVT prevention randomized 511 patients undergoing hip or knee replacement surgery to receive one of 6 oral doses of LY-517717 at 25, 50, 75, 100, 125, or 150 mg or enoxaparin at 40 mg/day SC initiated preoperatively for 6 to 10 doses. At 100, 125, and 150 mg, LY-517717 was found to be noninferior to enoxaparin in the incidence of symptomatic or venographically proven DVT or PE.118 LY-517717 produced a dose-dependent prolongation of PT and was well tolerated, with no differences in bleeding risk compared with enoxaparin. Because a lack of efficacy in the three lower dose arms of LY-517717, randomization into these groups was halted. Further research is pending to determine optimal dosing.119 Selective, Direct Factor IXa Inhibitors Despite being in an earlier stage in development than direct FXa inhibitors, FIXa inhibitors should possess similar theoretical advantages. TTP-889, is an orally active, direct FIXa inhibitor with a half-life of 20 hours, enabling once-daily dosing. The trial phase II proof-of346

principle study for VTE prevention in hip fracture surgery enrolled 206 patients who received standard in-hospital thromboprophylaxis. Efficacy and safety were compared between patients who were randomized to receive TTP889 vs placebo for 3 weeks or less after discharge.120 The primary efficacy outcome was higher in the TTP-889 group than in the placebo group, suggesting that TTP-889 lacks anticoagulation potential.121 RB006 is a parenteral factor IXa inhibitor and is an RNA aptamer that binds to factor IXa with high affinity.122 The agent was in phase I trials as of 2007123 and produced rapid, dose-dependent anticoagulation measured by aPTT. A potential advantage of this agent is that it may be rapidly neutralized by a complementary oligonucleotide, named RB007. The drug–antidote pair is planned to be studied in cardiopulmonary bypass and in other areas in which rapid reversal may be beneficial.124 New Fibrinolytics and Methods to Improve Endogenous Fibrinolysis Improved understanding has led to new focuses in the development of fibrinolytics as well as methods to possibly enhance endogenous fibrinolysis (Figure 12-2).1 Existing fibrinolytic agents are plasminogen activators such tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). Streptokinase, which is not an enzyme and is instead a protein produced by streptococci, creates plasmin 12 indirectly. Newer licensed plasminogen activators include reteplase (Retavase®), a truncated tPA, and tenecteplase (TNKase™). Both are recombinant forms of tPA and have longer half-lives. Tenecteplase also exhibits enhanced fibrin specificity and resistance to inhibition by plasminogen activator inhibitor-1 (PAI-1).125,126 Both reteplase and tenecteplase can be given by bolus injection because of their longer half-lives, which simplifies administration compared with tPA.127 Fibrinolytics that are undergoing testing include alfimeprase, BB10153, and desmoteplase. 347

348 Tifacogin NAPc2

TF/VIIa X

IX

Indirect Idraparinux Biotinylated idraparinux SR-123781 Direct DX-9065a Otamaxiban PRT 054021 Apixaban Rivaroxaban YM-150 DU-176b LY-517717

IXa

TTP-889 RB006

VIIIa Va Xa Indirect SNAC-Heparin

II

IIa

Direct Flovagatran Pegmusirudin Dabigatran TGN-167

Fibrinogen

Fibrin

TAFIa

Alfimeprase XIII

XIIIa

FXIIIa Inhibitors BB10153

TAFIa Inhibitors

tPA Desmoteplase

Plasminogen Fibrin-tPA Plasmin

X PAI-1

PAI-1 Inhibitors

Fibrin Degradation Products

349

Figure 12-2: New anticoagulant and fibrinolytic therapies. FDP=fibrogen degradation product; PAI-1=plasminogen activator inhibitor-1; SNAC=sodium N-[8(2-hydroxybenzoyl) amino] caprylate; TAFIa=activated thrombin-activatable fibrinolysis inhibitor; tPA=tissue plasminogen activator.

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Classes focused on enhancing endogenous fibrinolysis include inhibitors of activated thrombin-activatable fibrinolysis inhibitor (TAFIa), type 1 PAI-1s, and activated FXIII. Fibrinolytic Agents Alfimeprase is a direct-acting fibrinolytic that has been developed in the hopes of accelerating fibrinolysis. Desmoteplase and BB10153 have been developed because of their enhanced fibrin specificity. Alfimeprase Alfimeprase is a recombinant truncated form of fibrolase that was originally isolated from the venom of the Southern copperhead snake. Alfimeprase directly degrades the α-chain of fibrin and fibrinogen.128 The drug acts independently of the plasminogen content of the thrombus and is not inhibited by PAI-1. Because there is no need for plasmin generation, the agent has the potential to degrade fibrin more rapidly than tPA. Alfimeprase is rapidly inhibited by α2-macroglobulin in circulation, which limits its systemic effects and may reduce the bleeding potential.129 Clinical trials of alfimeprase have focused on catheter-directed lysis of peripheral arterial occlusions and on local delivery to restore flow in indwelling catheters blocked by thrombus to bypass α2macroglobulin in circulation.130 Because efficacy end points were not met, phase III trials were suspended. BB10153 BB10153 is a modified form of plasminogen, with the plasminogen activator cleavage site being replaced with a thrombin cleavage site.131 The agent has a half-life of approximately 4 hours when administered IV.132 In the same way as plasminogen, BB10153 binds to fibrin and is then converted to plasmin by fibrin-bound thrombin. A phase II dose-escalation study with a single-bolus IV included 350

50 patients with STEMI. The agent produced a dose-dependent increase in drug levels, with doses between 5 and 10 mg/kg achieving complete flow for 34% of patients in the affected artery.133 Of the 50 patients, major bleeding occurred in 3 patients, although none of the bleeds were intracranial. Minor bleeding occurred in 6 patients. Studies are ongoing. Desmoteplase Desmoteplase is a recombinant analog of the full-length plasminogen activator that binds to fibrin through its fibronectin fingerlike domain. The agent’s catalytic activity is enhanced in the presence of fibrin.134,135 Because of the theoretical advantages in bleeding, one of the goals of the study was to evaluate if the typical recommended window of 3 hours with tPA in these patients may be extended beyond that time frame.136 To evaluate this potential, patients presenting 3 to 9 hours after onset of stroke symptoms were randomized to one of two doses of desmoteplase or to placebo. The phase III study was stopped after an early interim analysis noted no efficacy in the desmoteplase-treated patients. Methods of Enhancing Endogenous Fibrinolysis Thrombin-Activatable Fibrinolysis Inhibitors In vitro data conclude that TAFIa cleaves carboxy– terminal lysine residues from fibrin and thereby attenuates 12 fibrinolysis.136 Removal of carboxy–terminal lysine residues decreases plasminogen or plasmin binding to fibrin, thereby hindering the lytic process. Initial studies in rabbits and dogs demonstrated that TAFIa inhibitors increased plasminogen activator–induced thrombolysis,137-141 which supports the theory that inhibitors of TAFIa should enhance fibrinolysis. Unfortunately, some studies have noted a paradoxical enhancement of TAFIa activity at low doses.142,143 Small molecule TAFIa inhibitors are being researched,144 but optimal dosing of these agents is an initial concern. 351

Plasminogen Activator Inhibitors–Type I PAI-1 is known to be the principal physiologic inhibitor of the serine proteases, tPA and uPA, which are activators of plasminogen. It is therefore a target to enhance fibrinolytic activity because inhibition of PAI-1 results in increased endogenous fibrinolytic activity. Although some drugs, including biacin and fibrates, have decreased PAI-1 synthesis in vitro,145,146 they are not selective for PAI-1. Some agents in vitro block PAI-1 activity either by converting PAI-1 into its latent conformation or by preventing insertion of the reactive center loop into the body of the inhibitor.147,148 Some experts hypothesize that small-molecule PAI-1 inhibitors may be more successful in promoting fibrinolysis, and certain agents have demonstrated in vivo antithrombotic activity.149 Factor XIIIa Inhibitors Inhibition of FXIIIa is another potential target for fibrinolytic enhancement by increasing the susceptibility of the thrombus to lysis.143 Tridegin and destabilase, two agents isolated from various leeches, appear to enhance fibrinolysis in vitro.150-152 At this point, no human trials have occurred with these agents. In conclusion, the development of new antithrombotics is currently one of the most active areas of pharmaceutical focus and will be for over the next decade, at least. With a wide array of targets on both the arterial and venous side, new agents will soon be available for both the prevention and treatment of thrombotic disease. Many new agents are striving for improved efficacy with similar safety, or improved safety with similar efficacy, as compared to current agents available. The outlook appears promising that in the very near future, we will indeed have improved agents available that may have advantages including the oral route, improved efficacy and safety, less monitoring, and improved pharmacodynamics and pharmacokinetics with a more predictable response. 352

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120. Rothlein R, Shen JM, Naser N, et al: TTP889, a novel orally active partial inhibitor of FIXa inhibits clotting in two A/V shunt models without prolonged bleeding. Blood 2005;106(11):535a536a. 121. Eriksson BI, Quinlan DJ: Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery. Drugs 2006;66(11):1411-1429. 122. Rusconi CP, Scardino E, Layzer J, et al: RNA aptamers as reversible antagonists of coagulation factor IXa. Nature 2002;419: 90-94. 123. Dyke CK, Steinhubl SR, Kleiman NS, et al: First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation 2006;114:2490-2497. 124. Nimjee SM, Keys JR, Pitoc GA, et al: A novel antidotecontrolled anticoagulant reduces thrombin generation and inflammation and improves cardiac function in cardiopulmonary bypass surgery. Mol Ther 2006;14:408-415. 125. Noble S, McTavish D: Reteplase: a review of its pharmacological properties and clinical efficacy in the management of acute myocardial infarction. Drugs 1996;52:589-605. 126. Dunn CJ, Goa KL. Tenetecplase: a review of its pharmacology and therapeutic efficacy in patients with acute myocardial infarction. Am J Cardiovasc Drugs 2001;1:51-66. 127. Llevadot J, Giugliano RP, Antman EM: Bolus fibrinolytic therapy in acute myocardial infarction. JAMA 2001;286:442-449. 128. Deitcher SR, Funk WD, Buchanan J, et al: Alfimeprase: a novel recombinant direct-acting fibrinolytic. Expert Opin Biol Ther 2006;6:1361-1369. 129. Toombs CF: Alfimeprase: pharmacology of a novel fibrinolytic metalloproteinase for thrombolysis. Haemostasis 2001;31:141-147. 130. Moll S, Kenyon P, Bertoli L, et al: Phase II trial of alfimeprase, a novel-acting fibrin degradation agent, for occluded central venous access devices. J Clin Oncol 2006;24:3056-3060. 131. Comer MB, Cackett KS, Gladwell S, et al: Thrombolytic activity of BB-10153, a thrombin-activatable plasminogen. J Thromb Haemost 2005;3:146-153.

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132. Curtis LD, Brown A, Comer MB, et al: Pharmacokinetics and pharmacodynamics of BB-10153, a thrombin-activatable plasminogen, in healthy volunteers. J Thromb Haemost 2005;3:11801186. 133. Gibson CM, Zorkun C, Molhoek P, et al: Dose escalation trial of the efficacy, safety, and pharmacokinetics of a novel fibrinolytic agent, BB-10153, in patients with ST elevation MI: results of the TIMI 31 trial. J Thromb Thrombolysis 2006;22:13-21. 134. Stewart RJ, Fredenburgh JC, Weitz JI: Characterization of the interactions of plasminogen and tissue and vampire bat plasminogen activators with fibrinogen, fibrin, and the complex of D-dimer noncovalently linked to fragment E. J Biol Chem 1998;273: 18292-18299. 135. Mellott MJ, Ramjit DR, Stabilito II, et al: Vampire bat salivary plasminogen activator evokes minimal bleeding relative to tissuetype plasminogen activator as assessed by a rabbit cuticle bleeding time model. Thromb Haemost 1995;73:478-483. 136. Hacke W, Albers G, Al-Rawi Y, et al: The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005;36:66-73. 137. Sakharov DV, Plow EF, Rijken DC: On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. J Biol Chem 1997; 272:14477-14482. 138. Redlitz A, Nicolini FA, Malycky JL, et al: Inducible carboxypeptidase activity: a role in clot lysis in vivo. Circulation 1996;93: 1328-1330. 139. Klement P, Liao P, Bajzar L: A novel approach to arterial thrombolysis. Blood 1999;94:2735-2743. 140. Nagashima M, Werner M, Wang M, et al: An inhibitor of activated thrombin-activatable fibrinolysis inhibitor potentiates tissue-type plasminogen activator-induced thrombolysis in a rabbit jugular vein thrombolysis model. Thromb Res 2000;98:333-342. 141. Guimarães AH, Barrett-Bergshoeff MM, Criscuoli M, et al: Fibrinolytic efficacy of Amediplase, Tenecteplase and scu-PA in different external plasma clot lysis models: sensitivity to the inhibitory action of thrombin activatable fibrinolysis inhibitor (TAFI). Thromb Haemost 2006;96:325-330.

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142. Schneider M, Nesheim M: Reversible inhibitors of TAFIa can both promote and inhibit fibrinolysis. J Thromb Haemost 2003; 1:147-154. 143. Walker J, Hughes B, James I, et al: Stabilization versus inhibition of TAFIa by competitive inhibitors in vitro. J Biol Chem 2003;278:8913-8921. 144. Islam I, Bryant J, May K, et al: 3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa). Bioorg Med Chem Lett 2007;17:1349-1354. 145. Fujii S, Sawa H, Sobel BE: Inhibition of endothelial cell expression of plasminogen activator inhibitor type-1 by gemfibrozil. Thromb Haemost 1993;70:642-647. 146. Brown SL, Sobel BE, Fujii S: Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin: a potential link between lipid lowering and fibrinolysis. Circulation 1995;92:767-772. 147. Kvassman J, Lawrence D, Shore J: The acid stabilization of plasminogen activator inhibitor-1 depends on protonation of a single group that affects loop insertion into beta-sheet A. J Biol Chem 1995; 270:27942-27947. 148. Eitzman DT, Fay WP, Lawrence DA, et al: Peptidemediated inactivation of recombinant and platelet plasminogen activator inhibitor-1 in vitro. J Clin Invest 1995;95:2416-2420. 149. Friederich P, Levi M, Biemond B, et al: Low-molecular-weight inhibitor of PAI-1 (XR5118) promotes endogenous fibrinolysis and reduces postthrombolysis thrombus growth in rabbits. Circulation 1997;96:916-921. 150. Seale L, Finney S, Sawyer RT, et al: Tridegin, a novel peptidic inhibitor of factor XIIIa from the leech, Haementeria ghilianii, enhances fibrinolysis in vitro. Thromb Haemost 1997;77:959-963. 151. Finney S, Seale L, Sawyer RT, et al: Tridegin, a new peptidic inhibitor of factor XIIIa, from the blood-sucking leech Haementeria ghilianii. Biochem J 1997;324:797-805. 152. Baskova IP, Nikonov GI: Destabilase, the novel epsilon(gamma-Glu)-Lys isopeptidase with thrombolytic activity. Blood Coagul Fibrinolysis 1991;2:167-172.

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Chapter 13

Frequently Asked Questions in Antithrombotic Management Alpesh N. Amin, Steven B. Deitelzweig

1. What is the incidence of appropriate venous thromboembolism (VTE) prevention in hospitalized patients? The incidence ranges between 10% and 50%, depending on the type of patient compared with national guideline recommendations. This shows that there is a significant opportunity for implementing processes to improve the prevention of VTE in hospitalized patients. VTE may be one of the most preventable causes of death in hospitalized patients. The use of anticoagulants plays an important role in preventing VTE. 2. What are the options for deep vein thrombosis (DVT) prevention in the hospital? Options include pharmacologic and nonpharmacologic alternatives. Nonpharmacologic options such as sequential prevention devices have limited data supporting their use 13 outside of select surgical settings. Pharmacologic options include unfractionated heparin (UFH), low-molecularweight heparin (LMWH), and fondaparinux (Arixtra®). Current guidelines suggest that the quality of the evidence supporting these options varies, and choices must be individualized. The American College of Chest Physicians’ 8th edition of its guidelines gives recommendations for the 367

use of UFH, LMWH, and fondaparinux in the prevention of DVT in medical at-risk patients. Recent meta-analyses suggest that LMWH may offer advantages over UFH. Desirudin (Iprivask®) is indicated for the prophylaxis of DVT in patients undergoing elective hip replacement surgery. 3. Describe the immunogenicity difference between lepirudin and desirudin? The immunogenicity of lepirudin is high, whereas desirudin is a weak allergen, even after repeated exposure. The incidence of skin reactions with desirudin in 263 healthy volunteers was found to be about 0.5%. No anaphylaxis or immune reactions were associated with desirudin in the TIMI 9B and GUSTO IIB studies (which included more than 7,500 patients exposed for 2-3 days). Only 2 reports of anaphylactic or anaphylactoid reactions were reported in 19,000 patients (0.01%) in the Aventis desirudin pharmacovigilance database.. 4. What organizations are advocating for the prevention of VTE? In the past few years, a number of professional organizations have been advocating for the appropriate prevention of VTE as a standard of practice in at-risk hospitalized patients. These organizations include the Society of Hospital Medicine (SHM), the American College of Chest Physicians (ACCP), the American Society of Hematology (ASH), the American Society of Health-System Pharmacists (ASHP), the American Nurses Association (ANA), and the Case Management Society of America (CMSA). Governmental and private organizations advocating for the appropriate prevention of VTE include The Joint Commission, The Leapfrog Group, the National Quality Forum, the Agency for Healthcare Research and Quality, the Surgical Care Improvement Project, and the Surgeon General’s office. 368

5. What are the common risk factors for VTE? Table 13-1 lists the common risk factors for VTE. 6. What are the Wells criteria? Wells clinical prediction rule is a validated tool for assessing the likelihood of DVT in a patient. Based on the scoring system, a patient’s likelihood of having DVT can be determined to be low, intermediate, or high (Table 13-2). 7. What tools are available to determine the pretest probability for PE? Several commonly used scoring systems exist, and it is important to realize that neither a ventilation/perfusion (V/Q) scan nor computed tomography (CT) pulmonary angiography can be interpreted without determining the pretest probability. The scoring tool that is the easiest to use is the Wells score, which assigns points based on clinical history and presentation (Table 13-3). 8. What is the evidence regarding the role for CT angiography in the diagnosis of PE? Large observational trials and randomized, controlled trials have now established CT scanning as an alternative to V/Q scans for diagnosing PE. The positive predictive value of a CT scan is high, and patients managed via either CT or V/Q have similar outcomes. 9. If recombinant tissue-type plasminogen activator (rtPA) is to be used in the setting of an acute ischemic stroke, it should be given no more than how many 13 hours after the onset of symptoms? The drug must be given within 3 hours from the onset of symptoms, which means that the patient must generally arrive at a properly equipped and organized hospital within 2 hours of symptom onset to have the necessary evaluations. In all cases, strict protocol needs to be closely followed, and patients must be carefully selected (Table 7-7). 369

Table 13-1: Common Risk Factors for Venous Thromboembolism Inherited Risk Factors Antithrombin III deficiency Dysfibrinogenemia Protein C deficiency Protein S deficiency Factor V Leiden Prothrombin 20210A Acquired Risk Factors Trauma (major or lower extremity) Surgery Immobility or paresis Malignancy Cancer therapy (hormonal, chemotherapy or radiotherapy) Previous VTE

VTE=venous thromboembolism

10. A 70-year-old woman with a history of a transient ischemic attack (TIA) and well-controlled diabetes is admitted for cellulitis of the left leg. On examination, she is noted to have an irregular pulse. An electrocardiogram confirms atrial fibrillation with a rate of 80 beats per minute. She is otherwise healthy and plays tennis three times a week. She had 370

Acquired Risk Factors (continued) Increasing age (older than 65 years) Pregnancy and postpartum state Hormone replacement therapy or estrogen-containing oral contraception Acute medical illness Heart or respiratory failure Inflammatory bowel disease Nephrotic syndrome Myeloproliferative disorders Paroxysmal nocturnal hemoglobinuria Obesity Tobacco use Varicose veins Central venous catheterization Acquired hypercoagulable states (antiphospholipid syndrome)

13 a stress test 1 year earlier that showed no evidence of ischemia. Should she be started on warfarin? Yes. Based on her CHADS2 (congestive heart failure, hypertension, age >75 years, diabetes, prior stroke or TIA) score of 3 (1 point for diabetes and 2 points for her history of a TIA), she is at moderate risk of having another embolic event. In addition, she does not seem have 371

Table 13-2: Pretest Probability of Deep Vein Thrombosis Using Wells Criteria Clinical Feature

Score

Active cancer (treatment ongoing or within the previous 6 mo or palliative)

1

Paralysis, paresis, or recent plaster immobilization of the lower extremities

1

Recently bedridden for more than 3 d or major surgery within 4 wk

1

Localized tenderness along the distribution of the deep venous system

1

Entire leg swollen

1

Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured below the tibial tuberosity)

1

Pitting edema (greater in the symptomatic leg)

1

Collateral superficial veins (nonvaricose)

1

Alternative diagnosis as likely or more likely than that of DVT

–2

Probability High probability: ≥3 Moderate probability: 1-2 Low probability: ≤0 DVT=deep vein thrombosis

372

Table 13-3: Modified Wells Criteria: Clinical Assessment for Pulmonary Embolism Clinical Feature

Score

Clinical symptoms of DVT

3

Other diagnosis less likely than pulmonary embolism

3

Heart rate >100 bpm

1

Immobilization or surgery in the previous 4 wk

1

Previous DVT or PE

1

Hemoptysis

1

Malignancy

1

Probability

Score

High:

>6

Moderate:

2-6

Low:

<2

13

DVT=deep vein thrombosis; PE=pulmonary embolism

373

a significant fall risk, making chronic warfarin therapy appropriate. 11. A 64-year-old man with a history of coronary artery disease (CAD) presents to the emergency department with abdominal pain. CT of the abdomen shows a mass in the descending colon. A drug-eluting stent (DES) was placed in his left anterior descending coronary (LAD) artery 2 months earlier for unstable angina. The gastroenterologist wants to perform a colonoscopy and states that he cannot perform a biopsy of the mass while the patient is taking aspirin and clopidogrel. He asks you to hold both agents for 5 days, and then he will then perform the procedure. What do you recommend? The duration of aspirin and clopidogrel therapy after a DES is placed is 1 year. When dual antiplatelet therapy is interrupted before 1 year, there is a risk of stent thrombosis, which has up to a 50% mortality. In difficult scenarios such as this, one option is to continue aspirin and hold the clopidogrel starting approximately 5 days before procedure. At 3 days before the biopsy, one could initiate a short-acting IV 2b3a antagonist and hold it 12 hours before the biopsy. The clopidogrel or 2b3a antagonist can then be restarted shortly after the biopsy. If the mass is a malignancy that requires surgery, the same approach can be taken. The most important concept here is to limit the amount of time that the patient’s DES is ‘unprotected.’ 12. How long does it take warfarin to reach its optimum affect? Warfarin takes 4 to 7 days to reach its optimal affect. Protein C has a very short half-life, so it is depleted quickly. Factors VII and IX have shorter half-lives, and increases in the International Normalized Ratio in the first 2 to 3 days are a reflection of the depletion of these factors. Factor II has a 50-hour half-life, so an optimal effect does not occur for 4 to 7 days. 374

13. What monitoring parameters should be used for heparin therapy? An activated partial thromboplastin time (aPTT) should be obtained 6 hours after the initial infusion and after each heparin dose adjustment until the target range is obtained with two consecutive samples. After two consecutive aPTTs are within the target range, the aPTT should be obtained daily thereafter. A complete blood count with platelets should be done every day for 2 days and then every other day while the patient is on the heparin infusion. A stool guaiac test should be done while the patient is taking heparin if a GI bleed is suspected. The patient should be inspected daily for bleeding. 14. Is it necessary to monitor anti-Xa levels for LMWHs? No. Regular monitoring is not needed. If it is possible to measure anti-Xa levels, some conditions in which it might be appropriate are in obese patients or renal insufficient patients taking LMWH. 15. Is heparin dosed the same for children as it is for adults? No. The dose per kilogram requirement for children is often higher than for adults, especially in neonates. Dosing requirements approach adult norms in teenagers. 16. Is LMWH an option in children? Yes. Although the data are still relatively limited compared 13 with those seen in adults, LMWH appears to be an effective alternative to UF and warfarin in pediatric patients. 17. Is thrombolytic therapy safe in children? In general, yes. Relative contraindications similar to those present in adults exist, and thrombolytic therapy is generally reserved for life- or organ-threatening throm375

boembolic events. Although minor bleeding is common, intracranial bleeding is surprisingly uncommon except in premature infants. 18. Which oral direct thrombin inhibitor is in the most advanced stages of development and expected to be on the market soonest? a. Draparinux b. Dabigatran c. Ximelagatran d. TGN-167 The answer is b. Dabigatran, an oral direct thrombin inhibitor, is in phase III trials. Ximelagatran has been withdrawn from the world market. Idraparinux and TGN-167 are not oral direct thrombin inhibitors. 19. Why does alfimeprase have the potential to degrade fibrin faster than tPA? a. It is rapidly inhibited by α2-macroglobulin. b. It has enhanced fibrin specificity for the fibrin–tPA complex. c. There is no need for generation of plasmin. d. It inhibits factor XIIIa. The answer is c. Alfimeprase directly degrades fibrin and fibrinogen and is not dependent on plasminogen or plasmin; therefore, it degrades fibrin faster than tPA, which requires plasmin for fibrin degradation. 20. Why is activation of prasugrel into its active metabolite, R-138727, more efficient than that of clopidogrel? a. Conversion to R-138727 through the cytochrome P-450 system involves multiple oxidative steps. b. Hepatic conversion to R-138727 involves a single-step oxidation. c. After absorption, esterases convert the drug into an inactive metabolite. d. Hepatic conversion is not necessary to convert it into its active metabolite. 376

The answer is b. Whereas clopidogrel is activated through the CYP system in multiple oxidative steps, hepatic conversion of prasugrel involves only a single-step oxidation, making prasugrel more efficient. 21. What is the length of therapy of anticoagulants in the treatment of patients with VTE? The duration of anticoagulant therapy varies. • Patients with the identifiable transient risk factors: 3 months • Patients with the first episode of idiopathic VTE: 6 to 12 months • Patients with recurrent idiopathic VTE: Lifelong • Patients with inherited or acquired thrombophilia in the setting of a DVT or at high risk for DVT development: Lifelong 22. Are all cancer patients at increased risk for developing VTE? Malignancy, in general, is a major risk factor for VTE. Cancer patients have a 2- to 7-fold increased risk of VTE compared to patients without cancer. However, some subgroups of cancer patients with risk factors such as those with particular types of cancer (gastrointestinal, lung, brain, genitourinary, lymphoma), advanced stage, older age, obesity, medical comorbidities, and those receiving chemotherapy and other treatments are at particularly high risk for VTE. Novel risk factors for VTE that have recently been identified include elevated platelet and leukocyte counts, tissue factor, and soluble P-selectin levels. 13 23. Should cancer patients receive prophylactic anticoagulation? All hospitalized cancer patients should receive prophylactic anticoagulation in the absence of contraindications. This recommendation is strongly supported by expert panel guidelines from ACCP, NCCN, and ASCO, and by random377

ized studies and meta-analyses. Unfractionated heparin, LMWHs, and fondaparinux are acceptable options. There is currently insufficient evidence to recommend prophylaxis in cancer outpatients, but studies are underway to evaluate this further. 24. How should cancer patients with a new diagnosis of venous thromboembolism be treated? Randomized studies have clearly shown improved outcomes with the use of LMWH compared to unfractionated heparin and warfarin in both the initial and long-term treatment of VTE in cancer patients. Current guidelines recommend that patients should be treated for at least 6 months with LMWHs, but in patients with active cancer and persistent risk factors, a longer duration of treatment may be considered. Mechanical filters should only be considered in patients with contraindications to anticoagulation or with failure of LMWH anticoagulation.

378

Index A abciximab (ReoPro®) 170, 171, 173, 186, 316 abdominal infections 66 abdominal surgery 18, 280282, 285, 337 abscess 75 acetaminophen 272 acidosis 69 Activase® 125, 179 activated clotting time (ACT) 229 activated partial thromboplastin time (aPTT) 19, 32, 121, 152, 157, 158, 172, 174, 181, 201, 203, 229, 232, 239, 241, 245, 246, 252, 269, 274, 277-279, 287, 333, 341, 343, 347, 375 aPTT monitoring 158 aPTT prolongation 19 Acute Catherization and Urgent Intervention Triage Strategy (ACUITY) Trial 8, 176 acute coronary syndromes (ACS) 7-9, 165, 166, 175, 186, 191, 214, 217, 274, 275, 321, 322, 325, 326, 342 guidelines 7, 201 adenosine diphosphate (ADP) 168, 169, 316, 317, 319, 321, 322 adenosine triphosphate (ATP) 316, 321 ADVANCE-1 342 aerobic exercise 41

Agency for Healthcare Research and Quality 8, 368 Aggrastat® 170 air plethysmography (APG) 41 alanine aminotransferase 332 alanine transaminase 341 alcohol 271-273 alfimeprase 347, 349, 350, 376 alteplase (Activase®) 125, 179, 187 Alzheimer’s disease 325 American Academy of Family Physicians 38, 127 American Academy of Orthopedic Surgeons (AAOS) 141 American College of Cardiology (ACC) 175, 205 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines 7, 8, 177, 189, 194, 196, 198 2007 ACC/AHA Focused Update to the 2004 Guidelines for the Management of STEMI 8 recommendations 205 American College of Chest Physicians (ACCP) 9, 10, 92, 125, 141, 147, 149, 153, 204, 216, 238, 272, 275, 301, 303, 367, 368, 377 Clinical Practice Guidelines 13, 18 American College of Physicians 38, 127, 128

379

American Heart Association (AHA) 175, 205 American Heart Association (AHA)/American Academy of Neurology guidelines 193 American Nurses Association (ANA) 368 American Society of Clinical Oncology (ASCO) 301, 303, 306, 377 American Society of HealthSystem Pharmacists (ASHP) 368 American Society of Hematology (ASH) 368 amiodarone 270, 272 amnesia 211 ampicillin/sulbactam 75 amputation 223, 226, 228, 231, 232 anabolic steroids 272 anaphylaxis 33, 223 Ancylostoma caninum 334 anemia 65 aneurysm 193 angina 165, 275, 280, 281, 284, 285, 334, 374 angiography 65, 67, 72, 115120, 126, 325, 369 Angiomax® 176, 228, 329 angioplasty 71, 176 anistreplase 181 antacids 271, 273 antiangiogenic agents 295, 296 antibiotics 245, 246, 270 anticardiolipin antibodies 60 anticoagulants 8, 10, 17, 24, 32-34, 36, 37, 121, 122, 125, 127, 140-142, 144, 146, 149, 153-155, 157-159, 172, 174, 176, 193, 194, 196, 197, 199,

380

anticoagulants (continued) 203, 204, 210, 211, 213, 222, 237, 242, 245, 250, 261, 262, 269, 274, 276, 301, 302, 306, 314, 315, 325-330, 333-338, 341, 349, 377 anticoagulation 9, 13, 16, 19, 23, 24, 32, 33, 36-38, 41, 46, 52-55, 57-59, 64-70, 72-75, 77, 111, 114, 116, 121, 123, 124, 128, 129, 150, 152, 153, 156, 165, 166, 172, 174, 176, 177, 182-184, 186, 188-190, 192-198, 200, 201, 204, 205, 222, 244-249, 255, 260, 262, 263, 269, 282, 290, 301-303, 327, 330, 347, 378 anticonvulsants 245 antiphospholipid syndrome 48, 65, 67, 72, 124, 371 antiplatelet agents 9, 249, 251, 316, 319 antiplatelet therapy 33, 165, 166, 169, 374 antithrombin (AT) 15, 17, 34, 35, 38, 94, 176, 182, 269, 336, 338, 345 antithrombin III 48, 168, 169 antithrombin III deficiency 370 antithrombotics 8, 9, 32, 141, 143, 144, 165, 192, 194-196, 213, 238, 249, 314, 315, 327, 334, 337, 338, 342, 345, 352, 367 anxiety 293 aortic occlusion 220 apixaban 315, 341, 349 appendicitis 76 argatroban (Argatroban® IV) 10, 176, 210, 222, 226-228, 230-232, 244-246, 326, 329 Arixtra® 17, 35, 121, 141, 175, 211, 298, 315, 336, 367

Arixtra for Thromboembolism Prevention in Medical Indications Study (ARTEMIS) 299, 300 arrhythmias 165, 182, 183 arteriotomy 37 arteriovenous malformation 180 ascites 67, 69 aspartate transaminase 341 asphyxia 252 aspirin 141, 144, 155, 166-169, 177, 186-188, 192, 195, 197, 200, 201, 204-206, 249, 250, 272, 280, 283, 285, 316, 322, 323, 325, 332, 374 atelectasis 106, 108 atenolol 270, 273 atherosclerosis 322 atherosclerotic disease 141 atrial fibrillation (AF) 165, 182, 183, 185, 188-199, 205, 232, 260, 314, 332, 339 atrial flutter 165, 182, 183, 195 atrophie blanche 39 avidin 338, 339 avocado 271, 273 azathioprine 273 AZD6140 321-323

bivalirudin (Angiomax®) 8, 168, 176, 182, 187, 210, 222, 228, 229, 244, 325, 329 bleeding 10, 16, 19, 20, 22-24, 32-34, 54, 59, 68, 121, 122, 124, 125, 127-129, 141, 142, 144, 146, 154, 157, 167, 172, 175-177, 180-182, 194-198, 200, 203, 206, 211, 217, 223, 228, 232, 243, 245, 247, 248, 250-253, 269, 276, 277, 280, 283, 291, 300, 302, 315, 316, 320-323, 325, 327, 331, 335, 336, 338, 340-343, 345, 346, 350, 351, 375, 376 intracranial bleeding 193, 376 bleeding diathesis 180 body mass index 294, 297 bradycardia 322 brain natriuretic peptide (BNP) 120, 123 breast-feeding 156 breast milk 156, 245 bronchospasm 323 Budd-Chiari syndrome 69, 70 Buerger’s disease 60 bumetanide 270, 273

B

C

β-blockers 68, 183 bacteremia 73, 75, 76 barbiturates 271, 273 bare metal stent (BMS) 169, 197, 198 bariatric surgery 149 BB10153 347, 349, 350 Behçet’s disease 70 benzyl alcohol 282, 283 bevacizumab 296 biliary malignancy 66 biliopancreatic diversion 149

C-reactive protein 295, 296 C-serotonin release assay (SRA) 218, 226 calcium channel blockers (CCBs) 183 cancer 9, 13, 14, 20, 23, 50, 51, 56, 57, 59, 68, 72, 106, 112, 152, 291, 293, 294, 298-303, 305, 370, 372, 377 ovarian 296 pancreatic 296

381

Cancer-associated Therapies: New Considerations in the Treatment and Prevention of Recurrent Venous Thromboembolism (CANTHANOX) study 305 cangrelor 316, 317, 319, 321 carbamazepine 271, 273 carbapenems 75, 76 cardiac arrest 95 cardiac tamponade 55, 128 cardiogenic shock 128 cardiomegaly 108 cardiopulmonary bypass (CPB) 128, 240, 241, 347 cardiopulmonary disease 95, 109 cardiopulmonary resuscitation 180 cardiovascular death 169, 170, 200, 320 Case Management Society of America (CMSA) 368 catheter infection 47 CEAP score 39-41 cefamandole 272 cefazolin 272 ceftriaxone 77 cellulitis 61, 370 Center for Medicare and Medicaid Services 8, 12 central venous catheters 23, 55 cerebral hemorrhage 66 cerebrovascular disease (CVD) 165, 190 cesarean section 158 CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke) score 188, 189, 191 chemosis 77

382

chemotherapy 50, 290, 291, 295, 296 chest pain 50, 105-107, 322 chloridiazepoxide 271, 273 cholestyramine 270, 273 chronic obstructive pulmonary disease 23 chronic thromboembolic pulmonary hypertension (CTEPH) 92, 121 chronic venous insufficiency (CVI) 28, 38, 39, 41 cimetidine 271, 272 ciprofloxacin 272 cirrhosis 66, 68, 71 clofibrate 270, 272 clopidogrel (Plavix®) 8, 166, 167, 169, 170, 177, 186, 187, 197, 206, 250, 251, 317, 320-323, 325, 374, 376, 377 Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) 177 Clopidogrel as Adjunctive Reperfusion Therapy– Thrombolysis in Myocardial Infarction (CLARITY-TIMI 28) 177 Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial 167, 169 clot 231 clot formation 335 clotting factors 261, 263, 269 coagulation 328, 335 coagulation disorders 287 coagulopathy 22 colonoscopy 293, 374 coma 65 community-acquired pneumonia 335

Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism (CLOT) trial 57, 303, 305 compression devices 300 compression garments 41 compression therapy 41 computed tomography (CT) 31, 52, 65, 67, 69, 72, 75-77, 111, 116-118, 193, 203, 291, 293, 369, 374 computed tomography pulmonary angiography (CTPA) 111, 114-118 congenital heart disease 237, 251, 253, 254 congestive heart failure (CHF) 20, 23, 39, 265, 269, 323, 371 contrast venography 30, 31 coronary artery bypass graft (CABG) surgery 167, 169, 182, 186, 213 coronary artery disease (CAD) 166, 195, 198, 323, 374 cotrimoxazole 270, 272 cough 50, 107 Coumadin® 18, 32, 53, 261 cyanosis 50, 106, 107, 254 cyclosporine 273

D D-dimer 106, 108-110, 114, 117, 252, 295, 296 testing 52 dabigatran (Pradaxa®) 232, 315, 331-333, 349, 376 dalteparin (Fragmin®) 18, 21, 153, 156, 280, 281, 298, 299, 303, 304 danaparoid (Orgaran®) 155, 244

death 231, 232 deep vein thrombosis (DVT) 9, 10, 12, 13, 15, 17-23, 28-31, 35-38, 41, 47, 50, 60-62, 64, 93, 106, 107, 112, 113, 125, 129, 148, 152, 154, 158, 211, 213, 218, 220, 232, 238, 243, 255, 260, 264, 280-286, 290, 292, 298, 303, 306, 314, 331, 334, 337-340, 342, 344-346, 368, 372, 373 DVT prophylaxis 16, 17, 19, 176, 261, 284, 286, 287, 329, 368 upper extremity DVT (UEDVT) 47, 50-60 dehydration 65, 72 demyelinating processes 191 desirudin (Iprivask®) 16, 19, 21, 24, 141-143, 145-147, 155, 156, 176, 231, 232, 261, 286, 287, 329, 368 desmoteplase 347, 349, 351 destabilase 352 dextropropoxyphene 272 diabetes 116, 172, 188, 194, 195, 199, 200, 371 dialysis 330 diarrhea 69, 76, 265 diathesis 274 diclofenac 63 dicloxacillin 273 diflunisal 270, 273 digoxin 183 diltiazem 273 diplopia 65 dipyridamole 206, 251 direct thrombin inhibitor (DTI) 9, 10, 16, 19, 36, 146, 187, 210, 222, 228, 230, 326, 329, 330, 376 subcutaneous administration 329

383

disopyramide 272 disulfiram 272 diverticulitis 48, 76 dizziness 322 Dose Confirmation Study Assessing Antiplatelet Effects of AZD6140 vs Clopidogrel in non–ST segment-elevation MI (DISPERSE 2) 322 draparinux 376 drug-eluting stent (DES) 8, 169, 197, 198 DU-176b 315, 345 DX-9065 340 dysfibrinogenemia 94, 370 dyspepsia 322 dysphasia 65 dyspnea 50, 105-107, 322

E E5555 324 echocardiogram 119, 184, 188 echocardiography 105, 120, 123, 127 edema 28, 29, 40, 41, 50, 52, 56, 64, 69, 113, 372 electrocardiogram 123, 370 electrocardiography 119, 166 electronic alerts 8, 29 embolectomy 123, 127, 128 embolism 37, 99, 103, 106, 183, 188, 194, 196, 201 embryopathy 248 end-stage renal disease (ESRD) 330 endocarditis 193 enoxacin 270, 273 enoxaparin (Lovenox®) 18, 19, 21, 34, 64, 142, 149, 153, 156, 174-176, 182, 189, 242244, 282-284, 286, 298-300, 303, 328, 331-333, 340-346

384

Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction (ExTRACT-TIMI 25) trial 182 enzyme-linked immunosorbent assay (ELISA) 106, 115, 117, 218, 221, 222, 226, 227 epinephrine 168 eptifibatide (Integrilin®) 170, 171, 186 erythema 29, 50, 56, 60, 61 erythromycin 270, 272 erythropoiesis 14 erythropoiesis-stimulating agents 295 esophageal varices 67 etretinate 273 exercise 47 Extended Clinical Prophylaxis in Acutely Ill Medical Patients (EXCLAIM) 300

F Factor anti-FA 242, 244 anti-factor Xa (anti-FXa) 16, 34, 35, 155, 174, 181, 239 anti-Xa 17, 32, 34, 35, 122, 149, 153, 155, 156, 158, 204, 274, 277-279, 375 coagulation factors 328 factor IIa 18 factor IIa/Xa inhibitor 329 factor IIB 169 factor IX 33, 374 factor IXa 18, 335 factor IXa inhibitor 346, 347

Factor (continued) factor VII 33, 374 factor VIII 157 factor VIIIa 335, 336 factor V leiden 48, 50, 67, 70, 72, 94, 370 factor X 33, 169, 327 factor Xa 18, 24, 35, 168, 169, 172, 335, 336, 338340, 345 factor Xa inhibitor 10, 31, 35, 300, 315, 328, 336, 337, 340-342, 345, 346 factor XIa 18, 168 factor XIIa 18 factor XIII 350 factor XIIIa 376 factor XIIIa inhibitor 349, 352 FIX 328 FV 328 FVIII 328 tissue factor VIIa (TF–FVIIa) 315, 327, 333, 334 tissue factor VIIa complex inhibitors 333, 335 famotidine 271, 273 febrile illnesses 265 felodipine 270, 273 fever 67, 72, 74-77, 265 fibrin 283, 314, 347, 349-351, 376 fibrinogen 157, 168, 184, 376 fibrinolysis 8, 19, 58, 106, 328, 329, 347, 351 fibrinolytics 9, 126, 184, 283, 315, 347 Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial 175 fish allergies 240

flovagatran 329, 349 fluconazole 270, 272 5-fluorouracil 56, 272 fluoxetine 271, 273 fondaparinux (Arixtra®) 9, 1618, 21, 23, 24, 31, 35, 121, 122, 124-126, 141, 142, 144, 146, 148, 150-152, 155, 175, 187, 211, 298-300, 302, 315, 326, 336-338, 367, 368, 378 Food and Drug Administration (FDA) 17, 35, 121, 192, 232, 280, 282, 331, 337 Fragmin® 18, 35, 280, 298 Fraxiparine® 34 fresh-frozen plasma (FFP) 247, 251-253 Fusobacterium necrophorum 74

G gangrene 241 gastric banding 149 gastric ulcers 76, 250 gastric varices 67 gastritis 250 gastroplasty 149 gemfibrozil 272 glycoprotein (GP) IIb/IIIa 187 glycoprotein (GP) IIb/IIIa inhibition 172 glycoprotein (GP) IIb/IIIa inhibitors 166, 168-170, 176, 186 graduated compression stockings (GCS) 19-21, 23, 51, 63, 150, 151, 300 griseofulvin 270, 273 GUSTO IIB study 368

H headache 65, 77, 322 heart disease 98, 238

385

heart failure (HF) 92, 94, 158, 188, 194, 195, 198 hematoma 142, 144 spinal 280 hematuria 72 hemiparesis 65 hemiplegia 94 hemodialysis 47, 116, 214, 330 hemoglobinuria 14, 371 hemoptysis 106, 107, 112, 113, 373 hemorrhage 33, 34, 36, 37, 67, 103, 106, 172, 192, 193, 202, 251, 252, 298 intracranial 37, 253 retroperitoneal 37 hemorrhagic infarction 218, 220 heparin 10, 17, 19, 21, 32, 35, 46, 53, 57, 63, 65, 67-70, 72, 121, 125, 126, 157, 167, 172, 174, 180, 183, 186, 189, 193, 196, 203, 204, 210, 211, 213-216, 218, 220, 224, 225, 231, 239, 242, 252, 261, 262, 272, 274-278, 316, 325, 328, 330, 335, 338-340, 375 heparin-induced thrombocytopenia (HIT) 9, 10, 17, 33, 34, 36, 46, 48, 57, 59, 63, 122, 124, 148, 155, 172, 174, 182, 187, 210-222, 224, 226, 228, 230-232, 240-242, 244, 277, 282, 326, 329, 337, 339 heparinoids 10, 36, 222 hepatic abnormalities 332 hepatic dysfunction 41, 265 hepatic failure 71 hepatobiliary cancer 66 hepatomegaly 69

386

himbacine 325 hip arthroplasty 15, 18, 213, 329, 343, 345 total hip arthroplasty (THR) 18, 19, 21, 280-282, 286, 342, 343, 345 hip fracture surgery 18, 140-142, 147, 337, 347 hip replacement surgery 140-142, 146, 147 hirudin (Refludan®) 10, 19, 222, 287, 330 histamine 94 Homan’s sign 29 hormone replacement therapy 14, 49, 62, 67, 98, 371 hospitalists 7-11, 38, 140, 165, 177 hydrocephalus 64 hyperamylasemia 69 hypercoagulability 33, 67 hyperhomocysteinemia 48, 67 hyperphosphatemia 69 hyperpigmentation 40 Hypertension 13, 181, 188, 193-195, 199, 200, 252, 274, 371 intracranial hypertension 64 malignant hypertension 34, 37 pulmonary hypertension 105, 120, 314 hyperthyroidism 265 hyperuricemia 322 hypokinesis 95, 120 hypopigmentation 39 hypotension 33, 102, 126, 184, 322 hypothyroidism 265 hypoxemia 99, 101, 106 hysterectomy 158

I ibuprofen 273 idraparinux 315, 337-339, 349 immobility 13, 14, 20, 23, 24, 49, 50, 60-62, 99, 295, 370 immobilization 112, 158, 372, 373 indomethacin 272 inferior vena cava (IVC) filters 37, 38, 128, 129, 254 placement 37 inflammation 66, 69 inflammatory bowel disease 14, 20, 48, 65, 70, 371 influenza 250 influenza vaccine 272 Innohep® 35, 303 insomnia 322 Institute of Safe Medical Practice 260 insulin 240 Integrilin® 170 intermittent pneumatic compression (IPC) 19-21, 23, 150, 151 International Normalized Ratio (INR) 17, 33, 53, 124, 125, 142-144, 146, 180, 181, 183, 184, 188, 194-198, 201, 203, 230, 245-249, 261, 262, 264268, 276, 303, 305, 331, 332, 338, 341, 344, 374 intestinal infarction 69 intracranial hemorrhage (ICH) 179, 180, 187, 192, 202, 203 intracranial neoplasm 34 iphosphamide 272 Iprivask® 19, 176, 231, 286, 329, 368 irritable bowel disease 98 ischemia 22, 51, 69, 102, 175, 176, 322, 371 retinal ischemia 206

ischemic stroke 196, 314 isoniazid 270, 272 itraconazole 272

J jaundice 69, 76 Joint Commission, The 8, 12, 260-263, 368 Joint Utilization of Medications to Block Platelets Optimally Thrombolysis in Myocardial Infarction trial (JUMBO TIMI-26) 320

K Kaplan-Meier analysis 173 Kawasaki’s disease 250 ketoconazole 273 ketoprofen 273 ketorolac 270, 273 knee arthroplasty 15, 213, 339, 340 total knee arthroplasty (TKR) 282, 284, 285, 331, 333, 334, 337, 340, 342, 344, 346 knee replacement surgery 140142, 147

L Leapfrog Group, The 368 left bundle branch block 187 left ventricular dysfunction 199 Lemierre’s syndrome 74 lenalidomide 296 lepirudin (Refludan®) 176, 210, 222, 223, 227, 228, 244, 326, 329 leukocytosis 69 levofloxacin 76 Limb edema 39

387

Limb (continued) gangrene 210, 212, 213, 218, 314 pain 28, 29, 113 lipedema 39 lipodermatosclerosis 39, 40 Liver disease 274 failure 269 toxicity 331 lovastatin 272 Lovenox® (enoxaparin) 18, 34, 149, 174, 242, 282, 284, 298 low-dose unfractionated heparin (LDUH) 15-17, 21-23 low-molecular-weight heparin (LMWH) 9, 10, 16-19, 21-24, 31, 34, 35, 38, 46, 53, 57, 59, 63, 64, 66, 121, 122, 125, 126, 128, 141, 143-151, 153-157, 168, 169, 174, 176, 181-183, 197, 198, 204, 210, 211, 213, 216, 217, 221, 222, 238, 242-245, 247, 261, 262, 277, 280, 297, 300, 302, 305, 306, 315, 326, 327, 335, 336, 339, 345, 367, 368, 375, 378 lung parenchymal disease 111 lupus erythematosus 65 LY-517717 346 lymphadenopathy 74 lymphedema 39 lysis 38, 192

M magnetic resonance imaging (MRI) 31, 52, 65, 67, 70, 72, 75-77, 115, 117, 118 malignancy 29, 47, 49, 50, 59, 60, 62, 63, 65, 68, 70, 72, 76, 94, 98, 113, 125, 265, 290, 291, 293, 370, 373, 374, 377

388

malnutrition 265 mannitol (Osmitrol®) 66 melagatran 329 meningitis 65, 191 methicillin-resistant Staphylococcus aureus (MRSA) 74, 77 metolazone 272 metoprolol 270, 273 metronidazole 74, 76, 77, 270, 272 miconazole 270, 272 migraines 191 mitral stenosis 188, 194 mitral valve disease 105 Mondial Assessment of Thromboembolism Treatment Initiated by Synthetic Pentasaccharide with Symptomatic Endpoints (MATISSE) 337 moricizine 270, 273 Moses’ sign 29 Multifactorial Etiology of Cancer Associated Venous Thrombosis (ONCENOX) 305 myeloma 296 myeloproliferative disorders 48, 66, 70, 371 myocardial infarction (MI) 36, 166, 167, 169, 170, 172, 173, 175, 176, 178, 184, 200, 202, 203, 211, 220, 264, 280, 281, 283-286, 290, 314, 316, 320323, 337 myocardial ischemia 166

N N-terminal fragment BNP (NT-proBNP) 120 nadroparin (Fraxiparine®) 34, 149 nafcillin 77, 270, 273

nalidixic acid 272 naproxen 270, 273 National Comprehensive Cancer Network (NCCN) 301, 303, 377 National Institutes of Health 192 National Patient Safety Goals 260, 262, 263 National Quality Forum 8, 368 nausea 69, 322, 328 nematode anticoagulant peptide C2 (NAPc2) 10, 36, 315, 334 nematode anticoagulant proteins (NAPs) 334 neoplasm 69, 76 nephropathy 71, 73, 116 nephrotic syndrome 14, 48, 65, 71-73, 371 neuraxial anesthesia 143, 148, 156 neuraxial blockade 143-145 neutropenia 167 nitrazepam 271, 273 nizatidine 271, 273 non–ST-segment elevation (NSTE) 7, 8 non–ST elevation myocardial infarction (NSTEMI) 166, 167, 169, 170, 172, 175, 177, 187, 334, 337 nonsteroidal anti-inflammatory drugs (NSAIDs) 63, 64 norfloxacin 272 numbness 56

O obesity 13, 14, 23, 60, 62, 94, 158, 294, 295, 371, 377 ocular muscle paralysis 77 ofloxacin 272 omeprazole 271, 272

oral contraceptives 14, 49, 62, 65, 69, 70, 72, 94, 99, 371 Orgaran® 155 orthopedic surgery 213, 214 Osmitrol® 66 osteoporosis 33, 157, 244, 277 otamixaban 340, 349

P P-selectin 295, 296 pacemakers 56 Paget-Schroetter syndrome 50 Pain 29, 47, 50-52, 56, 60, 157 abdominal pain 67, 69, 75, 76, 374 flank pain 72 limb pain 28, 29, 113 neck pain 74 pelvic pain 75 pancreatitis 48, 69, 72 papilledema 65 paralysis 158, 372 paralytic stroke 98 paresis 14, 370, 372 paresthesias 51 paroxysmal nocturnal hemoglobinuria 48 partial thromboplastin time (PTT) 274, 282, 286 pegmusirudin 329, 330, 349 penicillin 74 Pentasaccharide in General Surgery Study (PEGASUS) 18 peptic ulcer 181 peptic ulcer disease 34 percutaneous coronary intervention (PCI) 8, 167, 169, 172, 175, 177, 179, 186, 187, 197, 198, 214, 228, 283, 316, 321, 322, 325, 334, 340 peripheral vascular disease 22 peritonitis 48, 69

389

Persantine® 206 phenylbutazone 270, 272 phenytoin 273 phlebitis 60 piroxicam 270, 272 plasminogen 251, 349-351, 376 plasminogen activator inhibitor1 (PAI-1) 347, 349, 350, 352 platelet 10, 28, 35, 36, 63, 122, 124, 166, 167, 169-171, 200, 201, 210-212, 216, 217, 220222, 224, 225, 230, 240, 241, 249-252, 274, 276, 277, 282, 286, 296, 297, 314, 316, 317, 321-325, 327, 328, 330, 336, 338, 339, 342, 377 platelet activating factor 168, 169 platelet aggregation 324, 325, 342 platelet count recovery 232 platelet factor 4 (PF4) 330, 337-339 Plavix® 8, 167, 250, 317 pleural effusion 106, 108 polycythemia 65 polycythemia vera 48, 67, 69 popliteal (“baker’s”) cysts 39 postphlebitic syndrome 13 postthrombotic syndrome 10, 28, 31, 37, 40, 51, 54, 238, 314 Pradaxa® 232 prasugrel 316, 317, 319-321, 376 preeclampsia 158 pregnancy 156 Prevention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) study 303

390

Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study 206 propafenone 270, 272 Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) study 298, 299 propranolol 270, 272 proptosis 77 Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT) 298, 299 Prospective Investigation of Pulmonary Embolism Diagnosis) study (PIOPED) 109 Prospective Investigation of Pulmonary Embolism Diagnosis) study (PIOPED II) 111 protamine 33, 121, 174, 240, 242 protease activated receptor-1 (PAR-1) 316, 324, 325 protease activated receptor-1 (PAR-1) antagonists 319, 324 protease activated receptor-4 (PAR-4) 324 protein C 33, 48, 62, 67, 70, 72, 94, 124, 263, 328, 330, 336, 374 deficiency 370 protein S 33, 48, 60, 62, 72, 94, 124, 263, 370 prothrombin 48, 50, 67, 94, 168, 252, 335, 340, 370 prothrombin time (PT) 17, 261, 268, 269, 274, 282, 286, 341, 343, 345, 346

prothrombotic disorder 67 PRT 054021 340 psyllium 271, 273 ptosis 77 pulmonary artery shunts 253 pulmonary edema 108 pulmonary embolism (PE) 7, 9, 12, 13, 19, 22, 35-37, 46, 47, 51, 56, 57, 59, 61, 64, 66, 72, 92-96, 99, 101, 103, 105114, 116, 119-129, 148, 152, 154, 159, 211, 218, 220, 238, 264, 280-286, 290, 291, 303, 306, 314, 337-340, 342, 344, 346, 369, 373 pulmonary infarction 106 pyelonephritis 72 pylephlebitis 74, 76

Q QTc prolongation 343 quality of life 38 quinidine 272

R R-138727 376 radiation 290, 295 Randomized Evaluation of Long Term Anticoagulant Therapy (RELY) trial 332 ranitidine 271, 273 rash 322 razaxaban 340, 341 RB006 347 RE-MOBILIZE 333 RE-MODEL 333 RE-NOVATE 333 recanalization 47, 54, 68 recombinant tissue-type plasminogen activator (rtPA) 126, 192, 193, 200, 202, 369 Refludan® 10, 176, 222, 329

Regulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE (RECORD) 343, 344 renal disease 276, 294 renal impairment 36, 121, 122, 283, 285-287, 337 renal insufficiency 18, 24, 30, 116, 174, 182 renal transplantation 72 ReoPro® 170 respiratory alkalosis 103 respiratory disease 20, 98 respiratory failure 24, 94, 119, 126, 371 Retavase® 179, 347 reteplase (Retavase®) 179, 187, 347 revascularization 176, 179, 197 Reye’s syndrome 250 rifampin 270, 273 right ventricular dysfunction 103, 105, 119, 120, 123, 125, 128 rigors 74 rivaroxaban 315, 326, 342-344, 349 Roux-en-Y gastric bypass 149

S S18886 323 salicylates 272 saphenous vein ligation 63 SCH-530348 324-326 scintigraphy 109, 115, 118 sclerotherapy 41, 68 seizures 65, 252 sepsis 20, 23, 24, 48, 57, 58, 76, 154, 252, 335 serotonin 94 serotonin release assay (SRA) 221, 222, 227 shock 95

391

simvastatin 272 skin lesions 225 skin necrosis 63, 210, 211, 213, 218, 224, 230 SNAD (sodium N-amino decanoate) heparins 36 Society of Hospital Medicine (SHM) 368 sodium N-[8(2-hydroxybenzoyl) amino] caprylate (SNAC)-heparin 36, 328, 349 sore throat 74 spinal cord injury 13, 15, 94, 98, 150 spinal cord ischemia 142 splenomegaly 67, 69 sputum cytology 293 SR-123781 339 SSR-126517-E 338, 339 Staphylococcus aureus 77, 193 ST-segment elevation myocardial infarction (STEMI) 7, 8, 166, 176, 177, 182, 186, 275, 283-286, 337, 351 stent thrombosis 169 streptokinase 126, 179, 181, 187, 251, 347 stroke 15, 17, 20, 23, 24, 37, 65, 165, 167, 169, 170, 181, 188, 190, 191, 193, 194, 198-202, 204, 206, 211, 220, 232, 290, 320-323, 325, 332, 351, 369 ischemic stroke 180, 191193, 198, 200, 202 subarachnoid hemorrhage (SAH) 202, 203 sucralfate 271, 273 sulfinpyrazone 270, 272 sulfisoxazole 272 sulindac 272 superior vena cava (SVC) syndrome 47

392

Surgical Care Improvement Project 368 swelling 47, 51, 154 syncope 105-107, 322

T tachycardia 107 tachypnea 106, 107 tamoxifen 272 telangiectasis 39, 40 tenecteplase (TNKase™) 347 Tenecteplase® 179 teratogenicity 327 tetracycline 272 TGN-167 333, 376 thalidomide 296 thrombectomy 37, 58, 123, 253, 254 thrombin 94, 168, 212, 222, 231, 239, 269, 315, 324, 325, 327-329, 336, 339, 342, 350 thrombin-activatable fibrinolysis inhibitor, activated (TAFIa) 349-351 Thrombin inhibitors 15, 19, 145, 146, 228, 244, 327, 328, 333 direct thrombin inhibitors (DTIs) 9, 10, 16, 19, 36, 145, 146, 326, 329, 330, 376 indirect thrombin inhibitors 15, 176, 315, 326, 328 thrombin receptor agonist peptide (TRAP) 324, 325 thromboangiitis obliterans 60 thrombocythemia 48 thrombocytopenia 17, 158, 172, 176, 182, 210, 211, 213, 214, 216, 218, 219, 221, 224, 229, 231, 240, 252, 280, 283, 286, 323, 332, 338

thrombocytopenic purpura 167 thromboembolic disease 12, 238, 239, 249 Thromboembolism 32, 34, 94, 98, 114, 128, 189, 194-196, 198, 201, 210, 231, 252, 293, 294, 299, 305, 316 arterial 251, 252 arterial thromboembolism (ATE) 314, 315, 328 chemotherapy 297 venous thromboembolism (VTE) 251, 252, 274, 275, 280, 297 thrombolysis 36, 53, 54, 59, 70, 123, 176, 177, 181, 182, 184, 351 Thrombolysis in Myocardial Infarction (TIMI) 325 thrombolytics 9, 31, 36, 37, 41, 125-127, 165, 177, 182, 186, 238, 251-254, 283, 375 thrombolytic therapy 252-254, 375 thrombophilia 14, 50, 60, 62, 65, 66, 68, 71, 94, 99, 124, 158 Thrombophlebitis 46, 51, 61-64, 77 cavernous sinus thrombophlebitis 77 deep vein septic thrombophlebitis 74 ovarian vein thrombophlebitis 75 portal vein septic thrombophlebitis 76 puerperal septic pelvic thrombophlebitis 76 septic pelvic thrombophlebitis 75 septic thrombophlebitis 48, 73

Thrombophlebitis (continued) superficial thrombophlebitis 60, 61, 62, 63, 64 superficial vein septic thrombophlebitis 73 thromboplastin time 17 thromboprophylaxis 12, 13, 15, 16, 19, 20, 23, 24, 59, 60, 140, 141, 143, 144, 146, 147, 149, 153, 154, 158, 301, 315, 327, 329, 340, 347 Thrombosis 9, 17, 31, 33, 37, 39, 41, 46, 47, 51, 54-56, 60, 63, 64, 71, 72, 74, 75, 106, 154, 158, 168, 201, 204, 210-213, 217, 218, 220, 221, 223-226, 230-232, 241, 247, 250, 251, 286, 293-296, 305, 306, 320, 324, 326, 333, 336, 340, 342, 374 cancer-associated thrombosis 290, 294, 295 cerebral sinus thrombosis 66 cerebral venous thrombosis 64, 65, 66 chemotherapy-associated thrombosis 294 hepatic vein thrombosis 69 mesenteric thrombosis 69 mesenteric venous thrombosis 66, 68, 69 portal vein thrombosis 66, 67, 68 prosthetic valve thromboses 253 renal vein thrombosis 71, 72, 73 splenic vein thrombosis 69 venous thrombosis 73, 372

393

thromboxane A1 169, 319 thromboxane A2 166, 168, 316, 323 thrombus 40, 41, 58, 128, 241, 246, 252, 254, 352 thyroid disease 65 ticarcillin/clavulanate 74 Ticlid® 317 ticlopidine (Ticlid®) 251, 317 tifacogin 335, 349 TIMI 9B study 368 tinzaparin (Innohep®) 16, 21, 35, 152, 153, 156, 282, 303, 305 tirofiban (Aggrastat®) 170, 171, 186 tissue factor (TF) 290, 296 tissue factor (TF)–FVIIa complex 334 tissue factor (TF) pathway inhibitor (TFPI) 10, 36, 334, 335, 346 recombinant TFPI (rTFPI) 334 tissue plasminogen activator (tPA) 126, 127, 179, 187, 251-253, 347, 349-351, 376 TNK-tPA (Tenecteplase®) 179, 187 TNKase™ 347 tobacco 273, 371 tolmetin 272 total parenteral nutrition 47 tracheostomy 276 transesophageal echocardiography 190 transient ischemic attack (TIA) 165, 188, 194, 198, 199, 206, 276, 321, 370 trauma 14, 15, 17, 34, 40, 70, 72, 94, 98, 106, 124, 150, 180, 202, 203, 247, 280, 370 trazodone 273

394

Trial of the Effect of LowMolecular-Weight Heparin (LMWH) Versus Warfarin on Mortality in the LongTerm Treatment of Proximal Deep Vein Thrombosis (DVT) (LITE) 305 Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition trial (TRITON– TIMI-38) 320 tridegin 352 Trousseau’s syndrome 60 TTP-889 346 tumors 49, 290, 296

U ulcer 28, 34, 38-42, 76, 181, 250 ultrasonography 24, 30, 31, 41, 51, 52, 57, 61, 62, 67, 70, 72, 76, 115, 117, 118, 293, 298 ultrasound 41, 67 unfractionated heparin (UFH) 9, 10, 15, 17, 19, 31-34, 53, 57, 121, 122, 124, 125, 127, 128, 141-143, 146, 148-152, 154, 155, 157, 172, 174, 175, 176, 180, 182, 183, 186, 187, 189, 197, 198, 201, 203, 204, 210, 211, 213, 238-243, 245, 247, 253, 261, 269, 274, 277, 300, 302, 315, 326, 329, 336, 339, 344, 367, 368 unstable angina (UA) 166, 167, 169, 170, 172, 175, 177 urokinase 126, 251 urokinase plasminogen activator (uPA) 347, 352

V valve replacement 165 valvular dysfunction 41 vancomycin 74, 77, 273 Van Gogh Extension study 338 variceal band ligation 68 varicella 250 varicose veins 40, 60, 62, 63, 99, 371 vasculitis 48 vena cava filter 303, 306 venogram 115 venography 51, 52, 57, 65, 70, 72, 117, 118, 298, 343 venous foot pump (VFP) 19-21 venous gangrene 47, 51 venous hypertension 39, 41 venous stasis ulcers 38, 39, 41 venous thromboembolic disease 9, 31, 36 venous thromboembolism (VTE) 7, 10-12, 14, 16-20, 23, 24, 29, 31, 36, 92-94, 99, 114, 116, 124, 140, 141, 146-150, 152-155, 157, 158, 290-292, 294, 296-300, 302, 304, 315, 326-331, 333, 334, 337, 338, 340-345, 347, 367, 368, 370, 377, 378 cancer-associated 291, 293, 303 venous ulcers 42 venous varicosities 38, 39, 41

ventriculomegaly 64 visual loss 65 vitamin K 245, 247, 252, 261, 263, 271, 273 vitamin K antagonists (VKA) 9, 32, 124-126, 141-143, 147, 150, 151, 154, 156, 165, 194, 195, 197, 198, 245, 315, 326, 327, 339, 345 vomiting 69

W warfarin (Coumadin®) 9, 18, 31, 32, 53, 57, 59, 63, 70, 72, 124, 183, 185, 188, 189, 191, 197, 201, 203, 204, 212, 213, 218, 230, 231, 242, 245-249, 261- 270, 272, 274, 285, 302, 303, 315, 327, 330, 332, 338, 341, 344, 374, 375 weight loss 41, 67 Wells score 109, 112, 114, 369, 372 Westermark’s sign 108 Women’s Health Study 200

X ximelagatran 315, 330, 332, 376

Y YM-150 315, 345

395

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