anticoagulation guidelines 2008

DOI 10.1378/chest.08-0693 2008;133;71-109 Chest

Holger J. Schünemann Jack Hirsh, Gordon Guyatt, Gregory W. Albers, Robert Harrington and

Practice Guidelines (8th Edition)Chest Physicians Evidence-Based Clinical Executive Summary: American College of

http://chestjournal.organd services can be found online on the World Wide Web at: The online version of this article, along with updated information

). ISSN: 0012-3692. http://www.chestjournal.org/misc/reprints.shtml(of the copyright holder may be reproduced or distributed without the prior written permission Northbrook IL 60062. All rights reserved. No part of this article or PDFby the American College of Chest Physicians, 3300 Dundee Road,

2007Physicians. It has been published monthly since 1935. Copyright CHEST is the official journal of the American College of Chest

Copyright © 2008 by American College of Chest Physicians on December 3, 2008 chestjournal.orgDownloaded from

http://chestjournal.org

http://www.chestjournal.org

Executive Summary*American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines(8th Edition)

Jack Hirsh, MD, FCCP, Chair; Gordon Guyatt, MD, FCCP;Gregory W. Albers, MD; Robert Harrington, MD, FCCP;and Holger J. Schunemann, MD, PhD, FCCP

(CHEST 2008; 133:71S–105S)

Key words: guidelines; recommendations

Abbreviations: ACCP � American College of Chest Physicians;ACS � acute corronary syndromes; AF � atrial fibrillation;AIS � arterial ischemic stroke; APTT � activated partial throm-boplastin time; CABG � coronary artery bypass grafting;CrCl � creatinine clearance; CSVT � cerebral sinovenousthrombosis; CTPH � chronic thromboembolic pulmonary hy-pertension; CVL � central venous line; DVT � deep vein throm-bosis; GCS � graduated compression stockings; GP � glyco-protein; HIT � heparin-induced thrombocytopenia; IPC �intermittent pneumatic compression; INR � international nor-malized ratio; LDUH � low-dose unfractionated heparin;LMWH � low-molecular-weight heparin; MVP � mitral valveprolapse; NSTE � non–ST-segment elevation; PCI � percutanouscoronary intervention; PE � pulmonary embolism; PMBV �percutaneous mitral valve balloon valvotomy; PTS � postthromboticsyndrome; PVT � prosthetic valve thrombosis; SC � subcutaneous;SCI � spinal cord injury; TEE � transesophageal echocardiogra-phy; tPA � tissue plasminogen activator; UAC � umbilical arterycatheter; UFH � unfractionated heparin; VFP � venous foot pump;VKA � vitamin K antagonist; VTE � venous thromboembolism

T his executive summary accompanies the publica-tion of 8th edition of “Antithrombotic and

Thrombolytic Therapy: American College of ChestPhysicians (ACCP) Evidence-Based Clinical PracticeGuidelines.” These guidelines provide an extensive

critical review of the literature related to manage-ment of thromboembolic disorders.

In each chapter, the clinical question under consid-eration, the clinical trials evaluating the evidence, andthe recommendations are linked by a numberingscheme common to these three items. The recommen-dations are included at the beginning of the chaptersand are presented in this executive summary.

The grading system in the 8th edition of the ACCPguidelines reflects the system adopted for all ACCPguidelines, and is similar to the GRADE system, whichis being widely adopted by many guideline groups. Thestrength of any recommendation depends on two fac-tors: the trade-off between benefits, risks, burden, andcost, and the level of confidence in estimates of thosebenefits and risks. If benefits do or do not outweighrisks, burden, and costs, a strong recommendation isdesignated as Grade 1. If there is less certainty aboutthe magnitude of the benefits and risks, burden, andcosts, a weaker Grade 2 recommendation is made.Support for these recommendations may come fromhigh-quality, moderate-quality, or low-quality evidence,labeled, respectively, A, B, and C. The phrase “werecommend” is used for strong recommendations(Grade 1A, 1B, 1C) and “we suggest” for weakerrecommendations (2A, 2B, 2C). The full set of recom-mendations follows.

Parenteral Anticoagulants

2.2.3 Monitoring Antithrombotic Effect

2.2.3. In patients treated with low-molecular-weight heparin (LMWH), we recommendagainst routine coagulation monitoring (Grade1C). In pregnant women treated with therapeu-tic doses of LMWH, we recommend monitoringof anti-Xa levels (Grade 1C).

*From Hamilton Civic Hospitals (Dr. Hirsh), Henderson ResearchCentre, Hamilton, ON, Canada; McMaster University MedicalCentre (Dr. Guyatt), Hamilton, ON, Canada; Stanford UniversityMedical Center (Dr. Albers), Stanford Stroke Center, Palo Alto, CA;Duke Clinical Research Institute (Dr. Harrington), Duke UniversityMedical Center, Durham, NC; and Department of Clinical Epide-miology/INFORMA (Dr. Schunemann), Istituto Regina Elena,Rome, Italy.Manuscript accepted December 20, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Gordon H. Guyatt, MD, FCCP, McMasterUniversity Medical Centre, 2C12, 1200 Main St W, Hamilton,ON, L8N 3Z5, Canada; e-mail: [email protected]: 10.1378/chest.08-0693

CHEST SupplementANTITHROMBOTIC AND THROMBOLYTIC THERAPY 8TH ED: ACCP GUIDELINES

www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 71S



2.2.4 Dosing and Monitoring in Special Situations

2.2.4. In obese patients receiving LMWH pro-phylaxis or treatment, we suggest weight-baseddosing (Grade 2C). In patients with severe renalinsufficiency (creatinine clearance [CrCl] < 30mL/min) who require therapeutic anticoagula-tion, we suggest the use of unfractionated hep-arin (UFH) instead of LMWH (Grade 2C). IfLMWH is used in patients with severe renalinsufficiency (CrCl < 30 mL/min) who requiretherapeutic anticoagulation, we suggest using50% of the recommended dose (Grade 2C).

3.0 Direct Thrombin Inhibitors

3.0. In patients who receive either lepirudin ordesirudin and have renal insufficiency (CrCl < 60mL/min but > 30 mL/min), we recommend thatthe dose be reduced and the drug monitoredusing the activated partial thromboplastin time(APTT) [Grade 1C]. In patients with a CrCl < 30mL/min, we recommend against the use of lepi-rudin or desirudin (Grade 1C). In patients whorequire anticoagulation and have previously re-ceived lepirudin or desirudin, we recommendagainst repeated use of these drugs because of therisk of anaphylaxis (Grade 1C).

3.1 Monitoring of Direct Thrombin Inhibitors

3.1. In patients receiving argatroban who arebeing transitioned to a vitamin K antagonist(VKA), we suggest that factor X levels, mea-sured using a chromogenic assay, be used toadjust the dose of the VKA (Grade 2C).

Pharmacology and Management of VKAs

2.1 Initiation and Maintenance Dosing

2.1.1. In patients beginning VKA therapy, werecommend the initiation of oral anticoagula-tion with doses between 5 and 10 mg for thefirst 1 or 2 days for most individuals, with sub-sequent dosing based on the international nor-malized ratio (INR) response (Grade 1B). At thepresent time, for patients beginning VKA therapy,without evidence from randomized trials, we sug-gest against the use of pharmacogenetic-basedinitial dosing to individualize warfarin dosing(Grade 2C).

2.2 Initiation of Anticoagulation in the Elderly orOther Populations

2.2.1. In elderly patients or patients who aredebilitated, are malnourished, have congestive

heart failure, have liver disease, have had re-cent major surgery, or are taking medicationsknown to increase the sensitivity to warfarin(eg, amiodarone), we recommend the use of astarting dose of < 5 mg (Grade 1C), with subse-quent dosing based on the INR response.

2.3 Frequency of Monitoring

2.3.1. In patients beginning VKA therapy, wesuggest that INR monitoring should be startedafter the initial two or three doses of oralanticoagulation therapy (Grade 2C).2.3.2. For patients who are receiving a stabledose of oral anticoagulants, we suggest moni-toring at an interval of no longer than every 4weeks (Grade 2C).

2.4 Management of Nontherapeutic INRs

2.4.1. For patients with INRs above the therapeu-tic range, but < 5.0 and with no significant bleed-ing, we recommend lowering the dose or omittinga dose, monitoring more frequently, and resum-ing therapy at an appropriately adjusted dosewhen the INR is at a therapeutic level. If onlyminimally above therapeutic range, or associatedwith a transient causative factor, no dose reduc-tion may be required (all Grade 1C).2.4.2. For patients with INRs > 5.0 but < 9.0and no significant bleeding, we recommendomitting the next one or two doses, monitoringmore frequently, and resuming therapy at anappropriately adjusted dose when the INR is ata therapeutic level (Grade 1C). Alternatively, wesuggest omitting a dose and administering vita-min K (1 to 2.5 mg) orally, particularly if thepatient is at increased risk of bleeding (Grade2A). If more rapid reversal is required becausethe patient requires urgent surgery, we suggestvitamin K (< 5 mg) orally, with the expectationthat a reduction of the INR will occur in 24 h. Ifthe INR is still high, we suggest additionalvitamin K (1 to 2 mg) orally (Grade 2C).2.4.3. For patients with INRs of > 9.0 and nosignificant bleeding, we recommend holding war-farin therapy and administering a higher dose ofvitamin K (2.5 to 5 mg) orally, with the expecta-tion that the INR will be reduced substantially in24 to 48 h (Grade 1B). Clinicians should monitorthe INR more frequently, administer additionalvitamin K if necessary, and resume therapy at anappropriately adjusted dose when the INRreaches the therapeutic range.2.4.4. In patients with serious bleeding and ele-vated INR, regardless of the magnitude of the

72S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines



elevation, we recommend holding warfarin ther-apy and giving vitamin K (10 mg) by slow IVinfusion supplemented with fresh frozen plasma,prothrombin complex concentrate, or recombi-nant factor VIIa, depending on the urgency of thesituation. We recommend repeating vitamin Kadministration every 12 h for persistent INR ele-vation (all Grade 1C).2.4.5. In patients with life-threatening bleeding(eg, intracranial hemorrhage) and elevatedINR, regardless of the magnitude of the eleva-tion, we recommend holding warfarin therapyand administering fresh frozen plasma, pro-thrombin complex concentrate, or recombinantfactor VIIa supplemented with vitamin K, 10mg by slow IV infusion, repeated, if necessary,depending on the INR (Grade 1C).2.4.6. In patients with mild-to-moderately elevatedINRs without major bleeding, we recommend thatwhen vitamin K is to be given, it be administeredorally rather than subcutaneously (Grade 1A).

2.5 Management of Variable INRs

2.5.1. For patients receiving long-term warfarintherapy with a variable INR response not attrib-utable to any of the usual known causes forinstability, we suggest a trial of daily low-doseoral vitamin K (100 to 200 �g) with close mon-itoring of the INR and warfarin dose adjust-ment to counter an initial lowering of the INRin response to vitamin K (Grade 2B).

2.7 Management of INRs in AntiphospholipidSyndrome

2.7.1. In patients who have a lupus inhibitor, whohave no additional risk factors, and no lack ofresponse to therapy, we recommend a therapeu-tic target INR of 2.5 (INR range, 2.0 to 3.0) [Grade1A]. In patients who have recurrent thromboem-bolic events with a therapeutic INR or other addi-tional risk factors for thromboembolic events, wesuggest a target INR of 3.0 (INR range, 2.5 to 3.5)[Grade 2C].

4.1 Optimal Management of VKA Therapy

4.1.1. For health-care providers who manage oralanticoagulation therapy, we recommend that theydo so in a systematic and coordinated fashion,incorporating patient education, systematic INRtesting, tracking, follow-up, and good patient com-munication of results and dosing decisions as occursin an anticoagulation management service (Grade1B).

4.3 Patient Self-Testing and PatientSelf-Management

4.3.1. Patient self-management is a choice madeby patients and health-care providers that de-pends on many factors. In patients who aresuitably selected and trained, patient self-testingand patient self-management is an effective alter-native treatment model. We suggest that suchtherapeutic management be implemented wheresuitable (Grade 2B).

Perioperative Management ofAntithrombotic Therapy

2.0 Perioperative Management of Patients Who AreReceiving VKAs

2.1. In patients who require temporary inter-ruption of a VKA before surgery or a procedureand require normalization of the INR for thesurgery or procedure, we recommend stoppingVKAs approximately 5 days before surgery overstopping VKAs within a shorter time intervalbefore surgery to allow adequate time for theINR to normalize (Grade 1B).2.2. In patients who have had temporary inter-ruption of a VKA before surgery or a proce-dure, we recommend resuming VKAs approxi-mately 12 to 24 h (the evening of or the nextmorning) after surgery and when there is ade-quate hemostasis over resumption of VKAscloser to surgery (Grade 1C).2.3. In patients who require temporary inter-ruption of a VKA before surgery or a procedureand whose INR is still elevated (ie, > 1.5) 1 to 2days before surgery, we suggest administeringlow-dose (ie, 1 to 2 mg) oral vitamin K tonormalize the INR instead of not administeringvitamin K (Grade 2C).2.4. In patients with a mechanical heart valve oratrial fibrillation (AF) or venous thromboembo-lism (VTE) at high risk for thromboembolism, werecommend bridging anticoagulation with thera-peutic-dose subcutaneous (SC) LMWH or IVUFH over no bridging during temporary inter-ruption of VKA therapy (Grade 1C); we suggesttherapeutic-dose SC LMWH over IV UFH (Grade2C). In patients with a mechanical heart valve or ATor VTE at moderate risk for thromboembolism, wesuggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, orlow-dose SC LMWH over no bridging duringtemporary interruption of VKA therapy (Grade2C); we suggest therapeutic-dose SC LMWHover other management options (Grade 2C). In




patients with a mechanical heart valve or AF orVTE at low risk for thromboembolism, we sug-gest low-dose SC LMWH or no bridging overbridging with therapeutic-dose SC LMWH orIV UFH (Grade 2C).Underlying values and preferences: In patients at highor moderate risk for thromboembolism, the recom-mendations reflect a relatively high value on preventingthromboembolism and a relatively low value is onpreventing bleeding; in patients at low risk for throm-boembolism, the recommendations reflect a relativelyhigh value on preventing bleeding and a relatively lowvalue on preventing thromboembolism.

3.0 Perioperative Management of Patients Who AreReceiving Bridging Anticoagulation

3.1. In patients who require temporary inter-ruption of VKAs and are to receive bridginganticoagulation, from a cost-containment per-spective we recommend the use of SC LMWHadministered in an outpatient setting wherefeasible instead of inpatient administration ofIV UFH (Grade 1C).Underlying values and preferences: This recommen-dation reflects a consideration not only of the trade-offbetween the advantages and disadvantages of SCLMWH and IV UFH as reflected in their effects onclinical outcomes (LMWH at least as good, possiblybetter), but also the implications in terms of resourceuse (costs) in a representative group of countries(substantially less resource use with LMWH).3.2. In patients who are receiving bridging anti-coagulation with therapeutic-dose SC LMWH,we recommend administering the last dose ofLMWH 24 h before surgery or a procedureover administering LMWH closer to surgery(Grade 1C); for the last preoperative dose ofLMWH, we recommend administering approx-imately half the total daily dose instead of 100%of the total daily dose (Grade 1C). In patientswho are receiving bridging anticoagulation withtherapeutic-dose IV UFH, we recommend stop-ping UFH approximately 4 h before surgeryover stopping UFH closer to surgery (Grade 1C).3.3. In patients undergoing a minor surgical orother invasive procedure and who are receivingbridging anticoagulation with therapeutic-doseLMWH, we recommend resuming this regimenapproximately 24 h after (eg, the day after) theprocedure when there is adequate hemostasisover a shorter (eg, < 12 h) time interval (Grade1C). In patients undergoing major surgery or ahigh bleeding risk surgery/procedure and forwhom postoperative therapeutic-dose LMWH/UFH is planned, we recommend either delaying

the initiation of therapeutic-dose LMWH/UFHfor 48 to 72 h after surgery when hemostasis issecured, administering low-dose LMWH/UFHafter surgery when hemostasis is secured, orcompletely avoiding LMWH or UFH after sur-gery over the administration of therapeutic-dose LMWH/UFH in close proximity to surgery(Grade 1C). We recommend considering theanticipated bleeding risk and adequacy of post-operative hemostasis in individual patients todetermine the timing of LMWH or UFH re-sumption after surgery instead of resumingLMWH or UFH at a fixed time after surgery inall patients (Grade 1C).3.4. In patients who are receiving bridginganticoagulation with LMWH, we suggest againstthe routine use of anti-factor Xa levels tomonitor the anticoagulant effect of LMWHs(Grade 2C).

4.0 Perioperative Management of Patients Who AreReceiving Antiplatelet Therapy

4.2. In patients who require temporary inter-ruption of aspirin- or clopidogrel-containingdrugs before surgery or a procedure, we sug-gest stopping this treatment 7 to 10 days beforethe procedure over stopping this treatmentcloser to surgery (Grade 2C).4.3. In patients who have had temporary inter-ruption of aspirin therapy because of surgery ora procedure, we suggest resuming aspirin ap-proximately 24 h (or the next morning) aftersurgery when there is adequate hemostasis in-stead of resuming aspirin closer to surgery(Grade 2C). In patients who have had temporaryinterruption of clopidogrel because of surgeryor a procedure, we suggest resuming clopi-dogrel approximately 24 h (or the next morn-ing) after surgery when there is adequate he-mostasis instead of resuming clopidogrel closerto surgery (Grade 2C).4.4. In patients who are receiving antiplateletdrugs, we suggest against the routine use ofplatelet function assays to monitor the anti-thrombotic effect of aspirin or clopidogrel(Grade 2C).4.5. For patients who are not at high risk forcardiac events, we recommend interruption ofantiplatelet drugs (Grade 1C). For patients athigh risk of cardiac events (exclusive of coro-nary stents) scheduled for noncardiac surgery,we suggest continuing aspirin up to and beyondthe time of surgery (Grade 2C); if patients arereceiving clopidogrel, we suggest interruptingclopidogrel at least 5 days and, preferably,




within 10 days prior to surgery (Grade 2C). Inpatients scheduled for coronary artery bypassgrafting (CABG), we recommend continuing aspi-rin up to and beyond the time of CABG (Grade1C); if aspirin is interrupted, we recommend it bereinitiated between 6 h and 48 h after CABG(Grade 1C). In patients scheduled for CABG, werecommend interrupting clopidogrel at least 5days and, preferably, 10 days prior to surgery(Grade 1C). In patients scheduled for percutane-ous coronary intervention (PCI), we suggest con-tinuing aspirin up to and beyond the time of theprocedure; if clopidogrel is interrupted prior toPCI, we suggest resuming clopidogrel after PCIwith a loading dose of 300 to 600 mg (Grade 2C).4.6. In patients with a bare metal coronary stentwho require surgery within 6 weeks of stentplacement, we recommend continuing aspirinand clopidogrel in the perioperative period(Grade 1C). In patients with a drug-eluting coro-nary stent who require surgery within 12 monthsof stent placement, we recommend continuingaspirin and clopidogrel in the perioperative pe-riod (Grade 1C). In patients with a coronary stentwho have interruption of antiplatelet therapy be-fore surgery, we suggest against the routine use ofbridging therapy with UFH, LMWH, directthrombin inhibitors, or glycoprotein (GP) IIb/IIIainhibitors (Grade 2C).Underlying values and preferences: These recom-mendations reflect a relatively high value placed onpreventing stent-related coronary thrombosis, a con-sideration of complexity and costs of administeringbridging therapy in the absence of efficacy and safetydata in this clinical setting, and a relatively low valueon avoiding the unknown but potentially large in-crease in bleeding risk associated with the concom-itant administration of aspirin and clopidogrel duringsurgery.

5.0 Perioperative Management of AntithromboticTherapy in Patients Who Require Dental,Dermatologic, or Ophthalmologic Procedures

5.1. In patients who are undergoing minordental procedures and are receiving VKAs, werecommend continuing VKAs around the timeof the procedure and coadministering an oralprohemostatic agent (Grade 1B). In patients whoare undergoing minor dental procedures andare receiving aspirin, we recommend continu-ing aspirin around the time of the procedure(Grade 1C). In patients who are undergoingminor dental procedures and are receiving clo-pidogrel, please refer to the recommendationsoutlined in Section 4.5 and Section 4.6.

5.2. In patients who are undergoing minor der-matologic procedures and are receiving VKAs, werecommend continuing VKAs around the time ofthe procedure (Grade 1C). In patients who areundergoing minor dermatologic procedures andare receiving aspirin, we recommend continuingaspirin around the time of the procedure (Grade1C). In patients who are undergoing minor der-matologic procedures and are receiving clopi-dogrel, please refer to the recommendations out-lined in Section 4.5 and Section 4.6.5.3. In patients who are undergoing cataract re-moval and are receiving VKAs, we recommendcontinuing VKAs around the time of the proce-dure (Grade 1C). In patients who are undergoingcataract removal and are receiving aspirin, werecommend continuing aspirin around the timeof the procedure (Grade 1C). In patients who areundergoing cataract removal and are receivingclopidogrel, please refer to the recommendationsoutlined in Section 4.5 and Section 4.6.

6.0 Perioperative Management of AntithromboticTherapy Patients Who Require Urgent Surgical orOther Invasive Procedures

6.1. In patients who are receiving VKAs andrequire reversal of the anticoagulant effect foran urgent surgical or other invasive procedure,we recommend treatment with low-dose (2.5 to5.0 mg) IV or oral vitamin K (Grade 1C). Formore immediate reversal of the anticoagulanteffect, we suggest treatment with fresh-frozenplasma or another prothrombin concentrate in ad-dition to low-dose IV or oral vitamin K (Grade 2C).6.2. For patients receiving aspirin, clopidogrel, orboth, are undergoing surgery and have excessiveor life-threatening perioperative bleeding, wesuggest transfusion of platelets or administrationof other prohemostatic agents (Grade 2C).

Treatment and Prevention ofHeparin-Induced Thrombocytopenia

1.0 Recognition of Heparin-InducedThrombocytopenia

1.1 Platelet Count Monitoring for HIT

1.1. For patients receiving heparin in whom theclinician considers the risk of heparin-inducedthrombocytopenia (HIT) to be > 1.0%, we recom-mend platelet count monitoring over no plateletcount monitoring (Grade 1C). For patients receiv-ing heparin who have an estimated risk of HIT of0.1 to 1.0%, we suggest platelet count monitoringover no platelet count monitoring (Grade 2C).




1.1.1 Platelet Count Monitoring of PatientsRecently Treated With Heparin

1.1.1. For patients who are starting UFH orLMWH treatment and who have received UFHwithin the past 100 days, or those patients inwhom exposure history is uncertain, we recom-mend obtaining a baseline platelet count andthen a repeat platelet count within 24 h ofstarting heparin over not obtaining a repeatplatelet count (Grade 1C).

1.1.2 Anaphylactoid Reactions After IV UFH Bolus

1.1.2. For patients in whom acute inflammatory,cardiorespiratory, neurologic, or other unusualsymptoms and signs develop within 30 minfollowing an IV UFH bolus, we recommendperforming an immediate platelet count mea-surement, and comparing this value to recentprior platelet counts, over not performing aplatelet count (Grade 1C).

1.1.3 Platelet Count Monitoring in PatientsReceiving Therapeutic-Dose UFH

1.1.3. For patients who are receiving therapeutic-dose UFH, we suggest platelet count monitor-ing at least every 2 or 3 days from day 4 to day14 (or until heparin is stopped, whichever oc-curs first) over less frequent platelet countmonitoring (Grade 2C).

1.1.4 Platelet Count Monitoring in PostoperativePatients Receiving UFH AntithromboticProphylaxis (Highest Risk Group for HIT)

1.1.4. For patients who are receiving postoper-ative antithrombotic prophylaxis with UFH, ie,the patient population at highest risk for HIT(HIT risk > 1%), we suggest at least every-other-day platelet count monitoring betweenpostoperative days 4 to 14 (or until UFH isstopped, whichever occurs first) over less fre-quent platelet count monitoring (Grade 2C).

1.1.5 Platelet Count Monitoring in Patients inWhom HIT Is Infrequent (0.1 to 1%)

1.1.5. For medical/obstetrical patients who arereceiving prophylactic-dose UFH, postoperativepatients receiving prophylactic-dose LMWH,postoperative patients receiving intravascularcatheter UFH “flushes,” or medical/obstetricalpatients receiving LMWH after first receivingUFH (estimated HIT risk, 0.1 to 1%), we suggest

platelet count monitoring at least every 2 or 3days from day 4 to day 14 (or until heparin isstopped, whichever occurs first), when practical,over less frequent platelet count monitoring(Grade 2C).

1.1.6 Platelet Count Monitoring When HIT Is Rare(� 0.1%): UFH and LMWH

1.1.6. For medical/obstetrical patients who arereceiving only LMWH, or medical patients whoare receiving only intravascular catheter UFHflushes (HIT risk < 0.1%), we suggest cliniciansdo not use routine platelet count monitoring(Grade 2C).

1.1.7 Platelet Count Monitoring When HIT Is Rare(� 0.1%): Fondaparinux

1.1.7. For patients who are receiving fondapa-rinux thromboprophylaxis or treatment, we rec-ommend that clinicians do not use routineplatelet count monitoring (Grade 1C).

1.1.8 Management of Patients in Whom PlateletCounts Are Not Monitored

1.1.8. In outpatients who will receive heparinprophylaxis or treatment, informed consentshould include HIT and its typical sequelae(new thrombosis, skin lesions), and the pa-tient should be advised to seek medical adviceif these events occur (Grade 2C).

1.1.9 Screening for Subclinical HIT AntibodySeroconversion

1.1.9. In patients who receive heparin, or inwhom heparin treatment is planned (eg, forcardiac or vascular surgery), we recommendagainst routine HIT antibody testing in the ab-sence of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs pointing to apotential diagnosis of HIT (Grade 1C).

1.1.10 When Should HIT Be Suspected?

1.1.10. For patients who are receiving heparinor have received heparin within the previous 2weeks, we recommend investigating for a diag-nosis of HIT if the platelet count falls by > 50%,and/or a thrombotic event occurs, between days5 and 14 (inclusive) following initiation of hep-arin, even if the patient is no longer receivingheparin therapy when thrombosis or thrombo-cytopenia has occurred (Grade 1C).




1.2 Special Situation: Anticoagulant Prophylaxisand Platelet Count Monitoring After CardiacSurgery

1.2. For postoperative cardiac surgery patients,we recommend investigating for HIT antibodies ifthe platelet count falls by > 50%, and/or a throm-botic event occurs, between postoperative days 5and 14 (inclusive; day of cardiac surgery � day 0)[Grade 1C].

2.0 Treatment of HIT

2.1 Nonheparin Anticoagulants for Treating HIT(With or Without Thrombosis)

2.1.1. For patients with strongly suspected (orconfirmed) HIT, whether or not complicated bythrombosis, we recommend use of an alternative,nonheparin anticoagulant (danaparoid [Grade1B], lepirudin [Grade 1C], argatroban [Grade1C], fondaparinux [Grade 2C], bivalirudin[Grade 2C]) over the further use of UFH orLMWH therapy or initiation/continuation of aVKA (Grade 1B).2.1.2. For patients receiving lepirudin, theinitial lepirudin infusion rate should be nohigher than 0.10 mg/kg/h (patients with cre-atinine < 90 �mol/L), with lower infusionrates for patients with higher serum creati-nine levels (creatinine, 90 to 140 �mol/L:starting infusion rate, 0.05 mg/kg/h; creati-nine, 140 to 400 �mol/L: starting infusionrate, 0.01 mg/kg/h; creatinine > 400 �mol/L:starting infusion rate, 0.005 mg/kg/h) [Grade1C]. Furthermore, we recommend that theinitial IV bolus either be omitted or, in case ofperceived life- or limb-threatening thrombo-sis, be given at a reduced dose (0.2 mg/kg)[Grade 1C]. Further, we recommend thatAPTT monitoring be performed at 4-h inter-vals until it is apparent that steady statewithin the normal range (1.5 to 2.5 timespatient baseline [or mean laboratory] APTT)is achieved (Grade 1C).2.1.3. When argatroban is used to treat pa-tients who have heart failure, multiple organsystem failure, or severe anasarca, or who arepostcardiac surgery, we suggest beginningthe initial infusion at a rate between 0.5 and1.2 �g/kg/min, with subsequent adjustmentsusing the APTT, over the usual recommendedstarting dose of 2.0 �g/kg/min (Grade 2C).2.1.4. When danaparoid is used to treat pa-tients with strongly suspected (or confirmed)HIT, we recommend a therapeutic-dose regi-men (see text) administered (at least initially)

by the IV route over prophylactic-dose regi-mens or initial SC administration (Grade 1B).2.1.5. For patients with strongly suspected orconfirmed HIT, whether or not there is clinicalevidence of lower-limb deep vein thrombosis(DVT), we recommend routine ultrasonographyof the lower-limb veins for investigation of DVTover not performing routine ultrasonography(Grade 1C).

2.2 VKAs

2.2.1 Management of Direct ThrombinInhibitor-VKA Overlap

2.1.1. For patients with strongly suspected orconfirmed HIT, we recommend against the useof VKA (coumarin) therapy until after the plate-let count has substantially recovered (ie, usuallyto at least 150 � 109/L) over starting VKA ther-apy at a lower platelet count (Grade 1B); thatVKA therapy be started only with low, mainte-nance doses (maximum, 5 mg of warfarin or 6mg of phenprocoumon) rather than with higherinitial doses (Grade 1B); and the nonheparinanticoagulant (eg, lepirudin, argatroban, dan-aparoid) be continued until the platelet counthas reached a stable plateau, the INR hasreached the intended target range, and after aminimum overlap of at least 5 days betweennonheparin anticoagulation and VKA therapyrather than a shorter overlap (Grade 1B).

2.2.2 Reversal of VKA Anticoagulation

2.2.2. For patients receiving a VKA at the time ofdiagnosis of HIT, we recommend use of vitamin K(10 mg po or 5 to 10 mg IV) [Grade 1C].

2.3 LMWH for HIT

2.3.1. For patients with strongly suspected HIT,whether or not complicated by thrombosis, werecommend against use of LMWH (Grade 1B).

2.4 Prophylactic Platelet Transfusions for HIT

2.4.1. For patients with strongly suspected orconfirmed HIT who do not have active bleed-ing, we suggest that prophylactic platelet trans-fusions should not be given (Grade 2C).

3.0 Special Patient Populations

3.1 Patients With Previous HIT UndergoingCardiac or Vascular Surgery

3.1.1. For patients with a history of HIT who areHIT antibody negative and require cardiac sur-




gery, we recommend the use of UFH over anonheparin anticoagulant (Grade 1B).3.1.2. For patients with a history of HIT who areantibody positive by platelet factor 4-dependentenzyme immunosorbent assay but antibodynegative by washed platelet activation assay, werecommend the use of UFH over a nonheparinanticoagulant (Grade 2C).

Remark: Preoperative and postoperative anticoag-ulation, if indicated, should be given with a nonhe-parin anticoagulant.

3.2 Patients With Acute or Subacute HITUndergoing Cardiac Surgery

3.2.1. For patients with acute HIT (thrombocy-topenic, HIT antibody positive) who requirecardiac surgery, we recommend one of thefollowing alternative anticoagulant approaches(in descending order of preference): delayingsurgery (if possible) until HIT has resolved andantibodies are negative (then see Recommen-dation 3.1.1.) or weakly positive (then see Rec-ommendation 3.1.2.) [Grade 1B]; using bivaliru-din for intraoperative anticoagulation duringcardiopulmonary bypass (if techniques of cardiacsurgery and anesthesiology have been adapted tothe unique features of bivalirudin pharmacology)[Grade 1B] or during “off-pump” cardiac surgery(Grade 1B); using lepirudin for intraoperative an-ticoagulation (if ECT is available and patient hasnormal renal function and is judged to be at lowrisk for postcardiac surgery renal dysfunction)[Grade 2C]; using UFH plus the antiplatelet agentepoprostenol (if ECT monitoring is not availableor renal insufficiency precludes lepirudin use)[Grade 2C]; using UFH plus the antiplatelet agent,tirofiban (Grade 2C); or using danaparoid forintraoperative anticoagulation for off-pumpCABG (Grade 2C) over performing the surgerywith UFH when platelet-activating anti-plate-let factor 4/heparin antibodies are known tobe present in a patient with acute or recentHIT.3.2.2. For patients with subacute HIT (plate-let count recovery, but continuing HIT anti-body positive), we recommend delayingsurgery (if possible) until HIT antibodies(washed platelet activation assay) are nega-tive, then using heparin (see Recommenda-tion 3.1.1.) over using a nonheparin anticoag-ulant (Grade 1C). If surgery cannot bedelayed, we suggest the use of a nonheparinanticoagulant (see Recommendation 3.2.1.)over the use of UFH (Grade 2C).

3.3 PCIs

3.3.1. For patients with strongly suspected (orconfirmed) acute HIT who require cardiaccatheterization or PCI, we recommend a non-heparin anticoagulant (bivalirudin [Grade 1B],argatroban [Grade 1C], lepirudin [Grade 1C], ordanaparoid [Grade 1C]) over UFH or LMWH(Grade 1B).3.3.2. For patients with previous HIT (who areantibody negative) who require cardiac cathe-terization or PCI, we suggest use of a nonhepa-rin anticoagulant (see Recommendation 3.3.1.)over UFH or LMWH (Grade 2C).

Prevention of VTE

1.0 General Recommendations

Hospital Thromboprophylaxis Policy

1.2.1. For every general hospital, we recom-mend that a formal, active strategy that ad-dresses the prevention of VTE be developed(Grade 1A).1.2.2. We recommend that the local thrombo-prophylaxis strategy be in the form of a writ-ten, institution-wide thromboprophylaxis policy(Grade 1C).1.2.3. We recommend the use of strategiesshown to increase thromboprophylaxis adher-ence, including the use of computer decisionsupport systems (Grade 1A), preprinted orders(Grade 1B), and periodic audit and feedback(Grade 1C). Passive methods such as distributionof educational materials or educational meet-ings are not recommended as sole strategies toincrease adherence to thromboprophylaxis(Grade 1B).

Mechanical Methods of Thromboprophylaxis

1.4.3.1. We recommend that mechanical meth-ods of thromboprophylaxis be used primarily inpatients at high risk of bleeding (Grade 1A), orpossibly as an adjunct to anticoagulant-basedthromboprophylaxis (Grade 2A).1.4.3.2. For patients receiving mechanicalmethods of thromboprophylaxis, we recom-mend that careful attention be directed towardensuring the proper use of, and optimal adher-ence with, these methods (Grade 1A).

Aspirin as Thromboprophylaxis

1.4.4. We recommend against the use of aspirinalone as thromboprophylaxis against VTE forany patient group (Grade 1A).




Anticoagulant Dosing

1.4.5. For each of the antithrombotic agents, werecommend that clinicians follow manufacturer-suggested dosing guidelines (Grade 1C).

Renal Impairment and Anticoagulant Dosing

1.4.6. We recommend that renal function beconsidered when making decisions about theuse and/or the dose of LMWH, fondaparinux,and other antithrombotic drugs that are clearedby the kidneys, particularly in elderly patients,patients with diabetes mellitus, and those athigh risk for bleeding (Grade 1A). Depending onthe circumstances, we recommend one of thefollowing options in this situation: avoiding theuse of an anticoagulant that bioaccumulates inthe presence of renal impairment, using a lowerdose of the agent, or monitoring the drug levelor its anticoagulant effect (Grade 1B).

Antithrombotic Drugs and Neuraxial Anesthesia/Analgesia or Peripheral Nerve Blocks

1.5.1. For all patients undergoing neuraxialanesthesia or analgesia, we recommend appro-priate patient selection and caution when usinganticoagulant thromboprophylaxis (Grade 1A).1.5.2. For patients receiving deep peripheralnerve blocks, we recommend that the samecautions considered for neuraxial techniques beapplied when using anticoagulant thrombopro-phylaxis (Grade 1C).

2.0 General, Vascular, Gynecologic,Urologic, Laparoscopic, Bariatric,

Thoracic, and CABG Surgery

2.1 General Surgery

2.1.1. For low-risk general surgery patients whoare undergoing minor procedures and have noadditional thromboembolic risk factors, we rec-ommend against the use of specific thrombo-prophylaxis other than early and frequent am-bulation (Grade 1A).2.1.2. For moderate-risk general surgery pa-tients who are undergoing a major procedurefor benign disease, we recommend thrombo-prophylaxis with LMWH, low-dose UFH (LDUH),or fondaparinux (each Grade 1A).2.1.3. For higher-risk general surgery patientswho are undergoing a major procedure for can-cer, we recommend thromboprophylaxis withLMWH, LDUH tid, or fondaparinux (each Grade1A).

2.1.4. For general surgery patients with multi-ple risk factors for VTE who are thought to beat particularly high risk, we recommend that apharmacologic method (ie, LMWH, LDUH tid,or fondaparinux) be combined with the optimaluse of a mechanical method (ie, graduated com-pression stockings [GCS] and/or intermittentpneumatic compression [IPC]) [Grade 1C].2.1.5. For general surgery patients with a highrisk of bleeding, we recommend the optimal useof mechanical thromboprophylaxis with prop-erly fitted GCS or IPC (Grade 1A). When thehigh bleeding risk decreases, we recommendthat pharmacologic thromboprophylaxis besubstituted for or added to the mechanicalthromboprophylaxis (Grade 1C).2.1.6. For patients undergoing major generalsurgical procedures, we recommend that throm-boprophylaxis continue until discharge fromhospital (Grade 1A). For selected high-risk gen-eral surgery patients, including some of thosewho have undergone major cancer surgery orhave previously had VTE, we suggest that con-tinuing thromboprophylaxis after hospital dis-charge with LMWH for up to 28 days be con-sidered (Grade 2A).

2.2 Vascular Surgery

2.2.1. For patients undergoing vascular sur-gery, who do not have additional thromboem-bolic risk factors, we suggest that clinicians notroutinely use specific thromboprophylaxis otherthan early and frequent ambulation (Grade 2B).2.2.2. For patients undergoing major vascularsurgical procedures who have additional throm-boembolic risk factors, we recommend thrombo-prophylaxis with LMWH, LDUH, or fondapa-rinux (Grade 1C).

2.3 Gynecologic Surgery

2.3.1. For low-risk gynecologic surgery patientswho are undergoing minor procedures andhave no additional risk factors, we recommendagainst the use of specific thromboprophylaxisother than early and frequent ambulation(Grade 1A).2.3.2. For gynecology patients undergoing en-tirely laparoscopic procedures, we recommendagainst routine thromboprophylaxis, other thanearly and frequent ambulation (Grade 1B).2.3.3. For gynecology patients undergoing en-tirely laparoscopic procedures in whom addi-tional VTE risk factors are present, we recom-mend the use of thromboprophylaxis with one ormore of LMWH, LDUH, IPC, or GCS (Grade 1C).




2.3.4. For all patients undergoing major gyne-cologic surgery, we recommend that thrombo-prophylaxis be used routinely (Grade 1A).2.3.5 For patients undergoing major gyneco-logic surgery for benign disease, without addi-tional risk factors, we recommend LMWH(Grade 1A), LDUH (Grade 1A), or IPC started justbefore surgery and used continuously while thepatient is not ambulating (Grade 1B).2.3.6. For patients undergoing extensive sur-gery for malignancy, and for patients with ad-ditional VTE risk factors, we recommend rou-tine thromboprophylaxis with LMWH (Grade1A), or LDUH three times daily (Grade 1A), orIPC, started just before surgery and used con-tinuously while the patient is not ambulating(Grade 1A). Alternative considerations include acombination of LMWH or LDUH plus mechan-ical thromboprophylaxis with GCS or IPC, orfondaparinux (all Grade 1C).2.3.7. For patients undergoing major gyneco-logic procedures, we recommend that thrombo-prophylaxis continue until discharge fromhospital (Grade 1A). For selected high-riskgynecology patients, including some of thosewho have undergone major cancer surgery orhave previously had VTE, we suggest that con-tinuing thromboprophylaxis after hospital dis-charge with LMWH for up to 28 days be con-sidered (Grade 2C).

2.4 Urologic Surgery

2.4.1. For patients undergoing transurethral orother low-risk urologic procedures, we recom-mend against the use of specific thrombopro-phylaxis other than early and frequent ambula-tion (Grade 1A).2.4.2. For all patients undergoing major, openurologic procedures, we recommend that throm-boprophylaxis be used routinely (Grade 1A).2.4.3. For patients undergoing major, open uro-logic procedures, we recommend routine throm-boprophylaxis with LDUH bid or tid (Grade 1B),GCS, and/or IPC started just before surgery andused continuously while the patient is notambulating (Grade 1B), LMWH (Grade 1C),fondaparinux (Grade 1C), or the combination ofa pharmacologic method (ie, LMWH, LDUH, orfondaparinux) with the optimal use of a mechan-ical method (ie, GCS and/or IPC) [Grade 1C].2.4.4. For urologic surgery patients who areactively bleeding, or who are at very high riskfor bleeding, we recommend the optimal use ofmechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases

(Grade 1A). When the high bleeding risk de-creases, we recommend that pharmacologicthromboprophylaxis be substituted for or addedto the mechanical thromboprophylaxis (Grade1C).

2.5 Laparoscopic Surgery

2.5.1. For patients undergoing entirely laparo-scopic procedures who do not have additionalthromboembolic risk factors, we recommendagainst the routine use of thromboprophylaxis,other than early and frequent ambulation(Grade 1B).2.5.2. For patients undergoing laparoscopicprocedures, in whom additional VTE risk fac-tors are present, we recommend the use ofthromboprophylaxis with one or more ofLMWH, LDUH, fondaparinux, IPC, or GCS (allGrade 1C).

2.6 Bariatric Surgery

2.6.1. For patients undergoing in-patient bari-atric surgery, we recommend routine thrombo-prophylaxis with LMWH, LDUH tid, fondapa-rinux, or the combination of one of thesepharmacologic methods with optimally usedIPC (each Grade 1C).2.6.2. For patients undergoing inpatient bariat-ric surgery, we suggest that higher doses ofLMWH or LDUH than usual for nonobese pa-tients be used (Grade 2C).

2.7 Thoracic Surgery

2.7.1. For patients undergoing major thoracicsurgery, we recommend routine thrombopro-phylaxis with LMWH, LDUH, or fondaparinux(each Grade 1C).2.7.2. For thoracic surgery patients with a highrisk of bleeding, we recommend the optimal useof mechanical thromboprophylaxis with prop-erly fitted GCS and/or IPC (Grade 1C).

2.8 Coronary Bypass Surgery

2.8.1. For patients undergoing CABG, we rec-ommend the use of thromboprophylaxis withLMWH, LDUH, or optimally used bilateralGCS or IPC (Grade 1C).2.8.2. For patients undergoing CABG, we sug-gest the use of LMWH over LDUH (Grade 2B).2.8.3. For patients undergoing CABG with ahigh risk of bleeding, we recommend the opti-




mal use of mechanical thromboprophylaxis withproperly fitted bilateral GCS or IPC (Grade 1C).

3.0 Orthopedic Surgery

3.1 Elective Hip Replacement

3.1.1. For patients undergoing elective total hipreplacement, we recommend the routine use ofone of the following anticoagulant options: (1)LMWH (at a usual high-risk dose, started 12 hbefore surgery or 12 to 24 h after surgery, or 4to 6 h after surgery at half the usual high-riskdose and then increasing to the usual high-riskdose the following day); (2) fondaparinux (2.5mg started 6 to 24 h after surgery); or (3)adjusted-dose VKA started preoperatively orthe evening of the surgical day (INR target, 2.5;INR range, 2.0 to 3.0) [all Grade 1A].3.1.2. For patients undergoing total hip replace-ment, we recommended against the use of any ofthe following: aspirin, dextran, LDUH, GCS, orvenous foot pump (VFP) as the sole method ofthromboprophylaxis (all Grade 1A).3.1.3. For patients undergoing total hip replace-ment who have a high risk of bleeding, we recom-mend the optimal use of mechanical thrombopro-phylaxis with the VFP or IPC (Grade 1A). Whenthe high bleeding risk decreases, we recommendthat pharmacologic thromboprophylaxis be sub-stituted for or added to the mechanical thrombo-prophylaxis (Grade 1C).

3.2 Elective Knee Replacement

3.2.1. For patients undergoing total knee replace-ment, we recommend routine thromboprophy-laxis using LMWH (at the usual high-risk dose),fondaparinux, or adjusted-dose VKA (INR target,2.5; INR range, 2.0 to 3.0) [all Grade 1A].3.2.2. For patients undergoing total knee replace-ment, the optimal use of IPC is an alternativeoption to anticoagulant thromboprophylaxis(Grade 1B).3.2.3. For patients undergoing total knee replace-ment, we recommend against the use of any of thefollowing as the only method of thromboprophy-laxis: aspirin (Grade 1A), LDUH (Grade 1A), or VFP(Grade 1B).3.2.4. For patients undergoing total knee re-placement who have a high risk of bleeding,we recommend the optimal use of mechanicalthromboprophylaxis with IPC (Grade 1A) orVFP (Grade 1B). When the high bleeding riskdecreases, we recommend that pharmaco-

logic thromboprophylaxis be substituted foror added to the mechanical thromboprophy-laxis (Grade 1C).

3.3 Knee Arthroscopy

3.3.1. For patients undergoing knee arthroscopywho do not have additional thromboembolic riskfactors, we suggest that clinicians not routinelyuse thromboprophylaxis other than early mobili-zation (Grade 2B).3.3.2. For patients undergoing arthroscopicknee surgery who have additional thrombo-embolic risk factors or following a compli-cated procedure, we recommend thrombo-prophylaxis with LMWH (Grade 1B).

3.4 Hip Fracture Surgery

3.4.1. For patients undergoing hip fracture sur-gery, we recommend routine thromboprophylaxisusing fondaparinux (Grade 1A), LMWH (Grade1B), adjusted-dose VKA (INR target, 2.5; INRrange, 2.0 to 3.0) [Grade 1B], or LDUH (Grade 1B).3.4.2. For patients undergoing hip fracture sur-gery, we recommend against the use of aspirinalone (Grade 1A).3.4.3. For patients undergoing hip fracturesurgery in whom surgery is likely to be de-layed, we recommend that thromboprophy-laxis with LMWH or LDUH be initiated duringthe time between hospital admission and surgery(Grade 1C).3.4.4. For patients undergoing hip fracture sur-gery who have a high risk of bleeding, we recom-mend the optimal use of mechanical thrombopro-phylaxis (Grade 1A). When the high bleeding riskdecreases, we recommend that pharmacologicthromboprophylaxis be substituted for or addedto the mechanical thromboprophylaxis (Grade1C).

3.5 Other Thromboprophylaxis Issues in MajorOrthopedic Surgery

Commencement of Thromboprophylaxis

3.5.1.1. For patients receiving LMWH as throm-boprophylaxis in major orthopedic surgery, werecommend starting either preoperatively orpostoperatively (Grade 1A).3.5.1.2. For patients receiving fondaparinux asthromboprophylaxis in major orthopedic sur-gery, we recommend starting either 6 to 8 hafter surgery or the next day (Grade 1A).




Screening for DVT Before Hospital Discharge

3.5.2. For asymptomatic patients following ma-jor orthopedic surgery, we recommend againstthe routine use of DUS screening before hospi-tal discharge (Grade 1A).

Duration of Thromboprophylaxis

3.5.3.1. For patients undergoing total hip re-placement, total knee replacement, or hip frac-ture surgery, we recommend thromboprophy-laxis with one of the recommended options forat least 10 days (Grade 1A).3.5.3.2. For patients undergoing total hip re-placement, we recommend that thrombopro-phylaxis be extended beyond 10 days and up to35 days after surgery (Grade 1A). The recom-mended options for extended thromboprophy-laxis in total hip replacement include LMWH(Grade 1A), a VKA (Grade 1B), or fondaparinux(Grade 1C).3.5.3.3. For patients undergoing total knee re-placement, we suggest that thromboprophylaxisbe extended beyond 10 days and up to 35 daysafter surgery (Grade 2B). The recommended op-tions for extended thromboprophylaxis in totalknee replacement include LMWH (Grade 1C), aVKA (Grade 1C), or fondaparinux (Grade 1C).3.5.3.4. For patients undergoing hip fracture sur-gery, we recommend that thromboprophylaxis beextended beyond 10 days and up to 35 days aftersurgery (Grade 1A). The recommended optionsfor extended thromboprophylaxis in hip fracturesurgery include fondaparinux (Grade 1A), LMWH(Grade 1C), or a VKA (Grade 1C).

3.6 Elective Spine Surgery

3.6.1. For patients undergoing spine surgerywho do not have additional thromboembolicrisk factors, we suggest that clinicians not rou-tinely use specific thromboprophylaxis otherthan early and frequent ambulation (Grade 2C).3.6.2. For patients undergoing spine surgerywho have additional thromboembolic risk fac-tors, such as advanced age, malignancy, pres-ence of a neurologic deficit, previous VTE, oran anterior surgical approach, we recommendthat one of the following thromboprophylaxisoptions be used: postoperative LDUH (Grade1B), postoperative LMWH (Grade 1B), or opti-mal use of perioperative IPC (Grade 1B). Analternative consideration is GCS (Grade 2B).3.6.3. For patients undergoing spine surgerywho have multiple risk factors for VTE, we

suggest that a pharmacologic method (ie,LDUH or LMWH) be combined with the opti-mal use of a mechanical method (ie, GCS and/orIPC) [Grade 2C].

3.7 Isolated Lower-Extremity Injuries Distal to theKnee

3.7.1. For patients with isolated lower-extremityinjuries distal to the knee, we suggest thatclinicians do not routinely use thromboprophy-laxis (Grade 2A).

4.0 Neurosurgery

4.0.1. For patients undergoing major neurosur-gery, we recommend that thromboprophylaxisbe used routinely (Grade 1A), with optimal useof IPC (Grade 1A). Acceptable alternatives toIPC are postoperative LMWH (Grade 2A) orLDUH (Grade 2B).4.0.2. For patients undergoing major neurosur-gery who have a particularly high thrombosisrisk, we suggest that a mechanical method (ie,GCS and/or IPC) be combined with a pharma-cologic method (ie, postoperative LMWH orLDUH) [Grade 2B].

5.0 Trauma, Spinal Cord Injury, Burns

5.1 Trauma

5.1.1. For all major trauma patients, we recom-mend routine thromboprophylaxis, if possible(Grade 1A).5.1.2. For major trauma patients, in the absenceof a major contraindication, we recommendthat clinicians use LMWH thromboprophylaxisstarting as soon as it is considered safe to do so(Grade 1A). An acceptable alternative is thecombination of LMWH and the optimal use of amechanical method of thromboprophylaxis(Grade 1B).5.1.3. For major trauma patients, if LMWHthromboprophylaxis is contraindicated due toactive bleeding or high risk for clinically impor-tant bleeding, we recommend that mechanicalthromboprophylaxis with IPC, or possibly withGCS alone, be used (Grade 1B). When the highbleeding risk decreases, we recommend thatpharmacologic thromboprophylaxis be substi-tuted for or added to the mechanical thrombo-prophylaxis (Grade 1C).5.1.4. In trauma patients, we recommend against




routine DUS screening for asymptomatic DVT(Grade 1B). We do recommend DUS screening inpatients who are at high risk for VTE (eg, in thepresence of a spinal cord injury [SCI], lower-extremity or pelvic fracture, or major head injury)and who have received suboptimal thrombopro-phylaxis or no thromboprophylaxis (Grade 1C).5.1.5. For trauma patients, we recommendagainst the use of an inferior vena cava filter asthromboprophylaxis (Grade 1C).5.1.6. For major trauma patients, we recommendthe continuation of thromboprophylaxis until hos-pital discharge (Grade 1C). For trauma patientswith impaired mobility who undergo inpatientrehabilitation, we suggest continuing thrombo-prophylaxis with LMWH or a VKA (target INR,2.5; range, 2.0 to 3.0) [Grade 2C].

5.2 Acute SCI

5.2.1. For all patients with acute SCI, we rec-ommend that routine thromboprophylaxis beprovided (Grade 1A).5.2.2. For patients with acute SCI, we recom-mend thromboprophylaxis with LMWH, com-menced once primary hemostasis is evident(Grade 1B). Alternatives include the combineduse of IPC and either LDUH (Grade 1B) orLWMH (Grade 1C).5.2.3. For patients with acute SCI, we recom-mend the optimal use of IPC and/or GCS ifanticoagulant thromboprophylaxis is contrain-dicated because of high bleeding risk earlyafter injury (Grade 1A). When the high bleedingrisk decreases, we recommend that pharmaco-logic thromboprophylaxis be substituted for oradded to the mechanical thromboprophylaxis(Grade 1C).5.2.4. For patients with an incomplete SCI as-sociated with evidence of a spinal hematoma onCT or MRI, we recommend the use of mechan-ical thromboprophylaxis instead of anticoagu-lant thromboprophylaxis at least for the firstfew days after injury (Grade 1C).5.2.5. Following acute SCI, we recommendagainst the use of LDUH alone (Grade 1A).5.2.6. For patients with SCI, we recommendagainst the use of an inferior vena cava filter asthromboprophylaxis (Grade 1C).5.2.7. For patients undergoing rehabilitationfollowing acute SCI, we recommend the contin-uation of LMWH thromboprophylaxis or con-version to an oral VKA (INR target, 2.5; range,2.0 to 3.0) [Grade 1C].

5.3 Burns

5.3.1. For burn patients who have additionalrisk factors for VTE, including one or more ofthe following: advanced age, morbid obesity,extensive or lower-extremity burns, concomi-tant lower-extremity trauma, use of a femoralvenous catheter, and/or prolonged immobility,we recommend routine thromboprophylaxis ifpossible (Grade 1A).5.3.2. For burn patients who have additionalrisk factors for VTE, if there are no contraindi-cations, we recommend the use of eitherLMWH or LDUH, starting as soon as it isconsidered safe to do so (Grade 1C).5.3.3. For burn patients who have a high bleed-ing risk, we recommend mechanical thrombo-prophylaxis with GCS and/or IPC until thebleeding risk decreases (Grade 1A).

6.0 Medical Conditions

6.0.1. For acutely ill medical patients admittedto hospital with congestive heart failure orsevere respiratory disease, or who are confinedto bed and have one or more additional riskfactors, including active cancer, previous VTE,sepsis, acute neurologic disease, or inflamma-tory bowel disease, we recommend thrombo-prophylaxis with LMWH (Grade 1A), LDUH(Grade 1A), or fondaparinux (Grade 1A).6.0.2. For medical patients with risk factors forVTE, and in whom there is a contraindication toanticoagulant thromboprophylaxis, we recom-mend the optimal use of mechanical thrombo-prophylaxis with GCS or IPC (Grade 1A).

7.0 Cancer Patients

7.0.1. For cancer patients undergoing surgicalprocedures, we recommend routine thrombo-prophylaxis that is appropriate for the type ofsurgery (Grade 1A). Refer to the recommenda-tions in the relevant surgical subsections.7.0.2. For cancer patients who are bedriddenwith an acute medical illness, we recommendroutine thromboprophylaxis as for other high-risk medical patients (Grade 1A). Refer to therecommendations in Section 6.0.7.0.3. For cancer patients with indwelling centralvenous catheters, we recommend that cliniciansnot use either prophylactic doses of LMWH(Grade 1B) or mini-dose warfarin (Grade 1B) to tryto prevent catheter-related thrombosis.




7.0.4. For cancer patients receiving chemother-apy or hormonal therapy, we recommend againstthe routine use of thromboprophylaxis for theprimary prevention of VTE (Grade 1C).7.0.5. For cancer patients, we recommend againstthe routine use of primary thromboprophylaxis totry to improve survival (Grade 1B).

8.0 Critical Care

8.1. For patients admitted to a critical careunit, we recommend routine assessment forVTE risk and routine thromboprophylaxis inmost (Grade 1A).8.2. For critical care patients who are at moder-ate risk for VTE (eg, medically ill or postoperativegeneral surgery patients), we recommend usingLMWH or LDUH thromboprophylaxis (Grade 1A).8.3. For critical care patients who are at higherrisk (eg, following major trauma or orthopedicsurgery), we recommend LMWH thrombopro-phylaxis (Grade 1A).8.4. For critical care patients who are at high riskfor bleeding, we recommend the optimal use ofmechanical thromboprophylaxis with GCS and/orIPC at least until the bleeding risk decreases(Grade 1A). When the high bleeding risk de-creases, we recommend that pharmacologicthromboprophylaxis be substituted for or addedto the mechanical thromboprophylaxis (Grade1C).

9.0 Long-Distance Travel

9.1. For travelers who are taking flights > 8 h, werecommend the following general measures:avoidance of constrictive clothing around thelower extremities or waist, maintenance of ade-quate hydration, and frequent calf muscle con-traction (Grade 1C).9.2. For long-distance travelers with additionalrisk factors for VTE, we recommend the generalmeasures listed above. If active thromboprophy-laxis is considered because of a perceived highrisk of VTE, we suggest the use of properly fitted,below-knee GCS, providing 15 to 30 mm Hg ofpressure at the ankle (Grade 2C), or a singleprophylactic dose of LMWH, injected prior todeparture (Grade 2C).9.3. For long-distance travelers, we recommendagainst the use of aspirin for VTE prevention(Grade 1B).

Antithrombotic Therapy for VenousThromboembolic Disease

1.1 Initial Anticoagulation of Acute DVT of the Leg

1.1.1. For patients with objectively confirmedDVT, we recommend short-term treatmentwith SC LMWH (Grade 1A), IV UFH (Grade 1A),monitored SC UFH (Grade 1A), fixed-dose SCUFH (Grade 1A), or SC fondaparinux (Grade 1A)rather than no such acute treatment.1.1.2. For patients with a high clinical suspi-cion of DVT, we recommend treatment withanticoagulants while awaiting the outcome ofdiagnostic tests (Grade 1C).1.1.3. In patients with acute DVT, we recom-mend initial treatment with LMWH, UFH, orfondaparinux for at least 5 days and until theINR is > 2.0 for 24 h (Grade 1C).1.1.4. In patients with acute DVT, we recom-mend initiation of VKA together with LMWH,UFH, or fondaparinux on the first treatmentday rather than delayed initiation of VKA(Grade 1A).

1.2 IV UFH for the Initial Treatment of DVT

1.2.1. In patients with acute DVT, if IV UFH ischosen, we recommend that, after an initial IVbolus (80 U/kg or 5,000 U) it be administered bycontinuous infusion (initially at a dose of 18U/kg/h or 1,300 U/h) with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of 0.3to 0.7 IU/mL anti-Xa activity by the amidolyticassay rather than administration as IV bolusesthroughout treatment, or administration with-out coagulation monitoring (Grade 1C).

1.3 SC UFH Compared With IV Heparin for theInitial Treatment of DVT

1.3.1. In patients with acute DVT, if monitoredSC UFH is chosen, we recommend an initialdose of 17,500 U, or a weight-adjusted dose ofabout 250 U/kg, bid, with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of 0.3to 0.7 IU/mL anti-Xa activity when measured 6 hafter injection rather than starting with a smallerinitial dose (Grade 1C) [see also Section 1.5].1.3.2. In patients with acute DVT, if fixed-dose, unmonitored SC UFH is chosen, werecommend an initial dose of 333 U/kg fol-lowed by a twice-daily dose of 250 U/kg ratherthan nonweight-based dosing (Grade 1C) [seealso Section 1.5].




1.4 LMWH for the Initial Treatment of DVT

1.4.1. In patients with acute DVT, we recom-mend initial treatment with LMWH SC once ortwice daily, as an outpatient if possible (Grade1C) or as an inpatient if necessary (Grade 1A),rather than treatment with IV UFH.1.4.2. In patients with acute DVT treated withLMWH, we recommend against routine moni-toring with anti-factor Xa level measurements(Grade 1A).1.4.3. In patients with acute DVT and severerenal failure, we suggest UFH over LMWH(Grade 2C).

1.9 Catheter-Directed Thrombolysis for Acute DVT

1.9.1. In selected patients with extensive acuteproximal DVT (eg, iliofemoral DVT, symptomsfor < 14 days, good functional status, life ex-pectancy of > 1 year) who have a low risk ofbleeding, we suggest that catheter-directedthrombolysis may be used to reduce acutesymptoms and postthrombotic morbidity if ap-propriate expertise and resources are available(Grade 2B).1.9.2. After successful catheter-directed throm-bolysis in patients with acute DVT, we suggestcorrection of underlying venous lesions usingballoon angioplasty and stents (Grade 2C).1.9.3. We suggest pharmacomechanical throm-bolysis (eg, with inclusion of thrombus frag-mentation and/or aspiration) in preference tocatheter-directed thrombolysis alone to shortentreatment time if appropriate expertise and re-sources are available (Grade 2C).1.9.4. After successful catheter-directed throm-bolysis in patients with acute DVT, we recom-mend the same intensity and duration of antico-agulant therapy as for comparable patients whodo not undergo catheter-directed thrombolysis(Grade 1C).

1.10 Systemic Thrombolytic Therapy for AcuteDVT

1.10.1. In selected patients with extensive prox-imal DVT (eg, symptoms for < 14 days, goodfunctional status, life expectancy of > 1 year)who have a low risk of bleeding, we suggest thatsystemic thrombolytic therapy may be used toreduce acute symptoms and postthromboticmorbidity if catheter-directed thrombolysis isnot available (Grade 2C).

1.11 Percutaneous Venous Thrombectomy

1.11.1. In patients with acute DVT, we suggestthat they should not be treated with percutaneousmechanical thrombectomy alone (Grade 2C).

1.12 Operative Venous Thrombectomy for AcuteDVT

1.12.1. In selected patients with acute iliofem-oral DVT (eg, symptoms for < 7 days, goodfunctional status, and life expectancy of > 1year), we suggest that operative venous throm-bectomy may be used to reduce acute symptomsand postthrombotic morbidity if appropriateexpertise and resources are available (Grade2B). If such patients do not have a high risk ofbleeding, we suggest that catheter-directedthrombolysis is usually preferable to operativevenous thrombectomy (Grade 2C).1.12.2. In patients who undergo operative ve-nous thrombectomy, we recommend the sameintensity and duration of anticoagulant therapyafterwards as for comparable patients who donot undergo venous thrombectomy (Grade 1C).

1.13 Vena Caval Filters for the Initial Treatment ofDVT

1.13.1. For patients with DVT, we recommendagainst the routine use of a vena cava filter inaddition to anticoagulants (Grade 1A).1.13.2. For patients with acute proximal DVT, ifanticoagulant therapy is not possible because ofthe risk of bleeding, we recommend placementof an inferior vena cava filter (Grade 1C).1.13.3. For patients with acute DVT who havean inferior vena cava filter inserted as an alter-native to anticoagulation, we recommend thatthey should subsequently receive a conven-tional course of anticoagulant therapy if theirrisk of bleeding resolves (Grade 1C).

1.14 Immobilization for the Treatment of AcuteDVT

1.14.1. In patients with acute DVT, we recom-mend early ambulation in preference to initialbed rest when this is feasible (Grade 1A).

2.1 Duration of Anticoagulant Therapy

2.1.1. For patients with DVT secondary to atransient (reversible) risk factor, we recom-mend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A).




2.1.2. For patients with unprovoked DVT, werecommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patientswith unprovoked DVT should be evaluated forthe risk-benefit ratio of long-term therapy(Grade 1C). For patients with a first unpro-voked VTE that is a proximal DVT, and inwhom risk factors for bleeding are absent andfor whom good anticoagulant monitoring isachievable, we recommend long-term treat-ment (Grade 1A).Underlying values and preferences: This recom-mendation attaches a relatively high value toprevention of recurrent VTE and a lower value tothe burden of long-term anticoagulant therapy.For patients with a second episode of unpro-voked VTE, we recommend long-term treat-ment (Grade 1A). For patients with a firstisolated distal DVT that is unprovoked, wesuggest that 3 months of anticoagulant ther-apy is sufficient rather than indefinite ther-apy (Grade 2B).2.1.3. For patients with DVT and cancer, werecommend LMWH for the first 3 to 6 monthsof long-term anticoagulant therapy (Grade1A). For these patients, we recommend sub-sequent anticoagulant therapy with VKA orLMWH indefinitely or until the cancer isresolved (also, see Section 2.4) [Grade 1C].2.1.4. In patients who receive long-term anti-coagulant treatment, the risk-benefit ratio ofcontinuing such treatment should be reas-sessed in the individual patient at periodicintervals (Grade 1C).

2.2 Intensity of Anticoagulant Effect

2.2.1. In patients with DVT, we recommendthat the dose of VKA be adjusted to maintain atarget INR of 2.5 (INR range, 2.0 to 3.0) for alltreatment durations (Grade 1A). For patientswith unprovoked DVT who have a strong pref-erence for less frequent INR testing to monitortheir therapy, after the first 3 months of con-ventional-intensity anticoagulation (INR range,2.0 to 3.0), we recommend low-intensity ther-apy (INR range, 1.5 to 1.9) with less frequentINR monitoring over stopping treatment (Grade1A). We recommend against high-intensity VKAtherapy (INR range, 3.1 to 4.0) compared to anINR range of 2.0 to 3.0 (Grade 1A).

2.6 Treatment of Asymptomatic DVT of the Leg

2.6.1. In patients who are unexpectedly foundto have asymptomatic DVT, we recommend the

same initial and long-term anticoagulation asfor comparable patients with symptomatic DVT(Grade 1C).

3.1 Elastic Stockings and Compression BandagesTo Prevent Postthrombotic Syndrome

3.1.1. For a patient who has had a symptomaticproximal DVT, we recommend the use of anelastic compression stocking with an ankle pres-sure gradient of 30 to 40 mm Hg if feasible (Grade1A). Compression therapy, which may include useof bandages acutely, should be started as soon asfeasible after starting anticoagulant therapy andshould be continued for a minimum of 2 years,and longer if patients have symptoms of thepostthrombotic syndrome (PTS). (Note: feasibil-ity, both short and long term, refers to ability ofpatients and their caregivers to apply and removestockings.)Underlying values and preferences: This recommenda-tion attaches a relatively high value to long-term pre-vention of the postthrombotic syndrome (PTS) and alow value to the burden (eg, inconvenience or discom-fort) associated with wearing stockings.

3.2 Physical Treatment of PTS Without Venous LegUlcers

3.2.1. For patients with severe edema of theleg due to PTS, we suggest a course of IPC(Grade 2B).

3.2.2. For patients with mild edema of the legdue to PTS, we suggest the use of elastic com-pression stockings (Grade 2C).

3.3 Physical Treatment of Venous Leg Ulcers

3.3.1. In patients with venous ulcers resistant tohealing with wound care and compression, wesuggest the addition of IPC (Grade 2B).

3.4 Hyperbaric Oxygen and the Management ofPatients With Venous Ulcers

3.4.1. For patients with venous ulcers, we suggestthat hyperbaric oxygen not be used (Grade 2B).

3.5.1 Pentoxifylline

3.5.1. In patients with venous leg ulcers, wesuggest pentoxifylline, 400 mg po tid, in addi-tion to local care and compression and/or IPC(Grade 2B).




3.5.2 Micronized Purified Flavonoid Fraction orSulodexide for the Treatment of Venous Leg Ulcers

3.5.2. In patients with persistent venous ulcers,we suggest that rutosides, in the form of mi-cronized purified flavonoid fraction givenorally, or sulodexide administered intramuscu-larly and then orally, be added to local care andcompression (Grade 2B).

4.1 IV or SC UFH, SC LMWH, SC Fondaparinux,and VKA for the Initial Treatment of PulmonaryEmbolism

4.1.1. For patients with objectively confirmedpulmonary embolism (PE), we recommendshort-term treatment with SC LMWH (Grade1A), IV UFH (Grade 1A), monitored SC UFH(Grade 1A), fixed-dose SC UFH (Grade 1A), or SCfondaparinux (Grade 1A) rather than no suchacute treatment. Patients with acute PE shouldalso be routinely assessed for treatment withthrombolytic therapy (see Section 4.3 for re-lated discussion and recommendations).4.1.2. For patients in whom there is a highclinical suspicion of PE, we recommend treat-ment with anticoagulants while awaiting theoutcome of diagnostic tests (Grade 1C).4.1.3. In patients with acute PE, we recommendinitial treatment with LMWH, UFH, or fondapa-rinux for at least 5 days and until the INR is > 2.0for at least 24 h (Grade 1C).4.1.4. In patients with acute PE, we recommendinitiation of VKA together with LMWH, UFH, orfondaparinux on the first treatment day ratherthan delayed initiation of VKA (Grade 1A).4.1.5. In patients with acute PE, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it is administered bycontinuous infusion (initially at dose of 18U/kg/h or 1,300 U/h) with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of 0.3to 0.7 IU/mL anti-Xa activity by the amidolyticassay rather than administration as IV bolusesthroughout treatment, or administration with-out coagulation monitoring (Grade 1C).4.1.6. In patients with acute PE, if monitoredSC UFH is chosen, we recommend an initialdose of 17,500 U, or a weight-adjusted dose ofabout 250 U/kg, bid, with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of 0.3to 0.7 IU/mL anti-Xa activity when measured6 h after injection rather than starting with asmaller initial dose (Grade 1C).

4.1.7. In patients with acute PE, if fixed-dose,unmonitored SC UFH is chosen, we recom-mend an initial dose of 333 U/Kg followed by atwice-daily dose of 250 U/kg rather than non–weight-based dosing (Grade 1C).4.1.8. In patients with acute nonmassive PE, werecommend initial treatment with LMWH overIV UFH (Grade 1A). In patients with massive PE,in other situations where there is concern aboutSC absorption, or in patients in whom throm-bolytic therapy is being considered or planned,we suggest IV UFH over SC LMWH, SCfondaparinux, or SC UFH (Grade 2C).4.1.9. In patients with acute PE treated withLMWH, we recommend against routine monitoringwith anti-factor Xa level measurements (Grade 1A).4.1.10. In patients with acute PE and severerenal failure, we suggest UFH over LMWH(Grade 2C).

4.3 Systemically and Locally AdministeredThrombolytic Therapy for PE

4.3.1. All PE patients should undergo rapid riskstratification (Grade 1C). For patients with evi-dence of hemodynamic compromise, we recom-mend use of thrombolytic therapy unless thereare major contraindications owing to bleedingrisk (Grade 1B). Thrombolysis in these patientsshould not be delayed, because irreversiblecardiogenic shock may ensue. In selected high-risk patients without hypotension who arejudged to have a low risk of bleeding, wesuggest administration of thrombolytic therapy(Grade 2B). The decision to use thrombolytictherapy depends on the clinician’s assessmentof PE severity, prognosis, and risk of bleeding.For the majority of patients with PE, we recom-mend against using thrombolytic therapy(Grade 1B).4.3.2. In patients with acute PE, when a throm-bolytic agent is used, we recommend that treat-ment be administered via a peripheral veinrather than placing a pulmonary artery catheterto administer treatment (Grade 1B).4.3.3. In patients with acute PE, with adminis-tration of thrombolytic therapy, we recommenduse of regimens with short infusion times (eg, a2-h infusion) over those with prolonged infusiontimes (eg, a 24-h infusion) [Grade 1B].

4.4 Catheter Extraction or Fragmentation for theInitial Treatment of PE

4.4.1. For most patients with PE, we recom-mend against use of interventional catheteriza-




tion techniques (Grade 1C). In selected highlycompromised patients who are unable to re-ceive thrombolytic therapy because of bleedingrisk, or whose critical status does not allowsufficient time for systemic thrombolytic ther-apy to be effective, we suggest use of interven-tional catheterization techniques if appropriateexpertise is available (Grade 2C).

4.5 Pulmonary Embolectomy for the InitialTreatment of PE

4.5.1. In selected highly compromised patientswho are unable to receive thrombolytic therapybecause of bleeding risk, or whose critical sta-tus does not allow sufficient time for systemicthrombolytic therapy to be effective, we suggestthat pulmonary embolectomy may be used ifappropriate expertise is available (Grade 2C).

4.6 Vena Caval Filters for the Initial Treatmentof PE

4.6.1. For most patients with PE, we recom-mend against the routine use of a vena cavalfilter in addition to anticoagulants (Grade 1A).4.6.2. In patients with acute PE, if anticoagulanttherapy is not possible because of risk of bleed-ing, we recommend placement of an inferiorvena caval filter (Grade 1C).4.6.3. For patients with acute PE who have aninferior vena caval filter inserted as an alterna-tive to anticoagulation, we recommend thatthey should subsequently receive a conven-tional course of anticoagulant therapy if theirrisk of bleeding resolves (Grade 1C).

5.0 Long-term Treatment of Acute PE

5.1.1. For patients with PE secondary to atransient (reversible) risk factor, we recom-mend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A).5.1.2. For patients with unprovoked PE, werecommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patientswith unprovoked PE should be evaluated forthe risk-benefit ratio of long-term therapy(Grade 1C). For patients with a first unprovokedepisode of VTE that is a PE, and in whom riskfactors for bleeding are absent and for whomgood anticoagulant monitoring is achievable,we recommend long-term treatment (Grade 1A).Underlying values and preferences: This recommen-dation attaches a relatively high value to prevention

of recurrent VTE and a lower value to the burden oflong-term anticoagulant therapy.For patients with a second episode of unpro-voked VTE, we recommend long-term treat-ment (Grade 1A).5.1.3. For patients with PE and cancer, werecommend LMWH for the first 3 to 6 monthsof long-term anticoagulant therapy (Grade 1A).For these patients, we recommend subsequentanticoagulant therapy with VKA or LMWH in-definitely or until the cancer is resolved (Grade1C).5.1.4. In patients who receive long-term antico-agulant treatment, the risk-benefit ratio of con-tinuing such treatment should be reassessed inthe individual patient at periodic intervals(Grade 1C).5.1.5. In patients with PE, we recommend that thedose of VKA be adjusted to maintain a target INRof 2.5 (INR range, 2.0 to 3.0) for all treatmentdurations (Grade 1A). For patients with unpro-voked PE who have a strong preference for lessfrequent INR testing to monitor their therapy,after the first 3 months of conventional-intensityanticoagulation (INR range, 2.0 to 3.0), we rec-ommend low-intensity therapy (INR range,1.5 to 1.9) with less frequent INR monitoringover stopping treatment (Grade 1A). We rec-ommend against high-intensity VKA therapy(INR range, 3.1 to 4.0) compared with an INRrange of 2.0 to 3.0 (Grade 1A).5.1.6. In patients who are unexpectedly foundto have asymptomatic PE, we recommend thesame initial and long-term anticoagulation asfor comparable patients with symptomatic PE(Grade 1C).

6.1 Pulmonary Thromboendarterectomy, VKA, andVena Caval Filter for the Treatment of CTPH

6.1.1. In selected patients with chronic throm-boembolic pulmonary hypertension (CTPH),such as those with central disease under thecare of an experienced surgical/medical team,we recommend pulmonary thromboendarterec-tomy (Grade 1C).6.1.2. For all patients with CTPH, we recom-mend life-long treatment with a VKA targetedto an INR of 2.0 to 3.0 (Grade 1C).6.1.3. For patients with CTPH undergoingpulmonary thromboendarterectomy, we sug-gest the placement of a permanent vena cavalfilter before or at the time of the procedure(Grade 2C).6.1.4. For patients with inoperable CTPH, wesuggest referral to a center with expertise in




pulmonary hypertension so that patients canbe evaluated for alternative treatments, suchas vasodilator therapy or balloon pulmonaryangioplasty (Grade 2C).

7.1 Treatment of Infusion Thrombophlebitis

7.1.1. For patients with symptomatic infusionthrombophlebitis as a complication of IV infu-sion, we suggest oral diclofenac or anothernonsteroidal antiinflammatory drug (Grade 2B),topical diclofenac gel (Grade 2B), or heparin gel(Grade 2B) until resolution of symptoms or forup to 2 weeks. We recommend against the useof systemic anticoagulation (Grade 1C).

7.2 Treatment of Superficial Vein Thrombosis

7.2.1. For patients with spontaneous superficialvein thrombosis, we suggest prophylactic orintermediate doses of LMWH (Grade 2B) orintermediate doses of UFH (Grade 2B) for atleast 4 weeks. We suggest that as an alternativeto 4 weeks of LMWH or UFH, VKA (target INR,2.5; range, 2.0 to 3.0) can be overlapped with 5days of UFH and LMWH and continued for 4weeks (Grade 2C). We suggest that oral nonste-roidal antiinflammatory drugs should not beused in addition to anticoagulation (Grade 2B).We recommend medical treatment with antico-agulants over surgical treatment (Grade 1B).

Remark: It is likely that less extensive superficialvein thrombosis (ie, where the affected venous seg-ment is short in length or further from the saphe-nofemoral junction) does not require treatment withanticoagulants. It is reasonable to use oral or topicalnonsteroidal antiinflammatory drugs for symptomcontrol in such cases.

8.1 IV UFH or LMWH for the Initial Treatment ofUEDVT

8.1.1. For patients with acute upper-extremityDVT, we recommend initial treatment withtherapeutic doses of LMWH, UFH, or fondapa-rinux as described for leg DVT (see Section 1)[Grade 1C].

8.2 Thrombolytic Therapy for the Initial Treatmentof UEDVT

8.2.1. For most patients with acute upper-extremity DVT, we recommend against theroutine use of systemic or catheter-directedthrombolytic therapy (Grade 1C).8.2.2. In selected patients with acute upper-

extremity DVT (eg, in those with a low risk ofbleeding and severe symptoms of recent onset)we suggest a short course of catheter-directedthrombolytic therapy may be used for initial treat-ment if appropriate expertise and resources areavailable (Grade 2C).

8.3 Catheter Extraction, Surgical Thrombectomy,Transluminal Angioplasty, Stent Placement, StagedApproach of Lysis Followed by Interventional orSurgical Procedure, and Superior Vena CavaFilter Insertion, for the Initial Treatment ofUEDVT

8.3.1. For most patients with acute upper-extremityDVT, we recommend against the routine use ofcatheter extraction, surgical thrombectomy,transluminal angioplasty, stent placement, stagedapproach of lysis followed by interventional orsurgical procedure, or superior vena cava filterplacement (Grade 1C).8.3.2. In selected patients with acute upper-extremity DVT (eg, those with primary upper-extremity DVT and failure of anticoagulant orthrombolytic treatment who have severe persis-tent symptoms), we suggest that catheter extrac-tion, surgical thrombectomy, transluminal angio-plasty, or a staged approach of lysis followed by avascular interventional or surgical procedure maybe used, if appropriate expertise and resourcesare available (all Grade 2C).8.3.3. In selected patients with acute upper-extremity DVT (eg, those in whom anticoagulanttreatment is contraindicated and there is clearevidence of DVT progression or clinically signifi-cant PE), we suggest placement of a superior venacava filter (Grade 2C).

8.4 Anticoagulants for the Long-term Treatment ofUEDVT

8.4.1. For patients with acute upper-extremityDVT, we recommend treatment with a VKA for> 3 months (Grade 1C).

Remark: A similar process as for lower-extremityDVT (see Section 2) should be used to determinethe optimal duration of anticoagulation.8.4.2. For most patients with upper-extremityDVT in association with an indwelling centralvenous catheter, we suggest that the catheternot be removed if it is functional and there is anongoing need for the catheter (Grade 2C).8.4.3. For patients who have upper-extremityDVT in association with an indwelling centralvenous catheter that is removed, we do not recom-mend that the duration of long-term anticoagulanttreatment be shortened to < 3 months (Grade 2C).




8.5 Prevention of PTS of the Arm

8.5.1. For patients at risk for PTS after upper-extremity DVT, we do not suggest routine useof elastic compression or venoactive medica-tions (Grade 2C).

8.6 Treatment of PTS of the Arm

8.6.1. In patients with upper-extremity DVTwho have persistent edema and pain, we sug-gest elastic bandages or elastic compressionsleeves to reduce symptoms of PTS of the upperextremity (Grade 2C).

Antithrombotic Therapy in AF

1.1 AF

1.1.1. In patients with AF, including those withparoxysmal AF, who have had a prior ischemicstroke, transient ischemic attack, or systemicembolism, we recommend long-term anticoag-ulation with an oral VKA, such as warfarin,targeted at an INR of 2.5 (range, 2.0 to 3.0)because of the high risk of future ischemicstroke faced by this set of patients (Grade 1A).Timing of the initiation of VKA therapy after anacute ischemic stroke involves balancing the riskof hemorrhagic conversion with short-term risk ofrecurrent ischemic stroke and is addressed in“Ischemic Stroke” chapter by Albers et al in thissupplement.1.1.2. In patients with AF, including those withparoxysmal AF, who have two or more of thefollowing risk factors for future ischemic stroke,we recommend long-term anticoagulation with anoral VKA, such as warfarin, targeted at an INR of2.5 (range, 2.0 to 3.0) because of the increasedrisk of future ischemic stroke faced by this set ofpatients (Grade 1A). Two or more of the followingrisk factors apply: (1) age > 75 years, (2) history ofhypertension, (3) diabetes mellitus, and (4) mod-erately or severely impaired left ventricular sys-tolic function and/or heart failure.

Remark: Recommendations 1.1.1 and 1.1.2 corre-spond to a recommendation of oral VKA therapy forindividuals with a score � 2 using the CHADS2 classi-fication. For these and all other recommendations oflong-term therapy in this chapter, “long-term” meanslifelong unless a contraindication emerges.1.1.3. In patients with AF, including those withparoxysmal AF, with only one of the risk factorslisted below, we recommend long-term anti-thrombotic therapy (Grade 1A), either as anticoag-

ulation with an oral VKA, such as warfarin, tar-geted at an INR of 2.5 (range, 2.0 to 3.0) [Grade1A], or as aspirin, at a dose of 75 to 325 mg/d(Grade 1B). For these patients at intermediate riskof ischemic stroke, we suggest a VKA rather thanaspirin (Grade 2A). This set of patients with AF isdefined by having one of the following risk fac-tors: (1) age > 75 years, (2) history of hyperten-sion, (3) diabetes mellitus, and (4) moderately orseverely impaired left ventricular systolic func-tion and/or heart failure.1.1.4. In patients with AF, including those withparoxysmal AF, aged < 75 years and with none ofthe other risk factors listed above, we recommendlong-term aspirin therapy at a dose of 75 to 325mg/d (Grade 1B) because of their low risk ofischemic stroke.Underlying values and preferences: Anticoagula-tion with oral VKAs, such as warfarin, has fargreater efficacy than aspirin in preventing stroke,and particularly in preventing severe ischemicstroke, in AF. We recommend the option ofaspirin therapy for lower risk groups in 1.1.3 and1.1.4, above, estimating the absolute expectedbenefit of anticoagulant therapy may not be worththe increased hemorrhagic risk and burden ofanticoagulation. Individual lower-risk patients mayrationally choose anticoagulation over aspirin ther-apy to gain greater protection against ischemicstroke if they value protection against stroke muchmore highly than reducing risk of hemorrhage andthe burden of managing anticoagulation. Our rec-ommendations assume that the patient is not athigh risk for bleeding and that good control ofanticoagulation will occur.

Remarks: These recommendations apply to pa-tients with persistent or paroxysmal AF and not topatients with a single brief episode of AF due to areversible cause, such as an acute pulmonaryinfection. The optimal dose of aspirin for patientswith AF is unclear. The largest effect of aspirinwas seen in the first Stroke Prevention in AF(SPAF I) trial, which used aspirin at 325 mg/d.However, generalizing from trials of aspirin for allantithrombotic indications and from physiologicstudies, we feel the best balance of efficacy andsafety is achieved at low doses of aspirin, ie, 75 to100 mg/d (see the “Antiplatelet Drugs” chapter byPatrono et al in this supplement).

1.2 Atrial Flutter

1.2. For patients with atrial flutter, we recom-mend that antithrombotic therapy decisions fol-low the same risk-based recommendations asfor AF (Grade 1C).




1.3 Valvular Heart Disease and AF

1.3.1. For patients with AF and mitral stenosis,we recommend long-term anticoagulation withan oral VKA, such as warfarin (target INR 2.5;range, 2.0 to 3.0) [Grade 1B].1.3.2. For patients with AF and prostheticheart valves, we recommend long-term anti-coagulation with an oral VKA, such as warfa-rin, at a dose intensity appropriate for thespecific type of prosthesis (Grade 1B). See the“Valvular and Structural Heart Disease”chapter by Salem et al for antithromboticmanagement of patients with valvular heartdisease and AF.

1.4 AF Following Cardiac Surgery

1.4. For patients with AF occurring shortly afteropen-heart surgery and lasting > 48 h, we sug-gest anticoagulation with an oral VKA, such aswarfarin, if bleeding risks are acceptable (Grade2C). The target INR is 2.5 (range, 2.0 to 3.0). Wesuggest continuing anticoagulation for 4 weeksfollowing reversion to and maintenance of nor-mal sinus rhythm, particularly if patients haverisk factors for thromboembolism (Grade 2C).

2.1 Anticoagulation for Elective Cardioversionof AF

2.1.1. For patients with AF of > 48 h or ofunknown duration for whom pharmacologic orelectrical cardioversion is planned, we recom-mend anticoagulation with an oral VKA, such aswarfarin, at a target INR of 2.5 (range, 2.0 to3.0) for 3 weeks before elective cardioversionand for at least 4 weeks after sinus rhythm hasbeen maintained (Grade 1C).

Remark: This recommendation applies to all pa-tients with AF, including those whose risk factorstatus would otherwise indicate a low risk for stroke.Patients with risk factors for thromboembolismshould continue anticoagulation beyond 4 weeksunless there is convincing evidence that sinus rhythmis maintained. For patients with recurrent episodesof AF, Recommendations 1.1.1, 1.1.2, 1.1.3, and1.1.4 apply.2.1.2. For patients with AF of > 48 h or ofunknown duration who are undergoing phar-macologic or electrical cardioversion, we rec-ommend either immediate anticoagulation withIV UFH (target PTT, 60 s; range, 50 to 70 s), orLMWH (at full DVT treatment doses), or atleast 5 days of warfarin (target INR of 2.5;range, 2.0 to 3.0) at the time of cardioversion

and performance of a screening multiplaneTEE. If no thrombus is seen, cardioversion issuccessful, and sinus rhythm is maintained, werecommend anticoagulation (target INR, 2.5;range, 2.0 to 3.0) for at least 4 weeks. If athrombus is seen on TEE, then cardioversionshould be postponed and anticoagulationshould be continued indefinitely. We recom-mend obtaining a repeat TEE before attemptinglater cardioversion (all Grade 1B addressing theequivalence of TEE-guided vs non–TEE-guided car-dioversion; see Recommendation 2.1.1, above).

Remark: The utility of the conventional andTEE-guided approaches is likely comparable. Thisrecommendation applies to all patients with AF,including those whose risk factor status wouldotherwise indicate a low risk for stroke. Patientswith risk factors for thromboembolism shouldcontinue anticoagulation beyond 4 weeks unlessthere is convincing evidence that sinus rhythm ismaintained. For patients with recurrent episodesof AF, Recommendations 1.1.1, 1.1.2, 1.1.3, and1.1.4 apply.2.1.3. For patients with AF of known duration< 48 h, we suggest that cardioversion beperformed without prolonged anticoagulation(Grade 2C). However, in patients without con-traindications to anticoagulation, we suggestbeginning IV heparin (target PTT, 60 s;range, 50 to 70 s) or LMWH (at full DVTtreatment doses) at presentation (Grade 2C).

Remark: For patients with risk factors for stroke, itis particularly important to be confident that theduration of AF is � 48 h. In such patients with riskfactors, a TEE-guided approach (see section 2.12,previously) is a reasonable alternative strategy. Post-cardioversion anticoagulation is based on whetherthe patient has experienced more than one episodeof AF and on his or her risk factor status. Forpatients with recurrent episodes of AF, Recommen-dations 1.1.1, 1.1.2, 1.1.3, and 1.1.4 apply.2.1.4. For emergency cardioversion in the hemo-dynamically unstable patient, we suggest that IVUFH (target PTT of 60 s with a target range of 50to 70 s) or LMWH (at full DVT treatment doses)be started as soon as possible, followed by at least4 weeks of anticoagulation with an oral VKA, suchas warfarin (target INR of 2.5; range, 2.0 to 3.0) ifcardioversion is successful and sinus rhythm ismaintained (Grade 2C).

Remark: Long-term continuation of anticoagula-tion is based on whether the patient has experiencedmore than one episode of AF and on his or her riskfactor status. For patients experiencing more thanone episode of AF, Recommendations 1.1.1, 1.1.2,1.1.3, and 1.1.4 apply.




2.1.5. For cardioversion of patients with atrialflutter, we suggest use of anticoagulants in thesame way as for cardioversion of patients withAF (Grade 2C).

Valvular and Structural Heart Disease

1.1.1. For patients with rheumatic mitral valvedisease complicated singly or in combination bythe presence of AF, previous systemic embo-lism, or left atrial thrombus, we recommendVKA therapy (target INR, 2.5; range, 2.0 to 3.0)[Grade 1A].

1.1.2. For patients with rheumatic mitral valvedisease with AF who suffer systemic embolismor have left atrial thrombus while receivingVKAs at a therapeutic INR, we suggest theaddition of low-dose aspirin (50 to 100 mg/d)therapy after consideration of the additionalhemorrhagic risks (Grade 2C). An alternativestrategy might be the adjustment of VKA dosingto achieve a higher target INR (target INR, 3.0;range, 2.5 to 3.5) [Grade 2C].1.2.1. In patients with rheumatic mitral valvedisease and normal sinus rhythm with the leftatrial diamter > 55 mm, we suggest VKA ther-apy (target INR, 2.5; range, 2.0 to 3.0) [Grade2C].Underlying values and preferences: This recommen-dation places a relatively high value on preventingsystemic embolism and its consequences, and arelatively low value on avoiding the bleeding risk andinconvenience associated with VKA therapy.1.2.2. In patients with rheumatic mitral valvedisease and normal sinus rhythm with a leftatrial diameter < 55 mm, we do not suggestantithrombotic therapy, unless a separate indi-cation exists (Grade 2C).1.3.1. For patients being considered for percu-taneous mitral balloon valvotomy (PMBV), werecommend a preprocedural transesophagealechocardiography (TEE) to exclude left atrialthrombus (Grade 1C).1.3.2. For patients being considered for PMBVwith preprocedural TEE showing left atrialthrombus, we recommend postponement ofPMBV and VKA therapy (target INR 3.0; range,2.5 to 3.5) until thrombus resolution is documentedby repeat TEE (Grade 1C). If left atrial thrombusdoes not resolve with VKA therapy, we recommendthat PMBV not be performed (Grade 1C).2.0.1. In patients with mitral valve prolapse (MVP)who have not experienced systemic embolism, un-explained transient ischemic attacks or ischemic

stroke, and do not have AF, we recommend againstany antithrombotic therapy (Grade 1C).2.0.2. In patients with MVP who have docu-mented but unexplained transient ischemic at-tacks or ischemic stroke, we recommend long-term aspirin therapy (50 to 100 mg/d) [Grade 1B].2.0.3. In patients with MVP who have AF, doc-umented systemic embolism or recurrent tran-sient ischemic attacks despite aspirin therapy,we suggest long-term VKA therapy (target INR,2.5; range 2.0 to 3.0) [Grade 2C].3.0.1. In patients with mitral annular calcifica-tion complicated by systemic embolism, isch-emic stroke, or transient ischemic attack, whodo not have AF, we recommend aspirin (50 to100 mg/d) [Grade 1B]. For recurrent eventsdespite aspirin therapy, we suggest treatmentwith VKA therapy be considered (target INR,2.5; range, 2.0 to 3.0) [Grade 2C]. In patientswith mitral annular calcification who have asingle embolus documented to be calcific, thedata are not sufficient to allow recommendationfor or against antithrombotic therapy.3.0.2. In patients with mitral annular calcifica-tion and AF, we recommend long-term VKAtherapy (target INR, 2.5; range, 2.0 to 3.0)[Grade 1C].4.1.1. In patients with isolated calcific aortic valvedisease who have not had ischemic stroke ortransient ischemic attack, we suggest against an-tithrombotic therapy (Grade 2C).4.1.2. In patients with isolated calcific aorticvalve disease who have experienced ischemicstroke or transient ischemic attack not attrib-utable to another source, we suggest aspirin(50 to 100 mg/d) [Grade 2C].4.2.1. In patients with ischemic stroke associ-ated with aortic atherosclerotic lesions, werecommend low-dose aspirin (50 to 100 mg/d)over no therapy (Grade 1C). For patients withischemic stroke associated with mobile aorticarch thrombi, we suggest therapy with eitherVKAs (target INR, 2.5; range, 2.0 to 3.0) orlow-dose aspirin (50 to 100 mg/d) [Grade 2C].5.0.1. In patients with ischemic stroke and apatent foramen ovale, we recommend antipla-tet agent therapy (Grade 1A), and suggestantiplatet agent therapy over VKA therapy(Grade 2A).5.0.2. In patients with cryptogenic ischemicstroke and patent foramen ovale, with evi-dence of DVT or another indication for VKAtherapy, such as AF or an underlying hyper-coagulable state, we recommend VKAtherapy (target INR, 2.5; range, 2.0 to 3.0)[Grade 1C].




6.0.1. In patients with mechanical heart valves, werecommend VKA therapy (Grade 1A). In patientsimmediately following mechanical valve replace-ment, and as dictated by clinical concerns regard-ing postoperative bleeding, we suggest administra-tion of IV UFH or SC LMWH until the INR is stableand at a therapeutic level for 2 consecutive days(Grade 2C).6.0.2. In patients with a bileaflet mechanical valveor a Medtronic Hall tilting disk valve in the aorticposition who are in sinus rhythm and without leftatrial enlargement, we recommend long-termVKA therapy (target INR, 2.5; range, 2.0 to 3.0)[Grade 1B].6.0.3. In patients with a tilting disk or bileafletmechanical valve in the mitral position, werecommend VKA therapy (target INR, 3.0;range, 2.5 to 3.5) [Grade 1B].6.0.4. In patients with a caged ball or caged diskvalve, we recommend long-term VKA therapy(target INR, 3.0; range, 2.5 to 3.5) [Grade 1B].6.0.5. In patients with mechanical heart valvesin either or both the aortic or mitral positions,and additional risk factors for thromboembo-lism, such as AF, anterior-apical ST-segmentelevation myocardial infarction, left atrial en-largement, hypercoagulable state, or low ejec-tion fraction, we recommend VKA therapy (tar-get INR, 3.0; range, 2.5 to 3.5) [Grade 1B].6.0.6. In patients with mechanical heart valveswho have additional risk factors for thrombo-embolism, such as AF, hypercoagulable state, orlow ejection fraction, or who have a history ofatherosclerotic vascular disease, we recom-mend the addition of low-dose aspirin (50 to100 mg/d) to long-term VKA therapy (Grade 1B).We suggest aspirin not be added to VKA ther-apy in patients with mechanical heart valveswho are at particularly high risk of bleeding;such as in patients with history of GI bleed or inpatients > 80 years of age (Grade 2C).6.0.7. In patients with mechanical prostheticheart valves who suffer systemic embolism de-spite a therapeutic INR, we suggest the additionof aspirin (50 to 100 mg/d) if not previouslyprovided and/or upward titration of VKA ther-apy to achieve a higher target INR. For aprevious target INR of 2.5, we suggest the VKAdose be increased to achieve a target INR of 3.0(range, 2.5 to 3.5). For a previous target INR of3.0, we suggest the VKA dose be increased toachieve a target INR of 3.5 (range, 3.0 to 4.0)[Grade 2C].7.0.1. In patients with a bioprosthetic valve inthe mitral position, we recommend VKA ther-apy (target INR, 2.5; range, 2.0 to 3.0) for the

first 3 months after valve insertion (Grade 1B).In the early postoperative period, in the ab-sence of concerns for significant bleeding, wesuggest administration of IV UFH or SCLMWH until the INR is at therapeutic levelsfor 2 consecutive days (Grade 2C). After thefirst 3 months, in patients who are in sinusrhythm and have no other indication for VKAtherapy, we recommend aspirin (50 to 100mg/d) [Grade 1B].7.0.2. In patients with aortic bioprostheticvalves, who are in sinus rhythm and have noother indication for VKA therapy, we recom-mend aspirin (50 to 100 mg/d) [Grade 1B].7.0.3. In patients with bioprosthetic valves whohave a prior history of systemic embolism, werecommend VKA therapy (target INR 2.5;range, 2.0 to 3.0) for at least 3 months aftervalve insertion, followed by clinical reassess-ment (Grade 1C).7.0.4. In patients with bioprosthetic valves whohave evidence of a left atrial thrombus at sur-gery, we recommend VKA therapy (target INR,2.5; range, 2.0 to 3.0) until documented throm-bus resolution (Grade 1C).7.0.5. In patients with bioprosthetic valves who-have additional risk factors for thromboembo-lism, including AF, hypercoagulable state, orlow ejection fraction, we recommend VKA ther-apy (target INR, 2.5; range, 2.0 to 3.0) [Grade1C]. We suggest the addition of low-dose aspirin(50 to 100 mg/d) be considered, particularly inpatients with history of atherosclerotic vasculardisease (Grade 2C). We suggest aspirin not beadded to long-term VKA therapy patients withbioprosthetic heart valves who are at particu-larly high risk of bleeding, such as patients withhistory of GI bleed or in patients > 80 years ofage (Grade 2C).8.0.1. For patients with right-sided prostheticvalve thrombosis (PVT) with large thrombussize or New York Heart Association functionalclass III to IV, we recommend administrationof fibrinolytic therapy (Grade 1C).8.0.2. For patients with left-sided PVT, NewYork Heart Association functional class I to II,and small thrombus area (< 0.8 cm2), we sug-gest administration of fibrinolytic therapy. Al-ternatively, administration of IV UFH accompa-nied by serial Doppler echocardiography todocument thrombus resolution or improve-ment, can be considered for very small nonob-structive thrombus [Grade 2C].8.0.3. For patients with left-sided PVT, NewYork Heart Association functional class III toIV, and small thrombus area (< 0.8 cm2), we




suggest fibrinolytic therapy (Grade 2C).8.0.4. For patients with left-sided PVT and largethrombus area (> 0.8 cm2), we suggest emer-gency surgery be considered. If surgery is notavailable or considered high-risk, we suggestfibrinolytic therapy (Grade 2C).8.0.5. For patients who have had successfulresolution of PVT, we suggest initiation of IVUFH and VKA therapy. We suggest IV UFH becontinued until a therapeutic INR is achieved.For a mechanical valve in the aortic position, wesuggest maintaining a higher INR (target, 3.5;range, 3.0 to 4.0) plus aspirin (50 to 100 mg/d).For a mechanical valve in the mitral position,we suggest maintaining a higher INR (target4.0; range 3.5 to 4.5) plus aspirin (50 to 100mg/d) [Grade 2C].9.1.1. In patients with infective endocarditis, werecommend against routine antithrombotictherapy, unless a separate indication exists(Grade 1B).9.1.2. In the patient treated with VKA therapywho has infective endocarditis, we suggest VKAbe discontinued at the time of initial presenta-tion and UFH substituted, until it is clear thatinvasive procedures will not be required andthe patient has stabilized without signs of CNSinvolvement. When the patient is deemed stablewithout contraindications or neurologic compli-cations, we suggest reinstitution of long-termVKA therapy (Grade 2C).9.2.1. In patients with nonbacterial thromboticendocarditis and systemic or pulmonary emboli,we recommend treatment with full-dose IVUFH or SC LMWH (Grade 1C).9.2.2. In patients with disseminated cancer ordebilitating disease with aseptic vegetations, wesuggest administration of full-dose IV UFH orSC LMWH (Grade 2C).

Antithrombotic Therapy and ThrombolyticTherapy for Ischemic Stroke

1.1 IV Tissue Plasminogen Activator for AcuteIschemic Stroke Within 3 h of Symptom Onset

1.1.1. For eligible patients (see inclusion andexclusion criteria listed below) we recom-mend administration of IV tissue plasminogenactivator (tPA) in a dose of 0.9 mg/kg (maxi-mum of 90 mg), with 10% of the total dosegiven as an initial bolus and the remainderinfused over 60 min, provided that treatmentis initiated within 3 h of clearly defined symp-tom onset (Grade 1A).Underlying values and preferences: This recom-

mendation places relatively more weight on overallprospects for long-term functional improvementdespite the increased risk of symptomatic intrace-rebral hemorrhage in the immediate peristrokeperiod.1.1.2. We recommend that patients who areeligible for tPA be treated as quickly as pos-sible within the 3-h time limit (Grade 1A).

Remark: All unnecessary delays must be avoidedas the benefits of tPA therapy diminish rapidly overtime.1.1.3. For patients with extensive (> 1/3 of themiddle cerebral artery territory) and clearly iden-tifiable hypodensity on CT, we suggest not usingof tPA (Grade 2B).

1.2 IV tPA for Acute Ischemic Stroke Between 3 hand 6 h of Symptom Onset

1.2. For patients with acute ischemic stroke of> 3 h but < 4.5 h, we suggest clinicians do notuse IV tPA (Grade 2A). For patients with acutestroke onset of > 4.5 h we recommend againstthe use of IV tPA (Grade 1A).Underlying values and preferences: This recommen-dation assumes a relatively low value on small in-creases in long-term functional improvement, a rel-atively high value on avoiding acute intracranialhemorrhage and death, and a relatively high degreeof risk aversion.

1.3 IV Streptokinase for Acute Ischemic StrokeBetween 0 h and 6 h of Symptom Onset

1.3. For patients with acute ischemic stroke, werecommend against streptokinase (Grade 1A).

1.4 Intraarterial Thrombolysis for Acute IschemicStroke

1.4.1. For patients with angiographically dem-onstrated middle cerebral artery occlusion andwithout signs major early infarct signs on thebaseline CT or MRI scan, who can be treatedwithin 6 h of symptom onset, we suggest in-traarterial thrombolytic therapy with tPA forselected patients in centers with the appropri-ate neurologic and interventional expertise(Grade 2C).1.4.2. For patients with acute basilar arterythrombosis and without major CT/MRI evi-dence of infarction, we suggest either intraar-terial or IV thrombolysis with tPA depending onavailable resources and capabilities (Grade 2C).




2.1 Anticoagulants for Altering Outcomes AmongAcute Stroke in Patients Not Eligible forThrombolysis

2.1. For patients with acute ischemic stroke,we recommend against full-dose anticoagula-tion with IV, SC, or LMWHs or heparinoids(Grade 1B).

2.2 Antiplatelet Agents for Altering Outcomes inAcute Stroke Patients Not Eligible for Thrombolysis

2.2. For patients with acute ischemic strokewho are not receiving thrombolysis, we rec-ommend early aspirin therapy (initial dose of150 to 325 mg) [Grade 1A].

2.3 Antithrombotic Therapy for Prevention of DVTand PE in Acute Ischemic Stroke

2.3.1. For acute stroke patients with restrictedmobility, we recommend prophylactic low-doseSC heparin or LMWHs (Grade 1A).2.3.2. For patients who have contraindicationsto anticoagulants, we recommend IPC devicesor elastic stockings (Grade 1B).

3.1 IPC for DVT/PE Prophylaxis in Patients WithIntracerebral Hematoma

3.1. In patients with an acute intracerebralhematoma, we recommend the initial use ofIPC devices (Grade 1B).

3.2 Heparin for DVT/PE Prophylaxis in PatientsWith Intracerebral Hematoma

3.2. In stable patients, we suggest low-dose SCheparin as soon as the second day after theonset of the hemorrhage (Grade 2C).Underlying values and preferences: Given the uncer-tainty about the risk of heparin in this setting, thisrecommendation places a relatively high value onreducing the consequences of thromboembolismand a relatively lower value on minimizing the risk ofcerebral rebleeding.

4.1 Prevention of Cerebral Ischemic Events inPatients With Noncardioembolic TransientIschemic Attack or Stroke: Antiplatelet Drugs vsPlacebo or vs an Alternative Antiplatelet Drug

4.1.1. In patients who have experienced a non-cardioembolic stroke or transient ischemic at-tack (ie, atherothrombotic, lacunar, or crypto-genic), we recommend treatment with an

antiplatelet drug (Grade 1A). Aspirin, the com-bination of aspirin (25 mg) and extended-re-lease dipyridamole (200 mg bid) and clopi-dogrel (75 qd) are all acceptable options forinitial therapy. We recommend an aspirin doseof 50–100 mg/d over higher aspirin doses(Grade 1B).4.1.2. In patients who have experienced a non-cardioembolic stroke or transient ischemic at-tack, we recommend using the combination ofaspirin and extended-release dipyridamole (25/200 mg bid) over aspirin (Grade 1A) and suggestclopidogrel over aspirin (Grade 2B).Underlying values and preferences: The implemen-tation of the recommendation to use the combina-tion of aspirin and extended-release dipyridamoleover aspirin may vary based on cost, tolerability,availability, ease of use, and absolute risk.4.1.3. In most patients with a noncardioem-bolic stroke or transient ischemic attack, werecommend avoiding long-term use of thecombination of aspirin and clopidogrel (Grade1B). In those with a recent acute myocardialinfarction, other acute coronary syndrome, ora recently placed coronary stent, we recom-mend clopidogrel plus aspirin (75–100 mg)[Grade 1A]. The optimal duration of dual an-tiplatelet therapy depends on the specificcardiac indication (see other articles in thissupplement) for recommended for specificindications.4.1.4. For patients who are allergic to aspirin,we recommend clopidogrel (Grade 1A).

4.2 Prevention of Noncardioembolic CerebralIschemic Events: Oral Anticoagulants

4.2.1. For patients with noncardioembolicstroke or transient ischemic attack, we recom-mend antiplatelet agents over oral anticoagula-tion (Grade 1A).

4.3 Prevention of Cerebral Ischemic Events inPatients Undergoing Carotid Endarterectomy:Antiplatelet Agents

4.3. In patients undergoing carotid endarter-ectomy, we recommend aspirin (50 to 100mg/d) prior to and following the procedure(Grade 1A).

4.4 Prevention of Cardioembolic Cerebral IschemicEvents

4.4.1. In patients with AF who have suffered arecent stroke or transient ischemic attack, we




recommend long-term oral anticoagulation(target INR, 2.5; range, 2.0 to 3.0) [Grade 1A].4.4.2. For patients with cardioembolic stroke whohave contraindications to anticoagulant therapy,we recommend aspirin at a dose of 75–325 mg/d(Grade 1B).4.4.3. In patients with stroke associated with aor-tic atherosclerotic lesions, we recommend anti-platelet therapy over no therapy (Grade 1A). Forpatients with cryptogenic stroke associated withmobile aortic arch thrombi, we suggest either oralanticoagulation or antiplatelet agents (Grade 2C).4.4.4. In patients with cryptogenic ischemicstroke and a patent foramen ovale, we recom-mend antiplatelet therapy over no therapy (Grade1A) and suggest antiplatelet agents over anticoag-ulation (Grade 2A).4.4.5. In patients with mitral valve strands orprolapse, who have a history of transient ischemicattack or stroke, we recommend antiplatelet ther-apy (Grade 1A).

5.1 Anticoagulation for Cerebral Venous SinusThrombosis

5.1. In patients with venous sinus thrombosis,we recommend that clinicians use UFH (Grade1B) or LMWH (Grade 1B) over no anticoagu-lant therapy during the acute phase, even inthe presence of hemorrhagic infarction. Inthese patients, we recommend continued useof VKA therapy for up to 12 months (targetINR, 2.5; range, 2.0 –3.0) [Grade 1B].

Antithrombotic Therapy forNon–ST-Segment Acute Coronary

Syndromes

Antiplatelet Therapies

1. For all patients presenting with NSTEACS, without a clear allergy to aspirin, werecommend immediate aspirin (162 to325 mg po) and then daily oral aspirin (75to 100 mg) [Grade 1A].

2. For all NSTE ACS patients with an as-pirin allergy, we recommend immediatetreatment with clopidogrel, 300 mg pobolus, followed by 75 mg/d indefinitely(Grade 1A).

3. For NSTE ACS patients who are at moder-ate or greater risk (eg, ongoing chest pain,hemodynamic instability, positive troponin,or dynamic ECG changes) for an ischemicevent and who will undergo an earlyinvasive management strategy (ie, diagnos-

tic catheterization followed by anatomy-driven revascularization), we recommend:a. “Upstream” treatment either with clo-

pidogrel (300 mg po bolus, followed by75 mg/d) or a small-molecule IV GPIIb/IIIa inhibitor (eptifibatide or tirofiban)[Grade 1A]

b. We suggest upstream use of both clo-pidogrel and a small-molecule IV GPIIb/IIIa inhibitor (Grade 2A). Scrupu-lous attention to weight- and renal-based dosing algorithms must be partof eptifibatide or tirofiban adminis-tration

c. For patients presenting with NSTEACS, we recommend against abciximabas initial treatment except when coro-nary anatomy is known and PCI isplanned within 24 h (Grade 1A).

4. For NSTE ACS patients who are at mod-erate or greater risk for an ischemicevent and for whom an early conservativeor a delayed invasive strategy of manage-ment is to be used:a. We recommend upstream treatment

with clopidogrel (300 mg po bolus, fol-lowed by 75 mg/d) [Grade 1A]

b. We suggest upstream use of both clo-pidogrel and a small-molecule IV GPIIb/IIIa inhibitor (Grade 2B).

5. For NSTE ACS patients who undergoPCI, we recommend treatment with bothclopidogrel and an IV GP IIb/IIIa inhibi-tor (Grade 1A),a. We recommend a loading dose of 600

mg of clopidogrel given at least 2 hprior to planned PCI followed by 75mg/d (Grade 1B)

b. If ticlopidine is given, we suggest that aloading dose of 500 mg be given atleast 6 h before planned PCI (Grade 2C)

c. For PCI patients who cannot tolerateaspirin, we suggest that the loadingdose of clopidogrel (600 mg) or ticlopi-dine (500 mg) be given at least 24 hprior to planned PCI (Grade 2C)

d. We recommend use of a GP IIb/IIIaantagonist (abciximab or eptifibatide)[Grade 1A] for all NSTE ACS patientswith at least moderate risk featuresundergoing PCI in whom a GP IIb/IIIainhibitor has not been started up-stream; we recommend administrationof abciximab as a 0.25 mg/kg bolusfollowed by a 12-h infusion at a rate of




10 �g/min (Grade 1A) and eptifibatideas a double bolus (each 180 �g/kg,given 10 min apart) followed by an 18-hinfusion of 2.0 �g/kg/min (Grade 1A).Appropriate dose reduction of eptifi-batide must be based on renal function

e. In patients undergoing PCI in whom aGP IIb/IIIa inhibitor has not beenstarted upstream, we recommendagainst the use of tirofiban as an alter-native to abciximab (Grade 1B).

6. For NSTE ACS patients who have receivedclopidogrel and are scheduled for CABG,we suggest discontinuing clopidogrel for atleast 5 days prior to the scheduled surgery(Grade 2A).

Anticoagulant Therapies

1. For all patients presenting with NSTEACS, we recommend anticoagulationwith UFH or LMWH or bivalirudin orfondaparinux over no anticoagulation(Grade 1A).a. We recommend weight-based dosing

of UFH and maintenance of the APTTbetween 50 s and 70 s (Grade 1B)

b. We recommend against routine moni-toring of the anticoagulant effect ofLMWH (Grade 1C). Careful attention isneeded to appropriately adjust LMWHdose in patients with renal insuffi-ciency.

2. For NSTE ACS patients who will undergoan early invasive strategy of management(ie, diagnostic catheterization followed byanatomy-driven revascularization),a. We recommend UFH (with a GP IIb/IIIa

inhibitor) over either LMWH or fondapa-rinux (Grade 1B)

b. We suggest bivalirudin over UFH incombination with a thienopyridine asan initial antithrombotic strategy inpatients with moderate-to-high riskfeatures presenting with a NSTE ACSand scheduled for very early coro-nary angiography (< 6 h) [Grade 2B].

3. For NSTE ACS patients in whom an earlyconservative or a delayed invasive strat-egy of management is to be used:a. We recommend fondaparinux over enox-

aparin (Grade 1A). For patients treatedwith upstream fondaparinux and under-going PCI, we recommend that addi-tional IV boluses of UFH be given at thetime of the procedure (for example, 50 to

60 U/kg) as well as additional IV doses offondaparinux (2.5 mg if also receiving aGP IIb/IIIa inhibitor and 5 mg if not)[Grade 1B]. Additionally, PCI operatorsshould regularly flush the catheters withUFH during the procedure as well

b. We recommend LMWH over UFH(Grade 1B). We recommend continuingLMWH during PCI treatment of pa-tients with NSTE ACS when LMWH hasbeen started as the upstream anticoagu-lant (Grade 1B). If the last dose of enox-aparin was given < 8 h prior to PCI, werecommend no additional anticoagu-lant therapy (Grade 1B). If the lastdose of enoxaparin was given 8 to12 h before PCI, we recommend a 0.3mg/kg bolus of IV enoxaparin at thetime of PCI (Grade 1B).

4. In low-to-moderate risk patients withNSTE ACS undergoing PCI, we recom-mend either bivalirudin with provisional(“bail-out”) GP IIb/IIIa inhibitors or UFHplus a GP IIb/IIIa inhibitor over alterna-tive antithrombotic regimens (Grade 1B).

Acute St-Segment Elevation MyocardialInfarction

1.0 Reperfusion Therapy

1.0.1. For patients with ischemic symptomscharacteristic of acute myocardial infarctionof < 12 h duration and persistent ST-segmentelevation, we recommend that all undergorapid evaluation for reperfusion (primary PCI orfibrinolytic) therapy and have a reperfusion strat-egy implemented promptly after contact with thehealth-care system (Grade 1A).

1.1 Fibrinolysis

1.1.1. In patients with acute myocardial infatc-tion who are candidates for fibrinolytic therapy,we recommend administration as soon as possi-ble (ideally within 30 min) after arrival to thehospital or first contact with the health-caresystem (Grade 1A).1.1.2. In health-care settings where prehospitaladministration of fibrinolytic therapy is feasi-ble, we recommend prehospital administrationof fibrinolytic therapy (Grade 1A).1.1.3. For patients with ischemic symptoms




characteristic of acute myocardial infarction of< 12 h duration, and persistent ST-segmentelevation, we recommend administration ofstreptokinase, anistreplase, alteplase, reteplase,or tenecteplase over no fibrinolytic therapy (allGrade 1A).1.1.4. For patients with symptom duration < 6h, we recommend the administration of alte-plase (Grade 1A) or tenecteplase (Grade 1A), andsuggest reteplase (Grade 2B) over streptokinase.1.1.5. For patients receiving fibrinolytic ther-apy, we suggest the use of a bolus agent (eg,tenecteplase) to facilitate the ease of adminis-tration and potentially reduce the risk of non-intracranial hemorrhage- related bleeding (te-necteplase) [Grade 2A].1.1.6. For patients with ischemic symptomscharacteristic of acute myocardial infarction of< 12 h duration, and left bundle-branch blockwith associated ST-segment changes, we recom-mend fibrinolytic therapy if primary PCI is notreadily available (Grade 1B).1.1.7. For patients with ischemic symptomscharacteristic of acute myocardial infarction of< 12 h duration and ECG findings consistentwith a true posterior myocaardial infarction, wesuggest fibrinolytic therapy if primary PCI isnot readily available (Grade 2B).1.1.8. For high-risk patients with ongoing symp-toms characteristic of acute myocardial infarc-tion or hemodynamic compromise and durationof 12 to 24 h who have persistent ST-segmentelevation or left bundle-branch block with ST-segment changes, we suggest fibrinolytic ther-apy if primary PCI is not readily available(Grade 2B).1.1.9. In patients with any history of intracranialhemorrhage, or with history of head trauma, orwith ischemic stroke within the past 6 months,we recommend against administration of fi-brinolytic therapy (Grade 1C).

2.0 Antiplatelet/Antithrombotic Therapy

2.1 Aspirin

2.1.1. For patients with acute ST-segmentelevation myocardial infarction whether ornot they receive fibrinolytic therapy, we rec-ommend aspirin (160 to 325 mg po) over noaspirin therapy at initial evaluation by health-carepersonnel (Grade 1A) followed by indefinite ther-apy (75 mg to 162 mg/d po) [Grade 1A].

2.2 Clopidogrel

2.2.1. For patients with acute ST-segment ele-vation myocardial infarction, we recommendclopidogrel in addition to aspirin (Grade 1A).The recommended dosing for clopidogrel is 300mg po for patients age < 75 years and 75 mg pofor patients age > 75 years if they receive fibrino-lytic agents or no reperfusion therapy, followedby 75 mg/d po for up to 28 days (Grade 1A).2.2.2. For patients with acute ST-segment eleva-tion myocardial infarction who have not receiveda coronary stent, we suggest that clopidogrel 75mg/d could be continued beyond 28 days and upto 1 year (Grade 2B).2.2.3. For patients undergoing primary PCI, wesuggest clopidogrel in addition to aspirin with arecommended initial dosing of at least 300 mg(Grade 1B), followed by 75 mg daily (for durationof therapy, see chapter by Becker et al in thissupplement).

2.3 Antithrombin Therapy

2.3.1. For patients with acute ST-segment ele-vation myocardial infarction, in addition to as-pirin and other antiplatelet therapies, we rec-ommend the use of antithrombin therapy overno antithrombin therapy (Grade 1A), includingfor those patients receiving fibrinolysis (andregardless of which lytic agent is administered),primary PCI, or patients not receiving reperfu-sion therapy.

2.4 UFH

2.4.1. For patients receiving streptokinase, wesuggest administration of either IV UFH(5,000-U bolus followed by 1,000 U/h for pa-tients > 80 kg, 800 U/h for < 80 kg) with atarget APTT of 50 to 75 s or SC UFH (12,500U q12h) over no UFH therapy for 48 h (bothGrade 1B).2.4.2. For patients receiving alteplase, tenect-eplase, or reteplase for fibrinolysis in acutemyocardial infarction, we recommend adminis-tration of weight-adjusted heparin (60 U/kgbolus for a maximum of 4,000 U followed by 12U/kg/h [1,000 U/h maximum]) adjusted to main-tain an APTT 50 to 70 s for 48 h (Grade 1B).2.4.3. For patients with ST-segment elevationmyocardial infarction undergoing primary PCI,we recommend administration of IV UFH overno UFH therapy (Grade 1C). The recommendedperiprocedural dosing in patients receiving aGP IIb/IIIa inhibitor is 50 to 70 U/kg (target




activated clotting time > 200 s); in patients notreceiving a GP IIb/IIIa inhibitor, the recom-mended periprocedural dosing is 60 to 100U/kg (target activated clottint time, 250 to350 s).

2.5 LMWH

2.5.1. For patients with acute ST-segment ele-vation myocardial infarction, regardless ofwhether or not they receive reperfusion ther-apy, we recommend the use of reviparin overno therapy (Grade 1B). Recommended dosingfor reviparin is 3,436 IU for < 50 kg, 5,153 IUfor 50 to 75 kg, or 6,871 IU for > 75 kg q12h SCup to 7 days. For patients undergoing primaryPCI, UFH should be used periprocedurally andreviparin initiated 1 h after sheath removal.2.5.2. For patients with acute ST-segment ele-vation myocardial infarction receiving fibrino-lytic therapy who have preserved renal function(< 2.5 mg/dL [220 �mol/L] in males and < 2.0md/dL [175 �mol/L] in females), we recom-mend the use of enoxaparin over UFH, contin-ued up to 8 days (Grade 2A). Recommendeddosing for enoxaparin is for age < 75 years, 30mg IV bolus followed by 1 mg/kg SC q12h(maximum 100 mg for the first two SC doses);and for age > 75 years, no IV bolus, 0.75 mg/kgSC q12h (maximum, 75 mg for the first two SCdoses).

2.6 Fondaparinux

2.6.1. For patients with acute ST-segment ele-vation myocardial infarction and not receivingreperfusion therapy, we recommend fondapa-rinux over no therapy (Grade 1A). Recom-mended dosing for fondaparinux is 2.5 mg IVfor the first dose and then SC once daily up to 9days.2.6.2. For patients with acute ST-segment ele-vation myocardial infarction receiving fibrino-lytic therapy and thought not to have an indi-cation for anticoagulation, we recommendfondaparinux over no therapy (2.5 mg IV for thefirst dose and then SC qd up to 9 days) [Grade 1B].2.6.3. For patients with acute ST-segment ele-vation myocardial infarction receiving fibrino-lytic therapy and thought to have an indicationfor anticoagulation, we suggest fondaparinux(2.5 mg IV for the first dose and then SC qd upto 9 days) could be used as an alternative toUFH (Grade 2B).2.6.4. For patients with acute ST-segmentelevation myocardial infarction and undergo-

ing primary PCI, we recommend against us-ing fondaparinux (Grade 1A).

2.7 Direct Thrombin Inhibitors

2.7.1. For patients with acute ST-segment ele-vation myocardial infarction treated with strep-tokinase, we suggest clinicians not use bivaliru-din as an alternative to UFH (Grade 2B).Underlying values and preferences: This recom-mendation places a relatively higher value onavoiding excess of major bleeding and a relativelylower value on avoiding reinfarction. Recom-mended dosing for bivalirudin is 0.25 mg/kg IVbolus followed by an infusion of 0.5 mg/kg/h forthe first 12 h and then 0.25 mg/kg/h for thesubsequent 36 h; APTTs should be measured at12 h and 24 h with potential dose reductions asnoted (see previous text).

2.8 GP IIb/IIIa Inhibitors

2.8.1. For patients with acute ST-segment ele-vation myocardial infarction, we recommendagainst the combination of standard-dose abcix-imab and half-dose reteplase or tenecteplasewith low-dose IV UFH over standard-dose rete-plase or tenecteplase (Grade 1B).2.8.2. For patients with acute ST-segment ele-vation myocardial infarction, we suggest clini-cians not use the combination of streptokinaseand any GP IIb/IIIa inhibitor (Grade 2B).2.8.3. For patients with acute ST-segmentelevation myocardial infarction undergoingprimary PCI (with or without stenting), werecommend the use of abciximab (Grade 1B).Recommended dosing for abciximab is 0.25mg/kg IV bolus followed by 0.125 �g/kg/min(maximum, 10 �g/min) for 12 h.

3.0 Facilitated PCI

3.0.1. For patients with acute ST-segment eleva-tion myocardial infarction undergoing primaryPCI, we recommend against the use of fibrinolysis,with or without a GP IIb/IIIa inhibitor(Grade 1B).3.0.2. For patients with acute ST-segment ele-vation myocardial infarction who are to un-dergo primary PCI, we suggest administrationof a GP IIb/IIIa inhibitor prior to coronaryangiography (Grade 2B). The largest number ofpatients studied in this setting received abcix-imab 0.25 mg/kg IV bolus followed by 0.125�g/kg/min (maximum 10 �g/min) for 12 h; rec-




ommended dosing for eptifibatide is two 180 �gIV boluses (10 min apart) followed by 2.0 �g/kg/min infusion for 12–24 h; recommended dos-ing for tirofiban is 25 �g/kg IV bolus followedby 0.15 �g/kg/min for 24 h.

4.0 Rescue PCI

4.0.1. For patients with ST-segment elevationmyocardial infarction who have received fibri-nolysis but who have persistent ST-segmentelevation (< 50% resolution 90 min after treat-ment initiation compared with the pretreat-ment ECG), we recommend rescue PCI shouldbe performed over repeat fibrinolysis or noadditional reperfusion therapy (Grade 1B), andsuggest as soon as possible and within 2 h ofidentification of lack of ST-segment elevationresolution (Grade 2C).

The Primary and Secondary Prevention ofChronic Coronary Artery Disease

1.1.1. For patients with ACS with and withoutST-segment elevation, we recommend aspiringiven initially at a dose of 75–162 mg and thenindefinitely at a dose of 75–100 mg/d (Grade 1A).1.1.2. For patients with ST-segment elevationACS, with or without fibrinolytic therapy, werecommend clopidogrel, administered as a300-mg po loading dose for patients < 75 yearsof age and 75-mg starting dose for those > 75years of age and continued at a daily dose of 75mg for 2–4 weeks (Grade 1A). We suggest con-tinuing clopidogrel for up to 12 months follow-ing hospital discharge (Grade 2B).1.1.3. For patients with NSTE ACS, we recom-mend combination therapy with aspirin (75–100mg/d) and clopidogrel (75 mg/d) for 12 months(Grade 1A).1.1.4. For patients in whom aspirin is contrain-dicated or not tolerated, we recommend clopi-dogrel monotherapy (75 mg/d) [Grade 1A].1.1.5. For patients with symptomatic coronaryartery disease, we suggest aspirin (75–100mg/d) in combination with clopidogrel (75mg/d) [Grade 2B].Underlying values and preferences: This recommen-dation places a high value on the probable smallreduction in arterial vascular risk consequent onadding clopidogrel to aspirin and a low value onavoiding the additional bleeding and high cost asso-ciated with clopidogrel.2.1. For most patients (all except the high-risk

group described in recommendation 2.2 below)in most health-care settings, following ACS, werecommend aspirin alone (75–100 mg/d) overoral VKA alone or in combination with aspirin(Grade 1B).Underlying values and preferences: This recommen-dation places a relatively low value on prevention ofthromboembolism, and a relatively high value onavoiding the inconvenience, expense, and bleedingrisk associated with VKA therapy.2.1.1. For most patients after myocardial infarc-tion, in health-care settings in which meticulousINR monitoring and highly skilled VKA dosetitration are expected and widely accessible, wesuggest long-term (up to 4 years) high-intensityoral VKA (target INR, 3.5; range, 3.0 to 4.0) withoutconcomitant aspirin or moderate-intensityoral VKA (target INR, 2.5; range, 2.0 to 3.0)with aspirin (< 100 mg/d) over aspirin alone(both Grade 2B).2.2. For high-risk patients with myocardialinfarction, including those with a large ante-rior myocardial infarction, those with signifi-cant heart failure, those with intracardiacthrombus visible on transthoracic echocardi-ography, those with AF, and those with ahistory of a thromboembolic event, we sug-gest the combined use of moderate-intensity(INR, 2.0 to 3.0) oral VKA plus low-dose aspirin(< 100 mg/d) for at least 3 months after the MI(Grade 2A).2.4. For long-term treatment of patients afterPCI, we recommend aspirin at a dose of 75–100mg/d (Grade 1A).2.4.1. For patients undergoing PCI with baremetal stent placement, we recommend aspirin(75–100 mg/d) plus clopidogrel over aspirin alone(Grade 1A).2.4.1.1. For patients undergoing PCI with baremetal stent placement following ACS, we rec-ommend 12 months of aspirin (75–100 mg/d)plus clopidogrel (75 mg/d) over aspirin alone(Grade 1A).2.4.1.2. For patients undergoing PCI with drug-eluting stents, we recommend aspirin (75–100mg/d) plus clopidogrel (75 mg/d for at least 12months) [Grade 1A for 3 to 4 months; Grade 1B for4 to 12 months]. Beyond 1 year, we suggestcontinued treatment with aspirin plus clopi-dogrel indefinitely if no bleeding or other tol-erability issues (Grade 2C).2.4.2. For patients undergoing stent placementwith a strong concomitant indication for VKA, wesuggest triple antithrombotic therapy (Grade 2C).




We suggest 4 weeks of clopidogrel following baremetal stents and 1 year following drug-elutingstents (Grade 2C).Underyling values and preferences: This recommen-dation places a high value on the prevention ofthromboembolism, including stent thrombosis, and alower value on minimizing bleeding risk.For recommendations of use of antiplatelet agents inother patient populations with AF, see “Atrial Fibril-lation” chapter by Singer et al (reviewed in CHEST2007 Guidelines).2.5. For patients after stent placement, we sug-gest clopidogrel (Grade 1A) or ticlopidine (Grade2B) over cilostazol. We recommend clopidogrelover ticlopidine (Grade 1A).2.5.1. For aspirin-intolerant patients undergo-ing PCI, we recommend use of a thienopyridinederivative rather than dipyridamole (Grade 1B).2.6. For patients who undergo PCI with no otherindication for VKA, we recommend against VKA(Grade 1A).3.1. In patients with congestive heart failuredue to a nonischemic etiology, we recommendagainst routine use of aspirin or oral VKA(Grade 1B).4.1.5. For all patients with coronary arterydisease undergoing CABG, we recommend as-pirin, 75 to 100 mg/d, indefinitely (Grade 1A).We suggest that the aspirin be started postop-eratively (Grade 2A).4.1.6. For patients undergoing CABG, we rec-ommend against addition of dipyridamole toaspirin therapy (Grade 1A).4.1.8. For patients with coronary artery diseaseundergoing CABG who are allergic to aspirin,we recommend clopidogrel, 300 mg, as a load-ing dose 6 h after operation followed by 75mg/d po indefinitely (Grade 1B).4.1.8.1. In patients who undergo CABG follow-ing NSTE ACS, we suggest clopidogrel, 75mg/d, for 9 to 12 months following the proce-dure in addition to treatment with aspirin(Grade 2B).4.1.8.2. For patients who have received clopi-dogrel for ACS and are scheduled for CABG,we suggest discontinuing clopidogrel for 5days prior to the scheduled surgery (Grade2A).4.1.10. For patients undergoing CABG who haveno other indication for VKA, we recommend cli-nicians not administer VKAs (Grade 1C).4.1.10.1. For patients undergoing CABG inwhom oral anticoagulants are indicated, such asthose with heart valve replacement, we suggestclinicians administer VKA in addition to aspirin(Grade 2C).

4.2.1. For all patients with coronary arterydisease who undergo internal mammary arterybypass grafting, we recommend aspirin, 75 to162 mg/d, indefinitely (Grade 1A).4.2.2. For all patients undergoing internal mam-mary artery bypass grafting who have no otherindication for VKAs, we recommend against usingVKAs (Grade 1C).5.0. For patients with at least moderate risk fora coronary event (based on age and cardiac riskfactor profile with a 10-year risk of a cardiacevent of > 10%), we recommend 75–100 mg/dof aspirin over either no antithrombotic therapyor VKA (Grade 2A).5.1. For patients at particularly high risk ofevents in whom INR can be monitored withoutdifficulty, we suggest low-dose VKA with a tar-get INR of approximately 1.5 over aspirin ther-apy (Grade 2A).5.3. For all patients we recommend against theroutine addition of clopidogrel to aspirin therapyin primary prevention (Grade 1A). For patientswith an aspirin allergy who are at moderate tohigh risk for a cardiovascular event, we recom-mend monotherapy with clopidogrel (Grade 1B).5.4. For women < 65 years of age who are at riskfor an ischemic stroke, and in whom the concom-itant risk of major bleeding is low, we suggestaspirin at a dose of 75–100 mg/d over no aspirintherapy (Grade 2A).5.4.1. For women > 65 years of age at risk forischemic stroke or myocardial infarction, and inwhom the concomitant risk of major bleeding islow, we suggest aspirin at a dose of 75–100 mg/dover no aspirin therapy (Grade 2B).Underlying values and preferences: The recom-mendation of aspirin over VKA places a relativelylow value on a small absolute reduction in coro-nary events and deaths and a relatively high valueon avoiding the inconvenience, cost, and minorbleeding risk associated with oral VKA. The lowtarget INR value required in primary preventiontypically mandates less frequent monitoring; onaverage every 2 to 3 months and is associated withlower risk of bleeding.

Patients, particularly those in the highest riskgroups for whom systems permitting meticulousmonitoring of anticoagulant therapy are available,who place a relatively high value on small absoluterisk reductions in coronary events and are not influ-enced by an element of inconvenience and potentialbleeding risk associated with VKA are likely to derivethe greatest overall benefit from administration ofVKA rather than aspirin.




Antithrombotic Therapy in PeripheralArtery Occlusive Disease

1.0 Chronic Limb Ischemia andIntermittent Claudication

1.1.1.1. In peripheral artery occlusive diseasepatients with clinically manifest coronary orcerebrovascular disease, we recommend life-long antiplatelet therapy in comparison to noantiplatelet therapy (Grade 1A).1.1.1.2. In those without clinically manifest coro-nary or cerebrovascular disease, we suggest aspi-rin (75–100 mg/d) over clopidogrel (Grade 2B). Inpatients who are aspirin intolerant, we recom-mend clopidogrel over ticlopidine (Grade 1B).Underlying values and preferences: This recommenda-tion places a relatively high value on avoiding largeexpenditures to achieve uncertain, small reductions invascular events.1.1.2. In patients with peripheral artery occlu-sive disease and intermittent claudication, werecommend against the use of anticoagulants toprevent vascular mortality or cardiovascularevents (Grade 1A).1.1.4. For patients with moderate-to-severe dis-abling intermittent claudication who do notrespond to exercise therapy, and who are notcandidates for surgical or catheter-based inter-vention, we recommend cilostazol (Grade 1A).We suggest that clinicians not use cilostazol inthose with less disabling claudication (Grade2A). We recommend against the use of pentoxi-fylline (Grade 2B).Underlying values and preferences: Because of thecost of cilostazol therapy, and the safety and efficacyof an exercise program, we recommend cilostazoltreatment be reserved for patients with moderate-to-severe claudication who have tried and failed anexercise program, and are not candidates for vascularsurgical or endovascular procedures.1.1.5. For patients with intermittent claudication,we recommend against the use of anticoagulants(Grade 1A).1.1.6. For patients with limb ischemia, wesuggest clinicians do not use prostaglandins(Grade 2B).2.1. In patients who suffer from acute arterialemboli or thrombosis, we recommend immedi-ate systemic anticoagulation with UFH, over noanticoagulation (Grade 1C). In patients under-going embolectomy, we suggest following sys-temic anticoagulation with UFH with long-termanticoagulation with VKA (Grade 2C).2.2. In patients with short-term (< 14 days)

thrombotic or embolic disease, we suggest in-traarterial thrombolytic therapy (Grade 2B), pro-vided patients are at low risk of myonecrosis andischemic nerve damage developing during thetime to achieve revascularization by this method.Underlying values and preferences: This recommen-dation places relatively little value on small reduc-tions in the need for surgical intervention and rela-tively high value on avoiding large expenditures andpossible major hemorrhagic complications.3.1. For patients undergoing major vascularreconstructive procedures, we recommend IVUFH, prior to the application of vascular crossclamps (Grade 1A).3.2. For all patients undergoing infrainguinalarterial reconstruction, we recommend aspirin(75–100 mg, begun preoperatively) [Grade 1A].We recommend against the routine use of peri-operative dextran, heparin, or long-term anti-coagulation with VKA for all extremity recon-structions (Grade 1B).3.3. For patients receiving routine autogenousvein infrainguinal bypass, we recommend aspi-rin (75–100 mg, begun preoperatively) [Grade1A]. We suggest that VKA not be used routinelyin patients undergoing infrainguinal vein by-pass (Grade 2B). For those at high risk of bypassocclusion and limb loss, we suggest VKA plusaspirin (Grade 2B).Underlying values and preferences: These recom-mendations place relatively little value on smallincreases in long-term patency that may be statisti-cally uncertain, and a relatively high value on avoid-ing hemorrhagic complications.3.4. For patients receiving routine prostheticinfrainguinal bypass, we recommend aspirin(75–100 mg, begun preoperatively) [Grade 1A].We suggest that VKA not be used routinely inpatients undergoing prosthetic infrainguinalbypass (Grade 2A).Underlying values and preferences: These recom-mendations place relatively little value on smallincreases in long-term patency that may be statisti-cally uncertain, and a relatively high value on avoid-ing hemorrhagic complications.4.0. In patients undergoing carotid endarterec-tomy, we recommend that aspirin, 75–100 mg,preoperatively to prevent perioperative ischemicneurologic events. We recommend lifelong post-operative aspirin (75–100 mg/d) [Grade 1A].5.0. In nonoperative patients with asymptomaticcarotid stenosis (primary or recurrent), we rec-ommend lifelong aspirin, 75–100 mg/d (Grade 1C).In this patient group, we recommend against dualantiplatelet therapy with aspirin and clopidogrel(Grade 1B).




6.0. For patients undergoing lower-extremity bal-loon angioplasty (with or without stenting), werecommend long-term aspirin (75–100 mg/d)[Grade 1C]. For patients undergoing lower-extremity balloon angioplasty (with or withoutstenting), we recommend against anticoagula-tion with heparin or VKA (Grade 1A).

VTE, Thrombophilia, AntithromboticTherapy, and Pregnancy

2.1 VKA Exposure in Utero

2.1.1. For women receiving anticoagulation forthe management of VTE who become pregnant,we recommend that VKAs be substituted withUFH or LMWH (Grade 1A).

2.1.2. For women with mechanical valves whobecome pregnant, we suggest either adjusted-dose bid LMWH or UFH throughout pregnancyor adjusted-dose bid LMWH or UFH until thethirteenth week with substitution by VKAs untilLMWH or UFH are resumed close to delivery(Grade 1C). In pregnant women with high-riskmechanical valves (eg, older-generation valve inthe mitral position or history of thromboembo-lism), we suggest the use of oral anticoagulantsover heparin (Grade 2C).Underlying values and preferences: The suggestion toutilize VKAs during the first 12 weeks of pregnancyplaces similar value on avoiding maternal thromboem-bolic complications as on avoiding fetal risks.

2.2 Management of Women Receiving Long-termVKAs Who Are Considering Pregnancy

2.2.1. For women requiring long-term VKAswho are attempting pregnancy and are candi-dates for UFH or LMWH substitution, we sug-gest performing frequent pregnancy tests andsubstituting UFH or LMWH for VKAs whenpregnancy is achieved (Grade 2C).Underlying values and preferences: This recommenda-tion places a higher value on avoiding the risks, incon-venience, and costs of UFH or LMWH therapy ofuncertain duration while awaiting pregnancy comparedto minimizing the risks of early miscarriage associatedwith VKA therapy.

3.6 Pentasaccharide Exposure DuringBreastfeeding

3.6.1. For lactating women using warfarin orUFH who wish to breastfeed, we recommendcontinuing these medications (Grade 1A).

3.6.2. For lactating women using LMWH, danap-aroid, or r-hirudin who wish to breastfeed, wesuggest continuing these medications (Grade 2C).3.6.3. For breastfeeding women, we suggest alter-native anticoagulants rather than pentasacchar-ides (Grade 2C).

4.2 LMWH Therapy

4.2.1. For pregnant patients, we suggest LMWHover UFH for the prevention and treatment ofVTE (Grade 2C).

5.1 Risk of VTE Following Cesarean Section

5.1.1. We suggest that a thrombosis risk assess-ment be carried out in all women undergoingcesarean section to determine the need forthromboprophylaxis (Grade 2C).5.1.2. In patients without additional thrombosisrisk factors undergoing cesarean section, werecommend against the use of specific throm-boprophylaxis other than early mobilization(Grade 1B).

5.2 Thromboprophylaxis Following cesareanSection

5.2.1. For women considered at increased riskof VTE after cesarean section because of thepresence of at least one risk factor in addition topregnancy and cesarean section, we suggestpharmacologic thromboprophylaxis (prophylac-tic LMWH or UFH) or mechanical prophylaxis(GCS or IPC) while in hospital following deliv-ery (Grade 2C).5.2.2. For women with multiple additional riskfactors for thromboembolism who are undergo-ing cesarean section and are considered to be atvery high risk of VTE, we suggest that pharma-cologic prophylaxis be combined with the use ofGCS and/or IPC (Grade 2C).5.2.3. For selected high-risk patients in whomsignificant risk factors persist following deliv-ery, we suggest extended prophylaxis (up to 4 to6 weeks after delivery) following dischargefrom the hospital (Grade 2C).

6.1 Treatment of VTE During Pregnancy

6.1.1. For pregnant women with acute VTE, werecommend initial therapy with either adjusted-dose SC LMWH or adjusted-dose UFH (IVbolus, followed by a continuous infusion tomaintain the APTT within the therapeuticrange or SC therapy adjusted to maintain the




APTT 6 h after injection into the therapeuticAPTT range) for at least 5 days (Grade 1A).6.1.2. For pregnant women with acute VTE,after initial therapy, we recommend that SCLMWH or UFH should be continued through-out pregnancy (Grade 1B).6.1.3. For pregnant women with acute VTE, wesuggest that anticoagulants should be continuedfor at least 6 weeks postpartum (for a minimumtotal duration of therapy of 6 months) [Grade 2C].6.1.4. For pregnant women receiving adjusted-dose LMWH or UFH therapy, we recommenddiscontinuation of the heparin at least 24 h priorto elective induction of labor (Grade 1C).

7.2 Prevention of Recurrent VTE in Pregnant Women

7.2.1. For pregnant women with a single epi-sode of VTE associated with a transient riskfactor that is no longer present and no throm-bophilia, we recommend clinical surveillanceantepartum and anticoagulant prophylaxis post-partum (Grade 1C).7.2.2. If the transient risk factor associated with aprevious VTE event is pregnancy or estrogenrelated, we suggest antepartum clinical surveil-lance or prophylaxis (prophylactic LMWH/UFHor intermediate-dose LMWH/UFH) plus post-partum prophylaxis, rather than routine care(Grade 2C).7.2.3. For pregnant women with a single idio-pathic episode of VTE but without thrombo-philia and who are not receiving long-termanticoagulants, we recommend one of the fol-lowing, rather than routine care or adjusted-dose anticoagulation: prophylactic LMWH/UFH or intermediate-dose LMWH/UFH orclinical surveillance throughout pregnancyplus postpartum anticoagulants (Grade 1C).7.2.4. For pregnant women with thrombophilia(confirmed laboratory abnormality) who have hada single prior episode of VTE and are not receiv-ing long-term anticoagulants, we recommend oneof the following, rather than routine care oradjusted-dose anticoagulation: antepartum pro-phylactic or intermediate-dose LMWH or pro-phylactic or intermediate-dose UFH or clinicalsurveillance throughout pregnancy; plus postpar-tum anticoagulants (Grade 1C).7.2.5. For women with “higher-risk” thrombo-philias (eg, antithrombin deficiency, persistentpositivity for the presence of antiphospholipidantibodies; compound heterozygosity for pro-thrombin G20210A variant and factor V Leidenor homozygosity for these conditions) who havehad a single prior episode of VTE and are not

receiving long-term anticoagulants, we suggest,in addition to postpartum prophylaxis, antepar-tum prophylactic or intermediate-dose LMWHor prophylactic or intermediate-dose UFH,rather than clinical surveillance (Grade 2C).7.2.6. For pregnant women with multiple (> 2)episodes of VTE not receiving long-term antico-agulants, we suggest antepartum prophylactic,intermediate-dose, or adjusted-dose LMWH orprophylactic, intermediate-dose or adjusted-doseUFH followed by postpartum anticoagulantsrather than clinical surveillance (Grade 2C).7.2.7. For pregnant women receiving long-termanticoagulants for prior VTE, we recommendLMWH or UFH throughout pregnancy (eitheradjusted-dose LMWH or UFH, 75% of adjust-ed-dose LMWH, or intermediate-dose LMWH)followed by resumption of long-term anticoagu-lants postpartum (Grade 1C).7.2.8. For all pregnant women with previousDVT, we suggest the use of GCS both antepar-tum and postpartum (Grade 2C).Underlying values and preferences: This recommen-dation places a high value on uncertain incrementalbenefit with stockings and a low value on avoidingdiscomfort and inconvenience.

8.1 Risk of Pregnancy-Related VTE in WomenWith Thrombophilia

8.1.1. For pregnant patients with thrombophiliabut no prior VTE, we recommend that physi-cians do not use routine pharmacologic ante-partum prophylaxis but instead perform an in-dividualized risk assessment (Grade 1C).

8.2 Prevention of Pregnancy-Related VTE inWomen With Thrombophilia

8.2.1. For pregnant women with no history ofVTE but antithrombin deficiency, we suggestantepartum and postpartum prophylaxis (Grade2C).8.2.2. For all other pregnant women with throm-bophilia and no prior VTE, we suggest antepar-tum clinical surveillance or prophylactic LMWHor UFH, plus postpartum anticoagulants (Grade 2C).

9.1 Risk of Pregnancy Complications in WomenWith Thrombophilia

9.1.1. For women with recurrent early pregnancyloss (three or more miscarriages) or unexplainedlate pregnancy loss, we recommend screening forantiphospholipid antibodies (Grade 1A).9.1.2. For women with severe or recurrent




preeclampsia or IUGR, we suggest screeningfor antiphospholipid antibodies (Grade 2C).

9.2 Prevention of Pregnancy Complications inWomen With Thrombophilia

9.2.1. For women with antiphospholipid anti-bodies and recurrent (three or more) pregnancyloss or late pregnancy loss and no history ofvenous or arterial thrombosis, we recommendantepartum administration of prophylactic orintermediate-dose UFH or prophylactic LMWHcombined with aspirin (Grade 1B).

10.1 Prevention of Recurrent Preeclampsia inWomen Without Thrombophilia

10.1.1. For women considered high risk forpreeclampsia, we recommend low-dose aspirintherapy throughout pregnancy (Grade 1B).10.1.2. For women with a history of preeclamp-sia, we suggest that UFH and LMWH should notbe used as prophylaxis in subsequent pregnan-cies (Grade 2C).

11.1 Anticoagulant Management of MechanicalProsthetic Valves in Pregnant Women

11.1.1. For pregnant women with mechanicalheart valves we recommend that the decisionabout anticoagulant management during preg-nancy include an assessment of additional riskfactors for thromboembolism including valvetype, position, and history of thromboembolismand that the decision should also be influencedstrongly by patient preferences (Grade 1C).11.1.2. For pregnant women with mechanicalheart valves, we recommend one of the followinganticoagulant regimens in preference to no anti-coagulation:

a. Adjusted-dose bid LMWH throughoutpregnancy (Grade 1C); we suggest thatdoses be adjusted to achieve the manufac-turer peak anti-Xa LMWH 4 h after SCinjection (Grade 2C)

b. Adjusted-dose UFH throughout pregnancyadministered SC q12h in doses adjusted tokeep the mid-interval APTT at least twicecontrol or attain an anti-Xa heparin levelof 0.35 to 0.70 U/mL (Grade 1C)

c. UFH or LMWH (as above) until the thir-teenth week with warfarin substitution un-til close to delivery when UFH or LMWH isresumed (Grade 1C).

In women judged to be at very high risk of

thromboembolism in whom concerns exist aboutthe efficacy and safety of UFH or LMWH as dosedabove (eg, older-generation prosthesis in the mi-tral position or history of thromboembolism), wesuggest VKAs throughout pregnancy with re-placement by UFH or LMWH (as above) close todelivery, rather than one of the regimens above;after a thorough discussion of the potential risksand benefits of this approach (Grade 2C).Underlying values and preferences: In contrast to ourother recommendations, which place a high value onavoiding fetal risk, the recommendation for womenat very high risk of thromboembolism places equalvalue on avoiding maternal complications.

Remark: For all the recommendations above,usual long-term anticoagulants should be resumedpostpartum.11.1.3. For pregnant women with prostheticvalves at high risk of thromboembolism, werecommend the addition of low-dose aspirin,75 to 100 mg/d (Grade 2C).

Antithrombotic Therapy in Neonatesand Children

In Neonates With VTE (CVL and Non-CVLRelated)

1.1.1. We suggest that central venous lines (CVL)or UVCs associated with confirmed thrombosis beremoved, if possible, after 3 to 5 days of antico-agulation (Grade 2C).1.1.2. We suggest either initial anticoagulation,or supportive care with radiologic monitoring(Grade 2C); however, we recommend subse-quent anticoagulation if extension of the throm-bosis occurs during supportive care (Grade 1B).1.1.3. We suggest anticoagulation should bewith either of the following: (1) LMWH givenbid and adjusted to achieve an anti-FXa level of0.5–1.0 U/mL: or (2) UFH for 3 to 5 daysadjusted to achieve an anti-FXa of 0.35 to 0.7U/mL or a corresponding APTT range, followedby LMWH. We suggest a total duration ofanticoagulation of between 6 weeks and 3months (Grade 2C).1.1.4. We suggest that if either a CVL or a UVCis still in place on completion of therapeuticanticoagulation, a prophylactic dose of LMWHbe given to prevent recurrent VTE until suchtime as the CVL or UVC is removed (Grade 2C).1.1.5. We recommend against thrombolytictherapy for neonatal VTE unless major vesselocclusion is causing critical compromise of or-gans or limbs (Grade 1B).




1.1.6. We suggest that if thrombolysis is re-quired the clinician use tPA and supplementwith plasminogen (fresh frozen plasma) prior tocommencing therapy (Grade 2C).

In Children With DVT

1.2.1. We recommend anticoagulant therapywith either UFH or LMWH (Grade 1B). Foradditional information, see Section 1.2 (DVT inChildren).1.2.2. We recommend initial treatment withUFH or LMWH for at least 5 to 10 days (Grade1B). For patients in whom clinicians will subse-quently prescribe VKAs, we recommend begin-ning oral therapy as early as day 1 and discon-tinuing UFH/LMWH on day 6 or later than day6 if the INR has not exceeded 2.0 (Grade 1B).After the initial 5- to 10-day treatment period,we suggest LMWH rather than VKA therapy iftherapeutic levels are difficult to maintain onVKA therapy or if VKA therapy is challengingfor the child and family (Grade 2C).1.2.3. We suggest children with idiopathicthromboembolism receive anticoagulant ther-apy for at least 6 months, using VKAs to achievea target INR of 2.5 (INR range, 2.0 to 3.0) oralternatively using LMWH to maintain an anti-FXa level of 0.5 to 1.0 U/mL (Grade 2C).Underlying values and preferences: The suggestionto use anticoagulation therapy to treat idiopathicDVTs in children for at least 6 months rather than ona lifelong basis places a relatively high value onavoiding the inconvenience and bleeding risk associ-ated with antithrombotic therapy, and a relative lowvalue on avoiding the unknown risk of recurrence inthe absence of an ongoing risk factor.1.2.4. In children with secondary thrombosis inwhom the risk factor has resolved, we suggestanticoagulant therapy be administered for atleast 3 months using VKAs to achieve a targetINR of 2.5 (INR range, 2.0 to 3.0) or alterna-tively using LMWH to maintain an anti-FXalevel of 0.5 to 1.0 U/mL (Grade 2C).1.2.5. In children who have ongoing, but poten-tially reversible risk factors, such as active ne-phrotic syndrome or ongoing l-asparaginasetherapy, we suggest continuing anticoagulanttherapy in either therapeutic or prophylacticdoses until the risk factor has resolved (Grade2C).1.2.6. For children with recurrent idiopathicthrombosis, we recommend indefinite treat-ment with VKAs to achieve a target INR of 2.5(INR range, 2.0 to 3.0) [Grade 1A].

Remark: For some patients, long-term LMWH

may be preferable; however, there are little or nodata about the safety of long-term LMWH inchildren.1.2.7. For children with recurrent secondarythromboembolisms with an existing reversiblerisk factor for thrombosis, we suggest antico-agulation until the removal of the precipitat-ing factor but for a minimum of 3 months(Grade 2C).1.2.8. If a CVL is no longer required, or isnonfunctioning, we recommend it be re-moved (Grade 1B). We suggest at least 3 to 5days of anticoagulation therapy prior to itsremoval (Grade 2C). If CVL access is requiredand the CVL is still functioning, we suggestthat the CVL remain in situ and the patient beanticoagulated (Grade 2C).1.2.9. For children with a first CVL-relatedDVT, we suggest initial management as forsecondary thromboembolism as previouslydescribed. We suggest, after the initial 3months of therapy, that prophylactic doses ofVKAs (INR range 1.5 to 1.9) or LMWH (anti-FXa level range, 0.1 to 0.3) be given until theCVL is removed (Grade 2C). If recurrentthrombosis occurs while the patient is receiv-ing prophylactic therapy, we suggest continu-ing therapeutic doses until the CVL is re-moved but at least for a minimum of 3 months(Grade 2C).1.3.1. In children with DVT, we suggest thatthrombolysis therapy not be used routinely(Grade 2C). If thrombolysis is used, in thepresence of physiologic or pathologic defi-ciencies of plasminogen, we suggest supple-mentation with plasminogen (Grade 2C).1.4.1. If life-threatening VTE is present, wesuggest thrombectomy (Grade 2C).1.4.2. We suggest, following thrombectomy,anticoagulant therapy be initiated (Grade 2C).1.4.3. In children > 10 kg body weight withlower-extremity DVT and a contraindicationto anticoagulation, we suggest placement of atemporary inferior vena cava filter (Grade 2C).1.4.4. We suggest that temporary inferiorvena cava filters be removed as soon as pos-sible if thrombosis is not present in the basketof the filter and when the risk of anticoagula-tion decreases (Grade 2C).1.4.5. In children who receive an inferiorvena cava filter, we recommend appropriateanticoagulation for DVT (see Section 1.2) assoon as the contraindication to anticoagula-tion is resolved (Grade 1B).1.5.1. In children with cancer, we suggest man-agement of VTE follow the general recommen-




dations for management of DVT in children.We suggest the use of LMWH in the treatmentof VTE for a minimum of 3 months until theprecipitating factor has resolved (eg, use ofasparaginase) [Grade 2C].

Remark: The presence of cancer, and the need forsurgery, chemotherapy, or other treatments maymodify the risk benefit ratio for treatment of DVT,and clinicians should consider these factors on anindividual basis.1.5.2. We suggest clinicians not use primary anti-thrombotic prophylaxis in children with cancerand central venous access devices (Grade 2C).1.6. For children with VTE, in the setting ofantiphospholipid antibodies, we suggest man-agement as per general recommendations forVTE management in children.

Remark: Depending on the age of the patient, itmay be more appropriate to follow adult guidelinesfor management of VTE in the setting of antiphos-pholipid antibodies.1.7.1. For neonates or children with unilateralrenal vein thrombosis (RVT) in the absence ofrenal impairment or extension into the inferiorvena cava, we suggest supportive care withmonitoring of the RVT for extension or antico-agulation with UFH/LMWH or LMWH in ther-apeutic doses; we suggest continuation for 3months (Grade 2C).1.7.2. For unilateral RVT that extends into theinferior vena cava, we suggest anticoagulationwith UFH/LMWH or LMWH for 3 months(Grade 2C).1.7.3. For bilateral RVT with various degrees ofrenal failure, we suggest anticoagulation withUFH and initial thrombolytic therapy with tPA,followed by anticoagulation with UFH/LMWH(Grade 2C).

Remark: LMWH therapy requires careful monitor-ing in the presence of significant renal impairment.1.8.1. In children with CVLs, we recommendagainst the use of routine systemic thrombopro-phylaxis (Grade 1B).1.8.2. In children receiving long-term hometotal parenteral nutrition, we suggest thrombo-prophylaxis with VKAs with a target INR of 2.5(range 2.0–3.0) [Grade 2C].1.8.3. For blocked CVLs, we suggest tPA orrecombinant urokinase to restore patency(Grade 2C). If 30 min following local thrombo-lytic instillation CVL patency is not restored, wesuggest a second dose be administered. If theCVL remains blocked following two doses oflocal thrombolytic agent, we suggest investiga-tions to rule out a CVL-related thrombosis beinitiated (Grade 2C).

1.9. For pediatric patients having a modifiedBlalock-Taussig shunt, we suggest intraopera-tive therapy with UFH followed by either aspi-rin (1–5 mg/kg/d) or no further antithrombotictherapy compared to prolonged LMWH orVKAs (Grade 2C).1.10. For patients who underwent the Norwoodprocedure, we suggest UFH immediately afterthe procedure, with or without ongoing anti-platelet therapy (Grade 2C).1.11. In patients who have bilateral cavopulmo-nary shunts, we suggest postoperative UFH(Grade 2C). For additional information, see Sec-tion 1.11 (Primary Prophylaxis for Glenn orBilateral Cavopulmonary Shunts in Children).1.12. For children after Fontan surgery, werecommend aspirin (1–5 mg/kg/d) or therapeu-tic UFH followed by VKAs to achieve a targetINR of 2.5 (range, 2.0 to 3.0) [Grade 1B].

Remark: The optimal duration of therapy is un-known. Whether patients with fenestrations requiremore intensive therapy until fenestration closure isunknown.1.13. For children having endovascular stentsinserted, we suggest administration of UFHperioperatively (Grade 2C).1.14. We suggest that pediatric patients withcardiomyopathy receive VKAs to achieve a tar-get INR of 2.5 (range, 2.0 to 3.0) no later thantheir activation on a cardiac transplant waitinglist (Grade 2C).Underlying values and preferences: Our suggestionfor administration of VKAs places a high value onavoiding thrombotic complications, and a relativelylow value on avoiding the inconvenience, discomfortand limitations of anticoagulant monitoring, in chil-dren who are eligible for transplant, which is apotentially curative therapy.1.15. In children with primary pulmonary hy-pertension, we suggest anticoagulation withVKAs commencing when other medical therapyis commenced (Grade 2C).1.16. For children with biological prosthetic heartvalves, we recommend that clinicians follow therelevant recommendations from the adult popu-lation.1.17. For children with mechanical prostheticheart valves, we recommend that clinicians followthe relevant recommendations from the adultpopulation with respect to the intensity of antico-agulation therapy.1.17.2. For children with mechanical prostheticheart valves who have had thrombotic eventswhile on therapeutic antithrombotic therapy or in




patients in whom there is a contraindication tofull-dose VKAs, we suggest adding aspirin therapy(Grade 2C).1.18.1. Following ventricular assistance device(VAD) placement, in the absence of bleeding wesuggest administration of UFH targeted to ananti-factor Xa of 0.35 to 0.7 u/mL (Grade 2C).We suggest starting UFH between 8 h and 48 hfollowing implantation (Grade 2C).1.18.2. We suggest antiplatelet therapy (eitheraspirin, 1 to 5 mg/kg/d, and/or dipyridamole, 3 to10 mg/kg/d) to commence within 72 h of VADplacement (Grade 2C).1.18.3. We suggest that once clinically stable,pediatric patients be weaned from UFH toeither LMWH (target anti-FXa 0.5–1.0 U/mL)or VKA (target INR, 3.0; range, 2.5–3.5) untiltransplanted or weaned from ventricular assis-tance device (Grade 2C).1.19.1. For neonates and children requiring CCvia an artery, we recommend administration ofIV UFH prophylaxis (Grade 1A).1.19.2. We recommend the use of UFH dosesof 100 to 150 U/kg as a bolus (Grade 1B). Wesuggest further doses of UFH rather than nofurther therapy in prolonged procedures(Grade 2B).1.19.3. We recommend against the use of aspi-rin therapy for prophylaxis for cardiac catheter-ization (Grade 1B).1.20.1. For pediatric patients with a femoralartery thrombosis, we recommend therapeuticdoses of IV UFH (Grade 1B). We suggest treat-ment for at least 5–7 days (Grade 2C).1.20.2. We recommend administration of throm-bolytic therapy for pediatric patients with limb-threatening or organ-threatening (via proximalextension) femoral artery thrombosis who fail torespond to initial UFH therapy and who have noknown contraindications (Grade 1B).1.20.3. For children with femoral artery throm-bosis, we suggest surgical intervention whenthere is a contraindication to thrombolytictherapy and organ or limb death is imminent(Grade 2C).1.20.4. We suggest that for children in whomthrombolysis or surgery is not required, con-version to LMWH to complete 5 to 7 days oftreatment (Grade 2C).1.21.1. For pediatric patients with peripheralarterial catheters in situ, we recommend UFHthrough the catheter, preferably by continuousinfusion (5 U/mL at 1 mL/h) [Grade 1A].1.21.2. For children with a peripheral arterialcatheter-related thromboembolism, we suggestimmediate removal of the catheter (Grade 1B).

We suggest UFH anticoagulation with or with-out thrombolysis, or surgical thrombectomy(Grade 2C).1.22.1 To maintain umbilical artery catheter(UAC) patency, we suggest prophylaxis with alow-dose UFH infusion via the UAC (heparinconcentration of 0.25–1 U/mL) [Grade 2A].1.22.2. For neonates with UAC-related throm-bosis, we suggest therapy with UFH or LMWHfor at least 10 days (Grade 2C).1.22.3. For neonates with UAC-related throm-bosis, we recommend UAC removal (Grade 1B).1.22.4. For neonates with UAC-related thrombo-sis with potentially life-, limb-, or organ-threateningsymptoms, we suggest thrombolysis with tPA.When thrombolysis is contraindicated, we suggestsurgical thrombectomy (Grade 2C).1.23. We suggest UACs placement in a highposition rather than a low position (Grade 2B).

1.24 Neonatal Aortic Thrombosis–Spontaneous. Foradditional information, see Section 1.24 “NeonatalAortic Thrombosis–Spontaneous”

1.25. In patients undergoing hemodialysis, wesuggest against routine use of VKAs or LMWHfor prevention of thrombosis related to centralvenous lines or fistulas (Grade 2C).1.26. We suggest the use of UFH or LMWH inhemodialysis (Grade 2C).1.27.1. In children with Kawasaki disease, werecommend aspirin in high doses (80 to 100mg/kg/d during the acute phase, for up to 14days) as an antiinflammatory agent, then inlower doses (1 to 5 mg/kg/d for 6 to 8 weeks) asan antiplatelet agent (Grade 1B).1.27.2. In children with Kawasaki disease, wesuggest against concomitant use of ibuprofen orother nonsteroidal antiinflammatory drugs dur-ing aspirin therapy (Grade 2C).1.27.3. In children with Kawasaki disease, werecommend IV gamma globulin (2 g/kg, singledose) within 10 days of the onset of symptoms(Grade 1A).1.27.4. In children with giant coronary aneu-rysms following Kawasaki disease, we suggestwarfarin (target INR, 2.5; INR range, 2.0 to3.0) in addition to therapy with low-doseaspirin be given as primary thromboprophy-laxis (Grade 2C).1.28.1. For neonates with cerebral sinovenousthrombosis (CSVT) without significant intracra-nial hemorrhage, we suggest anticoagulation,initially with UFH, or LMWH and subsequentlywith LMWH or VKA for a minimum of 6 weeks,and no longer than 3 months (Grade 2C).




1.28.2. For children with cerebral sinovenousthrombosis (CSVT) with significant hemor-rhage, we suggest radiologic monitoring ofthe thrombosis at 5 to 7 days and anticoagu-lation if thrombus propagation is noted (Grade2C).1.29.1. For children with CSVT without signifi-cant intracranial hemorrhage, we recommendanticoagulation initially with UFH or LMWHand subsequently with LMWH or VKA for aminimum of 3 months relative to no anticoagu-lation (Grade 1B).1.29.2. We suggest that if after 3 months oftherapy there is incomplete radiologic recanal-isation of CSVT or ongoing symptoms, adminis-tration of a further 3 months of anticoagulation(Grade 2C).1.29.3. For children with CSVT with significanthemorrhage, we suggest radiologic monitoringof the thrombosis at 5 to 7 days. If thrombuspropagation is noted at that time, we suggestanticoagulation (Grade 2C).1.29.4. We suggest children with CSVT in thecontext of a potentially recurrent risk factors (forexample nephrotic syndrome, L-asparaginasetherapy) should receive prophylactic antico-agulation at times of risk factor recurrence(Grade 2C).1.29.5. We suggest thrombolysis thrombectomyor surgical decompression only in children withsevere CSVT in whom there is no improvementwith initial UFH therapy (Grade 2C).1.30.1. In the absence of a documented ongoingcardioembolic source, we recommend againstanticoagulation or aspirin therapy for neonateswith a first arterial ischemic stroke (AIS) (Grade1B).1.30.2. In neonates with recurrent AIS, we sug-gest anticoagulant or aspirin therapy (Grade 2C).1.31.1. For children with non–sickle-cell disease-related acute AIS, we recommend UFH orLMWH or aspirin (1 to 5 mg/kg/d) as initialtherapy until dissection and embolic causes havebeen excluded (Grade 1B).

1.31.2. We recommend, once dissection and car-dioembolic causes are excluded, daily aspirin pro-phylaxis (1–5 mg/kg/d) for a minimum of 2 years(Grade 1B).1.31.3. We suggest for AIS secondary to dissec-tion or cardioembolic causes, anticoagulanttherapy with LMWH or VKAs for at least 6weeks, with ongoing treatment dependent onradiologic assessment (Grade 2C).1.31.4. We recommend against the use of throm-bolysis (tPA) for AIS in children, outside of spe-cific research protocols (Grade 1B).1.31.5. We recommend for children with sickle-cell disease and AIS, IV hydration and exchangetransfusion to reduce sickle hemoglobin levelsto at least < 30% total hemoglobin (Grade 1B).1.31.6. For children with sickle-cell disease andAIS, after initial exchange transfusion we rec-ommend a long-term transfusion program(Grade 1B).1.31.7. In children with sickle-cell anemiawho have transcranial Doppler velocities> 200 cm/s on screening, we recommend reg-ular blood transfusion, which should be con-tinued indefinitely (Grade 1B).1.31.8. We recommend that children with moya-moya be referred to an appropriate center forconsideration of revascularization (Grade 1B).1.31.9. For children receiving aspirin who haverecurrent AIS or transient ischemic attack, wesuggest changing to clopidogrel or anticoagu-lant (LMWH or VKA) therapy (Grade 2C).1.32.1. For neonates with homozygous pro-tein C deficiency, we recommend administra-tion of either 10 to 20 mL/kg of fresh frozenplasma q12h or protein C concentrate, whenavailable, at 20 to 60 U/kg until the clinicallesions resolve (Grade 1B).1.31.2. We suggest long-term treatment withVKAs (Grade 2C), LMWH (Grade 2C), proteinC replacement (Grade 1B), or liver transplan-tation (Grade 2C).




DOI 10.1378/chest.08-0693 2008;133;71-109 Chest

Holger J. Schünemann Jack Hirsh, Gordon Guyatt, Gregory W. Albers, Robert Harrington and

Evidence-Based Clinical Practice Guidelines (8th Edition)Executive Summary: American College of Chest Physicians

This information is current as of December 3, 2008

& ServicesUpdated Information

http://chestjournal.org/cgi/content/full/133/6_suppl/71Shigh-resolution figures, can be found at: Updated information and services, including

Rapid Response

http://chestjournal.org/cgi/eletters/133/6_suppl/71Swhich you can access for free at: 3 rapid response(s) have been posted to this article,

Open Accessoption Freely available online through CHEST open access

Permissions & Licensing

http://chestjournal.org/misc/reprints.shtml(figures, tables) or in its entirety can be found online at: Information about reproducing this article in parts

Reprints http://chestjournal.org/misc/reprints.shtml

Information about ordering reprints can be found online:

Email alerting service

online article. article sign up in the box at the top right corner of the Receive free email alerts when new articles cite this

Images in PowerPoint format

format. See any online article figure for directions. downloaded for teaching purposes in PowerPoint slide Figures that appear in CHEST articles can be


http://chestjournal.org/cgi/content/full/133/6_suppl/71S

http://chestjournal.org/cgi/eletters/133/6_suppl/71S

http://chestjournal.org/misc/reprints.shtml

http://chestjournal.org/misc/reprints.shtml


anticoagulation guidelines 2008

Documents