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Antithrombotic and Thrombolytic Therapy, 8th Ed : ACCP Guidelines: ANTITHROMBOTIC AND THROMBOLYTIC THERAPY, 8TH ED: ACCP GUIDELINES |

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

Jack Hirsh, MD, FCCP, Chair; Gordon Guyatt, MD, FCCP; Gregory W. Albers, MD; Robert Harrington, MD, FCCP; Holger J. Schünemann, MD, PhD, FCCP
Author and Funding Information

*From Hamilton Civic Hospitals (Dr. Hirsh), Henderson Research Centre, Hamilton, ON, Canada; McMaster University Medical Centre (Dr. Guyatt), Hamilton, ON, Canada; Stanford University Medical Center (Dr. Albers), Stanford Stroke Center, Palo Alto, CA; Duke Clinical Research Institute (Dr. Harrington), Duke University Medical Center, Durham, NC; and Department of Clinical Epidemiology/INFORMA (Dr. Schünemann), Istituto Regina Elena, Rome, Italy.

Correspondence to: Gordon H. Guyatt, MD, FCCP, McMaster University Medical Centre, 2C12, 1200 Main St W, Hamilton, ON, L8N 3Z5, Canada; e-mail: guyatt@mcmaster.ca



Chest. 2008;133(6_suppl):71S-109S. doi:10.1378/chest.08-0693
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This executive summary accompanies the publication of 8th edition of “Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines.” These guidelines provide an extensive critical review of the literature related to management of thromboembolic disorders.

In each chapter, the clinical question under consideration, the clinical trials evaluating the evidence, and the recommendations are linked by a numbering scheme common to these three items. The recommendations are included at the beginning of the chapters and are presented in this executive summary.

The grading system in the 8th edition of the ACCP guidelines reflects the system adopted for all ACCP guidelines, and is similar to the GRADE system, which is being widely adopted by many guideline groups. The strength of any recommendation depends on two factors: the trade-off between benefits, risks, burden, and cost, and the level of confidence in estimates of those benefits and risks. If benefits do or do not outweigh risks, burden, and costs, a strong recommendation is designated as Grade 1. If there is less certainty about the magnitude of the benefits and risks, burden, and costs, a weaker Grade 2 recommendation is made. Support for these recommendations may come from high-quality, moderate-quality, or low-quality evidence, labeled, respectively, A, B, and C. The phrase “we recommend” is used for strong recommendations (Grade 1A, 1B, 1C) and “we suggest” for weaker recommendations (2A, 2B, 2C). The full set of recommendations follows.

2.2.3 Monitoring Antithrombotic Effect

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

2.2.4 Dosing and Monitoring in Special Situations

2.2.4. In obese patients receiving LMWH prophylaxis or treatment, we suggest weight-based dosing (Grade 2C). In patients with severe renal insufficiency (creatinine clearance [CrCl] < 30 mL/min) who require therapeutic anticoagulation, we suggest the use of unfractionated heparin (UFH) instead of LMWH (Grade 2C). If LMWH is used in patients with severe renal insufficiency (CrCl < 30 mL/min) who require therapeutic anticoagulation, we suggest using 50% of the recommended dose (Grade 2C).

3.0 Direct Thrombin Inhibitors

3.0. In patients who receive either lepirudin or desirudin and have renal insufficiency (CrCl < 60 mL/min but > 30 mL/min), we recommend that the dose be reduced and the drug monitored using the activated partial thromboplastin time (APTT) [Grade 1C]. In patients with a CrCl < 30 mL/min, we recommend against the use of lepirudin or desirudin (Grade 1C). In patients who require anticoagulation and have previously received lepirudin or desirudin, we recommend against repeated use of these drugs because of the risk of anaphylaxis (Grade 1C).

3.1 Monitoring of Direct Thrombin Inhibitors

3.1. In patients receiving argatroban who are being transitioned to a vitamin K antagonist (VKA), we suggest that factor X levels, measured using a chromogenic assay, be used to adjust the dose of the VKA (Grade 2C).

2.1 Initiation and Maintenance Dosing

2.1.1. In patients beginning VKA therapy, we recommend the initiation of oral anticoagulation with doses between 5 and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 1B). At the present time, for patients beginning VKA therapy, without evidence from randomized trials, we suggest against the use of pharmacogenetic-based initial dosing to individualize warfarin dosing (Grade 2C).

2.2 Initiation of Anticoagulation in the Elderly or Other Populations

2.2.1. In elderly patients or patients who are debilitated, are malnourished, have congestive heart failure, have liver disease, have had recent major surgery, or are taking medications known to increase the sensitivity to warfarin (eg, amiodarone), we recommend the use of a starting dose of ≤ 5 mg (Grade 1C), with subsequent dosing based on the INR response.

2.3 Frequency of Monitoring

2.3.1. In patients beginning VKA therapy, we suggest that INR monitoring should be started after the initial two or three doses of oral anticoagulation therapy (Grade 2C).

2.3.2. For patients who are receiving a stable dose of oral anticoagulants, we suggest monitoring at an interval of no longer than every 4 weeks (Grade 2C).

2.4 Management of Nontherapeutic INRs

2.4.1. For patients with INRs above the therapeutic range, but < 5.0 and with no significant bleeding, we recommend lowering the dose or omitting a dose, monitoring more frequently, and resuming therapy at an appropriately adjusted dose when the INR is at a therapeutic level. If only minimally above therapeutic range, or associated with a transient causative factor, no dose reduction may be required (all Grade 1C).

2.4.2. For patients with INRs ≥ 5.0 but < 9.0 and no significant bleeding, we recommend omitting the next one or two doses, monitoring more frequently, and resuming therapy at an appropriately adjusted dose when the INR is at a therapeutic level (Grade 1C). Alternatively, we suggest omitting a dose and administering vitamin K (1 to 2.5 mg) orally, particularly if the patient is at increased risk of bleeding (Grade 2A). If more rapid reversal is required because the patient requires urgent surgery, we suggest vitamin K (≤ 5 mg) orally, with the expectation that a reduction of the INR will occur in 24 h. If the INR is still high, we suggest additional vitamin K (1 to 2 mg) orally (Grade 2C).

2.4.3. For patients with INRs of > 9.0 and no significant bleeding, we recommend holding warfarin therapy and administering a higher dose of vitamin K (2.5 to 5 mg) orally, with the expectation that the INR will be reduced substantially in 24 to 48 h (Grade 1B). Clinicians should monitor the INR more frequently, administer additional vitamin K if necessary, and resume therapy at an appropriately adjusted dose when the INR reaches the therapeutic range.

2.4.4. In patients with serious bleeding and elevated INR, regardless of the magnitude of the elevation, we recommend holding warfarin therapy and giving vitamin K (10 mg) by slow IV infusion supplemented with fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa, depending on the urgency of the situation. We recommend repeating vitamin K administration every 12 h for persistent INR elevation (all Grade 1C).

2.4.5. In patients with life-threatening bleeding (eg, intracranial hemorrhage) and elevated INR, regardless of the magnitude of the elevation, we recommend holding warfarin therapy and administering fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa supplemented with vitamin K, 10 mg by slow IV infusion, repeated, if necessary, depending on the INR (Grade 1C).

2.4.6. In patients with mild-to-moderately elevated INRs without major bleeding, we recommend that when vitamin K is to be given, it be administered orally rather than subcutaneously (Grade 1A).

2.5 Management of Variable INRs

2.5.1. For patients receiving long-term warfarin therapy with a variable INR response not attributable to any of the usual known causes for instability, we suggest a trial of daily low-dose oral vitamin K (100 to 200 μg) with close monitoring of the INR and warfarin dose adjustment to counter an initial lowering of the INR in response to vitamin K (Grade 2B).

2.7 Management of INRs in Antiphospholipid Syndrome

2.7.1. In patients who have a lupus inhibitor, who have no additional risk factors, and no lack of response to therapy, we recommend a therapeutic target INR of 2.5 (INR range, 2.0 to 3.0) [Grade 1A]. In patients who have recurrent thromboembolic events with a therapeutic INR or other additional risk factors for thromboembolic events, we suggest 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 oral anticoagulation therapy, we recommend that they do so in a systematic and coordinated fashion, incorporating patient education, systematic INR testing, tracking, follow-up, and good patient communication of results and dosing decisions as occurs in an anticoagulation management service (Grade 1B).

4.3 Patient Self-Testing and Patient Self-Management

4.3.1. Patient self-management is a choice made by patients and health-care providers that depends on many factors. In patients who are suitably selected and trained, patient self-testing and patient self-management is an effective alternative treatment model. We suggest that such therapeutic management be implemented where suitable (Grade 2B).

2.0 Perioperative Management of Patients Who Are Receiving VKAs

2.1. In patients who require temporary interruption of a VKA before surgery or a procedure and require normalization of the INR for the surgery or procedure, we recommend stopping VKAs approximately 5 days before surgery over stopping VKAs within a shorter time interval before surgery to allow adequate time for the INR to normalize (Grade 1B).

2.2. In patients who have had temporary interruption of a VKA before surgery or a procedure, we recommend resuming VKAs approximately 12 to 24 h (the evening of or the next morning) after surgery and when there is adequate hemostasis over resumption of VKAs closer to surgery (Grade 1C).

2.3. In patients who require temporary interruption of a VKA before surgery or a procedure and whose INR is still elevated (ie, ≥ 1.5) 1 to 2 days before surgery, we suggest administering low-dose (ie, 1 to 2 mg) oral vitamin K to normalize the INR instead of not administering vitamin K (Grade 2C).

2.4. In patients with a mechanical heart valve or atrial fibrillation (AF) or venous thromboembolism (VTE) at high risk for thromboembolism, we recommend bridging anticoagulation with therapeutic-dose subcutaneous (SC) LMWH or IV UFH over no bridging during temporary interruption of VKA therapy (Grade 1C); we suggest therapeutic-dose SC LMWH over IV UFH (Grade 2C). In patients with a mechanical heart valve or AT or VTE at moderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, or low-dose SC LMWH over no bridging during temporary interruption of VKA therapy (Grade 2C); we suggest therapeutic-dose SC LMWH over other management options (Grade 2C). In patients with a mechanical heart valve or AF or VTE at low risk for thromboembolism, we suggest low-dose SC LMWH or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH (Grade 2C).

Underlying values and preferences: In patients at high or moderate risk for thromboembolism, the recommendations reflect a relatively high value on preventing thromboembolism and a relatively low value is on preventing bleeding; in patients at low risk for thromboembolism, the recommendations reflect a relatively high value on preventing bleeding and a relatively low value on preventing thromboembolism.

3.0 Perioperative Management of Patients Who Are Receiving Bridging Anticoagulation

3.1. In patients who require temporary interruption of VKAs and are to receive bridging anticoagulation, from a cost-containment perspective we recommend the use of SC LMWH administered in an outpatient setting where feasible instead of inpatient administration of IV UFH (Grade 1C).

Underlying values and preferences: This recommendation reflects a consideration not only of the trade-off between the advantages and disadvantages of SC LMWH and IV UFH as reflected in their effects on clinical outcomes (LMWH at least as good, possibly better), but also the implications in terms of resource use (costs) in a representative group of countries (substantially less resource use with LMWH).

3.2. In patients who are receiving bridging anticoagulation with therapeutic-dose SC LMWH, we recommend administering the last dose of LMWH 24 h before surgery or a procedure over administering LMWH closer to surgery (Grade 1C); for the last preoperative dose of LMWH, we recommend administering approximately half the total daily dose instead of 100% of the total daily dose (Grade 1C). In patients who are receiving bridging anticoagulation with therapeutic-dose IV UFH, we recommend stopping UFH approximately 4 h before surgery over stopping UFH closer to surgery (Grade 1C).

3.3. In patients undergoing a minor surgical or other invasive procedure and who are receiving bridging anticoagulation with therapeutic-dose LMWH, we recommend resuming this regimen approximately 24 h after (eg, the day after) the procedure when there is adequate hemostasis over a shorter (eg, < 12 h) time interval (Grade 1C). In patients undergoing major surgery or a high bleeding risk surgery/procedure and for whom postoperative therapeutic-dose LMWH/UFH is planned, we recommend either delaying the initiation of therapeutic-dose LMWH/UFH for 48 to 72 h after surgery when hemostasis is secured, administering low-dose LMWH/UFH after surgery when hemostasis is secured, or completely avoiding LMWH or UFH after surgery over the administration of therapeutic-dose LMWH/UFH in close proximity to surgery (Grade 1C). We recommend considering the anticipated bleeding risk and adequacy of postoperative hemostasis in individual patients to determine the timing of LMWH or UFH resumption after surgery instead of resuming LMWH or UFH at a fixed time after surgery in all patients (Grade 1C).

3.4. In patients who are receiving bridging anticoagulation with LMWH, we suggest against the routine use of anti-factor Xa levels to monitor the anticoagulant effect of LMWHs (Grade 2C).

4.0 Perioperative Management of Patients Who Are Receiving Antiplatelet Therapy

4.2. In patients who require temporary interruption of aspirin- or clopidogrel-containing drugs before surgery or a procedure, we suggest stopping this treatment 7 to 10 days before the procedure over stopping this treatment closer to surgery (Grade 2C).

4.3. In patients who have had temporary interruption of aspirin therapy because of surgery or a procedure, we suggest resuming aspirin approximately 24 h (or the next morning) after surgery when there is adequate hemostasis instead of resuming aspirin closer to surgery (Grade 2C). In patients who have had temporary interruption of clopidogrel because of surgery or a procedure, we suggest resuming clopidogrel approximately 24 h (or the next morning) after surgery when there is adequate hemostasis instead of resuming clopidogrel closer to surgery (Grade 2C).

4.4. In patients who are receiving antiplatelet drugs, we suggest against the routine use of platelet function assays to monitor the antithrombotic effect of aspirin or clopidogrel (Grade 2C).

4.5. For patients who are not at high risk for cardiac events, we recommend interruption of antiplatelet drugs (Grade 1C). For patients at high risk of cardiac events (exclusive of coronary stents) scheduled for noncardiac surgery, we suggest continuing aspirin up to and beyond the time of surgery (Grade 2C); if patients are receiving clopidogrel, we suggest interrupting clopidogrel at least 5 days and, preferably, within 10 days prior to surgery (Grade 2C). In patients scheduled for coronary artery bypass grafting (CABG), we recommend continuing aspirin up to and beyond the time of CABG (Grade 1C); if aspirin is interrupted, we recommend it be reinitiated between 6 h and 48 h after CABG (Grade 1C). In patients scheduled for CABG, we recommend interrupting clopidogrel at least 5 days and, preferably, 10 days prior to surgery (Grade 1C). In patients scheduled for percutaneous coronary intervention (PCI), we suggest continuing aspirin up to and beyond the time of the procedure; if clopidogrel is interrupted prior to PCI, we suggest resuming clopidogrel after PCI with a loading dose of 300 to 600 mg (Grade 2C).

4.6. In patients with a bare metal coronary stent who require surgery within 6 weeks of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C). In patients with a drug-eluting coronary stent who require surgery within 12 months of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C). In patients with a coronary stent who have interruption of antiplatelet therapy before surgery, we suggest against the routine use of bridging therapy with UFH, LMWH, direct thrombin inhibitors, or glycoprotein (GP) IIb/IIIa inhibitors (Grade 2C).

Underlying values and preferences: These recommendations reflect a relatively high value placed on preventing stent-related coronary thrombosis, a consideration of complexity and costs of administering bridging therapy in the absence of efficacy and safety data in this clinical setting, and a relatively low value on avoiding the unknown but potentially large increase in bleeding risk associated with the concomitant administration of aspirin and clopidogrel during surgery.

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

5.1. In patients who are undergoing minor dental procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure and coadministering an oral prohemostatic agent (Grade 1B). In patients who are undergoing minor dental procedures and are receiving aspirin, we recommend continuing aspirin around the time of the procedure (Grade 1C). In patients who are undergoing minor dental procedures and are receiving clopidogrel, please refer to the recommendations outlined in Section 4.5 and Section 4.6.

5.2. In patients who are undergoing minor dermatologic procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C). In patients who are undergoing minor dermatologic procedures and are receiving aspirin, we recommend continuing aspirin around the time of the procedure (Grade 1C). In patients who are undergoing minor dermatologic procedures and are receiving clopidogrel, please refer to the recommendations outlined in Section 4.5 and Section 4.6.

5.3. In patients who are undergoing cataract removal and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C). In patients who are undergoing cataract removal and are receiving aspirin, we recommend continuing aspirin around the time of the procedure (Grade 1C). In patients who are undergoing cataract removal and are receiving clopidogrel, please refer to the recommendations outlined in Section 4.5 and Section 4.6.

6.0 Perioperative Management of Antithrombotic Therapy Patients Who Require Urgent Surgical or Other Invasive Procedures

6.1. In patients who are receiving VKAs and require reversal of the anticoagulant effect for an urgent surgical or other invasive procedure, we recommend treatment with low-dose (2.5 to 5.0 mg) IV or oral vitamin K (Grade 1C). For more immediate reversal of the anticoagulant effect, we suggest treatment with fresh-frozen plasma or another prothrombin concentrate in addition to low-dose IV or oral vitamin K (Grade 2C).

6.2. For patients receiving aspirin, clopidogrel, or both, are undergoing surgery and have excessive or life-threatening perioperative bleeding, we suggest transfusion of platelets or administration of other prohemostatic agents (Grade 2C).

1.0 Recognition of Heparin-Induced Thrombocytopenia
1.1 Platelet Count Monitoring for HIT

1.1. For patients receiving heparin in whom the clinician considers the risk of heparin-induced thrombocytopenia (HIT) to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients receiving heparin who have an estimated risk of HIT of 0.1 to 1.0%, we suggest platelet count monitoring over no platelet count monitoring (Grade 2C).

1.1.1 Platelet Count Monitoring of Patients Recently Treated With Heparin

1.1.1. For patients who are starting UFH or LMWH treatment and who have received UFH within the past 100 days, or those patients in whom exposure history is uncertain, we recommend obtaining a baseline platelet count and then a repeat platelet count within 24 h of starting heparin over not obtaining a repeat platelet 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 unusual symptoms and signs develop within 30 min following an IV UFH bolus, we recommend performing an immediate platelet count measurement, and comparing this value to recent prior platelet counts, over not performing a platelet count (Grade 1C).

1.1.3 Platelet Count Monitoring in Patients Receiving Therapeutic-Dose UFH

1.1.3. For patients who are receiving therapeutic-dose UFH, we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C).

1.1.4 Platelet Count Monitoring in Postoperative Patients Receiving UFH Antithrombotic Prophylaxis (Highest Risk Group for HIT)

1.1.4. For patients who are receiving postoperative 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 between postoperative days 4 to 14 (or until UFH is stopped, whichever occurs first) over less frequent platelet count monitoring (Grade 2C).

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

1.1.5. For medical/obstetrical patients who are receiving prophylactic-dose UFH, postoperative patients receiving prophylactic-dose LMWH, postoperative patients receiving intravascular catheter UFH “flushes,” or medical/obstetrical patients receiving LMWH after first receiving UFH (estimated HIT risk, 0.1 to 1%), we suggest platelet count monitoring at least every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, 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 are receiving only LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (HIT risk < 0.1%), we suggest clinicians do 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 fondaparinux thromboprophylaxis or treatment, we recommend that clinicians do not use routine platelet count monitoring (Grade 1C).

1.1.8 Management of Patients in Whom Platelet Counts Are Not Monitored

1.1.8. In outpatients who will receive heparin prophylaxis or treatment, informed consent should include HIT and its typical sequelae (new thrombosis, skin lesions), and the patient should be advised to seek medical advice if these events occur (Grade 2C).

1.1.9 Screening for Subclinical HIT Antibody Seroconversion

1.1.9. In patients who receive heparin, or in whom heparin treatment is planned (eg, for cardiac or vascular surgery), we recommend against routine HIT antibody testing in the absence of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs pointing to a potential diagnosis of HIT (Grade 1C).

1.1.10 When Should HIT Be Suspected?

1.1.10. For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C).

1.2 Special Situation: Anticoagulant Prophylaxis and Platelet Count Monitoring After Cardiac Surgery

1.2. For postoperative cardiac surgery patients, we recommend investigating for HIT antibodies if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between postoperative days 5 and 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 (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], bivalirudin [Grade 2C]) over the further use of UFH or LMWH therapy or initiation/continuation of a VKA (Grade 1B).

2.1.2. For patients receiving lepirudin, the initial lepirudin infusion rate should be no higher than 0.10 mg/kg/h (patients with creatinine < 90 μmol/L), with lower infusion rates for patients with higher serum creatinine levels (creatinine, 90 to 140 μmol/L: starting infusion rate, 0.05 mg/kg/h; creatinine, 140 to 400 μmol/L: starting infusion rate, 0.01 mg/kg/h; creatinine > 400 μmol/L: starting infusion rate, 0.005 mg/kg/h) [Grade 1C]. Furthermore, we recommend that the initial IV bolus either be omitted or, in case of perceived life- or limb-threatening thrombosis, be given at a reduced dose (0.2 mg/kg) [Grade 1C]. Further, we recommend that APTT monitoring be performed at 4-h intervals until it is apparent that steady state within the normal range (1.5 to 2.5 times patient baseline [or mean laboratory] APTT) is achieved (Grade 1C).

2.1.3. When argatroban is used to treat patients who have heart failure, multiple organ system failure, or severe anasarca, or who are postcardiac surgery, we suggest beginning the initial infusion at a rate between 0.5 and 1.2 μg/kg/min, with subsequent adjustments using the APTT, over the usual recommended starting dose of 2.0 μg/kg/min (Grade 2C).

2.1.4. When danaparoid is used to treat patients with strongly suspected (or confirmed) HIT, we recommend a therapeutic-dose regimen (see text) administered (at least initially) by the IV route over prophylactic-dose regimens or initial SC administration (Grade 1B).

2.1.5. For patients with strongly suspected or confirmed HIT, whether or not there is clinical evidence of lower-limb deep vein thrombosis (DVT), we recommend routine ultrasonography of the lower-limb veins for investigation of DVT over not performing routine ultrasonography (Grade 1C).

2.2 VKAs
2.2.1 Management of Direct Thrombin Inhibitor-VKA Overlap

2.1.1. For patients with strongly suspected or confirmed HIT, we recommend against the use of VKA (coumarin) therapy until after the platelet count has substantially recovered (ie, usually to at least 150 × 109/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low, maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) rather than with higher initial doses (Grade 1B); and the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the INR has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B).

2.2.2 Reversal of VKA Anticoagulation

2.2.2. For patients receiving a VKA at the time of diagnosis 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, we recommend against use of LMWH (Grade 1B).

2.4 Prophylactic Platelet Transfusions for HIT

2.4.1. For patients with strongly suspected or confirmed HIT who do not have active bleeding, we suggest that prophylactic platelet transfusions should not be given (Grade 2C).

3.0 Special Patient Populations
3.1 Patients With Previous HIT Undergoing Cardiac or Vascular Surgery

3.1.1. For patients with a history of HIT who are HIT antibody negative and require cardiac surgery, we recommend the use of UFH over a nonheparin anticoagulant (Grade 1B).

3.1.2. For patients with a history of HIT who are antibody positive by platelet factor 4-dependent enzyme immunosorbent assay but antibody negative by washed platelet activation assay, we recommend the use of UFH over a nonheparin anticoagulant (Grade 2C).

Remark: Preoperative and postoperative anticoagulation, if indicated, should be given with a nonheparin anticoagulant.

3.2 Patients With Acute or Subacute HIT Undergoing Cardiac Surgery

3.2.1. For patients with acute HIT (thrombocytopenic, HIT antibody positive) who require cardiac surgery, we recommend one of the following alternative anticoagulant approaches (in descending order of preference): delaying surgery (if possible) until HIT has resolved and antibodies are negative (then see Recommendation 3.1.1.) or weakly positive (then see Recommendation 3.1.2.) [Grade 1B]; using bivalirudin for intraoperative anticoagulation during cardiopulmonary bypass (if techniques of cardiac surgery and anesthesiology have been adapted to the unique features of bivalirudin pharmacology) [Grade 1B] or during “off-pump” cardiac surgery (Grade 1B); using lepirudin for intraoperative anticoagulation (if ECT is available and patient has normal renal function and is judged to be at low risk for postcardiac surgery renal dysfunction) [Grade 2C]; using UFH plus the antiplatelet agent epoprostenol (if ECT monitoring is not available or renal insufficiency precludes lepirudin use) [Grade 2C]; using UFH plus the antiplatelet agent, tirofiban (Grade 2C); or using danaparoid for intraoperative anticoagulation for off-pump CABG (Grade 2C) over performing the surgery with UFH when platelet-activating anti-platelet factor 4/heparin antibodies are known to be present in a patient with acute or recent HIT.

3.2.2. For patients with subacute HIT (platelet count recovery, but continuing HIT antibody positive), we recommend delaying surgery (if possible) until HIT antibodies (washed platelet activation assay) are negative, then using heparin (see Recommendation 3.1.1.) over using a nonheparin anticoagulant (Grade 1C). If surgery cannot be delayed, we suggest the use of a nonheparin anticoagulant (see Recommendation 3.2.1.) over the use of UFH (Grade 2C).

3.3 PCIs

3.3.1. For patients with strongly suspected (or confirmed) acute HIT who require cardiac catheterization or PCI, we recommend a nonheparin anticoagulant (bivalirudin [Grade 1B], argatroban [Grade 1C], lepirudin [Grade 1C], or danaparoid [Grade 1C]) over UFH or LMWH (Grade 1B).

3.3.2. For patients with previous HIT (who are antibody negative) who require cardiac catheterization or PCI, we suggest use of a nonheparin anticoagulant (see Recommendation 3.3.1.) over UFH or LMWH (Grade 2C).

Hospital Thromboprophylaxis Policy

1.2.1. For every general hospital, we recommend that a formal, active strategy that addresses the prevention of VTE be developed (Grade 1A).

1.2.2. We recommend that the local thromboprophylaxis strategy be in the form of a written, institution-wide thromboprophylaxis policy (Grade 1C).

1.2.3. We recommend the use of strategies shown to increase thromboprophylaxis adherence, including the use of computer decision support systems (Grade 1A), preprinted orders (Grade 1B), and periodic audit and feedback (Grade 1C). Passive methods such as distribution of educational materials or educational meetings are not recommended as sole strategies to increase adherence to thromboprophylaxis (Grade 1B).

Mechanical Methods of Thromboprophylaxis

1.4.3.1. We recommend that mechanical methods of thromboprophylaxis be used primarily in patients at high risk of bleeding (Grade 1A), or possibly as an adjunct to anticoagulant-based thromboprophylaxis (Grade 2A).

1.4.3.2. For patients receiving mechanical methods of thromboprophylaxis, we recommend that careful attention be directed toward ensuring the proper use of, and optimal adherence with, these methods (Grade 1A).

Aspirin as Thromboprophylaxis

1.4.4. We recommend against the use of aspirin alone as thromboprophylaxis against VTE for any patient group (Grade 1A).

Anticoagulant Dosing

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

Renal Impairment and Anticoagulant Dosing

1.4.6. We recommend that renal function be considered when making decisions about the use and/or the dose of LMWH, fondaparinux, and other antithrombotic drugs that are cleared by the kidneys, particularly in elderly patients, patients with diabetes mellitus, and those at high risk for bleeding (Grade 1A). Depending on the circumstances, we recommend one of the following options in this situation: avoiding the use of an anticoagulant that bioaccumulates in the presence of renal impairment, using a lower dose of the agent, or monitoring the drug level or its anticoagulant effect (Grade 1B).

Antithrombotic Drugs and Neuraxial Anesthesia/Analgesia or Peripheral Nerve Blocks

1.5.1. For all patients undergoing neuraxial anesthesia or analgesia, we recommend appropriate patient selection and caution when using anticoagulant thromboprophylaxis (Grade 1A).

1.5.2. For patients receiving deep peripheral nerve blocks, we recommend that the same cautions considered for neuraxial techniques be applied when using anticoagulant thromboprophylaxis (Grade 1C).

2.1 General Surgery

2.1.1. For low-risk general surgery patients who are undergoing minor procedures and have no additional thromboembolic risk factors, we recommend against the use of specific thromboprophylaxis other than early and frequent ambulation (Grade 1A).

2.1.2. For moderate-risk general surgery patients who are undergoing a major procedure for benign disease, we recommend thromboprophylaxis with LMWH, low-dose UFH (LDUH), or fondaparinux (each Grade 1A).

2.1.3. For higher-risk general surgery patients who are undergoing a major procedure for cancer, we recommend thromboprophylaxis with LMWH, LDUH tid, or fondaparinux (each Grade 1A).

2.1.4. For general surgery patients with multiple risk factors for VTE who are thought to be at particularly high risk, we recommend that a pharmacologic method (ie, LMWH, LDUH tid, or fondaparinux) be combined with the optimal use of a mechanical method (ie, graduated compression stockings [GCS] and/or intermittent pneumatic compression [IPC]) [Grade 1C].

2.1.5. For general surgery patients with a high risk of bleeding, we recommend the optimal use of mechanical thromboprophylaxis with properly fitted GCS or IPC (Grade 1A). When the high bleeding risk decreases, we recommend that pharmacologic thromboprophylaxis be substituted for or added to the mechanical thromboprophylaxis (Grade 1C).

2.1.6. For patients undergoing major general surgical procedures, we recommend that thromboprophylaxis continue until discharge from hospital (Grade 1A). For selected high-risk general surgery patients, including some of those who have undergone major cancer surgery or have previously had VTE, we suggest that continuing thromboprophylaxis after hospital discharge with LMWH for up to 28 days be considered (Grade 2A).

2.2 Vascular Surgery

2.2.1. For patients undergoing vascular surgery, who do not have additional thromboembolic risk factors, we suggest that clinicians not routinely use specific thromboprophylaxis other than early and frequent ambulation (Grade 2B).

2.2.2. For patients undergoing major vascular surgical procedures who have additional thromboembolic risk factors, we recommend thromboprophylaxis with LMWH, LDUH, or fondaparinux (Grade 1C).

2.3 Gynecologic Surgery

2.3.1. For low-risk gynecologic surgery patients who are undergoing minor procedures and have no additional risk factors, we recommend against the use of specific thromboprophylaxis other than early and frequent ambulation (Grade 1A).

2.3.2. For gynecology patients undergoing entirely laparoscopic procedures, we recommend against routine thromboprophylaxis, other than early and frequent ambulation (Grade 1B).

2.3.3. For gynecology patients undergoing entirely laparoscopic procedures in whom additional VTE risk factors are present, we recommend the use of thromboprophylaxis with one or more of LMWH, LDUH, IPC, or GCS (Grade 1C).

2.3.4. For all patients undergoing major gynecologic surgery, we recommend that thromboprophylaxis be used routinely (Grade 1A).

2.3.5 For patients undergoing major gynecologic surgery for benign disease, without additional risk factors, we recommend LMWH (Grade 1A), LDUH (Grade 1A), or IPC started just before surgery and used continuously while the patient is not ambulating (Grade 1B).

2.3.6. For patients undergoing extensive surgery for malignancy, and for patients with additional VTE risk factors, we recommend routine thromboprophylaxis with LMWH (Grade 1A), or LDUH three times daily (Grade 1A), or IPC, started just before surgery and used continuously while the patient is not ambulating (Grade 1A). Alternative considerations include a combination of LMWH or LDUH plus mechanical thromboprophylaxis with GCS or IPC, or fondaparinux (all Grade 1C).

2.3.7. For patients undergoing major gynecologic procedures, we recommend that thromboprophylaxis continue until discharge from hospital (Grade 1A). For selected high-risk gynecology patients, including some of those who have undergone major cancer surgery or have previously had VTE, we suggest that continuing thromboprophylaxis after hospital discharge with LMWH for up to 28 days be considered (Grade 2C).

2.4 Urologic Surgery

2.4.1. For patients undergoing transurethral or other low-risk urologic procedures, we recommend against the use of specific thromboprophylaxis other than early and frequent ambulation (Grade 1A).

2.4.2. For all patients undergoing major, open urologic procedures, we recommend that thromboprophylaxis be used routinely (Grade 1A).

2.4.3. For patients undergoing major, open urologic procedures, we recommend routine thromboprophylaxis with LDUH bid or tid (Grade 1B), GCS, and/or IPC started just before surgery and used continuously while the patient is not ambulating (Grade 1B), LMWH (Grade 1C), fondaparinux (Grade 1C), or the combination of a pharmacologic method (ie, LMWH, LDUH, or fondaparinux) with the optimal use of a mechanical method (ie, GCS and/or IPC) [Grade 1C].

2.4.4. For urologic surgery patients who are actively bleeding, or who are at very high risk for bleeding, we recommend the optimal use of mechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases (Grade 1A). When the high bleeding risk decreases, we recommend that pharmacologic thromboprophylaxis be substituted for or added to the mechanical thromboprophylaxis (Grade 1C).

2.5 Laparoscopic Surgery

2.5.1. For patients undergoing entirely laparoscopic procedures who do not have additional thromboembolic risk factors, we recommend against the routine use of thromboprophylaxis, other than early and frequent ambulation (Grade 1B).

2.5.2. For patients undergoing laparoscopic procedures, in whom additional VTE risk factors are present, we recommend the use of thromboprophylaxis with one or more of LMWH, LDUH, fondaparinux, IPC, or GCS (all Grade 1C).

2.6 Bariatric Surgery

2.6.1. For patients undergoing in-patient bariatric surgery, we recommend routine thromboprophylaxis with LMWH, LDUH tid, fondaparinux, or the combination of one of these pharmacologic methods with optimally used IPC (each Grade 1C).

2.6.2. For patients undergoing inpatient bariatric surgery, we suggest that higher doses of LMWH or LDUH than usual for nonobese patients be used (Grade 2C).

2.7 Thoracic Surgery

2.7.1. For patients undergoing major thoracic surgery, we recommend routine thromboprophylaxis with LMWH, LDUH, or fondaparinux (each Grade 1C).

2.7.2. For thoracic surgery patients with a high risk of bleeding, we recommend the optimal use of mechanical thromboprophylaxis with properly fitted GCS and/or IPC (Grade 1C).

2.8 Coronary Bypass Surgery

2.8.1. For patients undergoing CABG, we recommend the use of thromboprophylaxis with LMWH, LDUH, or optimally used bilateral GCS or IPC (Grade 1C).

2.8.2. For patients undergoing CABG, we suggest the use of LMWH over LDUH (Grade 2B).

2.8.3. For patients undergoing CABG with a high risk of bleeding, we recommend the optimal use of mechanical thromboprophylaxis with properly fitted bilateral GCS or IPC (Grade 1C).

3.1 Elective Hip Replacement

3.1.1. For patients undergoing elective total hip replacement, we recommend the routine use of one of the following anticoagulant options: (1) LMWH (at a usual high-risk dose, started 12 h before surgery or 12 to 24 h after surgery, or 4 to 6 h after surgery at half the usual high-risk dose and then increasing to the usual high-risk dose the following day); (2) fondaparinux (2.5 mg started 6 to 24 h after surgery); or (3) adjusted-dose VKA started preoperatively or the 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 replacement, we recommended against the use of any of the following: aspirin, dextran, LDUH, GCS, or venous foot pump (VFP) as the sole method of thromboprophylaxis (all Grade 1A).

3.1.3. For patients undergoing total hip replacement who have a high risk of bleeding, we recommend the optimal use of mechanical thromboprophylaxis with the VFP or IPC (Grade 1A). When the high bleeding risk decreases, we recommend that pharmacologic thromboprophylaxis be substituted for or added to the mechanical thromboprophylaxis (Grade 1C).

3.2 Elective Knee Replacement

3.2.1. For patients undergoing total knee replacement, we recommend routine thromboprophylaxis 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 replacement, the optimal use of IPC is an alternative option to anticoagulant thromboprophylaxis (Grade 1B).

3.2.3. For patients undergoing total knee replacement, we recommend against the use of any of the following as the only method of thromboprophylaxis: aspirin (Grade 1A), LDUH (Grade 1A), or VFP (Grade 1B).

3.2.4. For patients undergoing total knee replacement who have a high risk of bleeding, we recommend the optimal use of mechanical thromboprophylaxis with IPC (Grade 1A) or VFP (Grade 1B). When the high bleeding risk decreases, we recommend that pharmacologic thromboprophylaxis be substituted for or added to the mechanical thromboprophylaxis (Grade 1C).

3.3 Knee Arthroscopy

3.3.1. For patients undergoing knee arthroscopy who do not have additional thromboembolic risk factors, we suggest that clinicians not routinely use thromboprophylaxis other than early mobilization (Grade 2B).

3.3.2. For patients undergoing arthroscopic knee surgery who have additional thromboembolic risk factors or following a complicated procedure, we recommend thromboprophylaxis with LMWH (Grade 1B).

3.4 Hip Fracture Surgery

3.4.1. For patients undergoing hip fracture surgery, we recommend routine thromboprophylaxis using fondaparinux (Grade 1A), LMWH (Grade 1B), adjusted-dose VKA (INR target, 2.5; INR range, 2.0 to 3.0) [Grade 1B], or LDUH (Grade 1B).

3.4.2. For patients undergoing hip fracture surgery, we recommend against the use of aspirin alone (Grade 1A).

3.4.3. For patients undergoing hip fracture surgery in whom surgery is likely to be delayed, we recommend that thromboprophylaxis with LMWH or LDUH be initiated during the time between hospital admission and surgery (Grade 1C).

3.4.4. For patients undergoing hip fracture surgery who have a high risk of bleeding, we recommend the optimal use of mechanical thromboprophylaxis (Grade 1A). When the high bleeding risk decreases, we recommend that pharmacologic thromboprophylaxis be substituted for or added to the mechanical thromboprophylaxis (Grade 1C).

3.5 Other Thromboprophylaxis Issues in Major Orthopedic Surgery
Commencement of Thromboprophylaxis

3.5.1.1. For patients receiving LMWH as thromboprophylaxis in major orthopedic surgery, we recommend starting either preoperatively or postoperatively (Grade 1A).

3.5.1.2. For patients receiving fondaparinux as thromboprophylaxis in major orthopedic surgery, we recommend starting either 6 to 8 h after surgery or the next day (Grade 1A).

Screening for DVT Before Hospital Discharge

3.5.2. For asymptomatic patients following major orthopedic surgery, we recommend against the routine use of DUS screening before hospital discharge (Grade 1A).

Duration of Thromboprophylaxis