Prevention of Venous Thromboembolism

(for use in Europe and Canada)
Expert Reviewer: William Geerts, MD, FRCPC Thromboembolism Program Sunnybrook Health Sciences Centre University of Toronto

Rationale for Thromboprophylaxis General Risk Groups and Recommendations Group Specific Thromboprophylaxis Manufacturer Prescribing Information

For additional copies: guidelines@myguidelinescenter.com

Rationale for Thromboprophylaxis1
Î The rationale for use of thromboprophylaxis is based on solid principles and scientific evidence (Table 1). Table 1. Rationale for Thromboprophylaxis in Hospitalized Patients
I. High prevalence of venous thromboembolism (VTE)
Î Almost all hospitalized patients have at least one risk factor for VTE Î Deep vein thrombosis (DVT) is common in many hospitalized patient groups Î Hospital-acquired DVT and pulmonary embolism (PE) are usually clinically silent Î It is impossible to predict which at-risk patients will develop symptomatic thromboembolic complications Î Screening at-risk patients using physical examination or noninvasive testing is neither cost-effective nor effective

II. Adverse consequences of unprevented VTE
Î Symptomatic DVT and PE Î Fatal PE Î Costs of investigating symptomatic patients Î Risks and costs of treating unprevented VTE Î Increased future risk of recurrent VTE Î Chronic post-thrombotic syndrome

III. Efficacy and effectiveness of thromboprophylaxis
Î Thromboprophylaxis is highly efficacious at preventing DVT and proximal DVT Î Thromboprophylaxis is highly effective at preventing symptomatic VTE and fatal PE Î The prevention of DVT also prevents PE Î Cost-effectiveness of thromboprophylaxis has repeatedly been demonstrated

Rationale for Thromboprophylaxis1
Î The rationale for use of thromboprophylaxis is based on solid principles and scientific evidence (Table 1). Table 1. Rationale for Thromboprophylaxis in Hospitalized Patients
I. High prevalence of venous thromboembolism (VTE)
Î Almost all hospitalized patients have at least one risk factor for VTE Î Deep vein thrombosis (DVT) is common in many hospitalized patient groups Î Hospital-acquired DVT and pulmonary embolism (PE) are usually clinically silent Î It is impossible to predict which at-risk patients will develop symptomatic thromboembolic complications Î Screening at-risk patients using physical examination or noninvasive testing is neither cost-effective nor effective

II. Adverse consequences of unprevented VTE
Î Symptomatic DVT and PE Î Fatal PE Î Costs of investigating symptomatic patients Î Risks and costs of treating unprevented VTE Î Increased future risk of recurrent VTE Î Chronic post-thrombotic syndrome

III. Efficacy and effectiveness of thromboprophylaxis
Î Thromboprophylaxis is highly efficacious at preventing DVT and proximal DVT Î Thromboprophylaxis is highly effective at preventing symptomatic VTE and fatal PE Î The prevention of DVT also prevents PE Î Cost-effectiveness of thromboprophylaxis has repeatedly been demonstrated

General Risk Groups and Recommendations1
Î Simplification of classification system to readily identify the general patient risk group and general thromboprophylaxis recommendations.

Low Risk
Minor surgery in mobile patients Approximate DVT risk without thromboprophylaxis < 10% No specific thromboprophylaxis Early and “aggressive” ambulation

Medical patients who are fully mobile

Moderate Risk
Most general, open gynecologic or urologic surgery patients Medical patients, bed rest or sick Moderate VTE risk plus high bleeding risk Approximate DVT risk without thromboprophylaxis 10-40% LMWH (dalteparin, enoxaparin, nadroparin, tinzaparin) LDUH bid or tid fondaparinux Mechanical

High Risk
Hip or knee arthroplasty, hip fracture surgery Approximate DVT risk without thromboprophylaxis 40-80% LMWH (dalteparin, enoxaparin, nadroparin, tinzaparin) fondaparinux Major trauma, Spinal cord injury Oral Factor Xa inhibitor (rivaroxaban*) Oral direct thrombin inhibitor (dabigatran*) Oral VKA (acenocoumarol, warfarin) Mechanical
*Indicated for elective hip and knee replacement surgery.

High VTE risk plus high bleeding risk

Group Specific Thromboprophylaxis1
Î Implement group-specific thromboprophylaxis routinely for all patients who belong to each of the major target groups.
Bariatric Surgery Inpatient surgery Thromboprophylaxis LMWH, LDUH tid, fondaparinux, or combination of pharmacologic prophylaxis with IPC > Higher doses of LMWH or LDUH than for nonobese Thromboprophylaxis LMWH or LDUH > VTE risk factors: advanced age, morbid obesity, extensive or lower-extremity burns, concomitant lowerextremity trauma, femoral venous catheter, and/or prolonged immobility GCS and/or IPC until bleeding risk decreases Thromboprophylaxis Refer to relevant surgical subsections Refer to high-risk medical patients Do not use either prophylactic doses of LMWH or minidose warfarin to prevent catheter-related thrombosis Recommend against routine thromboprophylaxis for primary prevention of VTE Recommend against routine primary thromboprophylaxis to improve survival Thromboprophylaxis LMWH, LDUH, or bilateral GCS or IPC > Suggest use of LMWH over LDUH to try to reduce risk of heparin-induced thrombocytopenia (HIT) Properly fitted bilateral GCS or IPC Thromboprophylaxis LMWH or LDUH > VTE risk factors: medically ill or postoperative general surgery LMWH > VTE risk factors: following major trauma or orthopedic surgery GCS and/or IPC until bleeding risk decreases; then pharmacologic prophylaxis substituted for or added to mechanical method

Burns Burn patients with additional VTE risk factors

High risk of bleeding Cancer Patients Surgical procedures Bedridden with acute medical illness Indwelling central venous catheters Receiving chemotherapy or hormonal therapy For cancer patients Coronary Artery Bypass Graft (CABG) Surgery CABG surgery High risk of bleeding Critical Care Moderate risk for VTE Higher risk High risk of bleeding

General Surgery Minor procedures and no risk factors Major procedure for benign disease Major procedure for cancer Multiple risk factors High risk of bleeding Major procedure

Thromboprophylaxis Early and frequent ambulation LMWH, LDUH, or fondaparinux LMWH, LDUH tid, or fondaparinux LMWH, LDUH tid, or fondaparinux combined with GCS and/or IPC GCS or IPC Continue until hospital discharge High-risk (eg, major cancer surgery or previous VTE), consider continuation after hospital discharge with LMWH for ≤ 28 d Thromboprophylaxis Early and frequent ambulation Early and frequent ambulation LMWH, LDUH, IPC, or GCS LMWH, LDUH, or IPC started just before surgery and used continuously while not ambulating LMWH, or LDUH tid, or IPC started just before surgery and used continuously while not ambulating Alternatives: Combination LMWH or LDUH plus GCS or IPC fondaparinux Continue until hospital discharge High-risk (eg, major cancer surgery or previous VTE), consider continuation after hospital discharge with LMWH for ≤ 28 d Thromboprophylaxis fondaparinux, LMWH, adjusted-dose VKA (INR target, 2.5; INR range, 2.0 to 3.0), or LDUH Recommend against use of aspirin alone LMWH or LDUH initiated during time between admission and surgery Optimal use of mechanical methods; when high bleeding risk decreases, pharmacologic prophylaxis substituted for or added to mechanical method

Gynecologic Surgery Low-risk minor procedures and no risk factors Laparoscopic procedure Laparoscopic procedure with additional VTE risk factors Major gynecologic surgery for benign disease without additional risk factors Extensive surgery for malignancy and for patients with additional VTE risk factors Major procedure

Hip Fracture Surgery (HFS) HFS

Surgery likely to be delayed High risk of bleeding

Hip Replacement Total Hip Replacement (THR)

Thromboprophylaxis Options: > 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) > fondaparinux > Oral Factor Xa inhibitor (rivaroxaban*) > Oral direct thrombin inhibitor (dabigatran*) > Adjusted-dose VKA started preoperatively or the evening of the surgical day (INR target, 2.5; INR range, 2.0 to 3.0) Recommend against use of the following alone: aspirin, dextran, LDUH, GCS, or VFP

High risk of bleeding

IPC or VFP; when high bleeding risk decreases, then pharmacologic prophylaxis substituted for or added to mechanical method Thromboprophylaxis Early mobilization if appropraite LMWH Thromboprophylaxis Options: > LMWH (at usual high-risk dose) > fondaparinux > Oral Factor Xa inhibitor (rivaroxaban*) > Oral direct thrombin inhibitor (dabigatran*) > Adjusted-dose VKA (INR target, 2.5; INR range, 2.0 to 3.0) Alternative: > IPC Recommend against use of the following alone: aspirin, LDUH, or VFP

Knee Arthroscopy No additional risk factors Additional risk factors or complicated procedure Knee Replacement Total Knee Replacement (TKR)

High risk of bleeding

IPC or VFP; when high bleeding risk decreases, then pharmacologic prophylaxis substituted for or added to mechanical method Thromboprophylaxis Early and frequent ambulation LMWH, LDUH, fondaparinux, IPC, or GCS

Laparoscopic Surgery No additional risk factors Additional VTE risk factors

*Indicated for elective hip and knee replacement surgery.

Group Specific Thromboprophylaxis
Long-Distance Travel Flights > 8 h Thromboprophylaxis Avoidance of constrictive clothing around lower extremities or waist, maintenance of adequate hydration, and frequent calf muscle contraction General measures listed above; consider below-knee GCS (15 to 30 mmHg pressure at ankle), or single LMWH dose prior to departure Recommend against the use of aspirin for VTE prevention Thromboprophylaxis LMWH, LDUH, or fondaparinux > Risk factors: active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease GCS or IPC Thromboprophylaxis IPC Alternatives: > Postoperative LMWH or LDUH GCS and/or IPC combined with postoperative LMWH or LDUH Thromboprophylaxis LMWH (commenced once primary hemostasis evident) Alternatives: > Combined use of IPC and either LDUH or LMWH > If anticoagulant contraindicated because of high bleeding risk, use IPC and/or GCS; when bleeding risk decreases, pharmacologic prophylaxis substituted for or added to mechanical method

Additional VTE risk factors

Long-distance travelers Medical Conditions Acutely ill medical patients with CHF, severe respiratory disease, confined to bed, or ≥ 1 risk factors VTE risk factors and contraindication to anticoagulant Neurosurgery Major neurosurgery High thrombosis risk Spinal Cord Injury (SCI) For acute SCI

Incomplete SCI associated with Mechanical methods instead of anticoagulant at least for spinal hematoma on CT or MRI first few days For patients with SCI Rehabilitation following acute SCI Recommend against the use of IVC filter as primary prophylaxis Continuation of LMWH or conversion to oral VKA (INR target, 2.5; INR range 2.0 to 3.0)

Spine Surgery No additional VTE risk factors Additional VTE risk

Thromboprophylaxis Early and frequent ambulation Postoperative LDUH, postoperative LMWH, or perioperative IPC (Alternative: GCS) > VTE risk factors: advanced age, malignancy, presence of neurologic deficit, previous VTE, or anterior surgical approach Pharmacologic prophylaxis (LDUH or LMWH) combined with mechanical method (GCS and/or IPC) Thromboprophylaxis LMWH, LDUH, or fondaparinux GCS and/or IPC Thromboprophylaxis LMWH (starting when considered safe to do so) > Continuation until hospital discharge > For impaired mobility during inpatient rehabilitation, continue LMWH or VKA (INR target, 2.5; INR range, 2.0 to 3.0) Alternative: > Combination LMWH and mechanical method IPC or possibly GCS; when high bleeding risk decreases, then pharmacologic prophylaxis substituted for or added to mechanical method > Recommend against routine DUS screening for asymptomatic DVT > Recommend DUS screening in high VTE risk (eg, SCI, lower-extremity or pelvic fracture, or major head injury) and suboptimal or no thromboprophylaxis > Recommend against use of IVC filter as primary prophylaxis Thromboprophylaxis Early and frequent ambulation LDUH bid or tid, GCS and/or IPC just before surgery and used continuously while not ambulating, LMWH, fondaparinux, or combination pharmacologic (ie, LMWH, LDUH, or fondaparinux) with mechanical method (ie, GCS and/or IPC) Optimal use of mechanical method with GCS and/or IPC until bleeding risk decreases; then pharmacologic prophylaxis substituted for or added to mechanical method Thromboprophylaxis Early and frequent ambulation LMWH, LDUH, or fondaparinux

Multiple risk factors for VTE Thoracic Surgery Major thoracic surgery High risk of bleeding Trauma Major trauma

Major trauma if LMWH contraindicated Trauma

Urologic Surgery Transurethral or other low-risk urologic procedures Major open procedures

For patients actively bleeding or at very high-risk for bleeding Vascular Surgery No additional risk factors Undergoing major procedure with additional risk factors

Table 4. Manufacturer Prescribing Information for Thrombop

Drug
Low Dose Unfractionated Heparin2 (LDUH)

Prophylaxis Indication
Low-dose regimen for major abdominothoracic surgery

Oral Direct Thrombin Inhibitor dabigatran Hip replacement surgery (Pradax®, Pradaxa®)3
Knee replacement surgery

Indirect Factor Xa Inhibitor
fondaparinux (Arixtra®)4 Abdominal surgery Hip fracture surgery Hip replacement surgery Knee replacement surgery Hip replacement surgery Knee replacement surgery

Oral Direct Factor Xa Inhibitor
rivaroxaban (Xarelto®)5

Low-Molecular-Weight Heparins (LMWH)
dalteparin (Fragmin®)6 Abdominal surgery High risk of thromboembolic complications Alternative in malignancy Hip replacement surgery: Preoperative start - evening before surgery Preoperative start - day of surgery Postoperative start Medical patients enoxaparin (Lovenox®, Clexane®)7 Abdominal surgery

Hip replacement surgery Knee replacement surgery Medical patients nadroparin (Fraxiparine®)8 General surgery Hip replacement surgery tinzaparin (Innohep®)9 General surgery Hip surgery Knee surgery Vitamin K Antagonist (VKA)
Acenocoumarol (Sintrom®)10 Warfarin (Coumadin®)11 Venous thrombosis and its extension Venous thrombosis and its extension

prophylaxis Options

Dosage and Administration
5000 U SC 1 - 2 h before surgery, then 5000 U SC every 8 - 12 h

Comments

110 mg PO 1-4 h after surgery, then 220 mg PO once daily Severe renal dysfunction For patients older than 75 years or with moderate renal impairment (creatinine (CrCl < 30 mL/min): clearance 30-50 mL/min) 75 mg PO 1-4 h after surgery, then 150 mg PO once daily contraindicated

2.5 mg SC once daily with initial dose 6 - 8 h after surgery

Severe renal dysfunction (CrCl < 30 mL/min): contraindicated

10 mg PO once daily with initial dose 6 - 10 h after surgery

Severe renal dysfunction (CrCl < 30 mL/min): not recommended

2500 IU SC once daily, starting 1 - 2 h prior to surgery and repeated once daily 5000 IU SC evening before surgery, then once daily 2500 IU SC 1 to 2 h before surgery, then 2500 IU SC 12 h later, then 5000 IU SC once daily 5000 IU SC 10 - 14 h before surgery, then 5000 IU SC 4 - 8 h after surgery, then 5000 IU SC once daily 2500 IU SC within 2 h before surgery, then 2500 IU SC 4 - 8 h after surgery, then 5000 IU SC once daily 2500 IU SC 4 - 8 h after surgery, then 5000 IU SC once daily 5000 IU SC once daily 40 mg SC once daily with initial dose 2 h prior to surgery 30 mg SC every 12 h or 40 mg SC once daily (initial dose 12 h prior to surgery) 30 mg SC every 12 h 40 mg SC once daily 2850 IU SC once daily, initial dose 2 - 4 h before surgery 38 IU/kg SC 12 h before surgery, then 38 IU/kg SC 12 h after surgery, then 38 IU/kg SC once daily up to and including Day 3, then 57 IU/kg as of Day 4 3500 IU SC 2 h before surgery, then 3500 IU once daily 50 IU/kg SC 2 h before surgery followed by 50 IU/kg once daily or 75 IU/kg SC given post-operatively once daily 75 IU/kg SC given post-operatively once daily Severe renal dysfunction (CrCl < 30 mL/min): monitor anti-Xa levels to determine the appropriate dose

Severe renal dysfunction (CrCl < 30 mL/min): 30 mg SC once daily Severe renal dysfunction (CrCl < 30 mL/min): Reduce dose by 25 - 33% Severe renal dysfunction (CrCl < 30 mL/min): Consider dosage reduction

Individualized; dose adjusted by INR response Individualized; dose adjusted by INR response

INR target of 2.5 (INR range, 2.0 to 3.0)

This Pocketcard edition is intended for the European and Canadian healthcare communities and contains only the European Medicines Agency (EMEA) and the Canadian Agency for Drugs and Technologies in Health (CADTH) approved drugs. Abbreviations
bid, twice daily; CADTH, Canadian Agency for Drugs and Technologies in Health; CHF, congestive heart failure; CrCl, creatinine clearance; CT, computerized tomography; DUS, Doppler ultrasonography; DVT, deep vein thrombosis; EMEA, European Medicines Agency; GCS, graduated compression stockings; h, hour(s); HFS, hip fracture surgery; INR, international normalized ratio; IPC, intermittent pneumatic compression; IU, international units; IVC, inferior vena cava; kg, kilogram; LDUH, low-dose unfractionated heparin; LMWH, low-molecular-weight heparin; mg, milligram; min, minute(s); mL, milliliter, MRI, magnetic resonance imaging; PE, pulmonary embolism; PO, oral; PT, prothrombin time; SC, subcutaneous; SCI, spinal cord injury; THR, total hip replacement; tid, three times daily; TKR, total knee replacement; U, units; VFP, venous foot pump; VKA, vitamin K antagonist; VTE, venous thromboembolism

References
1. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:381S-453S. 2. Heparin [package insert]. Schaumburg, IL: APP Pharmaceuticals LLC; 2008. 3. Pradax [package insert]. Burlington, Ontario: Boehringer Ingelheim Canada Ltd; 2008. 4. Arixtra [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008. 5. Xarelto [package insert]. Toronto, Ontario: Bayer Inc; 2008. 6. Fragmin [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2007. 7. Lovenox [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; 2007. 8. Fraxiparine [package insert]. Mississauga, Ontario: GlaxoSmithKline Inc; 2008. 9. Innohep [package insert]. Thornhill, Ontario: Leo Pharma Inc; 2008. 10. Sintrom [package insert]. Montreal, Quebec: Squire Pharmaceuticals Inc; 2007. 11. Coumadin [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
Disclaimer This Guideline attempts to define principles of practice that should produce high-quality patient care. It is applicable to specialists, primary care, and providers at all levels. This Guideline should not be considered exclusive of other methods of care reasonably directed at obtaining the same results. The ultimate judgement concerning the propriety of any course of conduct must be made by the clinician after consideration of each individual patient situation. 5740 Executive Drive Suite 220 • Baltimore, MD 21228 TEL: 410-869-3332 • FAX: 410-744-2150 Orders and inquiries: guidelines@MyGuidelinesCenter.com Copyright © 2009 All rights reserved For additional copies: www.myguidelinescenter.com