Sylvia C. McKean, MD

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Journal of Hospital Medicine - 4(2)

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S16-S23

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diagnosis, secondary prevention, treatment, venous thromboembolism

Read more about VTE Diagnosis and Treatment

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Diagnosis of DVT

Assessment of Clinical Probability

Active cancer (treatment ongoing, within 6 months, or palliative)
Calf swelling >3 cm asymptomatic side (measured 10 cm below tibial tuberosity)
Collateral superficial veins (nonvaricose)
Entire leg swelling
Localized tenderness along the distribution of the deep venous system
Paralysis, paresis, or recent plaster immobilization of the lower extremities
Pitting edema confined to the symptomatic leg
Recently bedridden more than 3 days or major surgery within 4 weeks

In addition, 2 points are subtracted if an alternative diagnosis is as likely as or more likely than DVT. In patients with symptoms in both legs, the more symptomatic leg is used.

Patients with low (score <1), moderate (score 1‐2), and high (score 3) pretest probability of DVT have been shown to have DVT prevalence rates of 3%, 17%, and 75%, respectively.3

D‐Dimer Testing

Diagnostic Imaging

Diagnostic Strategy

Diagnosis of PE

Assessing Clinical Probability

D‐Dimer Testing

Diagnostic Imaging

Diagnostic Strategy

Treatment Options for VTE

Anticoagulant Treatment

Other Treatments

Guideline Recommendations

ACCP Guidelines

Table 1.2008 ACCP Recommendations for the Initial Treatment of VTE
Initial Anticoagulation Therapy	Grade	Acceptable Treatment Regimen*
NOTE: Adapted from Kearon et al20, 30 and Arixtra.31 Abbreviations: ACCP, American College of Chest Physicians; aPTT, activated partial thromboplastin time; HIT, heparin‐induced thrombocytopenia; IVC, inferior vena cava; LMWH, low molecular weight heparin; PT, prothrombin time; SC, subcutaneous; UFH, unfractionated heparin; VTE; venous thromboembolism. * All regimens include a minimum of 5 days warfarin therapy overlap. Dosages not provided by the ACCP guidelines. LMWHs should be used with caution in renal impairment; anti‐factor Xa monitoring and dose adjustments may be required. Follow prescribing information for dose adjustments and body weightbased dosing. Fondaparinux is contraindicated in severe renal impairment (creatinine clearance 30 mL/minute).
SC LMWH	1A	Enoxaparin: 1 mg/kg every 12 hours or 1.5 mg/kg once daily; Dalteparin: 200 IU/kg once daily (can be administered out of hospital)
Intravenous UFH	1A	Get baseline aPTT, PT, and platelet count; if no abnormalities, proceed with a weight‐based heparin infusion protocol such as:
Intravenous UFH	1A	Bolus of 80 U/kg, followed by an infusion of 18 U/kg per hour (treatment duration 72 days); check aPTT every 4‐6 hours and adjust according to the normogram; monitor platelet count every 3‐4 days for HIT
Monitored SC UFH; fixed‐dose, unmonitored, SC UFH	1A; 1A	Initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (can be administered out of hospital)
SC fondaparinux	1A	5 mg (body weight <50 kg), 7.5 mg (body weight 50‐100 kg), or 10 mg (body weight >100 kg) once daily (treatment duration 72 days)
IVC filter if anticoagulation contraindicated	1C

ACP/AAFP Guidelines

In 2007, the ACP and the AAFP collaborated to develop joint guidelines for the management of VTE.32 Several of their key recommendations are the following:32

LMWH, rather than UFH, should be used whenever possible for the initial inpatient treatment of DVT
Either UFH or LMWH is appropriate for the initial treatment of PE
Anticoagulation should be continued for 3 to 6 months for VTE secondary to transient risk factors, and for more than 12 months for recurrent VTE
LMWH is safe and effective for the long‐term treatment of VTE in selected patients (and may be preferable for patients with cancer)

ESC Guidelines for the Treatment of PE

NCCN Guidelines: Oncology Patients

FWG Guidelines: Oncology Patients

At the 2008 ASH annual meeting, the FWG presented updated guidelines for the treatment of VTE in cancer patients.34 The FWG guidelines contain the following key recommendations:

The treatment of VTE should be based on LMWH at curative doses for at least 3 months
During the initial treatment (up to 10 days), any approved drug (including LMWH, UFH, and fondaparinux) may be used
Beyond the first 10 days, VTE treatment should be based on LMWH at curative doses for at least 3 months and optimally 6 months, as validated with the following drugs and dosage regimens:
Dalteparin 200 IU/kg once daily for 1 month, then 150 IU/kg once daily
Enoxaparin 150 IU/kg (1.5 mg/kg) once daily
Tinzaparin 175 IU/kg once daily
Special treatment considerations include the following:
In severe renal impairment, UFH should be used and rapidly followed by a vitamin K agonist (VKA) for at least 3 months
In severe PE (representing hemodynamic failure), the indications and recommended uses of thrombolytic drugs in noncancer patients apply
In patients with an absolute contraindication to anticoagulation or VTE recurrence despite optimal anticoagulation, vena cava filters should be considered
In patients with intracranial malignancies, VTE treatment is the same as in cancer patients with nonintracranial tumors

Long‐Term Management of VTE

PTS

Recurrent VTE

Secondary Prevention

Table 2.Duration of Anticoagulation Therapy With VKA
Clinical Features	Duration	Grade
NOTE: Modified with permission from Ref. 20: Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):454S‐545S. Abbreviations: DVT, deep vein thrombosis; LMWH, low‐molecular‐weight heparin; VKA, vitamin K antagonist.
First episode and transient risk factors	3 months	1A
Unprovoked episode	3 months	1A
Unprovoked proximal DVT with low bleed risk	Long‐term	1A
Cancer	3 to 6 months with LMWH; then with a VKA or a LMWH indefinitely or until cancer is resolved	1A; 1C
Second unprovoked episode	Indefinite	2A

Transition to Outpatient Therapy

Conclusions

Diagnosis of DVT

Assessment of Clinical Probability

Active cancer (treatment ongoing, within 6 months, or palliative)
Calf swelling >3 cm asymptomatic side (measured 10 cm below tibial tuberosity)
Collateral superficial veins (nonvaricose)
Entire leg swelling
Localized tenderness along the distribution of the deep venous system
Paralysis, paresis, or recent plaster immobilization of the lower extremities
Pitting edema confined to the symptomatic leg
Recently bedridden more than 3 days or major surgery within 4 weeks

In addition, 2 points are subtracted if an alternative diagnosis is as likely as or more likely than DVT. In patients with symptoms in both legs, the more symptomatic leg is used.

Patients with low (score <1), moderate (score 1‐2), and high (score 3) pretest probability of DVT have been shown to have DVT prevalence rates of 3%, 17%, and 75%, respectively.3

D‐Dimer Testing

Diagnostic Imaging

Diagnostic Strategy

Diagnosis of PE

Assessing Clinical Probability

D‐Dimer Testing

Diagnostic Imaging

Diagnostic Strategy

Treatment Options for VTE

Anticoagulant Treatment

Other Treatments

Guideline Recommendations

ACCP Guidelines

Table 1.2008 ACCP Recommendations for the Initial Treatment of VTE
Initial Anticoagulation Therapy	Grade	Acceptable Treatment Regimen*
NOTE: Adapted from Kearon et al20, 30 and Arixtra.31 Abbreviations: ACCP, American College of Chest Physicians; aPTT, activated partial thromboplastin time; HIT, heparin‐induced thrombocytopenia; IVC, inferior vena cava; LMWH, low molecular weight heparin; PT, prothrombin time; SC, subcutaneous; UFH, unfractionated heparin; VTE; venous thromboembolism. * All regimens include a minimum of 5 days warfarin therapy overlap. Dosages not provided by the ACCP guidelines. LMWHs should be used with caution in renal impairment; anti‐factor Xa monitoring and dose adjustments may be required. Follow prescribing information for dose adjustments and body weightbased dosing. Fondaparinux is contraindicated in severe renal impairment (creatinine clearance 30 mL/minute).
SC LMWH	1A	Enoxaparin: 1 mg/kg every 12 hours or 1.5 mg/kg once daily; Dalteparin: 200 IU/kg once daily (can be administered out of hospital)
Intravenous UFH	1A	Get baseline aPTT, PT, and platelet count; if no abnormalities, proceed with a weight‐based heparin infusion protocol such as:
Intravenous UFH	1A	Bolus of 80 U/kg, followed by an infusion of 18 U/kg per hour (treatment duration 72 days); check aPTT every 4‐6 hours and adjust according to the normogram; monitor platelet count every 3‐4 days for HIT
Monitored SC UFH; fixed‐dose, unmonitored, SC UFH	1A; 1A	Initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (can be administered out of hospital)
SC fondaparinux	1A	5 mg (body weight <50 kg), 7.5 mg (body weight 50‐100 kg), or 10 mg (body weight >100 kg) once daily (treatment duration 72 days)
IVC filter if anticoagulation contraindicated	1C

ACP/AAFP Guidelines

In 2007, the ACP and the AAFP collaborated to develop joint guidelines for the management of VTE.32 Several of their key recommendations are the following:32

LMWH, rather than UFH, should be used whenever possible for the initial inpatient treatment of DVT
Either UFH or LMWH is appropriate for the initial treatment of PE
Anticoagulation should be continued for 3 to 6 months for VTE secondary to transient risk factors, and for more than 12 months for recurrent VTE
LMWH is safe and effective for the long‐term treatment of VTE in selected patients (and may be preferable for patients with cancer)

ESC Guidelines for the Treatment of PE

NCCN Guidelines: Oncology Patients

FWG Guidelines: Oncology Patients

At the 2008 ASH annual meeting, the FWG presented updated guidelines for the treatment of VTE in cancer patients.34 The FWG guidelines contain the following key recommendations:

The treatment of VTE should be based on LMWH at curative doses for at least 3 months
During the initial treatment (up to 10 days), any approved drug (including LMWH, UFH, and fondaparinux) may be used
Beyond the first 10 days, VTE treatment should be based on LMWH at curative doses for at least 3 months and optimally 6 months, as validated with the following drugs and dosage regimens:
Dalteparin 200 IU/kg once daily for 1 month, then 150 IU/kg once daily
Enoxaparin 150 IU/kg (1.5 mg/kg) once daily
Tinzaparin 175 IU/kg once daily
Special treatment considerations include the following:
In severe renal impairment, UFH should be used and rapidly followed by a vitamin K agonist (VKA) for at least 3 months
In severe PE (representing hemodynamic failure), the indications and recommended uses of thrombolytic drugs in noncancer patients apply
In patients with an absolute contraindication to anticoagulation or VTE recurrence despite optimal anticoagulation, vena cava filters should be considered
In patients with intracranial malignancies, VTE treatment is the same as in cancer patients with nonintracranial tumors

Long‐Term Management of VTE

PTS

Recurrent VTE

Secondary Prevention

Table 2.Duration of Anticoagulation Therapy With VKA
Clinical Features	Duration	Grade
NOTE: Modified with permission from Ref. 20: Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):454S‐545S. Abbreviations: DVT, deep vein thrombosis; LMWH, low‐molecular‐weight heparin; VKA, vitamin K antagonist.
First episode and transient risk factors	3 months	1A
Unprovoked episode	3 months	1A
Unprovoked proximal DVT with low bleed risk	Long‐term	1A
Cancer	3 to 6 months with LMWH; then with a VKA or a LMWH indefinitely or until cancer is resolved	1A; 1C
Second unprovoked episode	Indefinite	2A

Transition to Outpatient Therapy

Conclusions

References

Health Grades, Inc. The Fifth Annual Health Grades Patient Safety in American Hospitals Study. Available at: http://www.healthgrades.com/media/dms/pdf/PatientSafetyInAmericanHospitalsStudy2008.pdf. Accessed August2009.
Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th Edition.Chest2008;133(6 suppl):381S–453S.
Wells PS, Anderson DR, Bormanis J, et al.Value of assessment of pretest probability of deep‐vein thrombosis in clinical management.Lancet.1997;350(9094):1795–1798.
Wells PS, Anderson DR, Rodger M, et al.Evaluation of D‐dimer in the diagnosis of suspected deep‐vein thrombosis.N Engl J Med.2003;349:1227–1235.
Brotman DJ, Segal JB, Jani JT, et al.Limitations of D‐dimer testing in unselected inpatients with suspected venous thromboembolism.Am J Med.2003;114(4):276–282.
Qaseem A, Snow V, Barry P, et al.Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians.Ann Fam Med.2007;5(1):57–62.
Kearon C, Ginsberg JS, Hirsh J.The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism.Ann Intern Med.1998;129:1044–1049.
Perrier A, Bounameaux H.Ultrasonography of leg veins in patients suspected of having pulmonary embolism.Ann Intern Med.1998;128:243–245.
Kanne JP, Lalani TA.Role of computed tomography and magnetic resonance imaging for deep venous thrombosis and pulmonary embolism.Circulation.2004;109(12 suppl 1):I15–I21.
Torbicki A, Perrier A, Konstantinides S, et al.Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology.Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC).Eur Heart J.2008;29(18):2276–2315.
Wells PS, Anderson DR, Rodger M, et al.Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D‐dimer.Thromb Haemost.2000;83(3):416–420.
Wolf SJ, McCubbin TR, Feldhaus KM, et al.Prospective validation of Wells criteria in the evaluation of patients with suspected pulmonary embolism.Ann Emerg Med.2004;44(5):503–510.
Kline JA, Mitchell AM, Kabrhel C, et al.Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.J Thromb Haemost.2004;2(8):1247–1255.
Kline JA, Courtney DM, Kabrhel C, et al.Prospective multicenter evaluation of the pulmonary embolism rule‐out criteria.J Thromb Haemost.2008;6(5):772–780.
Kruip MJ, Söhne M, Nijkeuter M, et al.A simple diagnostic strategy in hospitalized patients with clinically suspected pulmonary embolism.J Intern Med.2006;260(5):459–466.
Le Gal G, Righini M.Is computed tomographic venography of lower limbs useful in suspected pulmonary embolism?Rev Med Suisse.2008;4(143):354,356–359.
Stein PD, Fowler SE, Goodman LR, et al.Multidetector computed tomography for acute pulmonary embolism.N Engl J Med.2006;354(22):2317–2327.
Van Belle A, Büller HR, Huisman MV, et al.Christopher Study Investigators.Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D‐dimer testing, and computed tomography.JAMA.2006;295(2):172–179.
Aklog L, Williams CS, Byrne JG, Goldhaber SZ.Acute pulmonary embolectomy: a contemporary approach.Circulation.2002;105:1416–1419.
Kearon C, Kahn SR, Agnelli G, et al.Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th Edition).Chest.2008;133(6 suppl):454S–545S.
Buller HR, Davidson BL, Decousus H, et al.Subcutaneous fondaparinux versus unfractionated heparin in the initial treatment of pulmonary embolism.N Engl J Med.2003;349:1695–1702.
Warkentin TE.Heparin‐induced thrombocytopenia associated with fondaparinux.N Engl J Med.2007;356:2653–2655.
Wan S, Quinlan DJ, Agnelli G, Eikelboom JW.Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta‐analysis of the randomized controlled trials.Circulation.2004;110:744–749.
Seshadri T, Tran H, Lau KK, et al.Ins and outs of inferior vena cava filters in patients with venous thromboembolism: the experience at Monash Medical Centre and review of the published reports.Intern Med J.2008;38(1):38–43.
PREPIC Study Group.Eight‐year follow‐up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) randomized study.Circulation.2005;112:416–422.
Failla PJ, Reed KD, Summer WR, Karam GH.Inferior vena cava filters: key considerations.Am J Med Sci.2005;330:82–87.
Ferris EJ, McCowan TC, Carver DK, McFarland DR.Percutaneous inferior vena cava filters: follow‐up of 7 designs in 320 patients.Radiology.1993;188:851–856.
Karmy‐Jones R, Jurkovich GJ, Velmahos GC, et al.Practice patterns and outcomes of retrievable vena cava filters in trauma patients: an AAST multicenter study.J Trauma.2007;62:17–24.
Protack CD, Bakken AM, Patel N, Saad WE, Waldman DL, Davies MG.Long‐term outcomes of catheter directed thrombolysis for lower extremity deep venous thrombosis without prophylactic inferior vena cava filter placement.J Vasc Surg.2007;45(5):992–997.
Kearon C, Ginsberg JS, Julian JA, et al.Comparison of fixed‐dose weight‐adjusted unfractionated heparin and low‐molecular‐weight heparin for acute treatment of venous thromboembolism.JAMA.2006;296(8):935–942.
Arixtra prescribing information. Last updated October 2008. Research Triangle Park, NC: GlaxoSmithKline. Available at: http://us.gsk.com/products/assets/us_arixtra.pdf. Accessed August2009.
Snow V, Qaseem A, Barry P, et al.American College of Physicians;American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism.Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians.Ann Intern Med.2007;146(3):204–210.
National Comprehensive Cancer Network (NCCN). Venous thromboembolic disease. Practice Guidelines in Oncology. V.1.2009. Available at: http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf. Accessed August2009.
Farge D, Bosquet L, Chahmi DK, et al. Guidelines for the treatment of venous thromboembolism in cancer patients: report from the French Working Group. Presented at the 50th Annual Meeting of the American College of Hematology; San Francisco, CA; December 6‐9, 2008. Abstract 1284.
Heit JA, Mohr DN, Silverstein MD, et al.Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population‐based cohort study.Arch Intern Med.2000;160(6):761–768.
Rahme E, Dasgupta K, Burman M, et al.Postdischarge thromboprophylaxis and mortality risk after hip‐or knee‐replacement surgery.CMAJ.2008;178(12):1545–1554.
Kahn SR, Shrier I, Julian JA, et al.Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis.Ann Intern Med.2008;149(10):698–707.
Prandoni P, Noventa F, Ghirarduzzi A, et al.The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients.Haematologica.2007;92(2):199–205.
Prandoni P.Risk factors of recurrent venous thromboembolism: the role of residual vein thrombosis.Pathophysiol Haemost Thromb.2003/2004;33(5‐6):351–353.
McRae S, Tran H, Schulman S, et al.Effect of patient's sex on risk of recurrent venous thromboembolism: a meta‐analysis.Lancet.2006;368:371–378.
Spyropoulos AC, Lin J.Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations.J Manag Care Pharm.2007;13(6):475–486.
Du Breuil AL, Umland EM.Outpatient management of anticoagulation therapy.Am Fam Physician.2007;75:1031–1042.

References

Health Grades, Inc. The Fifth Annual Health Grades Patient Safety in American Hospitals Study. Available at: http://www.healthgrades.com/media/dms/pdf/PatientSafetyInAmericanHospitalsStudy2008.pdf. Accessed August2009.
Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th Edition.Chest2008;133(6 suppl):381S–453S.
Wells PS, Anderson DR, Bormanis J, et al.Value of assessment of pretest probability of deep‐vein thrombosis in clinical management.Lancet.1997;350(9094):1795–1798.
Wells PS, Anderson DR, Rodger M, et al.Evaluation of D‐dimer in the diagnosis of suspected deep‐vein thrombosis.N Engl J Med.2003;349:1227–1235.
Brotman DJ, Segal JB, Jani JT, et al.Limitations of D‐dimer testing in unselected inpatients with suspected venous thromboembolism.Am J Med.2003;114(4):276–282.
Qaseem A, Snow V, Barry P, et al.Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians.Ann Fam Med.2007;5(1):57–62.
Kearon C, Ginsberg JS, Hirsh J.The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism.Ann Intern Med.1998;129:1044–1049.
Perrier A, Bounameaux H.Ultrasonography of leg veins in patients suspected of having pulmonary embolism.Ann Intern Med.1998;128:243–245.
Kanne JP, Lalani TA.Role of computed tomography and magnetic resonance imaging for deep venous thrombosis and pulmonary embolism.Circulation.2004;109(12 suppl 1):I15–I21.
Torbicki A, Perrier A, Konstantinides S, et al.Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology.Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC).Eur Heart J.2008;29(18):2276–2315.
Wells PS, Anderson DR, Rodger M, et al.Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D‐dimer.Thromb Haemost.2000;83(3):416–420.
Wolf SJ, McCubbin TR, Feldhaus KM, et al.Prospective validation of Wells criteria in the evaluation of patients with suspected pulmonary embolism.Ann Emerg Med.2004;44(5):503–510.
Kline JA, Mitchell AM, Kabrhel C, et al.Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.J Thromb Haemost.2004;2(8):1247–1255.
Kline JA, Courtney DM, Kabrhel C, et al.Prospective multicenter evaluation of the pulmonary embolism rule‐out criteria.J Thromb Haemost.2008;6(5):772–780.
Kruip MJ, Söhne M, Nijkeuter M, et al.A simple diagnostic strategy in hospitalized patients with clinically suspected pulmonary embolism.J Intern Med.2006;260(5):459–466.
Le Gal G, Righini M.Is computed tomographic venography of lower limbs useful in suspected pulmonary embolism?Rev Med Suisse.2008;4(143):354,356–359.
Stein PD, Fowler SE, Goodman LR, et al.Multidetector computed tomography for acute pulmonary embolism.N Engl J Med.2006;354(22):2317–2327.
Van Belle A, Büller HR, Huisman MV, et al.Christopher Study Investigators.Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D‐dimer testing, and computed tomography.JAMA.2006;295(2):172–179.
Aklog L, Williams CS, Byrne JG, Goldhaber SZ.Acute pulmonary embolectomy: a contemporary approach.Circulation.2002;105:1416–1419.
Kearon C, Kahn SR, Agnelli G, et al.Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th Edition).Chest.2008;133(6 suppl):454S–545S.
Buller HR, Davidson BL, Decousus H, et al.Subcutaneous fondaparinux versus unfractionated heparin in the initial treatment of pulmonary embolism.N Engl J Med.2003;349:1695–1702.
Warkentin TE.Heparin‐induced thrombocytopenia associated with fondaparinux.N Engl J Med.2007;356:2653–2655.
Wan S, Quinlan DJ, Agnelli G, Eikelboom JW.Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta‐analysis of the randomized controlled trials.Circulation.2004;110:744–749.
Seshadri T, Tran H, Lau KK, et al.Ins and outs of inferior vena cava filters in patients with venous thromboembolism: the experience at Monash Medical Centre and review of the published reports.Intern Med J.2008;38(1):38–43.
PREPIC Study Group.Eight‐year follow‐up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) randomized study.Circulation.2005;112:416–422.
Failla PJ, Reed KD, Summer WR, Karam GH.Inferior vena cava filters: key considerations.Am J Med Sci.2005;330:82–87.
Ferris EJ, McCowan TC, Carver DK, McFarland DR.Percutaneous inferior vena cava filters: follow‐up of 7 designs in 320 patients.Radiology.1993;188:851–856.
Karmy‐Jones R, Jurkovich GJ, Velmahos GC, et al.Practice patterns and outcomes of retrievable vena cava filters in trauma patients: an AAST multicenter study.J Trauma.2007;62:17–24.
Protack CD, Bakken AM, Patel N, Saad WE, Waldman DL, Davies MG.Long‐term outcomes of catheter directed thrombolysis for lower extremity deep venous thrombosis without prophylactic inferior vena cava filter placement.J Vasc Surg.2007;45(5):992–997.
Kearon C, Ginsberg JS, Julian JA, et al.Comparison of fixed‐dose weight‐adjusted unfractionated heparin and low‐molecular‐weight heparin for acute treatment of venous thromboembolism.JAMA.2006;296(8):935–942.
Arixtra prescribing information. Last updated October 2008. Research Triangle Park, NC: GlaxoSmithKline. Available at: http://us.gsk.com/products/assets/us_arixtra.pdf. Accessed August2009.
Snow V, Qaseem A, Barry P, et al.American College of Physicians;American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism.Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians.Ann Intern Med.2007;146(3):204–210.
National Comprehensive Cancer Network (NCCN). Venous thromboembolic disease. Practice Guidelines in Oncology. V.1.2009. Available at: http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf. Accessed August2009.
Farge D, Bosquet L, Chahmi DK, et al. Guidelines for the treatment of venous thromboembolism in cancer patients: report from the French Working Group. Presented at the 50th Annual Meeting of the American College of Hematology; San Francisco, CA; December 6‐9, 2008. Abstract 1284.
Heit JA, Mohr DN, Silverstein MD, et al.Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population‐based cohort study.Arch Intern Med.2000;160(6):761–768.
Rahme E, Dasgupta K, Burman M, et al.Postdischarge thromboprophylaxis and mortality risk after hip‐or knee‐replacement surgery.CMAJ.2008;178(12):1545–1554.
Kahn SR, Shrier I, Julian JA, et al.Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis.Ann Intern Med.2008;149(10):698–707.
Prandoni P, Noventa F, Ghirarduzzi A, et al.The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients.Haematologica.2007;92(2):199–205.
Prandoni P.Risk factors of recurrent venous thromboembolism: the role of residual vein thrombosis.Pathophysiol Haemost Thromb.2003/2004;33(5‐6):351–353.
McRae S, Tran H, Schulman S, et al.Effect of patient's sex on risk of recurrent venous thromboembolism: a meta‐analysis.Lancet.2006;368:371–378.
Spyropoulos AC, Lin J.Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations.J Manag Care Pharm.2007;13(6):475–486.
Du Breuil AL, Umland EM.Outpatient management of anticoagulation therapy.Am Fam Physician.2007;75:1031–1042.

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Journal of Hospital Medicine - 4(2)

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Optimizing management of venous thromboembolism: Diagnosis, treatment, and secondary prevention

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Optimizing management of venous thromboembolism: Diagnosis, treatment, and secondary prevention

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Improving thromboprophylaxis: Performance measures and practical strategies

Author(s)

Patrick J. Connor, MD, FAAEM

Despite the availability of evidence‐based guidelines for the prevention of thromboembolic morbidity and mortality, venous thromboembolism (VTE) remains a pervasive threat to public health. Prophylaxis is underused for a variety of reasons, which were summarized in the first article of this Supplement. Overcoming these barriers and reducing the incidence of VTE has become a major priority for public health policy.

The Office of the Surgeon General released a report in September 2008 that reflects this sense of urgency and national focus by calling for a coordinated, multifaceted plan to reduce the incidence of VTE in the United States.1 The Surgeon General report is one of the latest in a string of national initiatives designed to improve outcomes in patients at risk of VTE. In the past several years, public and private agencies have launched a range of programs aimed at improving deficiencies in the awareness, prevention, and treatment of VTE in hospitalized patients (these are summarized in Table 1). New performance measures and improvement initiatives may reduce the discrepancies between recommendations and practice, ultimately improving patient outcomes. These measures may possibly become benchmarks for pay‐for‐performance initiatives or future hospital accreditation.

Table 1.VTE Performance Measures and Initiatives
Measure/Initiative	Description
Abbreviation: VTE, venous thromboembolism.
National Quality Forum/The Joint Commission (NQF/TJC)	Public reporting of hospital performance in 6 performance measures; will apply to all medical and surgical patients
Surgical Care Improvement Project (SCIP)	Two performance measures enacted with reimbursement implications; 2 outcomes measures
American Medical Association Physician Consortium for Performance Improvement (PCPI)	Medical societies collaborating to identify gaps in care and develop performance measures; 1 measure has been endorsed
Leapfrog Hospital Quality and Safety Survey	Web database allowing consumers to compare performance among participating hospitals; includes 2 NQF safe practices
TJC National Patient Safety Goals (NPSG)	Goals for solving patient safety problems; compliance required for Joint Commission accreditation, with online reporting of results (Quality Check website)
North American Thrombosis Forum (NATF)	Nonprofit organization addressing unmet needs related to VTE and other thrombotic disorders
American Venous Forum National Venous Screening Program	National VTE awareness campaign; promotes compliance with protocols

Herein, we review a variety of VTE performance measures, including those from the National Quality Forum (NQF), The Joint Commission (TJC), and the Surgical Care Improvement Project (SCIP). To illustrate how performance measures may be applied in the hospital setting to improve patient care, performance improvement programs that have proven effective in select hospitals across the United States are described.

Performance Measures and Initiatives

National Quality Forum Performance Measures

The NQF and TJC (formerly known as the Joint Commission on Accreditation of Healthcare Organizations) have already enacted performance measures for pneumonia, heart failure, acute myocardial infarction (MI), and other conditions. Since 2005, the NQF and TJC have been collaborating to develop national consensus performance measures for the prevention and care of VTE. The VTE performance measures will apply to all medical and surgical patients and include process measures in the areas of prevention and treatment, as well as outcome measures. After pilot‐testing a range of measures for 3 years, TJC recommended 7 candidate measures in November 2007. In May 2008, the NQF endorsed 6 of these, embracing all TJC recommendations except one relating to the use and documentation of vena cava filter quality improvement (Table 2).2

Table 2.NQF Performance Measures for the Prevention and Care of VTE
NOTE: The Joint Commission. National Consensus Standards for Prevention and Care of Venous Thromboembolism (VTE). Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/VTE.htm. Abbreviations: ICU, intensive care unit; INR, international normalized ratio; NQF, National Quality Forum; UFH, unfractionated heparin; VTE, venous thromboembolism.
Risk assessment and prophylaxis
1. Documentation of VTE risk/prophylaxis within 24 hours of hospital admission or surgery end‐time
2. Documentation of VTE risk/prophylaxis within 24 hours after ICU admission, transfer to ICU, or surgery end‐time
Treatment
3. Patients with VTE with overlap of parenteral and warfarin anticoagulation therapy for at least 5 days with an INR 2 before discontinuation of parenteral therapy; for > 5 days with an INR < 2 and discharged on overlap therapy; or discharged in < 5 days on overlap therapy
4. Patients with VTE receiving UFH with dosages/platelet count monitoring by protocol or nomogram
5. Patients with VTE or their caregivers are given written discharge instructions or other educational material addressing all of the following: follow‐up monitoring, compliance issues, dietary restrictions, and potential for adverse drug reactions and interactions
Outcomes
6. Incidence of potentially preventable hospital‐acquired VTE measured by patients who received no VTE prophylaxis before VTE diagnosis

The next step is for the NQF to develop a specification manual that defines which patients should be given prophylaxis using International Classification of Diseases, 9th edition (ICD‐9) codes and identifies which interventions are appropriate for each patient population. Current clinical guidelines provide important guidance for appropriate inclusion and exclusion criteria for medical and surgical prophylaxis, as well as evidence‐based recommendations for the treatment of VTE.3, 4

SCIP

The SCIP has a stated goal of reducing surgical complications by 25% by 2010.5 To accomplish this, the SCIP is targeting improvement in 4 areas: surgical‐site infection, cardiac events, postoperative pneumonia, and VTE prophylaxis. The SCIP performance measures for VTE prophylaxis in surgical patients are as follows:

Recommended VTE prophylaxis ordered during admission; and
Appropriate VTE prophylaxis received within 24 hours prior to surgical incision time to 24 hours after surgery end time.

After the success seen by a core group of hospitals who volunteered to participate, all Medicare‐accredited hospitals were required to submit SCIP data beginning with discharges in the first quarter of 2007 to obtain full reimbursement from the Centers for Medicare and Medicaid Services (CMS). Institutions can gauge whether they are in compliance with the SCIP VTE measures by answering a series of yes or no questions about whether prophylaxis has been ordered and received for specific patient groups and procedures. In a recent study, almost one‐half of all surgical patients at risk of VTE did not receive recommended and timely prophylaxis as specified by the SCIP performance measures.6

In addition to the 2 enacted SCIP performance measures for VTE prophylaxis, 2 outcome measures are under development. These measures address the rate at which intraoperative or postoperative pulmonary embolism (PE; SCIP VTE‐3) and deep vein thrombosis (DVT; SCIP VTE‐4) are diagnosed during the index hospitalization and within 30 days after surgery. If implemented, these measures will capture the efficacy of thromboprophylaxis.5

Other VTE Performance Initiatives

Several professional and consumer organizations are developing standards and compiling performance data for public reporting and other purposes:

The American Medical Association Physician Consortium for Performance Improvement (PCPI) comprises more than 100 national medical specialty and state medical societies working to identify gaps in care that can be addressed with evidence‐based medicine and formal performance measures. The PCPI has endorsed a measure requiring low‐molecular‐weight heparin (LMWH), low‐dose unfractionated heparin (UFH), adjusted‐dose warfarin, fondaparinux, or mechanical prophylaxis to be given within 24 hours prior to incision time or within 24 hours after surgery end‐time for adults undergoing a procedure for which prophylaxis is indicated.7
The Leapfrog Hospital Quality and Safety Survey hosts a searchable web‐based database that consumers can use to compare performance among participating hospitals in specific geographic regions. The Leapfrog survey includes NQF safe practices #28 (reduce occurrence of VTE) and #29 (ensure long‐term anticoagulation is effective and safe).8
TJC National Patient Safety Goals (NPSG) target specific improvements in patient safety by providing healthcare organizations with solutions to prevalent patient safety problems. Compliance is necessary for Joint Commission accreditation, and results are reported on the Quality Check website. NPSG Goal 3 is focused on improving the safety of medications, and Goal 3E specifically addresses patient harm associated with the use of anticoagulation therapy. The 2008 NPSG goals must be implemented by January 2009.2
The North American Thrombosis Forum (NATF), a nonprofit organization, was recently organized to address unmet needs in North America related to VTE and other thrombotic disorders. It is designed to complement existing organizations dealing with thrombosis‐related issues, with 5 major focus areas: basic translational research; clinical research; prevention and education; public policy; and advocacy. Each month, its website (http://www.natfonline.org) features several scientific papers dealing with venous and arterial thrombosis‐related issues.
The American Venous Forum National Venous Screening Program is a national campaign designed to increase VTE awareness and promote the importance of compliance with prophylaxis protocols.9

As different organizations work to develop performance measures for VTE, conflicting standards have emerged. Although this remains a major challenge, the NQF is attempting to develop voluntary consensus standards that will harmonize VTE performance measures across all sites of care, including the acute medical, surgical, and oncology settings. Major clinical guidelines from the American College of Physicians (ACP), American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), the European Society of Cardiology (ESC), and other organizations provide data to support standardized, evidence‐based measures for VTE.

Implications of Performance Data

Hospital‐Level Performance Reporting

Performance results may affect an institution's ability to contract best rates with payors, obtain full reimbursement for services, and be eligible for bonus payments. For example, pay‐for‐reporting legislation from CMS provides targeted financial incentives to improve the rates at which hospitals report data on quality measures. The current legislation stipulates that hospitals must submit performance data, including data on compliance with the 2 SCIP‐VTE measures, or lose 2% of their annual CMS payment update. For a 500‐bed hospital with 80% occupancy and 50% CMS patients, failure to report data on SCIP‐VTE measures would result in an estimated annual loss of $2.6 million.10

In 2007, the first year of the CMS pay‐for‐reporting program, 93% of hospitals met the reporting goals. As penalties for nonreporting increase, an even higher compliance rate may be expected. CMS is proposing a new system that would withhold 5% of the base operating diagnosis‐related group payment from a hospital's budget; hospitals would be required to earn this back through reporting and meeting specific performance goals. Using a phase‐in system, CMS would reimburse 2.5% in the first year for pay‐for‐reporting and 2.5% for pay‐for‐performance. Ultimately, the full 5% bonus would be based on performance results.11

Performance ratings play a central role in hospital accreditation, which is critical for negotiating terms for tiered contracting arrangements with private insurers. In addition, hospital performance rankings are becoming more publicly accessible. TJC reports hospital performance in meeting the SCIP measures on its website (http://www.qualitycheck.org), and CMS will incorporate performance measures into its public reporting system, Hospital Compare (http://www.hospitalcompare.hhs.gov). Considering the widespread availability of performance ratings and the fact that payors encourage members to consider performance results when selecting their venue of care, customer choice may increasingly become a factor in a hospital's financial viability.

Physician‐Level Performance Reporting

In new quality assessment programs, physicians will also be rewarded or penalized according to their individual performance. The CMS Physician Quality Reporting Initiative (PQRI) is a claims‐based, voluntary, pay‐for‐reporting initiative targeted to Medicare providers. The PQRI program currently pays physicians 2% of total charges for covered services in exchange for voluntary reporting, and it is moving toward results‐based reimbursement.12 The 2009 PQRI Measures List describes 186 quality measures, including 2 related to VTE:13

Quality Measure 23: Percentage of patients aged 18 years and older undergoing procedures for which VTE prophylaxis is indicated in all patients, who had an order for LMWH, low‐dose UFH, adjusted‐dose warfarin, fondaparinux, or mechanical prophylaxis to be given within 24 hours prior to incision time or within 24 hours after surgery end‐time; and
Quality Measure 31: Percentage of patients aged 18 years and older with a diagnosis of ischemic stroke or intracranial hemorrhage who received DVT prophylaxis by end of hospital day 2.

In the PQRI, physicians report quality measures on process and patient outcomes to CMS using G‐codes or current procedural terminology (CPT)‐II codes. Approximately one‐half of the 100,000 providers who submitted quality codes during the first PQRI reporting period (July 1 to December 31, 2007) qualified for the incentive payment, totaling $36 million.12

More stringent pay‐for‐performance initiatives that hold physicians personally accountable for performance results are being developed in the private sector. For example, the Consumer‐Purchaser Disclosure Project (CPDP) is a consumer‐advocacy group that aims to improve healthcare and lower costs by holding healthcare providers publicly accountable for their quality of treatment. The CPDP has partnered with the National Committee for Quality Assurance to develop guidelines for reporting NQF performance measures.14

VTE as a Nonreimbursable Never Event

In a program that began with hospital discharges on October 1, 2008, hospitals will not receive CMS payment for 12 selected conditions that were not present on admission and were caused by medical error. These hospital‐acquired conditions (HAC), commonly known as never events, include pressure ulcers, catheter‐associated urinary tract infections, postoperative infections, and other complications. Beginning in fiscal year 2009, CMS has added hospital‐acquired VTE following hip or knee replacement surgery as a nonreimbursable never event.15 While CMS acknowledges that prophylaxis will not prevent every occurrence of DVT/PE, they feel it is a reasonably preventable HAC.15 Similar policies are expanding to state and private payor programs that require neither the patient nor the payor to reimburse the hospital for care related to reasonably preventable complications.

Improving Performance and Patient Outcomes

Despite the growing volume of evidence supporting the use of thromboprophylaxis, its use remains inadequate. The consequences are clear: between 2004 and 2006, the number of cases of postoperative VTE increased by 11%.1 This lack of progress may be due to clinicians' lack of awareness of evidence‐based interventions and to hospitals' lack of protocols for the provision of high‐quality preventive treatment.1 Successful strategies for improving thromboprophylaxis and other VTE performance measures are urgently needed. Over the past several years, researchers have been evaluating the utility of different strategies for improving guideline compliance, such as computer‐aided decision‐making and auditing and feedback programs.

Several initiatives seem to have been successful. In one review, Tooher et al.16 found that computerized reminders are, in general, one of the most effective strategies for improving prescribing practice. Paper‐based systems are easier to ignore without a challenge, while electronic systems may force users to acknowledge alerts. Stand‐alone protocols and reminder systems at the point of care can improve prophylaxis rates by about 50%, and decision‐support systems that integrate orders for prophylaxis can increase rates by up to 85%. Importantly, education‐only programs have not been sufficiently effective.16

Regardless of the strategy chosen, Tooher et al identified.16 several general features that, when included as part of the initiative, increase the likelihood of program success:

A process for demonstrating the importance and relevance of VTE prophylaxis in the local clinical setting (eg, presenting findings of a local audit of current practice to clinical staff);
A process for improving clinician knowledge about VTE risk assessment and prophylaxis practice, such as through a continuing education program;
A method of reminding clinicians to assess patients for VTE risk, accompanied by aids to assist in the documentation of patient risk;
A process for assisting clinicians in prescribing the appropriate prophylaxis; and
A method for assessing the effectiveness of any changes and for refining local policy to further improve practice, such as through clinical audit and feedback.

Table 3 lists several resources and tools that may be useful when designing and implementing strategies to improve performance and quality of care for hospitalized patients at risk of VTE.

Table 3.Resources and Tools for Improving Performance in VTE
Resource	Description
Abbreviation: VTE, venous thromboembolism. * Available at htttp://www.hospitalmedicine.org/ResourceRoomRedesign/RR_VTE/VTE_Home.cfm. Available at http://www.asco.org/ASCO/Downloads/Cancer Policy and Clinical Affairs/Clinical Affairs (derivative products)/VTE Flow Sheet.pdf. Available at http://www.chestnet.org. Available at http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf.
Society of Hospital Medicine, VTE Resource Room*	A website with educational resources, prophylaxis and treatment algorithms, and sample VTE protocols for various patient populations
American Society of Clinical Oncology; VTE Prophylaxis Orders and Flow Sheet	A sheet to consult and fill out when prescribing pharmacologic VTE prophylaxis for cancer patients; includes justifications for use, contraindications, anticoagulant options and doses, and other important details
American College of Chest Physicians	A source of guidelines, clinical research, education, and other resources for building an evidence‐based VTE protocol
National Comprehensive Cancer Network, Clinical Practice GuidelinesVTE	A concise source of algorithms for VTE prophylaxis, diagnosis, and treatment in cancer patients; also includes tables detailing recommended prevention/treatment regimens and warnings/contraindications

Case Studies in Performance Improvement

Several institutions have reported success stories and shared details of their quality improvement initiatives. Whether paper‐based, electronic, physician‐targeted, or pharmacist‐led, these programs were designed to meet the unique needs of each institution and can serve as models for other hospitals wishing to implement similar programs to improve VTE prophylaxis rates and patient outcomes.

Brigham and Women's Hospital, Boston, MA

In 2005, Kucher et al.17 published a landmark report illustrating the benefits of an electronic alert system in increasing thromboprophylaxis and reducing VTE rates among hospitalized patients. The randomized trial identified high‐risk patients who were not receiving prophylaxis and assigned them to the intervention group, in which the treating physician was alerted to the VTE risk (n = 1255), or to the control group, in which no alert was made (n = 1251). Compared with patients in the control arm, those in the intervention arm were more than twice as likely to receive mechanical or pharmacologic prophylaxis (14.5% vs. 33.5%) and 41% less likely to develop VTE within 90 days (P < 0.001).17

In 2008, this system was evaluated in a new cohort study to determine the ongoing effectiveness of electronic alerts in a real hospital setting.18 The following steps were taken:

Alerts were dispatched for all high‐risk cases; and
The responsible physician for each high‐risk patient not receiving prophylaxis was issued a single alert detailing the patient's risk and encouraging the use of thromboprophylaxis

During the study period, the use of prophylaxis increased by 50% (P < 0.001). Still, nearly two‐thirds of physicians ignored the electronic alerts.18 Thus, while computer alert systems are helpful, other strategies must be employed to further improve prophylaxis rates in high‐risk medical patients.18

Roswell Park Cancer Institute, Buffalo, NY

Roswell Park Cancer Institute (RPCI), a Comprehensive Cancer Center with 24,000 active patients, initiated an institute‐wide quality improvement initiative in 2006 to improve the rates of VTE prophylaxis for all adult inpatients.19 This initiative included efforts to improve compliance with NCCN guidelines on all medical services and follow guidelines in accordance with NCCN, surgical best practices, and published standards on all surgical services. To accomplish this objective, RPCI:

Implemented mandatory, computerized physician order entry forms;
Promoted VTE awareness via staff education, field in‐services, and seminars; and
Tracked compliance with manual audits of patient charts every 3 months.

When the initiative began in the fourth quarter of 2006, the rate of NCCN‐recommended VTE prophylaxis was 61% with the medical services and 86% with the surgical services. As of the second quarter of 2008, guideline compliance had increased to 90% and 100% with the medical and surgical services, respectively. Accompanying this increase in compliance was a corresponding decrease in the incidence of VTE, from 0.39% in the fourth quarter of 2006 to 0.08% in the second quarter of 2008 (P < 0.0001). The most pronounced reductions in VTE incidence were observed within the medical services and among outpatients.19

Hartford Hospital, Hartford, CT

Hartford Hospital is an 819‐bed acute‐care community hospital with 300 designated medical beds. In an effort to improve thromboprophylaxis rates among medical patients, the pharmacy, medicine, and information technology departments collaborated to develop an alert within the computerized prescriber‐order‐entry system that reminded clinicians to assess patients for VTE risk factors and the need for prophylaxis.20 When a patient met predefined criteria for VTE risk, the message was displayed until either mechanical or pharmacologic VTE prophylaxis was an active order on the patient's treatment profile (Figure 1). The program was implemented in conjunction with an extensive educational program targeting hospital staff, pharmacists, physicians, nurse practitioners, physician assistants, and nurses.20

Example of a VTE assessment reminder for a computerized prescriber order entry system. Reprinted with permission from Sobieraj.20

Compliance with institutional prophylaxis guidelines increased from 49% to 93% following implementation (P < 0.001). Interestingly, the initiative at Hartford Hospital was able to increase the use of mechanical prophylaxis among patients with a contradiction to pharmacologic therapy from 25% prior to the program to 100% after its implementation (P < 0.001).20

Saint Elizabeth's Hospital, Collinsville, IL

In 2008, Bauer et al.21 reported the benefits of a pharmacist‐led program for VTE prevention in Saint Elizabeth's Hospital, a 278‐bed hospital with more than 13,000 admissions per year. As part of the initiative, hospital pharmacists:

Received daily reports of all new admissions cross‐referenced with an accounting of patients currently prescribed UFH or LMWH;
Assessed the remaining patients at risk of VTE; and
Placed recommendations in patient charts in the form of a bold sticker alerting the physician to the patient's risk factors, their overall risk of VTE, and treatment recommendations (Figure 2).

Sticker placed by pharmacist in patient medical record. CVA, cerebrovascular accident; DVT, deep vein thrombosis; HF, heart failure; IBW, ideal body weight; MI, myocardial infarction; PE, pulmonary embolism. Reprinted with permission from Bauer21

The program ran 7 days per week, involved 1 pharmacist per day, and required an average of 4 hours per day. Patients in the maternity, nursery, pediatric, and psychiatric units were excluded from the program.

The program led to a significant increase in the use of VTE prophylaxis and a significant reduction in the rate of DVT (P < 0.002).21 These findings suggest that innovative programs tailored to the needs of individual institutions can dramatically increase thromboprophylaxis rates and decrease the incidence of VTE in at‐risk hospitalized patients.

Conclusions

VTE is a serious disease that leads to excess morbidity and mortality among hospitalized patients. The impact of hospital reporting on reimbursement and patient outcomes necessitates the adoption of strategies and protocols proven to enhance the management of VTE and improve patient outcomes. Several successful VTE initiatives have been described in the literature and can serve as models for institutions wishing to develop policies and procedures for preventing VTE. In addition, a number of online resources exist that can aid in the development of VTE protocols.

References

U.S. Department of Health and Human Services. The surgeon general's call to action to prevent deep vein thrombosis and pulmonary embolism. Available at: http://www.surgeongeneral.gov/topics/deepvein/calltoaction/call‐to‐action‐on‐dvt‐2008.pdf. Accessed June2009.
The Joint Commission. National consensus standards for prevention and care of venous thromboembolism (VTE). Last updated April 2009. Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/VTE.htm. Accessed June2009.
Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines (8th edition).Chest2008;133(6 suppl):381S–453S.
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ;American College of Chest Physicians.Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th edition).Chest.2008;133(6 suppl):454S–545S.
The Joint Commission. Surgical Care Improvement Project Core Measure Set. Updated November 2008. Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/SCIP+Core+Measure+Set.htm. Accessed June2009.
Deitelzweig S, Lin J, Hussein M, et al.Are surgical patients at risk of venous thromboembolism current meeting the surgical care improvement performance target goal for appropriate and timely prophylaxis?Chest.2008;134:s46003.
American Medical Association. Perioperative Care: Physician Performance Measurement Set. October 2006. Available at http://www.ama‐assn.org/ama1/pub/upload/mm/370/perioperativews1206.pdf. Accessed June2009.
Leapfrog Group. The Leapfrog Group Hospital Quality and Safety Survey: What's New in the 2009 Survey (Version 5.1). Available at: https://leapfrog.medstat.com/pdf/final.pdf. Accessed June2009.
McLafferty RB, Passman MA, Caprini JA, et al.Increasing awareness about venous disease: The American Venous Forum expands the National Venous Screening Program.J Vasc Surg.2008;48(2):394–399.
Federal Register. Medicare Program; Proposed Changes to the Hospital Inpatient Prospective Payment Systems and Fiscal Year 2007 Rates. Available at: http://edocket.access.gpo.gov/2006/pdf/06‐3629.pdf. Accessed December 10,2008.
Department of Health and Human Services, Centers for Medicare 241(3):397–415.
Kucher N, Koo S, Quiroz R, et al.Electronic alerts to prevent venous thromboembolism among hospitalized patients.N Engl J Med.2005;352(10):969–977.
Baroletti S, Munz K, Sonis J, et al.Electronic alerts for hospitalized high‐VTE risk patients not receiving prophylaxis: a cohort study.J Thromb Thrombolysis.2008;25(2):146–150.
Ahluwalia MS, Klein K, Kuvshinoff BW, et al. Improving compliance with guidelines for venous thromboembolism (VTE) prophylaxis significantly reduces VTE events. Presented at the 50th Annual Meeting of the American College of Hematology; San Francisco, CA; December 6‐9, 2008. Abstract 1288.
Sobieraj DM.Development and implementation of a program to assess medical patients' need for venous thromboembolism prophylaxis.Am J Health Syst Pharm.2008;65(18):1755–1760.
Bauer JB, Chun DS, Karpinski TA.Pharmacist‐led program to improve venous thromboembolism prophylaxis in a community hospital.Am J Health Syst Pharm.2008;65(17):1643–1647.

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performance measures, strategies, thromboprophylaxis, venous thromboembolism

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Patrick J. Connor, MD, FAAEM

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Patrick J. Connor, MD, FAAEM

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Table 1.VTE Performance Measures and Initiatives
Measure/Initiative	Description
Abbreviation: VTE, venous thromboembolism.
National Quality Forum/The Joint Commission (NQF/TJC)	Public reporting of hospital performance in 6 performance measures; will apply to all medical and surgical patients
Surgical Care Improvement Project (SCIP)	Two performance measures enacted with reimbursement implications; 2 outcomes measures
American Medical Association Physician Consortium for Performance Improvement (PCPI)	Medical societies collaborating to identify gaps in care and develop performance measures; 1 measure has been endorsed
Leapfrog Hospital Quality and Safety Survey	Web database allowing consumers to compare performance among participating hospitals; includes 2 NQF safe practices
TJC National Patient Safety Goals (NPSG)	Goals for solving patient safety problems; compliance required for Joint Commission accreditation, with online reporting of results (Quality Check website)
North American Thrombosis Forum (NATF)	Nonprofit organization addressing unmet needs related to VTE and other thrombotic disorders
American Venous Forum National Venous Screening Program	National VTE awareness campaign; promotes compliance with protocols

Performance Measures and Initiatives

National Quality Forum Performance Measures

Table 2.NQF Performance Measures for the Prevention and Care of VTE
NOTE: The Joint Commission. National Consensus Standards for Prevention and Care of Venous Thromboembolism (VTE). Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/VTE.htm. Abbreviations: ICU, intensive care unit; INR, international normalized ratio; NQF, National Quality Forum; UFH, unfractionated heparin; VTE, venous thromboembolism.
Risk assessment and prophylaxis
1. Documentation of VTE risk/prophylaxis within 24 hours of hospital admission or surgery end‐time
2. Documentation of VTE risk/prophylaxis within 24 hours after ICU admission, transfer to ICU, or surgery end‐time
Treatment
3. Patients with VTE with overlap of parenteral and warfarin anticoagulation therapy for at least 5 days with an INR 2 before discontinuation of parenteral therapy; for > 5 days with an INR < 2 and discharged on overlap therapy; or discharged in < 5 days on overlap therapy
4. Patients with VTE receiving UFH with dosages/platelet count monitoring by protocol or nomogram
5. Patients with VTE or their caregivers are given written discharge instructions or other educational material addressing all of the following: follow‐up monitoring, compliance issues, dietary restrictions, and potential for adverse drug reactions and interactions
Outcomes
6. Incidence of potentially preventable hospital‐acquired VTE measured by patients who received no VTE prophylaxis before VTE diagnosis

SCIP

Recommended VTE prophylaxis ordered during admission; and
Appropriate VTE prophylaxis received within 24 hours prior to surgical incision time to 24 hours after surgery end time.

Other VTE Performance Initiatives

Several professional and consumer organizations are developing standards and compiling performance data for public reporting and other purposes:

The American Medical Association Physician Consortium for Performance Improvement (PCPI) comprises more than 100 national medical specialty and state medical societies working to identify gaps in care that can be addressed with evidence‐based medicine and formal performance measures. The PCPI has endorsed a measure requiring low‐molecular‐weight heparin (LMWH), low‐dose unfractionated heparin (UFH), adjusted‐dose warfarin, fondaparinux, or mechanical prophylaxis to be given within 24 hours prior to incision time or within 24 hours after surgery end‐time for adults undergoing a procedure for which prophylaxis is indicated.7
The Leapfrog Hospital Quality and Safety Survey hosts a searchable web‐based database that consumers can use to compare performance among participating hospitals in specific geographic regions. The Leapfrog survey includes NQF safe practices #28 (reduce occurrence of VTE) and #29 (ensure long‐term anticoagulation is effective and safe).8
TJC National Patient Safety Goals (NPSG) target specific improvements in patient safety by providing healthcare organizations with solutions to prevalent patient safety problems. Compliance is necessary for Joint Commission accreditation, and results are reported on the Quality Check website. NPSG Goal 3 is focused on improving the safety of medications, and Goal 3E specifically addresses patient harm associated with the use of anticoagulation therapy. The 2008 NPSG goals must be implemented by January 2009.2
The North American Thrombosis Forum (NATF), a nonprofit organization, was recently organized to address unmet needs in North America related to VTE and other thrombotic disorders. It is designed to complement existing organizations dealing with thrombosis‐related issues, with 5 major focus areas: basic translational research; clinical research; prevention and education; public policy; and advocacy. Each month, its website (http://www.natfonline.org) features several scientific papers dealing with venous and arterial thrombosis‐related issues.
The American Venous Forum National Venous Screening Program is a national campaign designed to increase VTE awareness and promote the importance of compliance with prophylaxis protocols.9

Implications of Performance Data

Hospital‐Level Performance Reporting

Physician‐Level Performance Reporting

Quality Measure 23: Percentage of patients aged 18 years and older undergoing procedures for which VTE prophylaxis is indicated in all patients, who had an order for LMWH, low‐dose UFH, adjusted‐dose warfarin, fondaparinux, or mechanical prophylaxis to be given within 24 hours prior to incision time or within 24 hours after surgery end‐time; and
Quality Measure 31: Percentage of patients aged 18 years and older with a diagnosis of ischemic stroke or intracranial hemorrhage who received DVT prophylaxis by end of hospital day 2.

VTE as a Nonreimbursable Never Event

Improving Performance and Patient Outcomes

Regardless of the strategy chosen, Tooher et al identified.16 several general features that, when included as part of the initiative, increase the likelihood of program success:

A process for demonstrating the importance and relevance of VTE prophylaxis in the local clinical setting (eg, presenting findings of a local audit of current practice to clinical staff);
A process for improving clinician knowledge about VTE risk assessment and prophylaxis practice, such as through a continuing education program;
A method of reminding clinicians to assess patients for VTE risk, accompanied by aids to assist in the documentation of patient risk;
A process for assisting clinicians in prescribing the appropriate prophylaxis; and
A method for assessing the effectiveness of any changes and for refining local policy to further improve practice, such as through clinical audit and feedback.

Table 3 lists several resources and tools that may be useful when designing and implementing strategies to improve performance and quality of care for hospitalized patients at risk of VTE.

Table 3.Resources and Tools for Improving Performance in VTE
Resource	Description
Abbreviation: VTE, venous thromboembolism. * Available at htttp://www.hospitalmedicine.org/ResourceRoomRedesign/RR_VTE/VTE_Home.cfm. Available at http://www.asco.org/ASCO/Downloads/Cancer Policy and Clinical Affairs/Clinical Affairs (derivative products)/VTE Flow Sheet.pdf. Available at http://www.chestnet.org. Available at http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf.
Society of Hospital Medicine, VTE Resource Room*	A website with educational resources, prophylaxis and treatment algorithms, and sample VTE protocols for various patient populations
American Society of Clinical Oncology; VTE Prophylaxis Orders and Flow Sheet	A sheet to consult and fill out when prescribing pharmacologic VTE prophylaxis for cancer patients; includes justifications for use, contraindications, anticoagulant options and doses, and other important details
American College of Chest Physicians	A source of guidelines, clinical research, education, and other resources for building an evidence‐based VTE protocol
National Comprehensive Cancer Network, Clinical Practice GuidelinesVTE	A concise source of algorithms for VTE prophylaxis, diagnosis, and treatment in cancer patients; also includes tables detailing recommended prevention/treatment regimens and warnings/contraindications

Case Studies in Performance Improvement

Brigham and Women's Hospital, Boston, MA

In 2008, this system was evaluated in a new cohort study to determine the ongoing effectiveness of electronic alerts in a real hospital setting.18 The following steps were taken:

Alerts were dispatched for all high‐risk cases; and
The responsible physician for each high‐risk patient not receiving prophylaxis was issued a single alert detailing the patient's risk and encouraging the use of thromboprophylaxis

Roswell Park Cancer Institute, Buffalo, NY

Implemented mandatory, computerized physician order entry forms;
Promoted VTE awareness via staff education, field in‐services, and seminars; and
Tracked compliance with manual audits of patient charts every 3 months.

Hartford Hospital, Hartford, CT

Saint Elizabeth's Hospital, Collinsville, IL

Received daily reports of all new admissions cross‐referenced with an accounting of patients currently prescribed UFH or LMWH;
Assessed the remaining patients at risk of VTE; and
Placed recommendations in patient charts in the form of a bold sticker alerting the physician to the patient's risk factors, their overall risk of VTE, and treatment recommendations (Figure 2).

Conclusions

Table 1.VTE Performance Measures and Initiatives
Measure/Initiative	Description
Abbreviation: VTE, venous thromboembolism.
National Quality Forum/The Joint Commission (NQF/TJC)	Public reporting of hospital performance in 6 performance measures; will apply to all medical and surgical patients
Surgical Care Improvement Project (SCIP)	Two performance measures enacted with reimbursement implications; 2 outcomes measures
American Medical Association Physician Consortium for Performance Improvement (PCPI)	Medical societies collaborating to identify gaps in care and develop performance measures; 1 measure has been endorsed
Leapfrog Hospital Quality and Safety Survey	Web database allowing consumers to compare performance among participating hospitals; includes 2 NQF safe practices
TJC National Patient Safety Goals (NPSG)	Goals for solving patient safety problems; compliance required for Joint Commission accreditation, with online reporting of results (Quality Check website)
North American Thrombosis Forum (NATF)	Nonprofit organization addressing unmet needs related to VTE and other thrombotic disorders
American Venous Forum National Venous Screening Program	National VTE awareness campaign; promotes compliance with protocols

Performance Measures and Initiatives

National Quality Forum Performance Measures

Table 2.NQF Performance Measures for the Prevention and Care of VTE
NOTE: The Joint Commission. National Consensus Standards for Prevention and Care of Venous Thromboembolism (VTE). Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/VTE.htm. Abbreviations: ICU, intensive care unit; INR, international normalized ratio; NQF, National Quality Forum; UFH, unfractionated heparin; VTE, venous thromboembolism.
Risk assessment and prophylaxis
1. Documentation of VTE risk/prophylaxis within 24 hours of hospital admission or surgery end‐time
2. Documentation of VTE risk/prophylaxis within 24 hours after ICU admission, transfer to ICU, or surgery end‐time
Treatment
3. Patients with VTE with overlap of parenteral and warfarin anticoagulation therapy for at least 5 days with an INR 2 before discontinuation of parenteral therapy; for > 5 days with an INR < 2 and discharged on overlap therapy; or discharged in < 5 days on overlap therapy
4. Patients with VTE receiving UFH with dosages/platelet count monitoring by protocol or nomogram
5. Patients with VTE or their caregivers are given written discharge instructions or other educational material addressing all of the following: follow‐up monitoring, compliance issues, dietary restrictions, and potential for adverse drug reactions and interactions
Outcomes
6. Incidence of potentially preventable hospital‐acquired VTE measured by patients who received no VTE prophylaxis before VTE diagnosis

SCIP

Recommended VTE prophylaxis ordered during admission; and
Appropriate VTE prophylaxis received within 24 hours prior to surgical incision time to 24 hours after surgery end time.

Other VTE Performance Initiatives

Several professional and consumer organizations are developing standards and compiling performance data for public reporting and other purposes:

The American Medical Association Physician Consortium for Performance Improvement (PCPI) comprises more than 100 national medical specialty and state medical societies working to identify gaps in care that can be addressed with evidence‐based medicine and formal performance measures. The PCPI has endorsed a measure requiring low‐molecular‐weight heparin (LMWH), low‐dose unfractionated heparin (UFH), adjusted‐dose warfarin, fondaparinux, or mechanical prophylaxis to be given within 24 hours prior to incision time or within 24 hours after surgery end‐time for adults undergoing a procedure for which prophylaxis is indicated.7
The Leapfrog Hospital Quality and Safety Survey hosts a searchable web‐based database that consumers can use to compare performance among participating hospitals in specific geographic regions. The Leapfrog survey includes NQF safe practices #28 (reduce occurrence of VTE) and #29 (ensure long‐term anticoagulation is effective and safe).8
TJC National Patient Safety Goals (NPSG) target specific improvements in patient safety by providing healthcare organizations with solutions to prevalent patient safety problems. Compliance is necessary for Joint Commission accreditation, and results are reported on the Quality Check website. NPSG Goal 3 is focused on improving the safety of medications, and Goal 3E specifically addresses patient harm associated with the use of anticoagulation therapy. The 2008 NPSG goals must be implemented by January 2009.2
The North American Thrombosis Forum (NATF), a nonprofit organization, was recently organized to address unmet needs in North America related to VTE and other thrombotic disorders. It is designed to complement existing organizations dealing with thrombosis‐related issues, with 5 major focus areas: basic translational research; clinical research; prevention and education; public policy; and advocacy. Each month, its website (http://www.natfonline.org) features several scientific papers dealing with venous and arterial thrombosis‐related issues.
The American Venous Forum National Venous Screening Program is a national campaign designed to increase VTE awareness and promote the importance of compliance with prophylaxis protocols.9

Implications of Performance Data

Hospital‐Level Performance Reporting

Physician‐Level Performance Reporting

Quality Measure 23: Percentage of patients aged 18 years and older undergoing procedures for which VTE prophylaxis is indicated in all patients, who had an order for LMWH, low‐dose UFH, adjusted‐dose warfarin, fondaparinux, or mechanical prophylaxis to be given within 24 hours prior to incision time or within 24 hours after surgery end‐time; and
Quality Measure 31: Percentage of patients aged 18 years and older with a diagnosis of ischemic stroke or intracranial hemorrhage who received DVT prophylaxis by end of hospital day 2.

VTE as a Nonreimbursable Never Event

Improving Performance and Patient Outcomes

Regardless of the strategy chosen, Tooher et al identified.16 several general features that, when included as part of the initiative, increase the likelihood of program success:

A process for demonstrating the importance and relevance of VTE prophylaxis in the local clinical setting (eg, presenting findings of a local audit of current practice to clinical staff);
A process for improving clinician knowledge about VTE risk assessment and prophylaxis practice, such as through a continuing education program;
A method of reminding clinicians to assess patients for VTE risk, accompanied by aids to assist in the documentation of patient risk;
A process for assisting clinicians in prescribing the appropriate prophylaxis; and
A method for assessing the effectiveness of any changes and for refining local policy to further improve practice, such as through clinical audit and feedback.

Table 3 lists several resources and tools that may be useful when designing and implementing strategies to improve performance and quality of care for hospitalized patients at risk of VTE.

Table 3.Resources and Tools for Improving Performance in VTE
Resource	Description
Abbreviation: VTE, venous thromboembolism. * Available at htttp://www.hospitalmedicine.org/ResourceRoomRedesign/RR_VTE/VTE_Home.cfm. Available at http://www.asco.org/ASCO/Downloads/Cancer Policy and Clinical Affairs/Clinical Affairs (derivative products)/VTE Flow Sheet.pdf. Available at http://www.chestnet.org. Available at http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf.
Society of Hospital Medicine, VTE Resource Room*	A website with educational resources, prophylaxis and treatment algorithms, and sample VTE protocols for various patient populations
American Society of Clinical Oncology; VTE Prophylaxis Orders and Flow Sheet	A sheet to consult and fill out when prescribing pharmacologic VTE prophylaxis for cancer patients; includes justifications for use, contraindications, anticoagulant options and doses, and other important details
American College of Chest Physicians	A source of guidelines, clinical research, education, and other resources for building an evidence‐based VTE protocol
National Comprehensive Cancer Network, Clinical Practice GuidelinesVTE	A concise source of algorithms for VTE prophylaxis, diagnosis, and treatment in cancer patients; also includes tables detailing recommended prevention/treatment regimens and warnings/contraindications

Case Studies in Performance Improvement

Brigham and Women's Hospital, Boston, MA

In 2008, this system was evaluated in a new cohort study to determine the ongoing effectiveness of electronic alerts in a real hospital setting.18 The following steps were taken:

Alerts were dispatched for all high‐risk cases; and
The responsible physician for each high‐risk patient not receiving prophylaxis was issued a single alert detailing the patient's risk and encouraging the use of thromboprophylaxis

Roswell Park Cancer Institute, Buffalo, NY

Implemented mandatory, computerized physician order entry forms;
Promoted VTE awareness via staff education, field in‐services, and seminars; and
Tracked compliance with manual audits of patient charts every 3 months.

Hartford Hospital, Hartford, CT

Saint Elizabeth's Hospital, Collinsville, IL

Received daily reports of all new admissions cross‐referenced with an accounting of patients currently prescribed UFH or LMWH;
Assessed the remaining patients at risk of VTE; and
Placed recommendations in patient charts in the form of a bold sticker alerting the physician to the patient's risk factors, their overall risk of VTE, and treatment recommendations (Figure 2).

Conclusions

References

U.S. Department of Health and Human Services. The surgeon general's call to action to prevent deep vein thrombosis and pulmonary embolism. Available at: http://www.surgeongeneral.gov/topics/deepvein/calltoaction/call‐to‐action‐on‐dvt‐2008.pdf. Accessed June2009.
The Joint Commission. National consensus standards for prevention and care of venous thromboembolism (VTE). Last updated April 2009. Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/VTE.htm. Accessed June2009.
Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines (8th edition).Chest2008;133(6 suppl):381S–453S.
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ;American College of Chest Physicians.Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th edition).Chest.2008;133(6 suppl):454S–545S.
The Joint Commission. Surgical Care Improvement Project Core Measure Set. Updated November 2008. Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/SCIP+Core+Measure+Set.htm. Accessed June2009.
Deitelzweig S, Lin J, Hussein M, et al.Are surgical patients at risk of venous thromboembolism current meeting the surgical care improvement performance target goal for appropriate and timely prophylaxis?Chest.2008;134:s46003.
American Medical Association. Perioperative Care: Physician Performance Measurement Set. October 2006. Available at http://www.ama‐assn.org/ama1/pub/upload/mm/370/perioperativews1206.pdf. Accessed June2009.
Leapfrog Group. The Leapfrog Group Hospital Quality and Safety Survey: What's New in the 2009 Survey (Version 5.1). Available at: https://leapfrog.medstat.com/pdf/final.pdf. Accessed June2009.
McLafferty RB, Passman MA, Caprini JA, et al.Increasing awareness about venous disease: The American Venous Forum expands the National Venous Screening Program.J Vasc Surg.2008;48(2):394–399.
Federal Register. Medicare Program; Proposed Changes to the Hospital Inpatient Prospective Payment Systems and Fiscal Year 2007 Rates. Available at: http://edocket.access.gpo.gov/2006/pdf/06‐3629.pdf. Accessed December 10,2008.
Department of Health and Human Services, Centers for Medicare 241(3):397–415.
Kucher N, Koo S, Quiroz R, et al.Electronic alerts to prevent venous thromboembolism among hospitalized patients.N Engl J Med.2005;352(10):969–977.
Baroletti S, Munz K, Sonis J, et al.Electronic alerts for hospitalized high‐VTE risk patients not receiving prophylaxis: a cohort study.J Thromb Thrombolysis.2008;25(2):146–150.
Ahluwalia MS, Klein K, Kuvshinoff BW, et al. Improving compliance with guidelines for venous thromboembolism (VTE) prophylaxis significantly reduces VTE events. Presented at the 50th Annual Meeting of the American College of Hematology; San Francisco, CA; December 6‐9, 2008. Abstract 1288.
Sobieraj DM.Development and implementation of a program to assess medical patients' need for venous thromboembolism prophylaxis.Am J Health Syst Pharm.2008;65(18):1755–1760.
Bauer JB, Chun DS, Karpinski TA.Pharmacist‐led program to improve venous thromboembolism prophylaxis in a community hospital.Am J Health Syst Pharm.2008;65(17):1643–1647.

References

U.S. Department of Health and Human Services. The surgeon general's call to action to prevent deep vein thrombosis and pulmonary embolism. Available at: http://www.surgeongeneral.gov/topics/deepvein/calltoaction/call‐to‐action‐on‐dvt‐2008.pdf. Accessed June2009.
The Joint Commission. National consensus standards for prevention and care of venous thromboembolism (VTE). Last updated April 2009. Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/VTE.htm. Accessed June2009.
Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines (8th edition).Chest2008;133(6 suppl):381S–453S.
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ;American College of Chest Physicians.Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th edition).Chest.2008;133(6 suppl):454S–545S.
The Joint Commission. Surgical Care Improvement Project Core Measure Set. Updated November 2008. Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/SCIP+Core+Measure+Set.htm. Accessed June2009.
Deitelzweig S, Lin J, Hussein M, et al.Are surgical patients at risk of venous thromboembolism current meeting the surgical care improvement performance target goal for appropriate and timely prophylaxis?Chest.2008;134:s46003.
American Medical Association. Perioperative Care: Physician Performance Measurement Set. October 2006. Available at http://www.ama‐assn.org/ama1/pub/upload/mm/370/perioperativews1206.pdf. Accessed June2009.
Leapfrog Group. The Leapfrog Group Hospital Quality and Safety Survey: What's New in the 2009 Survey (Version 5.1). Available at: https://leapfrog.medstat.com/pdf/final.pdf. Accessed June2009.
McLafferty RB, Passman MA, Caprini JA, et al.Increasing awareness about venous disease: The American Venous Forum expands the National Venous Screening Program.J Vasc Surg.2008;48(2):394–399.
Federal Register. Medicare Program; Proposed Changes to the Hospital Inpatient Prospective Payment Systems and Fiscal Year 2007 Rates. Available at: http://edocket.access.gpo.gov/2006/pdf/06‐3629.pdf. Accessed December 10,2008.
Department of Health and Human Services, Centers for Medicare 241(3):397–415.
Kucher N, Koo S, Quiroz R, et al.Electronic alerts to prevent venous thromboembolism among hospitalized patients.N Engl J Med.2005;352(10):969–977.
Baroletti S, Munz K, Sonis J, et al.Electronic alerts for hospitalized high‐VTE risk patients not receiving prophylaxis: a cohort study.J Thromb Thrombolysis.2008;25(2):146–150.
Ahluwalia MS, Klein K, Kuvshinoff BW, et al. Improving compliance with guidelines for venous thromboembolism (VTE) prophylaxis significantly reduces VTE events. Presented at the 50th Annual Meeting of the American College of Hematology; San Francisco, CA; December 6‐9, 2008. Abstract 1288.
Sobieraj DM.Development and implementation of a program to assess medical patients' need for venous thromboembolism prophylaxis.Am J Health Syst Pharm.2008;65(18):1755–1760.
Bauer JB, Chun DS, Karpinski TA.Pharmacist‐led program to improve venous thromboembolism prophylaxis in a community hospital.Am J Health Syst Pharm.2008;65(17):1643–1647.

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Improving thromboprophylaxis: Performance measures and practical strategies

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Improving thromboprophylaxis: Performance measures and practical strategies

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Department of Hospital Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195

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VTE Risk Factors and Barriers

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Assessing the risk of venous thromboembolism and identifying barriers to thromboprophylaxis in the hospitalized patient

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Venous thromboembolism (VTE) is a common and potentially devastating complication of medical illness and surgical intervention. Among patients discharged from acute‐care hospitals in 2003, more than 12 million (31%) had a moderate or high risk of VTE during hospitalization, including 11% at risk due to surgical procedures and 20% at risk due to medical illnesses.1 The incidence of VTEwhich can present as deep vein thrombosis (DVT) or pulmonary embolism (PE)is rising in hospitalized patients.2 Despite the availability of effective prophylaxis, VTE is the third most common cause of hospital‐related death and the most common preventable cause of hospital mortality.3

The clinical impact of VTE is significant. While total incidence, prevalence, and mortality rates of VTE are elusive, the annual incidence of DVT is thought to be as high as 2 million.4 The most serious complication of DVT is acute PE, which occurs in approximately 600,000 patients per year, one‐third of whom die.5 DVT may also be complicated by recurrent episodes of VTE and postthrombotic sequelae such as chronic venous stasis, venous ulceration, debilitating pain, and intractable edema.6 One prospective cohort study found that 30% of patients who had experienced a first episode of DVT developed recurrent VTE within 8 years, and the incidence of postthrombotic syndrome (PTS) was 23% after just 2 years.6

The economic burden of VTE is substantial, due both to the initial event and to the high rate of hospital readmission. The estimated average cost of DVT management (including initial acute care and 6 months of follow‐up care) is $10,072 per patient, and the corresponding cost for PE is $14,649.7 Hospital readmission occurs in 5% to 14% of patients, more than one‐half of whom are readmitted within 90 days.8 For patients with recurrent DVT or PE, the mean total hospitalization costs of readmission are $11,862 and $14,722, respectively.8

The clinical and economic burden of VTE can be significantly mitigated by the use of effective prophylaxis. Because VTE is difficult to diagnose antemortem, it is easier and safer to prevent with appropriate prophylaxis than to diagnose after it has occurred. Unfortunately, VTE prophylaxis is markedly underused, particularly among high‐risk, hospitalized medical patients who would most benefit from it.9

This article summarizes specific risk factors for VTE and provides guidance in identifying patients who may require thromboprophylaxis. Barriers to optimal VTE prophylaxis in the hospital setting will also be explored.

Methodology

For this article and the ones that follow, relevant literature was identified through a Medline search (January 1980 to December 2008) using the following search terms: venous thromboembolism, pulmonary embolism, deep vein thrombosis, epidemiology, risk factors, prophylaxis, mechanical prophylaxis, diagnosis, treatment, anticoagulants, monitoring, secondary prevention, guideline, adherence, treatment protocol, performance measure, and quality improvement. The bibliographies of all key texts were searched for additional relevant articles. The websites of the American College of Chest Physicians (ACCP), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and Society of Hospital Medicine (SHM) were also searched for annual meeting abstracts, position statements, and other key publications.

Evidence‐based clinical guidelines were identified through a search of the National Guideline Clearinghouse (http://www.guidelines.gov), and ongoing clinical trials in the area of VTE prophylaxis were identified in the National Institutes of Health clinical trials database (www.clinicaltrials.gov). The websites of the Centers for Medicare and Medicaid Services (CMS) and the Joint Commission were searched for information related to VTE performance measures and quality improvement initiatives.

Pathogenesis of VTE

Venous thrombosis occurs as a result of at least 1 of 3 underlying factors: alterations in blood flow, vascular endothelial injury, and alterations in the constitution of the blood.10 Each potential underlying factor encompasses a wide range of risk factors and clinical scenarios. Alterations in venous blood flow can include several situations, including venous stasis, venous hypertension, and valvular incompetence. Endothelial injury can arise from shear stress, direct trauma, infection, hypertension, or other sources of endothelial damage. Hypercoagulability from alterations in the constitution of the blood may be due to antithrombin deficiency, cancer, surgery, pregnancy, or other risk factors. The presence of any of these factors indicates an elevated risk of VTE, and the presence of multiple factors further increases risk.10

Risk Factors for VTE

VTE can occur in a wide variety of clinical circumstances. Recognized risk factors for VTE include hospitalization for an acute medical illness, cardiovascular disease, pulmonary disease, major surgery, multiple trauma, obesity, and increasing age.10 Additional factors that place patients at increased risk of VTE (independent of age) include a history of prior VTE, known hypercoagulable states, active cancer, and acute infection.11 Hospital‐acquired risk factors such as immobility, acute illness, or medical interventions may lead to the development of VTE in these patients. Severity of illness must be factored into the risk assessment, and all patients need to be assessed for VTE risk at the time of hospital admission and daily thereafter if pharmacologic therapy is not initiated.

In a review of 1231 consecutive patients treated for acute DVT and/or PE, 96.3% had at least 1 risk factor for VTE, and more than one‐third (39%) had 3 or more risk factors (Table 1).10 The incidence of VTE in hospitalized patients is directly related to the number of risk factors present:10

1 risk factor: 11%
2 risk factors: 24%
3 risk factors: 36%
4 risk factors: 50%
5 risk factors: > 90%

Table 1.Risk Factors Among 1231 Hospitalized Patients Treated for Acute VTE
Risk Factor	Patients (%)
NOTE: Modified with permission from Ref. 10: Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1):I9‐I16. Available at: http://circ.ahajournals.org/cgi/content/full/107/23_suppl_1/I‐9. Abbreviation: VTE, venous thromboembolism.
Age 40 years	88.5
Obesity	37.8
History of VTE	26.0
Cancer	22.3
Bed rest 5 days	12.0
Major surgery	11.2
Congestive heart failure	8.2
Varicose veins	5.8
Fracture (hip or leg)	3.7
Estrogen treatment	2.0
Stroke	1.8
Multiple trauma	1.1
Childbirth	1.1
Myocardial infarction	0.7

Current or Recent Prior Hospitalization

The risk of VTE is elevated among hospitalized patients. The prevalence of DVT varies across hospital specialties, reaching up to 80% in major trauma, spinal cord injury, and critical care.3 The Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study evaluated the prevalence of VTE risk factors in the acute hospital care setting.12 Among the 68,183 patients enrolled, more than one‐half (52%) were judged to be at risk of VTE. In a case‐control study examining 625 patients with a first lifetime VTE, confinement to a hospital (among other risk factors) was found to be an independent and important predictor of VTE (odds ratio [OR], 8.0; 95% confidence interval [CI], 4.514.2) (Figure 1).13 Recent hospitalization is also an important risk factor for VTE, and patients who are readmitted to the hospital should be considered moderate or high risk.13

Odds ratio of risk factors for definite DVT (deep vein thrombosis) or PE (pulmonary embolism). CHF, congestive heart failure; VTE, venous thromboembolism. Reprinted with permission from Heit et al.13

Age

Patient age must be considered when assessing VTE risk. VTE is predominantly a disease of older age, and age older than 75 years is an important risk factor for the condition.11 In general, patients older than 40 years have a significantly increased risk compared with younger patients, and the risk approximately doubles with each additional decade.10 Given the aging population, the prevalence of VTE and its complications are expected to increase.

Women of childbearing age experience VTE more frequently than men of the same age, due to pregnancy and exposure to contraceptive therapy.14 This risk, however, is modest compared with the risk among older patients. After age 45 years, the incidence of VTE increases markedly for both sexes, becoming more prominent in men.14 Compared with women, men also have an increased risk of recurrent VTE.15

Despite the effect of age on VTE risk, the risk among patients younger than 40 years may be underestimated because this subgroup has not been extensively studied. For reasons that are not well‐understood, the risk of VTE associated with heart failure is higher in patients younger than 40 years, and the relative risk of PE in patients with chronic obstructive pulmonary disease (COPD) is also higher in younger patients.16, 17

Cancer and Its Treatment

Cancer patients, on average, have twice the risk of VTE compared with noncancer patients.18 This risk, however, varies considerably by cancer type. According to an assessment of nearly 41 million hospitalized patients in the National Hospital Discharge Survey (NHDS), the relative risk of VTE varied from 1.02 in patients with bladder cancer to 4.34 in patients with cancer of the pancreas.18

VTE is one of the most common complications of cancer and cancer therapy, and it is the second leading cause of death among hospitalized cancer patients.19 Molecular mechanisms underlying thromboembolic events in cancer patients include tumor cell procoagulants, inflammatory cell cytokines, mediators of platelet adhesion, and tumor‐related stasis and endothelial damage.20 The clinical implications of these processes are severe. Cancer exacerbates the natural course of VTE, increasing the risk of recurrent VTE and major bleeding, and VTE worsens the prognosis of cancer, increasing the risk of death among cancer patients.

Various cancer therapiesincluding surgery, chemotherapy, hematopoietic stem cell transplantation, and even growth factor supportalso increase the risk of VTE, in part because extrinsic factors such as surgery or chemotherapy can intensify the hypercoagulable process.18, 2123 In the NHDS, cancer patients undergoing surgery had at least twice the risk of postoperative DVT and more than 3 times the risk of PE compared with noncancer patients undergoing similar procedures.18

Cancer is an independent predictor of thromboprophylaxis failure following surgery. The @RISTOS Project found that VTE was the most common cause of death among 2373 patients undergoing general, urologic, or gynecologic surgery for cancer.24 A multivariate analysis identified 5 independent risk factors for VTE after cancer surgery:

Previous VTE (OR, 5.98; 95% CI, 2.1316.80)
Anesthesia 2 hours (OR, 4.50; 95% CI, 1.0619.04)
Bed rest 4 days (OR, 4.37; 95% CI, 2.457.78)
Age 60 years (OR, 2.63; 95% CI, 1.215.71)
Advanced‐stage cancer (OR, 2.68; 95% CI, 1.375.24)

Cardiovascular Disease

The risk of VTE is pronounced among patients with cardiovascular disease. After stroke and coronary disease, VTE is the third most common cardiovascular disorder, and PE causes more deaths each year than myocardial infarction (MI).25 Several cardiovascular diseases, including hypertension, stroke, acute MI, and heart failure, are independently associated with VTE.10, 2627 Related disorders, including diabetes and the metabolic syndrome, also increase the risk of VTE.26, 28

Congestive heart failure (CHF) is a risk factor for VTE, and the severity of illness increases risk. In the DVT‐Free Prospective Registry, 13% of patients with ultrasound‐confirmed DVT had CHF.29 In a subgroup analysis of patients of the Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) study, the incidence of VTE exceeded 20% in patients with New York Heart Association (NYHA) class IV heart failure, compared with 12% in patients with NYHA class III heart failure.30 Another study found that VTE risk increases as left ventricular ejection fraction (LVEF) decreases, with an LVEF of less than 20% associated with a VTE OR of 38.3 (95% CI, 9.6152.5).31

Infectious Disease

Acute infection may increase the relative risk of VTE by as much as 50% and is associated with VTE event rates of up to 26%.11 Acute infections may be associated with acute inflammation, adverse effects on cardiac or pulmonary function, and prolonged immobilization.30, 32, 33 Human immunodeficiency virus (HIV) patients may also have an increased risk of VTE due to a circulating lupus anticoagulant and/or the presence of acute infection.34

Obesity

The 2008 ACCP guideline update recognizes obesity, for the first time, as a risk factor for VTE.3 Obesity was 1 of the 5 most frequent comorbidities found in patients with DVT in the DVT‐Free Prospective Registry.29 It increases the risk of both incident and recurrent VTE, with every 1‐point increase in body mass index (BMI) increasing the risk of recurrent VTE by 4.4% (95% CI, 1.37.6%; P < 0.001).35

Pregnancy and Puerperium

Pregnancy, particularly the postpartum period, is associated with an increased risk of VTE in women, even though the absolute risk is small.36 Still, PE is one of the leading causes of maternal death following childbirth.10 Smoking, prior VTE, and inherited thrombophilias all increase the risk of VTE in pregnant women.10 The risk begins to rise in the first trimester, and when prophylaxis is needed, it should be started early in gestation.37

Pulmonary Disease

COPD is another risk factor for the development of VTE. COPD patients who develop VTE tend to be older, hospitalized in the intensive care unit (ICU), and on mechanical ventilation.38 In the DVT‐Free Prospective Registry, 12% of patients with ultrasound‐confirmed DVT had COPD.29

Trauma and Surgery

Injury to the body tissue, via trauma or surgery, stimulates the body's clotting mechanism and increases the risk of thromboembolic complications. During the perioperative period, the circulatory system must balance a variety of assaults: an immune response to surgical stress, prolonged immobilization during surgery and recovery, vasodilation associated with general or regional anesthesia, and hypercoagulability due to venous stasis and vascular injury.39 Renal transplant recipients have an increased risk of VTE due to a chronic hypercoagulable state.40 In surgery patients, perioperative complications such as dehydration and acute infection increase the risk of VTE beyond the risk associated with the surgical procedure itself.10

VTE risk is increased approximately 13‐fold by recent major trauma or lower‐extremity injury.13 In the absence of prophylaxis, the overall risk of VTE among patients undergoing major surgery is increased nearly 22‐fold.13 After controlling for the type of surgery, additional independent risk factors for VTE within 3 months of major surgery include:41, 42

Obesity
Central venous catheter placement
Malignancy
Smoking
Heart failure
Previous DVT
Prolonged immobility
Infection

Many surgical and medical inpatients share common risk factors, and without prophylaxis, the incidence of hospital‐acquired DVT ranges from 10% to 40% for both groups.3

Inherited or Acquired Risk Factors

VTE is a multifactorial disease, and recent evidence indicates that some heritable traits may be potent risk factors for VTE.43 Approximately 35% of patients with DVT will have at least 1 of 5 traits related to an inherited blood clotting disorder:43

Deficiencies in the anticoagulation factors protein C, protein S, or antithrombin, or
Mutations in the factor V and prothrombin genes, resulting in Factor V Leiden and prothrombin G20210A, respectively.

Certain inherited traits and genetic polymorphisms increase the risk of VTE by interacting with clinical risk factors such as contraceptive use, pregnancy, surgery, trauma, and cancer. One recent study found that oral estrogen therapy among women with the CYP3A5*1 allele was associated with a particularly high risk of VTE.44 Although widespread screening for inherited risk factors is not currently practical, future tools may incorporate genetic polymorphisms to more precisely identify patients who would benefit from aggressive prophylaxis.

Lifestyle Factors

Lifestyle factors have a significant effect on VTE risk. Smoking increases the risk of VTE by 20% to 30%, and a sedentary lifestyle also increases the risk of VTE.26, 45 In fact, women who exercise regularly and consume alcohol in moderation have one‐half the risk of VTE as women who have a sedentary lifestyle and drink little or no alcohol.42 For both men and women, a diet high in fruits, vegetables, and fish is associated with a lower lifetime risk of VTE.46

Medications

Medications may also increase the risk of VTE. In cancer patients with anemia, for example, the use of erythropoiesis‐stimulating agents such as recombinant erythropoietin and darbepoetin was recently shown to increase the risk of VTE by 57% (95% CI, 3187%) and increase mortality risk by 10% (95% CI, 120%).23 In addition, combination hormone replacement therapy in women is associated with a higher risk of VTE compared with estrogen monotherapy, and transdermal contraceptive systems more than double the risk of VTE compared with oral contraceptives (95% CI, 1.33.8).47, 48 Recent studies have also reported an increased risk of VTE with some psychiatric drugs, including amitriptyline, clozapine, olanzapine, and risperidone.4952

Thromboprophylaxis in the Hospital Setting

Despite the prevalence of risk factors and compelling evidence regarding the value of prophylaxis, VTE prophylaxis is suboptimal in hospitalized medical and surgical patients. In a study of 123,304 hospitalized patients who were determined to be at risk of VTE, only 13.3% received prophylaxis in accordance with ACCP guidelines.53 Compliance ranged from a high of 52.4% among patients undergoing orthopedic surgery to a low of 2.8% among patients undergoing neurosurgery.53 Results from several other large trials echo these findings (Table 2).12, 5456

Table 2.Use of Thromboprophylaxis in At‐Risk Medical and Surgical Patients
Trial	Patient Type	Total Patients	Patients at Risk of VTE (Based on ACCP Criteria) (%)	At‐Risk Patients Receiving Recommended Prophylaxis
Trial	Patient Type	Total Patients	Patients at Risk of VTE (Based on ACCP Criteria) (%)	Medical Patients (%)	Surgical Patients (%)
NOTE: Adapted from Tapson et al.54 (2007), Cohen et al.12 (2008), Jois‐Bilowich et al.55 (2008), and Amin et al.56 (2008). Abbreviations: ACCP, American College of Chest Physicians; ADHERE, Acute Decompensated Heart Failure National Registry; ENDORSE, Epidemiologic International Day for the Evaluation of Patients At Risk for Venous Thromboembolism in the Acute Hospital Care Setting; IMPROVE, International Medical Prevention Registry on Venous Thromboembolism; n/a, not available; VTE, venous thromboembolism.
IMPROVE	Medical patients	15,156	52	61	n/a
ENDORSE	Medical and surgical patients	68,183	51.8	39.5	58.5
ADHERE	Hospitalized heart failure patients	155,073	46	30.6	n/a
Amin et al.56 (2008)	Medical and surgical patients	258,556	26.4	9.8	17.9

Reasons for Inadequate Prophylaxis

Researchers have identified a range of barriers to adequate VTE prophylaxis (Table 3).57 Some of these barriers are outlined below.

Table 3.Barriers to VTE Prophylaxis
NOTE: Adapted from Tooher et al.57 (2005). Abbreviation: VTE, venous thromboembolism.
Variability in clinician knowledge of risk assessment and appropriate prophylaxis
Lack of agreement with, and inconsistency between, guidelines in certain patient populations
Perceived lack of need
Concerns about adverse effects
Lack of hospital support systems and policies
Lack of established responsibilities for prophylaxis

Underestimation of Risk of Clotting

VTE is often clinically silent, leading some physicians to mistakenly believe that it is rare.58 In hospitalized surgical patients, for example, the incidence of thromboembolic complications during a short postoperative stay may be low. Given that many cases of symptomatic VTE occur after hospital discharge, hospitalists and surgeons may be unaware of the true incidence of DVT.59

Overestimation of the Risk of Bleeding

Physicians may also overestimate the risk of possible side effects of prophylaxis, such as major bleeding or heparin‐induced thrombocytopenia (HIT).58 Fear of excess bleeding has been cited by physicians as a leading reason for their decision to withhold thromboprophylaxis from at‐risk hospitalized patients.60 Physicians are particularly fearful of complications among elderly patients, who are less likely to receive adequate prophylaxis than younger patients with a similar risk of VTE.61 When bleeding does occur, it rarely results in death. On the other hand, PE may account for as many as 10% of hospital deaths.9

Guideline Confusion and Complexity

Discrepancies between guidelines published by different medical societies contribute to confusion in choosing a management approach. The American Academy of Orthopedic Surgeons (AAOS), for example, describes aspirin alone as a reasonable choice for VTE prophylaxis in some patients, but the ACCP guidelines advise against the use of aspirin monotherapy.58 The cumbersome nature of multiple risk‐assessment and treatment algorithms can also be problematic.61 Furthermore, certain patient subgroups, such as those with cirrhosis, severe renal failure, and epidural catheters, have been excluded from randomized controlled trials, and the management of such patients is not straightforward.

Absence of Institutional Protocols and Information Technology Support

The lack of institution‐level guidance and support can have a detrimental effect on patient care. In a 2007 survey of 127 community hospitals, the prevalence of institutional protocols related to VTE was low: only 60% had protocols to encourage prophylaxis in at‐risk patients, 54% had guidelines to assist in appropriate drug selection, and 43% had guidelines for the dosing of prophylaxis regimens.62 A lack of systems for data collection and audit has also been identified as a barrier to the implementation of prophylaxis guidelines.57 Thus, hospitals need to adopt protocols such as:3

Written, institution‐wide thromboprophylaxis policies
Preprinted order forms and computer decision‐support systems
Policies specifying responsibilities for assessing VTE risk and prescribing prophylaxis

Conclusions

VTE is the most common preventable cause of hospital death, and prophylaxis is underused in hospitalized patients. Although VTE risk factors are numerous and complex, deciding whether to use prophylaxis need not be complicated. In general, elderly patients, medically‐ill patients, and patients undergoing surgery will benefit from prophylaxis, as well as those who are hospitalized for more than 1 night. Hospitalized patients with at least 1 risk factor should be considered for pharmacologic prophylaxis. In general, the risk of hospital‐acquired VTE greatly exceeds the risk of bleeding with prophylactic doses of anticoagulation. A patient's risk of VTE may change, and regular assessment of this risk should be mandated if pharmacologic therapy is not initiated at the time of admission.

Numerous barriers to the optimal use of VTE prophylaxis exist, and hospitals must implement systems changes and multidisciplinary approaches to overcome these barriers. The fourth article in this supplement provides detailed strategies for meeting VTE performance measures and overcoming barriers to the optimal use of prophylaxis.

References

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Stein PD, Beemath A, Olson RE.Trends in the incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients.Am J Cardiol.2005;95(12):1525–1526.
Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th ed.Chest.2008;133(6 suppl):381S–453S.
Hirsh J, Hoak J.Management of deep vein thrombosis and pulmonary embolism. A statement for healthcare professionals. Council on Thrombosis (in consultation with the Council on Cardiovascular Radiology), American Heart Association.Circulation.1996;93(12)2212–2245.
Anderson FA, Wheeler HB, Goldberg RJ, et al.A population‐based perspective of the hospital incidence and case‐fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study.Arch Intern Med.1991;151(5):933–938.
Prandoni P, Lensing AW, Cogo A, et al.The long‐term clinical course of acute deep venous thrombosis.Ann Intern Med.1996;125(1):1–7.
O'Brien JA, Caro JJ.Direct medical cost of managing deep vein thrombosis according to the occurrence of complications.Pharmacoeconomics.2002;20(9):603–615.
Spyropoulos AC, Lin J.Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations.J Manag Care Pharm.2007;13(6):475–486.
Piazza G, Seddighzadeh A, Goldhaber SZ.Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent.Chest.2007;132(2):554–561.
Anderson FA, Spencer FA.Risk factors for venous thromboembolism.Circulation.2003;107(23 suppl 1):I9–I16.
Alikhan R, Cohen AT, Combe S, et al.Risk factors for VTE in hospitalized patients with acute medical illness: analysis of the MEDENOX Study.Arch Intern Med.2004;164(9):963–968.
Cohen AT, Tapson VF, Bergmann JF, et al.;ENDORSE Investigators.Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross‐sectional study.Lancet.2008;371(9610):387–394.
Heit JA, Silverstein MD, Mohr DN, et al.Risk factors for deep vein thrombosis and pulmonary embolism: a population‐based case‐control study.Arch Intern Med.2000;160(6):809–815.
Heinemann LA, Dinger JC.Range of published estimates of venous thromboembolism incidence in young women.Contraception.2007;75(5):328–336.
Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S.The risk of recurrent venous thromboembolism in men and women.N Engl J Med.2004;350(25):2558–2563.
Beemath A, Stein PD, Skaf E, et al.Risk of venous thromboembolism in patients hospitalized with heart failure.Am J Cardiol.2006;98(6):793–795.
Stein PD, Beemath A, Meyers FA, et al.Pulmonary embolism and deep venous thrombosis in hospitalized adults with chronic obstructive pulmonary disease.J Cardiovasc Med.2007;8(4):253–257.
Stein PD, Beemath A, Meyers FA, et al.Incidence of venous thromboembolism in patients hospitalized with cancer.Am J Med.2006;119(1):60–68.
Ambrus JL, Ambrus CM, Mink IB, et al.Causes of death in cancer patients.J Med.1975;6(1):61–64.
Fernandez PM, Rickles FR.Tissue factor and angiogenesis in cancer.Curr Opin Hematol.2002;9(5):401–406.
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Gerber DE, Segal JB, Levy MY, Kane J, Jones RJ, Streiff MB.The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention.Blood.2008;112(3):504–510.
Bennett CL, Silver SM, Djulbegovic B, et al.Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer‐associated anemia.JAMA.2008;299(8):914–924.
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Braekkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, Størmer J, Hansen JB.Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsø study.J Thromb Haemost.2008;6(11):1851–1857.
Borch KH, Brækkan SK, Mathiesen EB, et al.Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome—the Tromsø study.J Thromb Haemost.2009;7(5):739–745.
Goldhaber SZ, Tapson VF.A prospective registry of 5,451 patients with ultrasound‐confirmed deep vein thrombosis.Am J Cardiol.2004;93(2):259–262.
Alikhan R, Cohen AT, Combe , et al.Prevention of venous thromboembolism in medical patients with enoxaparin; a subgroup analysis of the MEDENOX study.Blood Coagul Fibrinolysis.2003;14:341–348.
Howell MD, Geraci JM, Knowlton AA.Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case‐control study.J Clin Epidemiol.2001;54(8):810–816.
Cohen AT, Davidson BL, Gallus AS, et al;ARTEMIS Investigators.Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.BMJ.2006;332(7537):325–329.
Gardlund B.Randomised, controlled trial of low‐dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group.Lancet.1996;347(9012):1357–1361.
Copur AS, Smith PR, Gomez V, et al.HIV infection is a risk factor for venous thromboembolism.AIDS Patient Care STDS.2002;16(5):205–209.
Eichinger S, Hron G, Bialonczyk C, et al.Overweight, obesity, and the risk of recurrent venous thromboembolism.Arch Intern Med.2008;168(15):1678–1683.
Rathbun S.Venous thromboembolism in women.Vasc Med.2008;13(3):255–266.
James AH, Tapson VF, Goldhaber SZ.Thrombosis during pregnancy and the postpartum period.Am J Obstet Gynecol.2005;193(1):216–219.
Shetty R, Seddighzadeh A, Piazza G, et al.Chronic obstructive pulmonary disease and deep vein thrombosis: a prevalent combination.J Thromb Thrombolysis.2008;26(1):35–40.
Meissner MH, Chandler WL, Elliott JS.Venous thromboembolism in trauma: a local manifestation of systemic hypercoagulability?J Trauma.2003;54(2):224–231.
Kazory A, Ducloux D.Acquired hypercoagulable state in renal transplant recipients.Thromb Haemost.2004;91(4):646–654.
Seddighzadeh A, Zurawska U, Shetty R, Goldhaber SZ.Venous thromboembolism in patients undergoing surgery: low rates of prophylaxis and high rates of filter insertion.Thromb Haemost.2007;98(6):1220–1225.
Shackford SR, Rogers FB, Terrien CM, Bouchard P, Ratliff J, Zubis R.A 10‐year analysis of venous thromboembolism on the surgical service: the effect of practice guidelines for prophylaxis.Surgery.2008;144(1):3–11.
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Canonico M, Bouaziz E, Carcaillon L, et al;Estrogen and Thromboembolism Risk (ESTHER) Study Group.Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women.J Clin Endocrinol Metab.2008;93(8):3082–3087.
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Jois‐Bilowich P, Michota F, Bartholomew JR, et al.Adhere Scientific Advisory Committee and Investigators. Venous thromboembolism prophylaxis in hospitalized heart failure patients.J Card Fail.2008;14(2):127–132.
Amin A, Spyropolous A, Dobesh P, et al. Are hospitals following guidelines for VTE Prevention? The Venous Thromboembolism Study to Assess the Rate of Thromboprophylaxis. Presented at the 50th Annual Meeting of the American College of Hematology, San Francisco, CA, December 6–9, 2008. Abstract 1286.
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Journal of Hospital Medicine - 4(2)

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Page Number

S1-S7

Legacy Keywords

prophylaxis barriers, risk assessment, venous thromboembolism

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Author(s)

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Methodology

Pathogenesis of VTE

Risk Factors for VTE

1 risk factor: 11%
2 risk factors: 24%
3 risk factors: 36%
4 risk factors: 50%
5 risk factors: > 90%

Table 1.Risk Factors Among 1231 Hospitalized Patients Treated for Acute VTE
Risk Factor	Patients (%)
NOTE: Modified with permission from Ref. 10: Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1):I9‐I16. Available at: http://circ.ahajournals.org/cgi/content/full/107/23_suppl_1/I‐9. Abbreviation: VTE, venous thromboembolism.
Age 40 years	88.5
Obesity	37.8
History of VTE	26.0
Cancer	22.3
Bed rest 5 days	12.0
Major surgery	11.2
Congestive heart failure	8.2
Varicose veins	5.8
Fracture (hip or leg)	3.7
Estrogen treatment	2.0
Stroke	1.8
Multiple trauma	1.1
Childbirth	1.1
Myocardial infarction	0.7

Current or Recent Prior Hospitalization

Age

Cancer and Its Treatment

Previous VTE (OR, 5.98; 95% CI, 2.1316.80)
Anesthesia 2 hours (OR, 4.50; 95% CI, 1.0619.04)
Bed rest 4 days (OR, 4.37; 95% CI, 2.457.78)
Age 60 years (OR, 2.63; 95% CI, 1.215.71)
Advanced‐stage cancer (OR, 2.68; 95% CI, 1.375.24)

Cardiovascular Disease

Infectious Disease

Obesity

Pregnancy and Puerperium

Pulmonary Disease

Trauma and Surgery

Obesity
Central venous catheter placement
Malignancy
Smoking
Heart failure
Previous DVT
Prolonged immobility
Infection

Many surgical and medical inpatients share common risk factors, and without prophylaxis, the incidence of hospital‐acquired DVT ranges from 10% to 40% for both groups.3

Inherited or Acquired Risk Factors

Deficiencies in the anticoagulation factors protein C, protein S, or antithrombin, or
Mutations in the factor V and prothrombin genes, resulting in Factor V Leiden and prothrombin G20210A, respectively.

Lifestyle Factors

Medications

Thromboprophylaxis in the Hospital Setting

Table 2.Use of Thromboprophylaxis in At‐Risk Medical and Surgical Patients
Trial	Patient Type	Total Patients	Patients at Risk of VTE (Based on ACCP Criteria) (%)	At‐Risk Patients Receiving Recommended Prophylaxis
Trial	Patient Type	Total Patients	Patients at Risk of VTE (Based on ACCP Criteria) (%)	Medical Patients (%)	Surgical Patients (%)
NOTE: Adapted from Tapson et al.54 (2007), Cohen et al.12 (2008), Jois‐Bilowich et al.55 (2008), and Amin et al.56 (2008). Abbreviations: ACCP, American College of Chest Physicians; ADHERE, Acute Decompensated Heart Failure National Registry; ENDORSE, Epidemiologic International Day for the Evaluation of Patients At Risk for Venous Thromboembolism in the Acute Hospital Care Setting; IMPROVE, International Medical Prevention Registry on Venous Thromboembolism; n/a, not available; VTE, venous thromboembolism.
IMPROVE	Medical patients	15,156	52	61	n/a
ENDORSE	Medical and surgical patients	68,183	51.8	39.5	58.5
ADHERE	Hospitalized heart failure patients	155,073	46	30.6	n/a
Amin et al.56 (2008)	Medical and surgical patients	258,556	26.4	9.8	17.9

Reasons for Inadequate Prophylaxis

Researchers have identified a range of barriers to adequate VTE prophylaxis (Table 3).57 Some of these barriers are outlined below.

Table 3.Barriers to VTE Prophylaxis
NOTE: Adapted from Tooher et al.57 (2005). Abbreviation: VTE, venous thromboembolism.
Variability in clinician knowledge of risk assessment and appropriate prophylaxis
Lack of agreement with, and inconsistency between, guidelines in certain patient populations
Perceived lack of need
Concerns about adverse effects
Lack of hospital support systems and policies
Lack of established responsibilities for prophylaxis

Underestimation of Risk of Clotting

Overestimation of the Risk of Bleeding

Guideline Confusion and Complexity

Absence of Institutional Protocols and Information Technology Support

Written, institution‐wide thromboprophylaxis policies
Preprinted order forms and computer decision‐support systems
Policies specifying responsibilities for assessing VTE risk and prescribing prophylaxis

Conclusions

Methodology

Pathogenesis of VTE

Risk Factors for VTE

1 risk factor: 11%
2 risk factors: 24%
3 risk factors: 36%
4 risk factors: 50%
5 risk factors: > 90%

Table 1.Risk Factors Among 1231 Hospitalized Patients Treated for Acute VTE
Risk Factor	Patients (%)
NOTE: Modified with permission from Ref. 10: Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1):I9‐I16. Available at: http://circ.ahajournals.org/cgi/content/full/107/23_suppl_1/I‐9. Abbreviation: VTE, venous thromboembolism.
Age 40 years	88.5
Obesity	37.8
History of VTE	26.0
Cancer	22.3
Bed rest 5 days	12.0
Major surgery	11.2
Congestive heart failure	8.2
Varicose veins	5.8
Fracture (hip or leg)	3.7
Estrogen treatment	2.0
Stroke	1.8
Multiple trauma	1.1
Childbirth	1.1
Myocardial infarction	0.7

Current or Recent Prior Hospitalization

Age

Cancer and Its Treatment

Previous VTE (OR, 5.98; 95% CI, 2.1316.80)
Anesthesia 2 hours (OR, 4.50; 95% CI, 1.0619.04)
Bed rest 4 days (OR, 4.37; 95% CI, 2.457.78)
Age 60 years (OR, 2.63; 95% CI, 1.215.71)
Advanced‐stage cancer (OR, 2.68; 95% CI, 1.375.24)

Cardiovascular Disease

Infectious Disease

Obesity

Pregnancy and Puerperium

Pulmonary Disease

Trauma and Surgery

Obesity
Central venous catheter placement
Malignancy
Smoking
Heart failure
Previous DVT
Prolonged immobility
Infection

Many surgical and medical inpatients share common risk factors, and without prophylaxis, the incidence of hospital‐acquired DVT ranges from 10% to 40% for both groups.3

Inherited or Acquired Risk Factors

Deficiencies in the anticoagulation factors protein C, protein S, or antithrombin, or
Mutations in the factor V and prothrombin genes, resulting in Factor V Leiden and prothrombin G20210A, respectively.

Lifestyle Factors

Medications

Thromboprophylaxis in the Hospital Setting

Table 2.Use of Thromboprophylaxis in At‐Risk Medical and Surgical Patients
Trial	Patient Type	Total Patients	Patients at Risk of VTE (Based on ACCP Criteria) (%)	At‐Risk Patients Receiving Recommended Prophylaxis
Trial	Patient Type	Total Patients	Patients at Risk of VTE (Based on ACCP Criteria) (%)	Medical Patients (%)	Surgical Patients (%)
NOTE: Adapted from Tapson et al.54 (2007), Cohen et al.12 (2008), Jois‐Bilowich et al.55 (2008), and Amin et al.56 (2008). Abbreviations: ACCP, American College of Chest Physicians; ADHERE, Acute Decompensated Heart Failure National Registry; ENDORSE, Epidemiologic International Day for the Evaluation of Patients At Risk for Venous Thromboembolism in the Acute Hospital Care Setting; IMPROVE, International Medical Prevention Registry on Venous Thromboembolism; n/a, not available; VTE, venous thromboembolism.
IMPROVE	Medical patients	15,156	52	61	n/a
ENDORSE	Medical and surgical patients	68,183	51.8	39.5	58.5
ADHERE	Hospitalized heart failure patients	155,073	46	30.6	n/a
Amin et al.56 (2008)	Medical and surgical patients	258,556	26.4	9.8	17.9

Reasons for Inadequate Prophylaxis

Researchers have identified a range of barriers to adequate VTE prophylaxis (Table 3).57 Some of these barriers are outlined below.

Table 3.Barriers to VTE Prophylaxis
NOTE: Adapted from Tooher et al.57 (2005). Abbreviation: VTE, venous thromboembolism.
Variability in clinician knowledge of risk assessment and appropriate prophylaxis
Lack of agreement with, and inconsistency between, guidelines in certain patient populations
Perceived lack of need
Concerns about adverse effects
Lack of hospital support systems and policies
Lack of established responsibilities for prophylaxis

Underestimation of Risk of Clotting

Overestimation of the Risk of Bleeding

Guideline Confusion and Complexity

Absence of Institutional Protocols and Information Technology Support

Written, institution‐wide thromboprophylaxis policies
Preprinted order forms and computer decision‐support systems
Policies specifying responsibilities for assessing VTE risk and prescribing prophylaxis

Conclusions

References

Anderson FA, Zayaruzny M, Heit JA, Fidan D, Cohen AT.Estimated annual numbers of US acute‐care hospital patients at risk for venous thromboembolism.Am J Hematol.2007;82(9):777–782.
Stein PD, Beemath A, Olson RE.Trends in the incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients.Am J Cardiol.2005;95(12):1525–1526.
Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th ed.Chest.2008;133(6 suppl):381S–453S.
Hirsh J, Hoak J.Management of deep vein thrombosis and pulmonary embolism. A statement for healthcare professionals. Council on Thrombosis (in consultation with the Council on Cardiovascular Radiology), American Heart Association.Circulation.1996;93(12)2212–2245.
Anderson FA, Wheeler HB, Goldberg RJ, et al.A population‐based perspective of the hospital incidence and case‐fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study.Arch Intern Med.1991;151(5):933–938.
Prandoni P, Lensing AW, Cogo A, et al.The long‐term clinical course of acute deep venous thrombosis.Ann Intern Med.1996;125(1):1–7.
O'Brien JA, Caro JJ.Direct medical cost of managing deep vein thrombosis according to the occurrence of complications.Pharmacoeconomics.2002;20(9):603–615.
Spyropoulos AC, Lin J.Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations.J Manag Care Pharm.2007;13(6):475–486.
Piazza G, Seddighzadeh A, Goldhaber SZ.Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent.Chest.2007;132(2):554–561.
Anderson FA, Spencer FA.Risk factors for venous thromboembolism.Circulation.2003;107(23 suppl 1):I9–I16.
Alikhan R, Cohen AT, Combe S, et al.Risk factors for VTE in hospitalized patients with acute medical illness: analysis of the MEDENOX Study.Arch Intern Med.2004;164(9):963–968.
Cohen AT, Tapson VF, Bergmann JF, et al.;ENDORSE Investigators.Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross‐sectional study.Lancet.2008;371(9610):387–394.
Heit JA, Silverstein MD, Mohr DN, et al.Risk factors for deep vein thrombosis and pulmonary embolism: a population‐based case‐control study.Arch Intern Med.2000;160(6):809–815.
Heinemann LA, Dinger JC.Range of published estimates of venous thromboembolism incidence in young women.Contraception.2007;75(5):328–336.
Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S.The risk of recurrent venous thromboembolism in men and women.N Engl J Med.2004;350(25):2558–2563.
Beemath A, Stein PD, Skaf E, et al.Risk of venous thromboembolism in patients hospitalized with heart failure.Am J Cardiol.2006;98(6):793–795.
Stein PD, Beemath A, Meyers FA, et al.Pulmonary embolism and deep venous thrombosis in hospitalized adults with chronic obstructive pulmonary disease.J Cardiovasc Med.2007;8(4):253–257.
Stein PD, Beemath A, Meyers FA, et al.Incidence of venous thromboembolism in patients hospitalized with cancer.Am J Med.2006;119(1):60–68.
Ambrus JL, Ambrus CM, Mink IB, et al.Causes of death in cancer patients.J Med.1975;6(1):61–64.
Fernandez PM, Rickles FR.Tissue factor and angiogenesis in cancer.Curr Opin Hematol.2002;9(5):401–406.
Fotopoulou C, duBois A, Karavas AN, et al.Incidence of venous thromboembolism in patients with ovarian cancer undergoing platinum/paclitaxel‐containing first‐line chemotherapy: an exploratory analysis by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group.J Clin Oncol.2008;26(16):2683–2689.
Gerber DE, Segal JB, Levy MY, Kane J, Jones RJ, Streiff MB.The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention.Blood.2008;112(3):504–510.
Bennett CL, Silver SM, Djulbegovic B, et al.Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer‐associated anemia.JAMA.2008;299(8):914–924.
Agnelli G, Bolis G, Capussotti L, et al.A clinical outcome‐based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project.Ann Surg.2006;243(1):89–95.
Goldhaber SZ.Pulmonary embolism in thrombolysis: a clarion call for international collaboration.J Am Coll Cardiol.1992;19:246–247.
Ageno W, Becattini C, Brighton T, et al.Cardiovascular risk factors and venous thromboembolism: a meta‐analysis.Circulation.2008;117(1):93–102.
Braekkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, Størmer J, Hansen JB.Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsø study.J Thromb Haemost.2008;6(11):1851–1857.
Borch KH, Brækkan SK, Mathiesen EB, et al.Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome—the Tromsø study.J Thromb Haemost.2009;7(5):739–745.
Goldhaber SZ, Tapson VF.A prospective registry of 5,451 patients with ultrasound‐confirmed deep vein thrombosis.Am J Cardiol.2004;93(2):259–262.
Alikhan R, Cohen AT, Combe , et al.Prevention of venous thromboembolism in medical patients with enoxaparin; a subgroup analysis of the MEDENOX study.Blood Coagul Fibrinolysis.2003;14:341–348.
Howell MD, Geraci JM, Knowlton AA.Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case‐control study.J Clin Epidemiol.2001;54(8):810–816.
Cohen AT, Davidson BL, Gallus AS, et al;ARTEMIS Investigators.Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.BMJ.2006;332(7537):325–329.
Gardlund B.Randomised, controlled trial of low‐dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group.Lancet.1996;347(9012):1357–1361.
Copur AS, Smith PR, Gomez V, et al.HIV infection is a risk factor for venous thromboembolism.AIDS Patient Care STDS.2002;16(5):205–209.
Eichinger S, Hron G, Bialonczyk C, et al.Overweight, obesity, and the risk of recurrent venous thromboembolism.Arch Intern Med.2008;168(15):1678–1683.
Rathbun S.Venous thromboembolism in women.Vasc Med.2008;13(3):255–266.
James AH, Tapson VF, Goldhaber SZ.Thrombosis during pregnancy and the postpartum period.Am J Obstet Gynecol.2005;193(1):216–219.
Shetty R, Seddighzadeh A, Piazza G, et al.Chronic obstructive pulmonary disease and deep vein thrombosis: a prevalent combination.J Thromb Thrombolysis.2008;26(1):35–40.
Meissner MH, Chandler WL, Elliott JS.Venous thromboembolism in trauma: a local manifestation of systemic hypercoagulability?J Trauma.2003;54(2):224–231.
Kazory A, Ducloux D.Acquired hypercoagulable state in renal transplant recipients.Thromb Haemost.2004;91(4):646–654.
Seddighzadeh A, Zurawska U, Shetty R, Goldhaber SZ.Venous thromboembolism in patients undergoing surgery: low rates of prophylaxis and high rates of filter insertion.Thromb Haemost.2007;98(6):1220–1225.
Shackford SR, Rogers FB, Terrien CM, Bouchard P, Ratliff J, Zubis R.A 10‐year analysis of venous thromboembolism on the surgical service: the effect of practice guidelines for prophylaxis.Surgery.2008;144(1):3–11.
Noboa S, Le Gal G, Lacut K, et al;EDITH Collaborative Study Group.Family history as a risk factor for venous thromboembolism.Thromb Res.2008;122(5):624–629.
Canonico M, Bouaziz E, Carcaillon L, et al;Estrogen and Thromboembolism Risk (ESTHER) Study Group.Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women.J Clin Endocrinol Metab.2008;93(8):3082–3087.
Lindqvist PG, Epstein E, Olsson H.The relationship between lifestyle factors and venous thromboembolism among women: a report from the MISS study.Br J Haematol.2009;144(2):234–240.
Steffen LM, Folsom AR, Cushman M, Jacobs DR, Rosamond WD.Greater fish, fruit, and vegetable intakes are related to lower incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology.Circulation.2007;115(2):188–195.
Sare GM, Gray LJ, Bath PM.Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta‐analysis.Eur Heart J.2008;29(16):2031–2041.
Cole JA, Norman H, Doherty M, Walker AM.Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users.Obstet Gynecol.2007;109(2 Pt 1):339–346.
Borras L, Eytan A, de Timary P, Constant EL, Huguelet P, Hermans C.Pulmonary thromboembolism associated with olanzapine and risperidone.J Emerg Med.2008;35(2):159–161.
Hägg S, Bate A, Stahl M, Spigset O.Associations between venous thromboembolism and antipsychotics. A study of the WHO database of adverse drug reactions.Drug Saf.2008;31(8):685–694.
Paciullo CA.Evaluating the association between clozapine and venous thromboembolism.Am J Health Syst Pharm.2008;65(19):1825–1829.
Jick SS, Li L.Antidepressant drug use and risk of venous thromboembolism.Pharmacotherapy.2008;28(2):144–150.
Yu HT, Dylan ML, Lin J, Dubois RW.Hospitals' compliance with prophylaxis guidelines for venous thromboembolism.Am J Health Syst Pharm.2007;64(1):69–76.
Tapson VF, Decousus H, Pini M, et al.Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients.Chest.2007;132:936–945.
Jois‐Bilowich P, Michota F, Bartholomew JR, et al.Adhere Scientific Advisory Committee and Investigators. Venous thromboembolism prophylaxis in hospitalized heart failure patients.J Card Fail.2008;14(2):127–132.
Amin A, Spyropolous A, Dobesh P, et al. Are hospitals following guidelines for VTE Prevention? The Venous Thromboembolism Study to Assess the Rate of Thromboprophylaxis. Presented at the 50th Annual Meeting of the American College of Hematology, San Francisco, CA, December 6–9, 2008. Abstract 1286.
Tooher R, Middleton P, Pham C, et al.A systematic review of strategies to improve prophylaxis for venous thromboembolism in hospitals.Ann Surg.2005;241(3):397–415.
Howard DP.A need for a simplified approach to venous thromboembolism prophylaxis in acute medical inpatients.Int J Clin Pract.2007;61(2):336–340.
Borris LC.Barriers to the optimal use of anticoagulants after orthopaedic surgery.Arch Orthop Trauma Surg.2008 (Published online Oct, 8.). [http://dx.doi.org/DOI 10.1007/s00402‐008‐0765‐9]
Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J.Venous thrombosis in cancer patients: Insights from the FRONTLINE survey.Oncologist.2003;8:381–388.
Deheinzelin D, Braga AL, Martins LC, et al.Incorrect use of thromboprophylaxis for venous thromboembolism in medical and surgical patients: results of a multicentric, observational and cross‐sectional study in Brazil.J Thromb Haemost.2006;4(6):1266–1270.
Vats V, Nutescu EA, Theobald JC, Wojtynek JE, Schumock GT.Survey of hospitals for guidelines, policies, and protocols for anticoagulants.Am J Health Syst Pharm.2007;64(11):1203–1208.

References

Anderson FA, Zayaruzny M, Heit JA, Fidan D, Cohen AT.Estimated annual numbers of US acute‐care hospital patients at risk for venous thromboembolism.Am J Hematol.2007;82(9):777–782.
Stein PD, Beemath A, Olson RE.Trends in the incidence of pulmonary embolism and deep venous thrombosis in hospitalized patients.Am J Cardiol.2005;95(12):1525–1526.
Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th ed.Chest.2008;133(6 suppl):381S–453S.
Hirsh J, Hoak J.Management of deep vein thrombosis and pulmonary embolism. A statement for healthcare professionals. Council on Thrombosis (in consultation with the Council on Cardiovascular Radiology), American Heart Association.Circulation.1996;93(12)2212–2245.
Anderson FA, Wheeler HB, Goldberg RJ, et al.A population‐based perspective of the hospital incidence and case‐fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study.Arch Intern Med.1991;151(5):933–938.
Prandoni P, Lensing AW, Cogo A, et al.The long‐term clinical course of acute deep venous thrombosis.Ann Intern Med.1996;125(1):1–7.
O'Brien JA, Caro JJ.Direct medical cost of managing deep vein thrombosis according to the occurrence of complications.Pharmacoeconomics.2002;20(9):603–615.
Spyropoulos AC, Lin J.Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations.J Manag Care Pharm.2007;13(6):475–486.
Piazza G, Seddighzadeh A, Goldhaber SZ.Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent.Chest.2007;132(2):554–561.
Anderson FA, Spencer FA.Risk factors for venous thromboembolism.Circulation.2003;107(23 suppl 1):I9–I16.
Alikhan R, Cohen AT, Combe S, et al.Risk factors for VTE in hospitalized patients with acute medical illness: analysis of the MEDENOX Study.Arch Intern Med.2004;164(9):963–968.
Cohen AT, Tapson VF, Bergmann JF, et al.;ENDORSE Investigators.Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross‐sectional study.Lancet.2008;371(9610):387–394.
Heit JA, Silverstein MD, Mohr DN, et al.Risk factors for deep vein thrombosis and pulmonary embolism: a population‐based case‐control study.Arch Intern Med.2000;160(6):809–815.
Heinemann LA, Dinger JC.Range of published estimates of venous thromboembolism incidence in young women.Contraception.2007;75(5):328–336.
Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S.The risk of recurrent venous thromboembolism in men and women.N Engl J Med.2004;350(25):2558–2563.
Beemath A, Stein PD, Skaf E, et al.Risk of venous thromboembolism in patients hospitalized with heart failure.Am J Cardiol.2006;98(6):793–795.
Stein PD, Beemath A, Meyers FA, et al.Pulmonary embolism and deep venous thrombosis in hospitalized adults with chronic obstructive pulmonary disease.J Cardiovasc Med.2007;8(4):253–257.
Stein PD, Beemath A, Meyers FA, et al.Incidence of venous thromboembolism in patients hospitalized with cancer.Am J Med.2006;119(1):60–68.
Ambrus JL, Ambrus CM, Mink IB, et al.Causes of death in cancer patients.J Med.1975;6(1):61–64.
Fernandez PM, Rickles FR.Tissue factor and angiogenesis in cancer.Curr Opin Hematol.2002;9(5):401–406.
Fotopoulou C, duBois A, Karavas AN, et al.Incidence of venous thromboembolism in patients with ovarian cancer undergoing platinum/paclitaxel‐containing first‐line chemotherapy: an exploratory analysis by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group.J Clin Oncol.2008;26(16):2683–2689.
Gerber DE, Segal JB, Levy MY, Kane J, Jones RJ, Streiff MB.The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention.Blood.2008;112(3):504–510.
Bennett CL, Silver SM, Djulbegovic B, et al.Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer‐associated anemia.JAMA.2008;299(8):914–924.
Agnelli G, Bolis G, Capussotti L, et al.A clinical outcome‐based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project.Ann Surg.2006;243(1):89–95.
Goldhaber SZ.Pulmonary embolism in thrombolysis: a clarion call for international collaboration.J Am Coll Cardiol.1992;19:246–247.
Ageno W, Becattini C, Brighton T, et al.Cardiovascular risk factors and venous thromboembolism: a meta‐analysis.Circulation.2008;117(1):93–102.
Braekkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, Størmer J, Hansen JB.Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsø study.J Thromb Haemost.2008;6(11):1851–1857.
Borch KH, Brækkan SK, Mathiesen EB, et al.Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome—the Tromsø study.J Thromb Haemost.2009;7(5):739–745.
Goldhaber SZ, Tapson VF.A prospective registry of 5,451 patients with ultrasound‐confirmed deep vein thrombosis.Am J Cardiol.2004;93(2):259–262.
Alikhan R, Cohen AT, Combe , et al.Prevention of venous thromboembolism in medical patients with enoxaparin; a subgroup analysis of the MEDENOX study.Blood Coagul Fibrinolysis.2003;14:341–348.
Howell MD, Geraci JM, Knowlton AA.Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case‐control study.J Clin Epidemiol.2001;54(8):810–816.
Cohen AT, Davidson BL, Gallus AS, et al;ARTEMIS Investigators.Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.BMJ.2006;332(7537):325–329.
Gardlund B.Randomised, controlled trial of low‐dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group.Lancet.1996;347(9012):1357–1361.
Copur AS, Smith PR, Gomez V, et al.HIV infection is a risk factor for venous thromboembolism.AIDS Patient Care STDS.2002;16(5):205–209.
Eichinger S, Hron G, Bialonczyk C, et al.Overweight, obesity, and the risk of recurrent venous thromboembolism.Arch Intern Med.2008;168(15):1678–1683.
Rathbun S.Venous thromboembolism in women.Vasc Med.2008;13(3):255–266.
James AH, Tapson VF, Goldhaber SZ.Thrombosis during pregnancy and the postpartum period.Am J Obstet Gynecol.2005;193(1):216–219.
Shetty R, Seddighzadeh A, Piazza G, et al.Chronic obstructive pulmonary disease and deep vein thrombosis: a prevalent combination.J Thromb Thrombolysis.2008;26(1):35–40.
Meissner MH, Chandler WL, Elliott JS.Venous thromboembolism in trauma: a local manifestation of systemic hypercoagulability?J Trauma.2003;54(2):224–231.
Kazory A, Ducloux D.Acquired hypercoagulable state in renal transplant recipients.Thromb Haemost.2004;91(4):646–654.
Seddighzadeh A, Zurawska U, Shetty R, Goldhaber SZ.Venous thromboembolism in patients undergoing surgery: low rates of prophylaxis and high rates of filter insertion.Thromb Haemost.2007;98(6):1220–1225.
Shackford SR, Rogers FB, Terrien CM, Bouchard P, Ratliff J, Zubis R.A 10‐year analysis of venous thromboembolism on the surgical service: the effect of practice guidelines for prophylaxis.Surgery.2008;144(1):3–11.
Noboa S, Le Gal G, Lacut K, et al;EDITH Collaborative Study Group.Family history as a risk factor for venous thromboembolism.Thromb Res.2008;122(5):624–629.
Canonico M, Bouaziz E, Carcaillon L, et al;Estrogen and Thromboembolism Risk (ESTHER) Study Group.Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women.J Clin Endocrinol Metab.2008;93(8):3082–3087.
Lindqvist PG, Epstein E, Olsson H.The relationship between lifestyle factors and venous thromboembolism among women: a report from the MISS study.Br J Haematol.2009;144(2):234–240.
Steffen LM, Folsom AR, Cushman M, Jacobs DR, Rosamond WD.Greater fish, fruit, and vegetable intakes are related to lower incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology.Circulation.2007;115(2):188–195.
Sare GM, Gray LJ, Bath PM.Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta‐analysis.Eur Heart J.2008;29(16):2031–2041.
Cole JA, Norman H, Doherty M, Walker AM.Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users.Obstet Gynecol.2007;109(2 Pt 1):339–346.
Borras L, Eytan A, de Timary P, Constant EL, Huguelet P, Hermans C.Pulmonary thromboembolism associated with olanzapine and risperidone.J Emerg Med.2008;35(2):159–161.
Hägg S, Bate A, Stahl M, Spigset O.Associations between venous thromboembolism and antipsychotics. A study of the WHO database of adverse drug reactions.Drug Saf.2008;31(8):685–694.
Paciullo CA.Evaluating the association between clozapine and venous thromboembolism.Am J Health Syst Pharm.2008;65(19):1825–1829.
Jick SS, Li L.Antidepressant drug use and risk of venous thromboembolism.Pharmacotherapy.2008;28(2):144–150.
Yu HT, Dylan ML, Lin J, Dubois RW.Hospitals' compliance with prophylaxis guidelines for venous thromboembolism.Am J Health Syst Pharm.2007;64(1):69–76.
Tapson VF, Decousus H, Pini M, et al.Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients.Chest.2007;132:936–945.
Jois‐Bilowich P, Michota F, Bartholomew JR, et al.Adhere Scientific Advisory Committee and Investigators. Venous thromboembolism prophylaxis in hospitalized heart failure patients.J Card Fail.2008;14(2):127–132.
Amin A, Spyropolous A, Dobesh P, et al. Are hospitals following guidelines for VTE Prevention? The Venous Thromboembolism Study to Assess the Rate of Thromboprophylaxis. Presented at the 50th Annual Meeting of the American College of Hematology, San Francisco, CA, December 6–9, 2008. Abstract 1286.
Tooher R, Middleton P, Pham C, et al.A systematic review of strategies to improve prophylaxis for venous thromboembolism in hospitals.Ann Surg.2005;241(3):397–415.
Howard DP.A need for a simplified approach to venous thromboembolism prophylaxis in acute medical inpatients.Int J Clin Pract.2007;61(2):336–340.
Borris LC.Barriers to the optimal use of anticoagulants after orthopaedic surgery.Arch Orthop Trauma Surg.2008 (Published online Oct, 8.). [http://dx.doi.org/DOI 10.1007/s00402‐008‐0765‐9]
Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J.Venous thrombosis in cancer patients: Insights from the FRONTLINE survey.Oncologist.2003;8:381–388.
Deheinzelin D, Braga AL, Martins LC, et al.Incorrect use of thromboprophylaxis for venous thromboembolism in medical and surgical patients: results of a multicentric, observational and cross‐sectional study in Brazil.J Thromb Haemost.2006;4(6):1266–1270.
Vats V, Nutescu EA, Theobald JC, Wojtynek JE, Schumock GT.Survey of hospitals for guidelines, policies, and protocols for anticoagulants.Am J Health Syst Pharm.2007;64(11):1203–1208.

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Assessing the risk of venous thromboembolism and identifying barriers to thromboprophylaxis in the hospitalized patient

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Assessing the risk of venous thromboembolism and identifying barriers to thromboprophylaxis in the hospitalized patient

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prophylaxis barriers, risk assessment, venous thromboembolism

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prophylaxis barriers, risk assessment, venous thromboembolism

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Guidelines‐Based Thromboprophylaxis

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Guidelines‐based use of thromboprophylaxis

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Thromboprophylaxis with anticoagulants has proven benefits in hospitalized patients. Despite this, venous thromboembolism (VTE) prophylaxis is underused and VTE remains the leading cause of preventable hospital mortality.1 Medical patients have a particularly high risk; those who develop a deep vein thrombosis (DVT) are significantly less likely to have received prophylaxis prior to the diagnosis of DVT than nonmedical patients. Even within the high‐risk setting of the intensive care unit (ICU), medical patients receive thromboprophylaxis only two‐thirds as often as nonmedical patients.2

In this article we summarize the evidence concerning the various prophylaxis options, including current guideline recommendations for VTE prevention in medical and surgical patients. We also discuss strategies for thromboprophylaxis in special populations and potential complications of prophylaxis.

Efficacy of Prophylaxis in Medical Patients

Several meta‐analyses have demonstrated the marked benefits of anticoagulant prophylaxis in medical patients. Dentali et al3 conducted a meta‐analysis of 9 randomized controlled trials enrolling a total of 19,958 at‐risk hospitalized medical patients. The selected trials compared standard anticoagulant regimens with no treatment and only included studies with objectively documented and independently adjudicated outcomes. Compared with patients receiving placebo, those receiving thromboprophylaxis had significant reductions in any PE by 57% (95% CI, 0.26‐0.71; absolute risk reduction, 0.29%) and fatal pulmonary embolism (PE) by 62% (95% CI, 0.21‐0.69; absolute risk reduction, 0.25%), with a nonsignificant reduction in symptomatic DVT (relative risk [RR], 0.47; 95% CI, 0.22‐1.00) and a nonsignificant increase in major bleeding (RR, 1.32; 95% CI, 0.73‐2.37). The researchers concluded that anticoagulant prophylaxis is effective in preventing symptomatic VTE in medical patients, though the optimal duration of therapy is not yet defined.3

Another meta‐analysis focusing on subclinical DVT in acutely ill medical patients examined the therapeutic effects of various prophylaxis regimens. Overall, anticoagulant prophylaxis reduced the risk of any asymptomatic DVT (assessed by venogram or ultrasound) by 49% (95% CI, 0.39‐0.67) and asymptomatic proximal DVT by 55% (95% CI, 0.31‐0.65) compared with placebo (absolute risk reduction, 2.6% and 1.8%, respectively). Although prophylaxis was associated with a 0.5% absolute risk increase in major bleeding, the authors concluded that the benefits of prophylaxis outweighed the risks of bleeding.4

Anticoagulant Agents in the Prevention of VTE

Currently available anticoagulants for the prevention of VTE include unfractionated heparin (UFH), low‐molecular‐weight heparins (LMWHs), fondaparinux, and warfarin. These agents interrupt thrombus formation, either indirectly (through interaction with antithrombin) or directly (by inhibiting the action of thrombin). Each class of therapy has advantages and limitations. Table 1 lists common anticoagulant options for VTE prophylaxis, along with dosing information and other important information.510

Table 1.Anticoagulant Agents for the Prevention of VTE
	Prophylactic Dose	Warnings/Contraindications/Adverse Reactions
NOTE: Adapted from Prescribing Information; Umland6 and Ansell et al.5 Abbreviations: aPTT, activated partial thromboplastin time; HIT, heparin‐induced thrombocytopenia; INR, International Normalized Ratio; LMWH, low‐molecular‐weight heparin; UFH, unfractionated heparin. * For elderly and other debilitated/malnourished patients, starting dose should be 5 mg. Before initiation, perform baseline aPTT and platelet count. This is the dose for DVT prophylaxis in abdominal surgery, hip replacement surgery, and medical patients; the dose in knee replacement surgery is 30 mg subcutaneously every 12 hours. Reduce the dose if creatinine clearance 30 mL/minute.
Warfarin	5 to 10 mg daily initially;* adjust dose based on INR; therapeutic INR goal: 2.5 (2‐3)	Warning: bleeding risk; requires frequent monitoring; contraindicated in patients for whom hazard of hemorrhage outweighs potential benefit (eg, in pregnant women)
UFH	5000 IU every 8‐12 hours subcutaneously	Contraindicated in the presence of active bleeding, uncontrolled hypertension, or severe thrombocytopenia; monitor platelet count every 4‐7 days for HIT
Dalteparin	5000 IU daily subcutaneously	Warning: spinal/epidural hematoma; monitor for signs and symptoms of neurological impairment. LMWHs should be used with caution in renal impairment; anti‐Xa monitoring and dose adjustments may be required. Follow prescribing information for dose adjustments and body weight‐based dosing. Most common adverse reactions: bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea
Enoxaparin	40 mg daily subcutaneously; reduce to 30 mg daily in renal impairment
Tinzaparin	3500 IU daily subcutaneously
Fondaparinux	2.5 mg daily subcutaneously	Warning: spinal/epidural hematoma; monitor for signs and symptoms of neurological impairment; contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/minute) and in patients < 50 kg

UFH

UFH, which is typically administered by subcutaneous injection, has the longest history as an anticoagulant in the prevention and treatment of VTE. It is an attractive option in patients with severe renal failure or those who may require a procedure in the near future. Although UFH is partially cleared by the kidney, its short half‐life can be perceived as a safety advantage in patients with severe renal impairment and an increased risk of bleeding. For most other patients, UFH holds several disadvantages compared with newer therapies, including the need for injections to be administered 3 times a day to be optimally effective, its effect on platelets, and its association with heparin‐induced thrombocytopenia (HIT).1 Given the costs of administration and potential complications, it is not less expensive than LMWHs, and it appears to be less cost‐effective.11

LMWHs

LMWHs have a higher bioavailability and longer half‐life than UFH, which translates to reliable anticoagulation levels when given subcutaneously on a weight‐based dosing schedule. Unlike UFH, LMWHs do not require laboratory tests to monitor the intensity of anticoagulation, except in special circumstances.1 The LMWHs dalteparin, enoxaparin, and tinzaparin are widely used for the prevention and treatment of VTE in the United States.

Two landmark clinical trials demonstrated the efficacy of appropriate thromboprophylaxis with LMWHs in reducing the burden of VTE in acutely ill, hospitalized medical patients. The Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial and Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT) demonstrated the benefits of enoxaparin and dalteparin, respectively, in reducing the risk of VTE. As shown in Table 2, thromboprophylaxis with these agents was associated with a 45% to 63% relative reduction in the risk of VTE compared with placebo.12, 13

Table 2.Anticoagulants for VTE Prophylaxis in Acutely Ill, Hospitalized Medical Patients
Trial	Number of Patients	Agent (vs. placebo)	Detection of VTE	Relative Risk Reduction	Number Needed to Treat
NOTE: Adapted from Samama et al,12 Leizorovicz et al,13 and Cohen et al.15 Abbreviations: ARTEMIS, Arixtra for Thromboembolism Prevention in a Medical Indications Study; CI, confidence interval; CUS, compression ultrasonography; DVT, deep vein thrombosis; MEDENOX, Prophylaxis in Medical Patients with Enoxaparin; PE, pulmonary embolism; PREVENT, Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial; SC, subcutaneously; VTE, venous thromboembolism.
MEDENOX	866	Enoxaparin 20 mg or 40 mg SC daily for 6‐14 days	Distal and proximal venographic DVT or documented PE	63% (with 40 mg; 97.6 CI, 0.22‐0.63; P <0.001)	10
PREVENT	3706	Dalteparin 5000 IU SC daily for up to 14 days	CUS DVT, symptomatic VTE, and fatal PE	45% (95% CI, 0.38‐0.80; P = 0.0015)	45
ARTEMIS	849	Fondaparinux 2.5 mg SC daily for 6‐14 days	Distal and proximal venographic DVT, symptomatic VTE, and fatal PE	47% (95% CI, 0.077‐0.693)	20

Pentasaccharides

Fondaparinux is a synthetic factor Xa antagonist that shares many features of LMWHs, including a high bioavailability and long half‐life. Fondaparinux does not require monitoring, but it is contraindicated in patients with renal failure (CrCl < 30 mL/minute) and in patients weighing less than 50 kg.1 Although PF4 antibodies have been associated with fondaparinux administration, this drug has not, to date, been associated with HIT.14 The Arixtra for Thromboembolism Prevention in a Medical Indications Study (ARTEMIS) trial demonstrated the advantage of fondaparinux over placebo in reducing the risk of VTE (Table 2).15 The American College of Chest Physicians (ACCP) guidelines state that fondaparinux appears to be as effective and safe as LMWH.1

Vitamin K Antagonists

Vitamin K antagonists (VKAs) such as warfarin inhibit the production of prothrombin, clotting factors VII, IX, and X, and the anticoagulants protein C and protein S. Warfarin is challenging to manage because of its narrow therapeutic window, its tendency to exhibit considerable variability in dose‐response, the time required to reach target international normalized ratio (INR), its potential for interaction with diet and concomitant medications, and its need for ongoing monitoring.5 Warfarin should usually be initiated within the same 24 hours as parenteral anticoagulation, with a goal of achieving INR results between 2.0 and 3.0. An initial dose of 5 to 10 mg for the first 1 or 2 days is appropriate for most patients, and subsequent dosing should be based on INR response.5 Warfarin prophylaxis is primarily used in patients in the US undergoing orthopedic surgery, including total hip replacement and hip and knee arthroplasty.1

Future Anticoagulants

New oral agents have the potential to improve the management of patients who have a moderate to high risk of thromboembolic disease.

Rivaroxaban

This oral factor Xa inhibitor is showing promise in patients undergoing major orthopedic surgery. A prespecified pooled analysis was performed on data from the four Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism (RECORD) trials to evaluate the effect of rivaroxaban on the composite of symptomatic VTE (DVT or PE) and death, and bleeding. In the analysis, patients undergoing hip or knee arthroplasty had a VTE rate of 0.8% with rivaroxaban vs. 1.6% with enoxaparin, the current gold standard for surgical prophylaxis (P < 0.001). Bleeding rates were not significantly different between treatment arms (P = 0.376).16

Apixaban

This oral, direct, reversible factor Xa inhibitor is under evaluation for the prevention and treatment of VTE. In the Apixaban Prophylaxis in Patients Undergoing Total Knee Replacement Surgery (APROPOS) study of patients undergoing knee replacement, apixaban had a lower composite rate of DVT, PE, and all‐cause mortality when compared with enoxaparin or warfarin.17 In the ADVANCE‐1 study of patients undergoing knee surgery, however, apixaban failed to meet criteria for noninferiority when compared with enoxaparin.18 Apixaban is now being evaluated for VTE prophylaxis in acutely ill medical patients.

Dabigatran

This oral direct thrombin inhibitor reversibly binds to free and fibrin‐bound thrombin. In the RE‐NOVATE trial, dabigatran was noninferior to enoxaparin in reducing the events of DVT, PE, and all‐cause mortality following total hip replacement surgery.19 In a Phase II dose‐ranging trial in patients with atrial fibrillation (Prevention of Embolic and Thrombotic Events in Patients with Persistent [AFPETRO]), dabigatran with or without aspirin was as effective as warfarin in reducing embolic events.20 In the RE‐MODEL study, dabigatran was as effective as enoxaparin in preventing VTE and all‐cause mortality following knee replacement surgery, but failed to show equivalence to a higher dose of enoxaparin in the RE‐MOBILIZE trial.21, 22 It should be noted that in the RE‐MODEL study, enoxaparin was not administered at the dosage recommended by the U.S. Food and Drug Administration (FDA) for knee replacement surgery.

Mechanical Prophylaxis

Mechanical methods of thromboprophylaxis include graduated compression stockings (GCS), intermittent pneumatic compression (IPC) devices, and the venous foot pump (VFP). Mechanical approaches to thromboprophylaxis should be used primarily in patients who have a high risk of bleeding or as an adjunct to pharmacotherapeutic prophylaxis.1 The ACCP guidelines summarize the advantages and limitations of mechanical prophylaxis in patients at risk of developing VTE (Table 3).1

Table 3.Advantages and Limitations of Mechanical Thromboprophylaxis
Advantages	Limitations
NOTE: Modified with permission from Geerts et al.1 Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism.
Does not increase the risk of bleeding	Not as intensively studied as pharmacologic thromboprophylaxis (fewer studies and smaller)
Can be used in patients who have a high risk of bleeding	No established standards for size, pressure, or physiologic features
Efficacy has been demonstrated in a number of patient groups	Many specific mechanical devices have never been assessed in any clinical trial
May enhance the effectiveness of anticoagulant thromboprophylaxis	Almost all mechanical thromboprophylaxis trials were unblinded and therefore have a potential for bias
May reduce leg swelling	Are less effective in high‐risk groups than anticoagulant thromboprophylaxis
May reduce leg swelling	Greater effect in reducing calf DVT than proximal DVT
Effect on PE and death unknown
May reduce or delay the use of more effective anticoagulant thromboprophylaxis
Compliance by patients and staff is often poor
Trials may overestimate the protection compared with routine use
Cost associated with purchase, storage, dispensing, and cleaning of the devices, as well as ensuring optimal compliance

When properly fitted, GCS increase venous blood return through external pressure, thereby reducing venous stasis. IPC devices or sequential compression devices are usually applied over compression stockings. In addition to improving venous blood flow, these devices stimulate endogenous fibrinolysis. Compliance is often a problem in medical patients, who may not use the devices properly. Furthermore, for patients with severe vascular insufficiency (ankle brachial index <0.05), IPC may worsen vascular insufficiency and digital gangrene.

Inferior vena cava (IVC) filters are barrier devices that may benefit patients with major bleeding risk in the acute VTE setting by preventing PE. These devices, however, do not prevent DVT and may promote further venous stasis and clotting below the device. Importantly, patients with HIT should not have IVC filters placed due to a very high thrombogenic state that could lead to limb ischemia or cerulea phlegmasia dolens.23

Thromboprophylaxis in Medical Patients

Duration

Although major trials support the use of short‐term prophylaxistypically 6 to 14 daysin‐hospital for acutely ill medical patients, the optimal duration of thromboprophylaxis in these patients is unclear.24 The Extended Clinical Prophylaxis in Acutely Ill Medical Patients (EXCLAIM) trial is the first randomized trial to evaluate the potential benefits of extended prophylaxis in acutely ill medical patients. In this study, 5101 hospitalized patients with varying levels of reduced mobility due to cancer, ischemic stroke, heart failure, respiratory failure, infection, and other acute medical conditions received open‐label enoxaparin 40 mg daily for a mean duration of 10 days. Patients were then randomly assigned to additional therapy with enoxaparin or placebo for a mean duration of 28 additional days.25 Preliminary findings from this trial suggest that high‐risk medical patients can benefit from extended thromboprophylaxis following hospital discharge, with significantly reduced VTE events (RR reduction, 44%; P = 0.0011). The benefits of thromboprophylaxis were apparent during the extended treatment period and persistent through 90 days.26

Guideline Recommendations

Incorrect use of thromboprophylaxis does not stem from a lack of evidence‐based recommendations. Within the past year, the ACCP, the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) have published updated guidelines for thromboprophylaxis in hospitalized patients at risk of VTE.1, 27, 28 The 2008 ACCP guidelines include more than 700 recommendations for VTE risk assessment and management, to be implemented by a variety of physicians, including pulmonologists, cardiologists, cardiothoracic surgeons, and critical care medicine specialists.1

The ACCP guidelines organize prophylaxis recommendations on the basis of patient risk (Table 4).1 Risk assessment remains relatively subjective, however, and validated risk assessment models are not yet widely available. The prudent approach is to consider thromboprophylaxis for all hospitalized medically ill patients who do not have a specific contraindication.

Table 4.Guideline‐Recommended Thromboprophylaxis for Hospitalized Patients by Level of VTE Risk
Levels of Risk	Approximate DVT Risk Without Thromboprophylaxis (%)	Suggested Thromboprophylaxis Options
NOTE: Modified with permission from Geerts WH, Bergqvist D, Pineo GF, et al.1 Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th ed. Chest 2008; 133(6 suppl):381S‐453S. Abbreviations: bid, twice daily; DVT, deep‐vein thrombosis; HFS, hip fracture surgery; INR, international normalized ratio; LMWH, low‐molecular‐weight heparin; SCI, spinal cord injury; tid, three times daily; UFH, unfractionated heparin; VTE, venous thromboembolism.
Low risk
Minor surgery in mobile patients	< 10	No specific thromboprophylaxis; early and aggressive ambulation
Medical patients who are fully mobile	< 10
Moderate risk
Most general, open gynecologic, or urologic surgery patients	10‐40	LMWH (at recommended doses), low‐dose UFH bid or tid, fondaparinux
Medical patients, bed rest or sick	10‐40
Moderate VTE risk plus high bleeding risk	Mechanical thromboprophylaxis
High risk
Hip or knee arthroplasty, HFS	40‐80	LMWH (at recommended doses), fondaparinux, oral vitamin K antagonist (INR 2‐3)
Major trauma, SCI	40‐80
High VTE risk plus high bleeding risk	Mechanical thromboprophylaxis

Key evidence‐based recommendations regarding thromboprophylaxis for hospitalized, acutely ill patients include the following:1

Every hospital should develop a formal strategy to addresses VTE prophylaxis;
Aspirin alone is not recommended to prevent VTE for any patient group;
Mechanical methods of thromboprophylaxis should be used primarily for patients who have a high bleeding risk or possibly as an adjunct to anticoagulant thromboprophylaxis;
Thromboprophylaxis with LMWH, UFH, or fondaparinux is recommended for patients admitted to hospital with an acute medical illness (Note: fondaparinux is recommended, but not FDA‐approved, for this indication in the United States);
On admission to the ICU, all patients should be assessed for risk of VTE, and most should receive thromboprophylaxis;
All major trauma and all spinal‐cord injury patients should receive thromboprophylaxis.

Thromboprophylaxis in Surgical Patients

For hospitalized surgical patients, the ACCP guidelines indicate the importance of the type of surgery (eg, gynecologic, urologic, or neurologic) in determining the appropriate prophylaxis strategy. In general, routine thromboprophylaxis is recommended for patients undergoing major general, gynecologic, or orthopedic surgery, as well as bariatric and coronary artery bypass surgery.1 Some specific recommendations regarding thromboprophylaxis for surgical patients include the following:

Major general surgery: LMWH, low‐dose UFH, or fondaparinux;
Major gynecologic surgery and major open urologic procedures: LMWH, low‐dose UFH, fondaparinux, and/or a mechanical device;
Elective hip or knee arthroplasty: Anticoagulant therapy (LMWH, fondaparinux, or a VKA);
Hip‐fracture surgery: Fondaparinux, LMWH, a VKA, or low‐dose UFH;
Patients undergoing hip or knee arthroplasty or hip‐fracture surgery should receive thromboprophylaxis for a minimum of 10 days; for hip arthroplasty and hip‐fracture surgery, thromboprophylaxis should continue for more than 10 days and up to 35 days.

Although the ACCP guidelines recommend against aspirin monotherapy for any patient group, the American Academy of Orthopaedic Surgeons (AAOS) guidelines state that aspirin alone is an effective option in preventing VTE in standard‐risk patients who are undergoing hip or knee replacement surgery.29 However, evidence for aspirin monotherapy is currently limited.1

The 2008 ACCP guidelines include a new chapter on the perioperative management of patients receiving long‐term antithrombotic treatment who must undergo surgery or other invasive procedures. To minimize surgical bleeding, the ACCP recommends the temporary discontinuation of antithrombotic treatment immediately before and during surgery for most patients. Discontinuing antithrombotics can increase the risk of a thromboembolic event, but this risk must be weighed against the risk of bleeding.1 The guidelines also offer specific recommendations for the use of perioperative bridging therapy in patients receiving VKAs based on the risk of VTE and whether the patient has a mechanical heart valve or atrial fibrillation. Guidelines recommend discontinuing bridging anticoagulation 24 hours prior to surgery if therapeutic subcutaneous LMWH is the agent used and approximately 4 hours prior to surgery if intravenous UFH is the agent used.

Thromboprophylaxis in Special Populations

Care must be taken when using thromboprophylaxis in certain high‐risk populations. The following section provides recommendations regarding prophylaxis in the presence of cancer, pregnancy, renal insufficiency, and epidural anesthesia.

Cancer Patients

The ASCO and NCCN guidelines endorse the use of VTE prophylaxis with anticoagulants in all hospitalized patients with active cancer or suspicion of cancer in the absence of contraindications.27, 28 The ACCP guidelines restrict this recommendation to hospitalized cancer patients who are bedridden.1 Thromboprophylaxis should continue at least through the duration of the hospital stay. Acceptable subcutaneous regimens include fondaparinux, dalteparin, or enoxaparin at the doses presented in Table 1; if UFH is chosen, the dose should be 5000 units every 8 hours.

Cancer patients who are scheduled to undergo major surgery require a different prophylaxis strategy. Even with prophylaxis, cancer patients have a 2‐fold higher risk of postoperative VTE compared with noncancer patients and more than a 3‐fold higher risk of fatal PE.30 To manage this risk, the ASCO, NCCN, and ACCP guidelines recommend extended prophylaxis in patients undergoing major cancer surgery.1, 27, 28 Specific recommendations include the following:

All patients undergoing major surgical intervention for malignant disease should be considered for VTE prophylaxis with anticoagulants, with or without mechanical prophylaxis;
Thromboprophylaxis should be initiated prior to the start of surgery or as early as possible following surgery;
Mechanical interventions may supplement pharmacologic prophylaxis, especially in patients who have the highest risk;
Prophylaxis with a LMWH should be initiated 12 to 24 hours after the surgical procedure;
Continue prophylaxis at least 7 to 10 days postoperatively;
Consider prolonged prophylaxis (ie, up to 4 weeks) with a LMWH for high‐risk patients (eg, patients undergoing major abdominal or pelvic surgery, those with residual malignant disease after surgery, obese patients, and patients with a history of VTE).

Routine prophylaxis with anticoagulants is not recommended for most outpatients, except for those with high‐risk factors (eg, thrombogenic chemotherapy or a central venous catheter). The strategy of restricting thromboprophylaxis to cancer outpatients with specific indications, however, may miss an opportunity to reduce VTE in this vulnerable patient population. In the PROTECHT study, 1166 ambulatory cancer patients were randomly assigned to placebo or the LMWH nadroparin for the duration of their chemotherapy. Treatment with nadroparin reduced the rate of clinical thrombosis by 47.2% compared with placebo (3.9% vs. 2.1%; P = 0.033). The risk reduction was consistent across all measured events, including DVT, PE, stroke, and visceral venous thrombosis.31

Pregnancy

Prophylaxis should be considered in pregnant women with known risk factors for VTE such as prior VTE, thrombophilia, and a history of prolonged immobility. In addition, women with a moderate to high risk of VTE associated with a cesarean section should be considered for postpartum thromboprophylaxis. For example, 1 of the following regimens may be appropriate for high‐risk women following a cesarean section:32

UFH 5000 units subcutaneously every 12 hours until fully mobile;
LMWH subcutaneously once daily for 5 days (such as enoxaparin 20 mg daily).

For pregnant women already receiving anticoagulant prophylaxis (eg, for hypercoagulable state, structural heart disease, or prior DVT/PE), ACCP guidelines recommend discontinuing VKAs before 6 weeks of fetal gestation to minimize the risk of birth defects and miscarriage. In general, a LMWH should be substituted for VKAs as soon as pregnancy is confirmed or prior to conception in preparation for pregnancy, as VKAs cross the placental barrier, but LMWH and UFH do not.1, 33

Renal Insufficiency

The ACCP guidelines recommend that renal function be considered when making decisions about the use and/or dose of LMWHs and fondaparinux. Because these agents are eliminated primarily via renal clearance, changes in renal function can reduce drug clearance, prolong the half‐life, and increase plasma concentrations. Consequently, the risk of treatment‐related bleeding complications is elevated in patients with renal impairment.1 Depending on the circumstances, one of the following options should be considered1:

Avoid using an anticoagulant that bioaccumulates in the presence of renal impairment;
Use a lower dose of the agent;
Monitor the drug level or its anticoagulant effect.

In severe renal impairment (creatinine clearance < 30 mL/minute):710

The prophylactic dose of enoxaparin should be adjusted to 30 mg subcutaneously once daily; no specific dosing adjustments have been recommended for dalteparin or tinzaparin;
Fondaparinux is contraindicated.

Epidural Anesthesia

Neuraxial blockade has several advantages over systemic opioids, but the risk of spinal or epidural hematoma may be increased with the concomitant use of antithrombotic drugs. Therefore, these agents must be used cautiously in patients with neuraxial blockade.1 Guidelines from the American Society of Regional Anesthesia and Pain Medicine (ASRA) contain the following recommendations:34

Subcutaneous UFH: No contraindication, consider delaying heparin until after block if technical difficulty is anticipated;
LMWH: Since twice daily dosing may be associated with an increased risk of spinal hematoma, delay initiation of LMWH until at least 24 hours after surgery, regardless of anesthetic technique; for single daily dosing, administer the first dose of LMWH 6 to 8 hours postoperatively and second dose no sooner than 24 hours after the first dose;
Warfarin: Document normal INR after discontinuation (prior to neuraxial technique); remove catheter when INR 1.5 (initiation of therapy).

Complications of Thromboprophylaxis

Before initiating thromboprophylaxis, it is important to evaluate the risk of bleeding, and patients should be assessed for contraindications that could increase that risk. HIT should also be considered.

Bleeding Risk

The ACCP and ASCO guidelines emphasize the importance of weighing the potential benefits of thromboprophylaxis against the potential risks of bleeding in individual patients. According to the ACCP, the overall risk of bleeding with intravenous UFH in patients with VTE is less than 3%, and thromboprophylaxis has not been shown to increase the risk of bleeding compared with placebo in major clinical trials.13, 15, 35 However, bleeding risk may increase in older patients and with higher doses of heparin. Warfarin therapy can be monitored with an INR to reduce the risk of bleeding during thromboprophylaxis.1

Anticoagulation therapy may be contraindicated in patients with certain factors and conditions that increase the risk of bleeding. These include:

Clinically significant active or chronic bleeding;
Recent central nervous system or spinal surgery with increased risk of bleeding;
Thrombocytopenia (excluding HIT) or severe platelet dysfunction;
Abnormalities associated with clotting factors.

The NCCN provides specific contraindications to anticoagulation therapy for the prevention and treatment of VTE in cancer patients.28 These include:

Recent central nervous system bleed; intracranial, or spinal lesions at high risk of bleeding;
Active major bleeding (> 2 units transfused in 24 hours);
Chronic, clinically significant measurable bleeding for more than 48 hours;
Thrombocytopenia (platelets < 50,000/L);
Severe platelet dysfunction;
Recent major operation with high risk of bleeding;
Underlying coagulopathy (eg, clotting factor abnormalities or elevated prothrombin time or activated partial thromboplastin time [aPTT]);
Spinal anesthesia or lumbar puncture;
High risk of falls.

HIT

HIT is a serious complication that can occur as a result of exposure to heparin. It is an immune response that causes platelet activation and platelet aggregation, among other effects, and is capable of leading to severe thrombosis, amputation, or death.36 The incidence of HIT varies with subpopulations of patients and more commonly develops in patients receiving heparin in therapeutic doses. Early diagnosis (through an interpretation of clinical and laboratory information) is important to improve clinical outcomes, but difficult to achieve.36 The ACCP guidelines note that enzyme‐linked immunosorbent assay (ELISA)‐based tests for HIT are often falsely positive after surgery. As an alternative, serotonin‐release tests are more specific, although they are not as widely available.1

Substantial clinical evidence suggests that LMWH poses less of a risk of HIT than UFH. Martel et al,37 for example, conducted a meta‐analysis of 15 randomized and nonrandomized controlled trials (a total of 7287 patients) that included studies that compared prophylactic doses of UFH and LMWH and assessed postoperative or medical inpatients who received prophylaxis. The analysis revealed that the risk of HIT was 2.6% following UFH use compared with 0.2% following LMWH use.37 Despite the inclusion of UFH in the ASCO guidelines, ASCO acknowledges that a lower risk of HIT is one of the potential advantages of LMWH over UFH in cancer surgery prophylaxis.27 In addition, the recommendation to transition to outpatient therapy as soon as possible is an indirect way of stating a preference for LMWH. For cancer patients with established VTE, the recommendation is more direct: LMWH is clearly preferred over UFH for both initial and continuing antithrombotic therapy.27

Conclusions

Thromboprophylaxis should be considered in all hospitalized patients who have a risk of VTE. Anticoagulants are the mainstays of prophylaxis, and recent clinical trials have clearly demonstrated the efficacy of LMWHs and fondaparinux in preventing VTE. Each class of anticoagulant carries a number of side effects and contraindications, and frequent patient evaluation and monitoring may be required. This is especially true in those with renal impairment, for whom UFH may be a logical choice. A number of organizations have released guidelines for VTE prophylaxis that provide specific recommendations regarding thromboprophylaxis in special patient populations and scenarios.

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Snow V, Qaseem A, Barry P, et al.Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians.Am Fam Med.2007;5:74–80.
Horlocker TT, Wedel DJ, Benzon H, et al.Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation).Reg Anesth Pain Med.2003;28(3):172–197.
Alikhan R, Cohen AT, Combe , et al.Prevention of venous thromboembolism in medical patients with enoxaparin; a subgroup analysis of the MEDENOX study.Blood Coagul Fibrinolysis.2003;14:341–348.
Prechel M, Walenga JM.The laboratory diagnosis and clinical management of patients with HIT: an update.Semin Thromb Hemost.2008;34(1):86–93.
Martel N, Lee J, Wells PS.Risk for heparin‐induced thrombocytopenia with unfractionated and low‐molecular‐weight heparin thromboprophylaxis: a meta‐analysis.Blood.2005;106(8):2710–2715.

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thromboprophylaxis, venous thromboembolism

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Efficacy of Prophylaxis in Medical Patients

Anticoagulant Agents in the Prevention of VTE

Table 1.Anticoagulant Agents for the Prevention of VTE
	Prophylactic Dose	Warnings/Contraindications/Adverse Reactions
NOTE: Adapted from Prescribing Information; Umland6 and Ansell et al.5 Abbreviations: aPTT, activated partial thromboplastin time; HIT, heparin‐induced thrombocytopenia; INR, International Normalized Ratio; LMWH, low‐molecular‐weight heparin; UFH, unfractionated heparin. * For elderly and other debilitated/malnourished patients, starting dose should be 5 mg. Before initiation, perform baseline aPTT and platelet count. This is the dose for DVT prophylaxis in abdominal surgery, hip replacement surgery, and medical patients; the dose in knee replacement surgery is 30 mg subcutaneously every 12 hours. Reduce the dose if creatinine clearance 30 mL/minute.
Warfarin	5 to 10 mg daily initially;* adjust dose based on INR; therapeutic INR goal: 2.5 (2‐3)	Warning: bleeding risk; requires frequent monitoring; contraindicated in patients for whom hazard of hemorrhage outweighs potential benefit (eg, in pregnant women)
UFH	5000 IU every 8‐12 hours subcutaneously	Contraindicated in the presence of active bleeding, uncontrolled hypertension, or severe thrombocytopenia; monitor platelet count every 4‐7 days for HIT
Dalteparin	5000 IU daily subcutaneously	Warning: spinal/epidural hematoma; monitor for signs and symptoms of neurological impairment. LMWHs should be used with caution in renal impairment; anti‐Xa monitoring and dose adjustments may be required. Follow prescribing information for dose adjustments and body weight‐based dosing. Most common adverse reactions: bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea
Enoxaparin	40 mg daily subcutaneously; reduce to 30 mg daily in renal impairment
Tinzaparin	3500 IU daily subcutaneously
Fondaparinux	2.5 mg daily subcutaneously	Warning: spinal/epidural hematoma; monitor for signs and symptoms of neurological impairment; contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/minute) and in patients < 50 kg

UFH

LMWHs

Table 2.Anticoagulants for VTE Prophylaxis in Acutely Ill, Hospitalized Medical Patients
Trial	Number of Patients	Agent (vs. placebo)	Detection of VTE	Relative Risk Reduction	Number Needed to Treat
NOTE: Adapted from Samama et al,12 Leizorovicz et al,13 and Cohen et al.15 Abbreviations: ARTEMIS, Arixtra for Thromboembolism Prevention in a Medical Indications Study; CI, confidence interval; CUS, compression ultrasonography; DVT, deep vein thrombosis; MEDENOX, Prophylaxis in Medical Patients with Enoxaparin; PE, pulmonary embolism; PREVENT, Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial; SC, subcutaneously; VTE, venous thromboembolism.
MEDENOX	866	Enoxaparin 20 mg or 40 mg SC daily for 6‐14 days	Distal and proximal venographic DVT or documented PE	63% (with 40 mg; 97.6 CI, 0.22‐0.63; P <0.001)	10
PREVENT	3706	Dalteparin 5000 IU SC daily for up to 14 days	CUS DVT, symptomatic VTE, and fatal PE	45% (95% CI, 0.38‐0.80; P = 0.0015)	45
ARTEMIS	849	Fondaparinux 2.5 mg SC daily for 6‐14 days	Distal and proximal venographic DVT, symptomatic VTE, and fatal PE	47% (95% CI, 0.077‐0.693)	20

Pentasaccharides

Vitamin K Antagonists

Future Anticoagulants

New oral agents have the potential to improve the management of patients who have a moderate to high risk of thromboembolic disease.

Rivaroxaban

Apixaban

Dabigatran

Mechanical Prophylaxis

Table 3.Advantages and Limitations of Mechanical Thromboprophylaxis
Advantages	Limitations
NOTE: Modified with permission from Geerts et al.1 Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism.
Does not increase the risk of bleeding	Not as intensively studied as pharmacologic thromboprophylaxis (fewer studies and smaller)
Can be used in patients who have a high risk of bleeding	No established standards for size, pressure, or physiologic features
Efficacy has been demonstrated in a number of patient groups	Many specific mechanical devices have never been assessed in any clinical trial
May enhance the effectiveness of anticoagulant thromboprophylaxis	Almost all mechanical thromboprophylaxis trials were unblinded and therefore have a potential for bias
May reduce leg swelling	Are less effective in high‐risk groups than anticoagulant thromboprophylaxis
May reduce leg swelling	Greater effect in reducing calf DVT than proximal DVT
Effect on PE and death unknown
May reduce or delay the use of more effective anticoagulant thromboprophylaxis
Compliance by patients and staff is often poor
Trials may overestimate the protection compared with routine use
Cost associated with purchase, storage, dispensing, and cleaning of the devices, as well as ensuring optimal compliance

Thromboprophylaxis in Medical Patients

Duration

Guideline Recommendations

Table 4.Guideline‐Recommended Thromboprophylaxis for Hospitalized Patients by Level of VTE Risk
Levels of Risk	Approximate DVT Risk Without Thromboprophylaxis (%)	Suggested Thromboprophylaxis Options
NOTE: Modified with permission from Geerts WH, Bergqvist D, Pineo GF, et al.1 Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th ed. Chest 2008; 133(6 suppl):381S‐453S. Abbreviations: bid, twice daily; DVT, deep‐vein thrombosis; HFS, hip fracture surgery; INR, international normalized ratio; LMWH, low‐molecular‐weight heparin; SCI, spinal cord injury; tid, three times daily; UFH, unfractionated heparin; VTE, venous thromboembolism.
Low risk
Minor surgery in mobile patients	< 10	No specific thromboprophylaxis; early and aggressive ambulation
Medical patients who are fully mobile	< 10
Moderate risk
Most general, open gynecologic, or urologic surgery patients	10‐40	LMWH (at recommended doses), low‐dose UFH bid or tid, fondaparinux
Medical patients, bed rest or sick	10‐40
Moderate VTE risk plus high bleeding risk	Mechanical thromboprophylaxis
High risk
Hip or knee arthroplasty, HFS	40‐80	LMWH (at recommended doses), fondaparinux, oral vitamin K antagonist (INR 2‐3)
Major trauma, SCI	40‐80
High VTE risk plus high bleeding risk	Mechanical thromboprophylaxis

Key evidence‐based recommendations regarding thromboprophylaxis for hospitalized, acutely ill patients include the following:1

Every hospital should develop a formal strategy to addresses VTE prophylaxis;
Aspirin alone is not recommended to prevent VTE for any patient group;
Mechanical methods of thromboprophylaxis should be used primarily for patients who have a high bleeding risk or possibly as an adjunct to anticoagulant thromboprophylaxis;
Thromboprophylaxis with LMWH, UFH, or fondaparinux is recommended for patients admitted to hospital with an acute medical illness (Note: fondaparinux is recommended, but not FDA‐approved, for this indication in the United States);
On admission to the ICU, all patients should be assessed for risk of VTE, and most should receive thromboprophylaxis;
All major trauma and all spinal‐cord injury patients should receive thromboprophylaxis.

Thromboprophylaxis in Surgical Patients

Major general surgery: LMWH, low‐dose UFH, or fondaparinux;
Major gynecologic surgery and major open urologic procedures: LMWH, low‐dose UFH, fondaparinux, and/or a mechanical device;
Elective hip or knee arthroplasty: Anticoagulant therapy (LMWH, fondaparinux, or a VKA);
Hip‐fracture surgery: Fondaparinux, LMWH, a VKA, or low‐dose UFH;
Patients undergoing hip or knee arthroplasty or hip‐fracture surgery should receive thromboprophylaxis for a minimum of 10 days; for hip arthroplasty and hip‐fracture surgery, thromboprophylaxis should continue for more than 10 days and up to 35 days.

Thromboprophylaxis in Special Populations

Cancer Patients

All patients undergoing major surgical intervention for malignant disease should be considered for VTE prophylaxis with anticoagulants, with or without mechanical prophylaxis;
Thromboprophylaxis should be initiated prior to the start of surgery or as early as possible following surgery;
Mechanical interventions may supplement pharmacologic prophylaxis, especially in patients who have the highest risk;
Prophylaxis with a LMWH should be initiated 12 to 24 hours after the surgical procedure;
Continue prophylaxis at least 7 to 10 days postoperatively;
Consider prolonged prophylaxis (ie, up to 4 weeks) with a LMWH for high‐risk patients (eg, patients undergoing major abdominal or pelvic surgery, those with residual malignant disease after surgery, obese patients, and patients with a history of VTE).

Pregnancy

UFH 5000 units subcutaneously every 12 hours until fully mobile;
LMWH subcutaneously once daily for 5 days (such as enoxaparin 20 mg daily).

Renal Insufficiency

Avoid using an anticoagulant that bioaccumulates in the presence of renal impairment;
Use a lower dose of the agent;
Monitor the drug level or its anticoagulant effect.

In severe renal impairment (creatinine clearance < 30 mL/minute):710

The prophylactic dose of enoxaparin should be adjusted to 30 mg subcutaneously once daily; no specific dosing adjustments have been recommended for dalteparin or tinzaparin;
Fondaparinux is contraindicated.

Epidural Anesthesia

Subcutaneous UFH: No contraindication, consider delaying heparin until after block if technical difficulty is anticipated;
LMWH: Since twice daily dosing may be associated with an increased risk of spinal hematoma, delay initiation of LMWH until at least 24 hours after surgery, regardless of anesthetic technique; for single daily dosing, administer the first dose of LMWH 6 to 8 hours postoperatively and second dose no sooner than 24 hours after the first dose;
Warfarin: Document normal INR after discontinuation (prior to neuraxial technique); remove catheter when INR 1.5 (initiation of therapy).

Complications of Thromboprophylaxis

Bleeding Risk

Anticoagulation therapy may be contraindicated in patients with certain factors and conditions that increase the risk of bleeding. These include:

Clinically significant active or chronic bleeding;
Recent central nervous system or spinal surgery with increased risk of bleeding;
Thrombocytopenia (excluding HIT) or severe platelet dysfunction;
Abnormalities associated with clotting factors.

The NCCN provides specific contraindications to anticoagulation therapy for the prevention and treatment of VTE in cancer patients.28 These include:

Recent central nervous system bleed; intracranial, or spinal lesions at high risk of bleeding;
Active major bleeding (> 2 units transfused in 24 hours);
Chronic, clinically significant measurable bleeding for more than 48 hours;
Thrombocytopenia (platelets < 50,000/L);
Severe platelet dysfunction;
Recent major operation with high risk of bleeding;
Underlying coagulopathy (eg, clotting factor abnormalities or elevated prothrombin time or activated partial thromboplastin time [aPTT]);
Spinal anesthesia or lumbar puncture;
High risk of falls.

HIT

Conclusions

Efficacy of Prophylaxis in Medical Patients

Anticoagulant Agents in the Prevention of VTE

Table 1.Anticoagulant Agents for the Prevention of VTE
	Prophylactic Dose	Warnings/Contraindications/Adverse Reactions
NOTE: Adapted from Prescribing Information; Umland6 and Ansell et al.5 Abbreviations: aPTT, activated partial thromboplastin time; HIT, heparin‐induced thrombocytopenia; INR, International Normalized Ratio; LMWH, low‐molecular‐weight heparin; UFH, unfractionated heparin. * For elderly and other debilitated/malnourished patients, starting dose should be 5 mg. Before initiation, perform baseline aPTT and platelet count. This is the dose for DVT prophylaxis in abdominal surgery, hip replacement surgery, and medical patients; the dose in knee replacement surgery is 30 mg subcutaneously every 12 hours. Reduce the dose if creatinine clearance 30 mL/minute.
Warfarin	5 to 10 mg daily initially;* adjust dose based on INR; therapeutic INR goal: 2.5 (2‐3)	Warning: bleeding risk; requires frequent monitoring; contraindicated in patients for whom hazard of hemorrhage outweighs potential benefit (eg, in pregnant women)
UFH	5000 IU every 8‐12 hours subcutaneously	Contraindicated in the presence of active bleeding, uncontrolled hypertension, or severe thrombocytopenia; monitor platelet count every 4‐7 days for HIT
Dalteparin	5000 IU daily subcutaneously	Warning: spinal/epidural hematoma; monitor for signs and symptoms of neurological impairment. LMWHs should be used with caution in renal impairment; anti‐Xa monitoring and dose adjustments may be required. Follow prescribing information for dose adjustments and body weight‐based dosing. Most common adverse reactions: bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea
Enoxaparin	40 mg daily subcutaneously; reduce to 30 mg daily in renal impairment
Tinzaparin	3500 IU daily subcutaneously
Fondaparinux	2.5 mg daily subcutaneously	Warning: spinal/epidural hematoma; monitor for signs and symptoms of neurological impairment; contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/minute) and in patients < 50 kg

UFH

LMWHs

Table 2.Anticoagulants for VTE Prophylaxis in Acutely Ill, Hospitalized Medical Patients
Trial	Number of Patients	Agent (vs. placebo)	Detection of VTE	Relative Risk Reduction	Number Needed to Treat
NOTE: Adapted from Samama et al,12 Leizorovicz et al,13 and Cohen et al.15 Abbreviations: ARTEMIS, Arixtra for Thromboembolism Prevention in a Medical Indications Study; CI, confidence interval; CUS, compression ultrasonography; DVT, deep vein thrombosis; MEDENOX, Prophylaxis in Medical Patients with Enoxaparin; PE, pulmonary embolism; PREVENT, Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial; SC, subcutaneously; VTE, venous thromboembolism.
MEDENOX	866	Enoxaparin 20 mg or 40 mg SC daily for 6‐14 days	Distal and proximal venographic DVT or documented PE	63% (with 40 mg; 97.6 CI, 0.22‐0.63; P <0.001)	10
PREVENT	3706	Dalteparin 5000 IU SC daily for up to 14 days	CUS DVT, symptomatic VTE, and fatal PE	45% (95% CI, 0.38‐0.80; P = 0.0015)	45
ARTEMIS	849	Fondaparinux 2.5 mg SC daily for 6‐14 days	Distal and proximal venographic DVT, symptomatic VTE, and fatal PE	47% (95% CI, 0.077‐0.693)	20

Pentasaccharides

Vitamin K Antagonists

Future Anticoagulants

New oral agents have the potential to improve the management of patients who have a moderate to high risk of thromboembolic disease.

Rivaroxaban

Apixaban

Dabigatran

Mechanical Prophylaxis

Table 3.Advantages and Limitations of Mechanical Thromboprophylaxis
Advantages	Limitations
NOTE: Modified with permission from Geerts et al.1 Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism.
Does not increase the risk of bleeding	Not as intensively studied as pharmacologic thromboprophylaxis (fewer studies and smaller)
Can be used in patients who have a high risk of bleeding	No established standards for size, pressure, or physiologic features
Efficacy has been demonstrated in a number of patient groups	Many specific mechanical devices have never been assessed in any clinical trial
May enhance the effectiveness of anticoagulant thromboprophylaxis	Almost all mechanical thromboprophylaxis trials were unblinded and therefore have a potential for bias
May reduce leg swelling	Are less effective in high‐risk groups than anticoagulant thromboprophylaxis
May reduce leg swelling	Greater effect in reducing calf DVT than proximal DVT
Effect on PE and death unknown
May reduce or delay the use of more effective anticoagulant thromboprophylaxis
Compliance by patients and staff is often poor
Trials may overestimate the protection compared with routine use
Cost associated with purchase, storage, dispensing, and cleaning of the devices, as well as ensuring optimal compliance

Thromboprophylaxis in Medical Patients

Duration

Guideline Recommendations

Table 4.Guideline‐Recommended Thromboprophylaxis for Hospitalized Patients by Level of VTE Risk
Levels of Risk	Approximate DVT Risk Without Thromboprophylaxis (%)	Suggested Thromboprophylaxis Options
NOTE: Modified with permission from Geerts WH, Bergqvist D, Pineo GF, et al.1 Prevention of venous thromboembolism: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th ed. Chest 2008; 133(6 suppl):381S‐453S. Abbreviations: bid, twice daily; DVT, deep‐vein thrombosis; HFS, hip fracture surgery; INR, international normalized ratio; LMWH, low‐molecular‐weight heparin; SCI, spinal cord injury; tid, three times daily; UFH, unfractionated heparin; VTE, venous thromboembolism.
Low risk
Minor surgery in mobile patients	< 10	No specific thromboprophylaxis; early and aggressive ambulation
Medical patients who are fully mobile	< 10
Moderate risk
Most general, open gynecologic, or urologic surgery patients	10‐40	LMWH (at recommended doses), low‐dose UFH bid or tid, fondaparinux
Medical patients, bed rest or sick	10‐40
Moderate VTE risk plus high bleeding risk	Mechanical thromboprophylaxis
High risk
Hip or knee arthroplasty, HFS	40‐80	LMWH (at recommended doses), fondaparinux, oral vitamin K antagonist (INR 2‐3)
Major trauma, SCI	40‐80
High VTE risk plus high bleeding risk	Mechanical thromboprophylaxis

Key evidence‐based recommendations regarding thromboprophylaxis for hospitalized, acutely ill patients include the following:1

Every hospital should develop a formal strategy to addresses VTE prophylaxis;
Aspirin alone is not recommended to prevent VTE for any patient group;
Mechanical methods of thromboprophylaxis should be used primarily for patients who have a high bleeding risk or possibly as an adjunct to anticoagulant thromboprophylaxis;
Thromboprophylaxis with LMWH, UFH, or fondaparinux is recommended for patients admitted to hospital with an acute medical illness (Note: fondaparinux is recommended, but not FDA‐approved, for this indication in the United States);
On admission to the ICU, all patients should be assessed for risk of VTE, and most should receive thromboprophylaxis;
All major trauma and all spinal‐cord injury patients should receive thromboprophylaxis.

Thromboprophylaxis in Surgical Patients

Major general surgery: LMWH, low‐dose UFH, or fondaparinux;
Major gynecologic surgery and major open urologic procedures: LMWH, low‐dose UFH, fondaparinux, and/or a mechanical device;
Elective hip or knee arthroplasty: Anticoagulant therapy (LMWH, fondaparinux, or a VKA);
Hip‐fracture surgery: Fondaparinux, LMWH, a VKA, or low‐dose UFH;
Patients undergoing hip or knee arthroplasty or hip‐fracture surgery should receive thromboprophylaxis for a minimum of 10 days; for hip arthroplasty and hip‐fracture surgery, thromboprophylaxis should continue for more than 10 days and up to 35 days.

Thromboprophylaxis in Special Populations

Cancer Patients

All patients undergoing major surgical intervention for malignant disease should be considered for VTE prophylaxis with anticoagulants, with or without mechanical prophylaxis;
Thromboprophylaxis should be initiated prior to the start of surgery or as early as possible following surgery;
Mechanical interventions may supplement pharmacologic prophylaxis, especially in patients who have the highest risk;
Prophylaxis with a LMWH should be initiated 12 to 24 hours after the surgical procedure;
Continue prophylaxis at least 7 to 10 days postoperatively;
Consider prolonged prophylaxis (ie, up to 4 weeks) with a LMWH for high‐risk patients (eg, patients undergoing major abdominal or pelvic surgery, those with residual malignant disease after surgery, obese patients, and patients with a history of VTE).

Pregnancy

UFH 5000 units subcutaneously every 12 hours until fully mobile;
LMWH subcutaneously once daily for 5 days (such as enoxaparin 20 mg daily).

Renal Insufficiency

Avoid using an anticoagulant that bioaccumulates in the presence of renal impairment;
Use a lower dose of the agent;
Monitor the drug level or its anticoagulant effect.

In severe renal impairment (creatinine clearance < 30 mL/minute):710

The prophylactic dose of enoxaparin should be adjusted to 30 mg subcutaneously once daily; no specific dosing adjustments have been recommended for dalteparin or tinzaparin;
Fondaparinux is contraindicated.

Epidural Anesthesia

Subcutaneous UFH: No contraindication, consider delaying heparin until after block if technical difficulty is anticipated;
LMWH: Since twice daily dosing may be associated with an increased risk of spinal hematoma, delay initiation of LMWH until at least 24 hours after surgery, regardless of anesthetic technique; for single daily dosing, administer the first dose of LMWH 6 to 8 hours postoperatively and second dose no sooner than 24 hours after the first dose;
Warfarin: Document normal INR after discontinuation (prior to neuraxial technique); remove catheter when INR 1.5 (initiation of therapy).

Complications of Thromboprophylaxis

Bleeding Risk

Anticoagulation therapy may be contraindicated in patients with certain factors and conditions that increase the risk of bleeding. These include:

Clinically significant active or chronic bleeding;
Recent central nervous system or spinal surgery with increased risk of bleeding;
Thrombocytopenia (excluding HIT) or severe platelet dysfunction;
Abnormalities associated with clotting factors.

The NCCN provides specific contraindications to anticoagulation therapy for the prevention and treatment of VTE in cancer patients.28 These include:

Recent central nervous system bleed; intracranial, or spinal lesions at high risk of bleeding;
Active major bleeding (> 2 units transfused in 24 hours);
Chronic, clinically significant measurable bleeding for more than 48 hours;
Thrombocytopenia (platelets < 50,000/L);
Severe platelet dysfunction;
Recent major operation with high risk of bleeding;
Underlying coagulopathy (eg, clotting factor abnormalities or elevated prothrombin time or activated partial thromboplastin time [aPTT]);
Spinal anesthesia or lumbar puncture;
High risk of falls.

HIT

Conclusions

References

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(6 suppl):381S–453S.
Piazza G, Seddighzadeh A, Goldhaber SZ.Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent.Chest.2007;132(2):554–561.
Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA.Meta‐analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients.Ann Intern Med.2007;146(4):278–288.
Lloyd NS, Douketis JD, Moinuddin I, Lim W, Crowther MA.Anticoagulant prophylaxis to prevent asymptomatic deep vein thrombosis in hospitalized medical patients: a systematic review and meta‐analysis.J Thromb Haemost.2008;6:405–414.
Ansell J, Hirsh J, Hylek E, et al.Pharmacology and Management of the Vitamin K Antagonists. American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. 8th Edition.Chest.2008;133:160S–198S.
Du Breuil AL, Umland EM.Outpatient management of anticoagulation therapy.Am Fam Physician.2007;75:1031–1042.
Fragmin prescribing information.Last updated April 2007.Woodcliff Lake, NJ:Eisai, Inc.;2007.
Lovenox prescribing information.Last updated 2008.Bridgewater, NJ:sanofi‐aventis U.S.;2008.
Innohep prescribing information.Last updated July 2000.Wilmington, DE:DuPont Pharma;2000.
Arixtra prescribing information.Last updated October 2008.Research Triangle Park, NC:GlaxoSmithKline;2008.
McGarry LJ, Thompson D, Weinstein MC, et al.Cost effectiveness of thromboprophylaxis with a low‐molecular‐weight heparin versus unfractionated heparin in acutely ill medical inpatients.Am J Manag Care.2004;10(9):632–642.
Samama MM, Cohen AT, Darmon JY, et al.A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients.N Engl J Med.1999;341(11):793–800.
Leizorovicz A, Cohen AT, Turpie AG, et al.Randomized, placebo‐controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.Circulation.2004;110:874–879.
Torbicki A, Perrier A, Konstantinides S, et al.Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC).Eur Heart J.2008;29(18):2276–2315.
Cohen AT, Davidson BL, Gallus AS, et al.ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.BMJ.2006;332(7537):325–329.
Turpie A, Lassen MR, Kakkar AK, et al.A pooled analysis of four pivotal studies of rivaroxaban for the prevention of venous thromboembolism after orthopaedic surgery: effect on symptomatic venous thromboembolism, death, and bleeding.Blood.2008;112:19–20.
Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D.The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.J Thromb Haemost.2007;5:2368–2375.
Bristol‐Myers Squibb and Pfizer. Bristol‐Myers Squibb and Pfizer provide update on apixaban clinical development program [Press release]. August 26, 2008. Available at: http://www.pfizer.com. Accessed August2009.
Eriksson BI, Rosencher N, Kurth AA, et al.Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double blind, non‐inferiority trial.Lancet.2007;370:949–956.
Ezekowitz M, Reilly PA, Nehmiz G, et al.Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with non‐valvular atrial fibrillation (PETRO Study).Am J Cardiol.2007;100:1419–1426.
Eriksson BI, Dahl OE, Kurth AA, et al.Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial.J Thromb Haemost.2007;5:2178–2185.
Friedman RJ, Caprini JA, Comp PC, et al.Dabigatran etexilate versus enoxaparin in preventing venous thromboembolism following total knee arthroplasty.J Thromb Haemost.2007;5(suppl 2):Abstract O‐W‐051.
Warkentin TE, Greinacher A, Koster A, Lincoff AM.Treatment and prevention of heparin‐induced thrombocytopenia: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th edition.Chest.2008;133:340–380.
Turpie AGG.Extended duration of thromboprophylaxis in acutely ill medical patients: optimizing therapy?J Thromb Haemost.2007;5:5–11.
Hull RD, Schellong SM, Tapson VF, et al.Extended‐duration thromboprophylaxis in acutely ill medical patients with recent reduced mobility: methodology for the EXCLAIM study.J Thromb Thrombolysis.2006;22:31–38.
Hull RD, Schellong SM, Tapson VF, et al.Extended‐duration venous thromboembolism prophylaxis in acutely ill medical patients with recent reduced mobility: the EXCLAIM study. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7–13,2007; Geneva, Switzerland. Abstract O‐S‐001.
Lyman GH, Khorana AA, Falanga A, et al.American Society of Clinical Oncology Guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer.J Clin Oncol.2007;25:5490–5505.
National Comprehensive Cancer Network (NCCN). Venous thromboembolic disease. Practice guidelines in oncology. V.1. 2009. Available at: http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf. Accessed August2006.
American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty. May 18, 2007. Available at http://www.aaos.org/research/guidelines/PE_guideline.pdf. Accessed August2009.
Stein PD, Beemath A, Meyers FA, et al.Incidence of venous thromboembolism in patients hospitalized with cancer.Am J Med.2006;119(1):60–68.
Agnelli G, Gussoni G, Bianchini C, et al.A randomized double‐blind placebo‐controlled study on nadroparin for prophylaxis of thromboembolic events in cancer patients receiving chemotherapy: The PROTECHT Study.Blood.2008;112(11):Abstract 6.
Kent N, Leduc L, Crane J, et al.Prevention and treatment of venous thromboembolism (VTE) in obstetrics.J SOGC.2000;22(9):736–749.
Snow V, Qaseem A, Barry P, et al.Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians.Am Fam Med.2007;5:74–80.
Horlocker TT, Wedel DJ, Benzon H, et al.Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation).Reg Anesth Pain Med.2003;28(3):172–197.
Alikhan R, Cohen AT, Combe , et al.Prevention of venous thromboembolism in medical patients with enoxaparin; a subgroup analysis of the MEDENOX study.Blood Coagul Fibrinolysis.2003;14:341–348.
Prechel M, Walenga JM.The laboratory diagnosis and clinical management of patients with HIT: an update.Semin Thromb Hemost.2008;34(1):86–93.
Martel N, Lee J, Wells PS.Risk for heparin‐induced thrombocytopenia with unfractionated and low‐molecular‐weight heparin thromboprophylaxis: a meta‐analysis.Blood.2005;106(8):2710–2715.

References

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(6 suppl):381S–453S.
Piazza G, Seddighzadeh A, Goldhaber SZ.Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent.Chest.2007;132(2):554–561.
Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA.Meta‐analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients.Ann Intern Med.2007;146(4):278–288.
Lloyd NS, Douketis JD, Moinuddin I, Lim W, Crowther MA.Anticoagulant prophylaxis to prevent asymptomatic deep vein thrombosis in hospitalized medical patients: a systematic review and meta‐analysis.J Thromb Haemost.2008;6:405–414.
Ansell J, Hirsh J, Hylek E, et al.Pharmacology and Management of the Vitamin K Antagonists. American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. 8th Edition.Chest.2008;133:160S–198S.
Du Breuil AL, Umland EM.Outpatient management of anticoagulation therapy.Am Fam Physician.2007;75:1031–1042.
Fragmin prescribing information.Last updated April 2007.Woodcliff Lake, NJ:Eisai, Inc.;2007.
Lovenox prescribing information.Last updated 2008.Bridgewater, NJ:sanofi‐aventis U.S.;2008.
Innohep prescribing information.Last updated July 2000.Wilmington, DE:DuPont Pharma;2000.
Arixtra prescribing information.Last updated October 2008.Research Triangle Park, NC:GlaxoSmithKline;2008.
McGarry LJ, Thompson D, Weinstein MC, et al.Cost effectiveness of thromboprophylaxis with a low‐molecular‐weight heparin versus unfractionated heparin in acutely ill medical inpatients.Am J Manag Care.2004;10(9):632–642.
Samama MM, Cohen AT, Darmon JY, et al.A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients.N Engl J Med.1999;341(11):793–800.
Leizorovicz A, Cohen AT, Turpie AG, et al.Randomized, placebo‐controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.Circulation.2004;110:874–879.
Torbicki A, Perrier A, Konstantinides S, et al.Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC).Eur Heart J.2008;29(18):2276–2315.
Cohen AT, Davidson BL, Gallus AS, et al.ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.BMJ.2006;332(7537):325–329.
Turpie A, Lassen MR, Kakkar AK, et al.A pooled analysis of four pivotal studies of rivaroxaban for the prevention of venous thromboembolism after orthopaedic surgery: effect on symptomatic venous thromboembolism, death, and bleeding.Blood.2008;112:19–20.
Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D.The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.J Thromb Haemost.2007;5:2368–2375.
Bristol‐Myers Squibb and Pfizer. Bristol‐Myers Squibb and Pfizer provide update on apixaban clinical development program [Press release]. August 26, 2008. Available at: http://www.pfizer.com. Accessed August2009.
Eriksson BI, Rosencher N, Kurth AA, et al.Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double blind, non‐inferiority trial.Lancet.2007;370:949–956.
Ezekowitz M, Reilly PA, Nehmiz G, et al.Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with non‐valvular atrial fibrillation (PETRO Study).Am J Cardiol.2007;100:1419–1426.
Eriksson BI, Dahl OE, Kurth AA, et al.Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial.J Thromb Haemost.2007;5:2178–2185.
Friedman RJ, Caprini JA, Comp PC, et al.Dabigatran etexilate versus enoxaparin in preventing venous thromboembolism following total knee arthroplasty.J Thromb Haemost.2007;5(suppl 2):Abstract O‐W‐051.
Warkentin TE, Greinacher A, Koster A, Lincoff AM.Treatment and prevention of heparin‐induced thrombocytopenia: American College of Chest Physicians evidence‐based clinical practice guidelines. 8th edition.Chest.2008;133:340–380.
Turpie AGG.Extended duration of thromboprophylaxis in acutely ill medical patients: optimizing therapy?J Thromb Haemost.2007;5:5–11.
Hull RD, Schellong SM, Tapson VF, et al.Extended‐duration thromboprophylaxis in acutely ill medical patients with recent reduced mobility: methodology for the EXCLAIM study.J Thromb Thrombolysis.2006;22:31–38.
Hull RD, Schellong SM, Tapson VF, et al.Extended‐duration venous thromboembolism prophylaxis in acutely ill medical patients with recent reduced mobility: the EXCLAIM study. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7–13,2007; Geneva, Switzerland. Abstract O‐S‐001.
Lyman GH, Khorana AA, Falanga A, et al.American Society of Clinical Oncology Guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer.J Clin Oncol.2007;25:5490–5505.
National Comprehensive Cancer Network (NCCN). Venous thromboembolic disease. Practice guidelines in oncology. V.1. 2009. Available at: http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf. Accessed August2006.
American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty. May 18, 2007. Available at http://www.aaos.org/research/guidelines/PE_guideline.pdf. Accessed August2009.
Stein PD, Beemath A, Meyers FA, et al.Incidence of venous thromboembolism in patients hospitalized with cancer.Am J Med.2006;119(1):60–68.
Agnelli G, Gussoni G, Bianchini C, et al.A randomized double‐blind placebo‐controlled study on nadroparin for prophylaxis of thromboembolic events in cancer patients receiving chemotherapy: The PROTECHT Study.Blood.2008;112(11):Abstract 6.
Kent N, Leduc L, Crane J, et al.Prevention and treatment of venous thromboembolism (VTE) in obstetrics.J SOGC.2000;22(9):736–749.
Snow V, Qaseem A, Barry P, et al.Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians.Am Fam Med.2007;5:74–80.
Horlocker TT, Wedel DJ, Benzon H, et al.Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation).Reg Anesth Pain Med.2003;28(3):172–197.
Alikhan R, Cohen AT, Combe , et al.Prevention of venous thromboembolism in medical patients with enoxaparin; a subgroup analysis of the MEDENOX study.Blood Coagul Fibrinolysis.2003;14:341–348.
Prechel M, Walenga JM.The laboratory diagnosis and clinical management of patients with HIT: an update.Semin Thromb Hemost.2008;34(1):86–93.
Martel N, Lee J, Wells PS.Risk for heparin‐induced thrombocytopenia with unfractionated and low‐molecular‐weight heparin thromboprophylaxis: a meta‐analysis.Blood.2005;106(8):2710–2715.

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When are vasoactive agents indicated in acute heart failure?

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When are vasoactive agents indicated in acute heart failure?

Author(s)

Prashant Vaishnava, MD

Anju Nohria, MD

Kenneth L. Baughman, MD

Case

A 72-year-old retired nurse with known nonischemic dilated cardiomyopathy with an ejection fraction of approximately 20% and status-post cardiac resynchronization therapy presents to the emergency department with dyspnea with minimal activity, three-pillow orthopnea, and paroxysmal nocturnal dyspnea.

She had been hospitalized twice during the past 60 days for similar symptoms. Her medications included losartan (20 mg po q daily), carvedilol (3.125 mg twice daily), spironolactone (25 mg daily), digoxin (0.125 mg daily), and furosemide (80 mg twice daily). Vital signs are notable for a blood pressure of 90/50 mmHg and an irregular pulse of 90 beats per minute. Physical examination is notable for marked jugular venous distension, lungs clear to auscultation bilaterally, biventricular heaves, a markedly displaced left ventricular point of maximal impulse, and a prominent S3 gallop.

Despite treatment with intravenous furosemide and temporary withdrawal of carvedilol, the patient remains symptomatic with persistent jugular venous distension.

Should she be given a vasoactive agent?

Key Points

Acute heart failure syndrome (AHFS) is the most common cause of hospitalization in patients over the age of 65 in the United States.

Initial management of AHFS depends on definition of the patient’s hemodynamic profile, in terms of elevation of filling pressures and adequacy of perfusion.

In the absence of symptomatic hypotension, intravenous vasodilators (nitroglycerin, nitroprusside, or nesiritide) may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms.

There is little evidence from randomized controlled trials guiding the use of inotropes and their use is generally limited to the following indications: short-term treatment for AHFS that is unresponsive to adequate doses of diuretics and especially when associated with systemic hypotension, bridge to recovery (as following myocarditis) or to definitive treatment (such as transplantation), or for palliation when relief of symptoms is the agreed upon goal.

Dobutamine and milrinone, the most commonly used inotropes, are associated with improvement in hemodynamic response and symptomatic relief, at the expense of increased mortality.

Additional Reading

Adams KF, Lindenfield J, Arnold J, et al. Executive summary: HFSA 2006 comprehensive heart failure practice guidelines. J Card Fail 2006;12:10-38.

Allen LA and O’Connor CM. Management of acute decompensated heart failure. CMAJ. 2007;176(6):797-805.

Nieminen MS, Bohm M, Cowie MR, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: The Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:384-416.

Mebazaa A, Gheorghiade M, Pina IL, et al. Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes. Crit Care Med. 2008;36(Suppl.):S129-S139.

Overview

Acute heart failure syndrome (AHFS), defined as a gradual or rapid change in heart failure signs and symptoms, is the most common cause of hospitalization in the United States1. It is associated with an average in-hospital mortality of 4% to 5%, a 30-day mortality of 7% to11%, and a one-year mortality of 33%2.

In patients with previously established myocardial dysfunction, AHFS commonly reflects exacerbation of symptoms after a period of stability. The clinical presentation and severity of AHFS may range from mild volume overload to life-threatening cardiogenic shock and multi-organ failure unresponsive to pharmacologic therapy.2

Initial management of AHFS depends on definition of the patient’s hemodynamic profile. To guide initial therapy, classify patients into one of four hemodynamic profiles during a brief bedside assessment that relies on evaluation of filling pressures (wet or dry) and adequacy of perfusion (hot or cold) (see figure 1).3

Treating volume overload or elevated filling pressures generally begins with diuretics. Diuretics have been shown to provide symptomatic relief, though they have not yet been proven safe.4 Initial treatment can include a loop diuretic at a dose higher than the patient’s chronic dose, with intravenous dosing offering greater bio-absorption and rapidity in onset of action.5 If perfusion is inadequate, escalate therapy beyond diuretics to include vasoactive agents.

Review of the Data

The use of vasoactive medications is largely based on anecdotal experiences and physiologic assumptions rather than on adequately powered prospective randomized controlled trials.6 Vasoactive therapy includes vasodilator and inotropic support and is generally limited for use in patients with advanced disease not responding to standard medical treatment and diuresis. The physiologic premise rests in the expected improvement in ventricular filling pressures and cardiac output with reduction in afterload and/or preload. Vasodilators counteract vascular constriction, reducing both preload and afterload. Positive inotropic agents amplify cardiac output by increasing the strength of myocardial contraction.

Vasodilators

The Heart Failure Society of America (HFSA) 2006 Comprehensive Heart Failure Practice Guidelines state, “In the absence of symptomatic hypotension, intravenous vasodilators (nitroglycerin, nitroprusside, or nesiritide) may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms.”7 The clinical utility of nesiritide remains in question with clinical and hemodynamic improvement demonstrated in three randomized trials 8-10; but tempered against meta-analyses 11-12 of selected trials, demonstrating a non-significant trend toward increased kidney dysfunction and death within 30 days (35/485 [7.2%] vs. 15/377 [4.0%] patients; risk ratio from meta-analyses, 1.74; 95% confidence interval, 0.97-3.12; p=0.059). In a randomized trial of 489 in-patients with dyspnea at rest from AHFS, treatment with three hours of intravenous nesiritide resulted in a significant improvement in dyspnea compared with placebo (p=0.03). Similar improvement was observed with intravenous nitroglycerin and did not differ statistically from that observed with nesiritide.8 Nitroprusside, an attractive option among those with hypertension and cardiogenic pulmonary edema, is limited by the need for invasive hemodynamic monitoring and potential for either cyanide toxicity or worsening myocardial ischemia.

Inotropes

Again, there is little evidence from adequately powered randomized controlled trials guiding the use of inotropes. Their use is generally limited to the following indications (see figure 2): (1) Short-term treatment for AHFS that is unresponsive to adequate doses of diuretics and especially when associated with systemic hypotension, (2) Bridge to recovery (as following myocarditis) or to definitive treatment (as with transplant), or (3) For palliation when symptomatic relief is the agreed upon goal.13 The HFSA 2006 guideline states: “Intravenous inotropes may be considered to relieve symptoms and improve end-organ function in patients with advanced HF characterized by left ventricle dilation, reduced left ventricular ejection fraction, and diminished peripheral perfusion or end-organ dysfunction, particularly if these patients have marginal systolic blood pressure, have symptomatic hypotension despite adequate filling pressures, or are unresponsive to, or intolerant of, intravenous vasodilators.”7

Dobutamine and milrinone are the most commonly used IV inotropes for the treatment of AHFS and increase contractility by increasing intracellular levels of cyclic adenylate monophosphate (cAMP). Dobutamine is a catechlamine agonist that increases cAMP production through stimulation of adenylate cyclase. Milrinone selectively inhibits phosphodiesterase III, which catalyzes the breakdown of cAMP.

Despite their frequent use when traditional treatments have failed, the data supporting the use of dobutamine and milrinone is limited. The largest registry of patients with AHFS to date associated excess mortality with intravenous inotrope use compared to nitroglycerin or nesiritide.14 In a study population of 255 patients randomized to receive either intravenous nesiritide or intravenous dobutamine, Burger et al.15 demonstrated that dobutamine significantly increased the mean number of ventricular tachycardia events per 24 hours (p=0.001), suggesting increased arrhythmogenicity associated with inotrope use. Nonetheless, in a randomized trial of 15 patients admitted with AHFS, functional class improved in six of eight dobutamine-treated patients, but in only two of seven patients treated with placebo, suggesting clinical improvement as a consequence of inotropic stimulation.16 Unverferth et al. demonstrated a similar sustained functional improvement up to 10 weeks following a 72-hour infusion of intravenous dobutamine. 17

The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure trial (OPTIME-CHF), randomized 951 patients with AHFS to receive either intravenous milrinone or placebo within 48 hours of hospitalization.18 Compared to placebo, milrinone was associated with a significant increase in sustained hypotension requiring intervention (10.7% vs. 3.2%; p<.001) and new atrial arrhythmias (4.6% vs. 1.5%; p=0.004), along with a non-significant trend toward increased mortality (3.8% vs. 2.3%; p=0.19). However, as measured by a visual analog scale, milrinone-treated patients reported feeling better than those treated with placebo at 30 days post-randomization (p=0.02).

Although there are not randomized data comparing the efficacy of milrinone and dobutamine in AHFS, a retrospective analysis of 329 patients compared the hemodynamic and clinical effects of these two inotropes.19 Milrinone consistently was associated with a more favorable hemodynamic response, including lower systemic vascular resistance (p=0.01); lower pulmonary artery wedge pressure (p<0.001); larger percentage increase in cardiac index (p=0.03); and larger percentage decrease in pulmonary vascular resistance (p=0.0001). In-hospital mortality (dobutamine 7.8% vs. milrinone 10%) was not significantly different.

Conclusion

Clearly, vasoactive and inotropic agents are available when AHFS is refractory to traditional diuresis and may offer short-term symptomatic relief, palliation in the context of end-of-life care, or bridge to recovery or more definitive treatment. Unfortunately, sufficient and robust evidence that supports the safety and efficacy of such agents is lacking and their use is largely guided by historical practices, clinical experience, and anticipation of theoretic physiologic changes. While adequately powered prospective randomized data emerge, newer agents such as vasopressin receptor antagonists, cardiac myosin activators, calcium sensitizers, and adenosine-receptor antagonists will offer additional pharmacologic options.20 When continued pharmacologic support becomes ineffective, device therapy is available to aid in the treatment of AHFS and includes ultrafiltration to reduce filling pressures and intra-aortic balloon pump counterpulsation or left ventricular assist device placement for pharmacologically resistant cardiogenic shock.21

Back to the Case

Despite maximal medical therapy for her chronic heart failure and biventricular pacing, the patient continued to have markedly limited functional status and repeated hospitalizations for AHFS. Given her advanced age and poor nutritional status, she was not a candidate for cardiac transplantation or placement of a left ventricular assist device. To allow for palliative tailored therapy, right heart catheterization was performed. Right heart catheterization revealed elevated filling pressures, as follows: right atrium, 20 mmHg; pulmonary artery, 63/34 mmHg (mean 47 mmHg); and pulmonary capillary wedge, 29 mmHg. Her mixed venous oxygen saturation was only 41% with a calculated cardiac output of 2.9 liters per minute and cardiac index of 2 liters per minute per meter squared.

As she expressed symptomatic relief as her goal, she was started on intravenous milrinone at 0.2 micrograms per kilogram per minute. This was done with the understanding her symptoms would likely would improve, at the expense of worsening longevity and prognosis. With uptitration of her intravenous milrinone and a continuous infusion of furosemide, she demonstrated the following filling pressures within 24 hours: right atrium, 18 mmHg; pulmonary artery, 63/33 mmHg (mean 43 mmHg); and pulmonary capillary wedge, 24. Importantly, her mixed venous oxygen saturation improved to 68% with a calculated cardiac output of 3.4 liters per minute and cardiac index of 2.4 liters per minute per meter squared. These favorable hemodynamic changes were accompanied by modest improvement in symptoms. After continued intravenous diuresis, she was transitioned back to an oral diuretic regimen and was ultimately discharged to home with a continuous infusion of milrinone for palliation. TH

Drs. Vaishnava, McKean, Nohria, and Baughman are from Brigham and Women’s Hospital and Harvard Medical School in Boston, Mass.

REFERENCES:

Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics – 2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:85-151.

Iong P, Vowinckel E, Liu PP, Gong Y, Tu JV. Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population-based study. Arch Intern Med. 2002;162:1689-94.

Nohria A, Lewis EF, Stevenson LW. Medical management of advanced heart failure. JAMA. 2002;287;628-40.

Faris R, Flather MD, Purcell H, et al. Diuretics for heart failure. Cochrane Database Syst Rev. 2006;1;CD003838.

Wang DJ and Gottlieb SS. Diuretics: Still the mainstay of treatment. Crit Care Med. 2008;36(Suppl.):S89-S94.

Fares WH. Management of acute decompensated heart failure in an evidence-based era: What is the evidence behind the current standard of care? Heart & Lung. 2008;37(3):173-8.

Adams KF, Lindenfield J, Arnold J, et al. Executive summary: HFSA 2006 comprehensive heart failure practice guidelines. J Card Fail. 2006;12:10-38.

Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;297:1531-40.

Peacock WF, Enerman CL, Silver MA, on behalf of the PROACTION Study Group. Am J Emerg Med. 2005;23:327-31.

Cotter G, Metzkor E, Kaluski E, et al. Randomized trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary edema. Lancet. 1998;351:389-93.

Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005;293:1900-5.

Sackner-Bernstein JD, Skopicki HA, Aaronson K. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005;111:1487-91.

Felker GM and O’Connor CM. Inotropic therapy for heart failure: An evidence-based approach. American Heart Journal. 2001; 142:393-401.

Abrahm WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005;46:57-64.

Burger AJ, Houton DP, LeJemtel T, et al. Effect of nesiritide and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. American Heart Journal. 2002;144:1102-8.

Liang CS, Sherman LG, Doherty JU, et al. Sustained improvement of cardiac function in patients with congestive heart failure after short-term infusion of dobutamine. Circulation. 1984;69:113-9.

Unverferth DV, Magorien RD, Lewis RP, et al. Long-term benefit of dobutamine in patients with congestive cardiomyopathy. American Heart Journal. 1980;100:622-30.

Cuffe MS, Califf RM, Adams KF Jr, et al. Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541-7.

Yamani MH, Haji SA, Starling RC, et al. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact. American Heart Journal. 2001;142:998-1002.

Shin, DD, Brandimarte F, De Luca L, et al. Review of current and investigational pharmacologic agents for acute heart failure syndromes. Am J Cardiol. 2007;99(suppl):4A-23A.

Kale P and Fang JC. Devices in acute heart failure. Crit Care Med. 2008;36(Suppl.):S121-128.

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Author(s)

Prashant Vaishnava, MD

Anju Nohria, MD

Kenneth L. Baughman, MD

Author(s)

Prashant Vaishnava, MD

Anju Nohria, MD

Kenneth L. Baughman, MD

Case

Despite treatment with intravenous furosemide and temporary withdrawal of carvedilol, the patient remains symptomatic with persistent jugular venous distension.

Should she be given a vasoactive agent?

Key Points

Acute heart failure syndrome (AHFS) is the most common cause of hospitalization in patients over the age of 65 in the United States.

Initial management of AHFS depends on definition of the patient’s hemodynamic profile, in terms of elevation of filling pressures and adequacy of perfusion.

In the absence of symptomatic hypotension, intravenous vasodilators (nitroglycerin, nitroprusside, or nesiritide) may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms.

There is little evidence from randomized controlled trials guiding the use of inotropes and their use is generally limited to the following indications: short-term treatment for AHFS that is unresponsive to adequate doses of diuretics and especially when associated with systemic hypotension, bridge to recovery (as following myocarditis) or to definitive treatment (such as transplantation), or for palliation when relief of symptoms is the agreed upon goal.

Dobutamine and milrinone, the most commonly used inotropes, are associated with improvement in hemodynamic response and symptomatic relief, at the expense of increased mortality.

Additional Reading

Adams KF, Lindenfield J, Arnold J, et al. Executive summary: HFSA 2006 comprehensive heart failure practice guidelines. J Card Fail 2006;12:10-38.

Allen LA and O’Connor CM. Management of acute decompensated heart failure. CMAJ. 2007;176(6):797-805.

Nieminen MS, Bohm M, Cowie MR, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: The Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:384-416.

Mebazaa A, Gheorghiade M, Pina IL, et al. Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes. Crit Care Med. 2008;36(Suppl.):S129-S139.

Overview

Review of the Data

Vasodilators

Inotropes

Conclusion

Back to the Case

Drs. Vaishnava, McKean, Nohria, and Baughman are from Brigham and Women’s Hospital and Harvard Medical School in Boston, Mass.

REFERENCES:

Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics – 2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:85-151.

Iong P, Vowinckel E, Liu PP, Gong Y, Tu JV. Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population-based study. Arch Intern Med. 2002;162:1689-94.

Nohria A, Lewis EF, Stevenson LW. Medical management of advanced heart failure. JAMA. 2002;287;628-40.

Faris R, Flather MD, Purcell H, et al. Diuretics for heart failure. Cochrane Database Syst Rev. 2006;1;CD003838.

Wang DJ and Gottlieb SS. Diuretics: Still the mainstay of treatment. Crit Care Med. 2008;36(Suppl.):S89-S94.

Fares WH. Management of acute decompensated heart failure in an evidence-based era: What is the evidence behind the current standard of care? Heart & Lung. 2008;37(3):173-8.

Adams KF, Lindenfield J, Arnold J, et al. Executive summary: HFSA 2006 comprehensive heart failure practice guidelines. J Card Fail. 2006;12:10-38.

Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;297:1531-40.

Peacock WF, Enerman CL, Silver MA, on behalf of the PROACTION Study Group. Am J Emerg Med. 2005;23:327-31.

Cotter G, Metzkor E, Kaluski E, et al. Randomized trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary edema. Lancet. 1998;351:389-93.

Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005;293:1900-5.

Sackner-Bernstein JD, Skopicki HA, Aaronson K. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005;111:1487-91.

Felker GM and O’Connor CM. Inotropic therapy for heart failure: An evidence-based approach. American Heart Journal. 2001; 142:393-401.

Abrahm WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005;46:57-64.

Burger AJ, Houton DP, LeJemtel T, et al. Effect of nesiritide and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. American Heart Journal. 2002;144:1102-8.

Liang CS, Sherman LG, Doherty JU, et al. Sustained improvement of cardiac function in patients with congestive heart failure after short-term infusion of dobutamine. Circulation. 1984;69:113-9.

Unverferth DV, Magorien RD, Lewis RP, et al. Long-term benefit of dobutamine in patients with congestive cardiomyopathy. American Heart Journal. 1980;100:622-30.

Cuffe MS, Califf RM, Adams KF Jr, et al. Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541-7.

Yamani MH, Haji SA, Starling RC, et al. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact. American Heart Journal. 2001;142:998-1002.

Shin, DD, Brandimarte F, De Luca L, et al. Review of current and investigational pharmacologic agents for acute heart failure syndromes. Am J Cardiol. 2007;99(suppl):4A-23A.

Kale P and Fang JC. Devices in acute heart failure. Crit Care Med. 2008;36(Suppl.):S121-128.

Case

Despite treatment with intravenous furosemide and temporary withdrawal of carvedilol, the patient remains symptomatic with persistent jugular venous distension.

Should she be given a vasoactive agent?

Key Points

Acute heart failure syndrome (AHFS) is the most common cause of hospitalization in patients over the age of 65 in the United States.

Initial management of AHFS depends on definition of the patient’s hemodynamic profile, in terms of elevation of filling pressures and adequacy of perfusion.

In the absence of symptomatic hypotension, intravenous vasodilators (nitroglycerin, nitroprusside, or nesiritide) may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms.

There is little evidence from randomized controlled trials guiding the use of inotropes and their use is generally limited to the following indications: short-term treatment for AHFS that is unresponsive to adequate doses of diuretics and especially when associated with systemic hypotension, bridge to recovery (as following myocarditis) or to definitive treatment (such as transplantation), or for palliation when relief of symptoms is the agreed upon goal.

Dobutamine and milrinone, the most commonly used inotropes, are associated with improvement in hemodynamic response and symptomatic relief, at the expense of increased mortality.

Additional Reading

Adams KF, Lindenfield J, Arnold J, et al. Executive summary: HFSA 2006 comprehensive heart failure practice guidelines. J Card Fail 2006;12:10-38.

Allen LA and O’Connor CM. Management of acute decompensated heart failure. CMAJ. 2007;176(6):797-805.

Nieminen MS, Bohm M, Cowie MR, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: The Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:384-416.

Mebazaa A, Gheorghiade M, Pina IL, et al. Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes. Crit Care Med. 2008;36(Suppl.):S129-S139.

Overview

Review of the Data

Vasodilators

Inotropes

Conclusion

Back to the Case

Drs. Vaishnava, McKean, Nohria, and Baughman are from Brigham and Women’s Hospital and Harvard Medical School in Boston, Mass.

REFERENCES:

Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics – 2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:85-151.

Iong P, Vowinckel E, Liu PP, Gong Y, Tu JV. Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population-based study. Arch Intern Med. 2002;162:1689-94.

Nohria A, Lewis EF, Stevenson LW. Medical management of advanced heart failure. JAMA. 2002;287;628-40.

Faris R, Flather MD, Purcell H, et al. Diuretics for heart failure. Cochrane Database Syst Rev. 2006;1;CD003838.

Wang DJ and Gottlieb SS. Diuretics: Still the mainstay of treatment. Crit Care Med. 2008;36(Suppl.):S89-S94.

Fares WH. Management of acute decompensated heart failure in an evidence-based era: What is the evidence behind the current standard of care? Heart & Lung. 2008;37(3):173-8.

Adams KF, Lindenfield J, Arnold J, et al. Executive summary: HFSA 2006 comprehensive heart failure practice guidelines. J Card Fail. 2006;12:10-38.

Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;297:1531-40.

Peacock WF, Enerman CL, Silver MA, on behalf of the PROACTION Study Group. Am J Emerg Med. 2005;23:327-31.

Cotter G, Metzkor E, Kaluski E, et al. Randomized trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary edema. Lancet. 1998;351:389-93.

Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005;293:1900-5.

Sackner-Bernstein JD, Skopicki HA, Aaronson K. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005;111:1487-91.

Felker GM and O’Connor CM. Inotropic therapy for heart failure: An evidence-based approach. American Heart Journal. 2001; 142:393-401.

Abrahm WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005;46:57-64.

Burger AJ, Houton DP, LeJemtel T, et al. Effect of nesiritide and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. American Heart Journal. 2002;144:1102-8.

Liang CS, Sherman LG, Doherty JU, et al. Sustained improvement of cardiac function in patients with congestive heart failure after short-term infusion of dobutamine. Circulation. 1984;69:113-9.

Unverferth DV, Magorien RD, Lewis RP, et al. Long-term benefit of dobutamine in patients with congestive cardiomyopathy. American Heart Journal. 1980;100:622-30.

Cuffe MS, Califf RM, Adams KF Jr, et al. Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541-7.

Yamani MH, Haji SA, Starling RC, et al. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact. American Heart Journal. 2001;142:998-1002.

Shin, DD, Brandimarte F, De Luca L, et al. Review of current and investigational pharmacologic agents for acute heart failure syndromes. Am J Cardiol. 2007;99(suppl):4A-23A.

Kale P and Fang JC. Devices in acute heart failure. Crit Care Med. 2008;36(Suppl.):S121-128.

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In reply: VTE prevention in major orthopedic surgery

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In reply: VTE prevention in major orthopedic surgery

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Alpesh N. Amin, MD

Editor's Note: This letter concerns an article in a Cleveland Clinic Journal of Medicine supplement (Preventing Venous Thromboembolism Throughout the Continuum of Care) distributed to only a portion of the Journal's regular readership, owing to the terms of the grant supporting the supplement.

In Reply: We appreciate the comments by Drs. Fishmann and Boyd, but we strongly disagree with their suggestion that aspirin monotherapy is an appropriate option for the prevention of venous thromboembolism (VTE) following major orthopedic surgery.

As discussed in our original article,¹ multiple large-scale clinical trials in patients undergoing elective hip arthroplasty, knee arthroplasty, or hip fracture surgery have demonstrated the thromboprophylactic efficacy of warfarin, unfractionated heparin, low-molecular-weight heparin (LMWH), fondaparinux, and oral direct thrombin inhibitors. The relative risk reduction with these agents has been greater than 50% in most studies. In contrast, in a large meta-analysis of VTE prophylaxis following total hip replacement, which included data from 56 randomized trials published between 1966 and 1993, aspirin was not beneficial in preventing DVT.¹⁴

The largest prospective randomized trial comparing aspirin with placebo for VTE prevention was conducted between 1992 and 1998 among 17,444 patients in five countries.⁵ It involved 13,356 patients requiring hip fracture surgery and 4,088 patients requiring elective hip arthroplasty. Patients were randomized to receive aspirin 160 mg/day or placebo for 35 days. However, additional forms of VTE prophylaxis were allowed if deemed necessary by the clinician. In fact, 26% of patients received LMWH in addition to aspirin, and dual therapy was probably more common in those patients at highest thromboembolic risk. As such, the 36% relative risk reduction in VTE ascribed to aspirin should be viewed with caution. Further, this is a smaller risk reduction than that observed in trials of other anticoagulant agents.

A large, well-designed, randomized clinical trial comparing aspirin to LMWH or fondaparinux remains to be conducted.

Dr. Fishmann cites a small study of patients undergoing knee arthroplasty who received spinal anesthesia and intermittent calf compression devices.⁷ In this underpowered study, 275 patients were randomized to receive aspirin 325 mg twice daily or enoxaparin 30 mg twice daily for 3 weeks. The overall DVT rates were 14.1% in the enoxaparin group vs 17.8% in the aspirin group (P = .27).⁷ Patients who received aspirin had significantly more postoperative drainage than those randomized to enoxaparin. In addition, the protocol for scheduling enoxaparin 48 hours postoperatively is not consistent with recommendations of the American College of Chest Physicians (ACCP) and may have reduced the efficacy of enoxaparin.

The other evidence in support of aspirin cited by Dr. Fishmann includes an editorial,⁹ an uncontrolled retrospective analysis,⁸ a single-center retrospective review,¹⁰ and a review article.⁶ Although there is evidence that the use of aspirin is probably associated with a modest reduction in postoperative VTE risk, it has been unequivocally surpassed in efficacy by other anticoagulants.

Both the latest (2004) ACCP guidelines on VTE² and the 2006 International Consensus Statement on VTE prevention and treatment¹⁵ advise against aspirin monotherapy as VTE prophylaxis in any patient groups. It is likely that the upcoming 2008 ACCP guidelines will also advocate against using aspirin as well.

Lastly, the most recent guideline from the American Academy of Orthopaedic Surgeons advocating aspirin as monotherapy¹¹ is based on the assumption that the major important clinical end point in the orthopedic surgery patient is clinical pulmonary embolism, an end point that was not included as a lone primary end point in any of the modern randomized controlled studies in major orthopedic surgery. This represents a flawed logic for the development of evidence-based guideline recommendations, and this recommendation has not been advocated by well-respected bodies such as the ACCP and the international groups that developed the International Consensus Statement. Furthermore, if this practice is going to be advocated by the American Academy of Orthopaedic Surgeons, then large rigorously designed randomized trials must be conducted to compare aspirin to currently available anticoagulants, and the type of joint surgery should be clearly defined.

References

Deitelzweig SB, McKean SC, Amin AN, Brotman DJ, Jaffer AK, Spyropoulos AC. Prevention of venous thromboembolism in the orthopedic surgery patient. Cleve Clin J Med 2008; 75(suppl 3):S27–S36.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 suppl):338S–400S.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 suppl):132S–175S.
Zimlich RH, Fulbright BM, Friedman RJ. Current status of anticoagulation therapy after total hip and total knee arthroplasty. J Am Acad Orthop Surg 1996; 4:54–62.
PEP Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302.
Berend KR, Lombardi AV. Multimodal venous thromboembolic disease prevention for patients undergoing primary or revision total joint arthroplasty: the role of aspirin. Am J Orthop 2006; 35:24–29.
Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J Arthroplasty 2006; 21(6 suppl 2):139–143.
Lotke PA, Lonner JH. The benefit of aspirin chemoprophylaxis for thromboembolism after total knee arthroplasty. Clin Orthop Relat Res 2006; 452:175–180.
Callaghan JJ, Dorr LD, Engh GA, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians—are they appropriate for orthopaedic surgery? J Arthroplasty 2005; 20:273–274.
Dorr LD, Gendelman V, Maheshwari AV, Boutary M, Wan Z, Long WT. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 2007; 89:2648–2657.
American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty: Summary of Recommendations. http://www.aaos.org/Research/guidelines/PE_summary.pdf. Accessed April 16, 2008.
Parvizi J, Ghanem E, Joshi A, Sharkey PF, Hozack WJ, Rothman RH. Does “excessive” anticoagulation predispose to periprosthetic infection? J Arthroplasty 2007; 22(6 suppl 2):24–28.
Bern M, Deshmukh RV, Nelson R, et al. Low-dose warfarin coupled with lower leg compression is effective prophylaxis against thromboembolic disease after hip arthroplasty. J Arthroplasty 2007; 22:644–650.
Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994; 271:1780–1785.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.

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Steven B. Deitelzweig, MD
Ochsner Health System, New Orleans, LA

Alpesh N. Amin, MD
University of California, Irvine

Daniel J. Brotman, MD
Johns Hopkins Hospital, Baltimore, MD

Sylvia C. McKean, MD
Brigham and Women’s Hospital, Boston, MA

Alex C. Spyropoulos, MD
Lovelace Medical Center, Albuquerque, NM

Amir K. Jaffer, MD
University of Miami, Miami, FL

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Steven B. Deitelzweig, MD
Ochsner Health System, New Orleans, LA

Alpesh N. Amin, MD
University of California, Irvine

Daniel J. Brotman, MD
Johns Hopkins Hospital, Baltimore, MD

Sylvia C. McKean, MD
Brigham and Women’s Hospital, Boston, MA

Alex C. Spyropoulos, MD
Lovelace Medical Center, Albuquerque, NM

Amir K. Jaffer, MD
University of Miami, Miami, FL

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Steven B. Deitelzweig, MD
Ochsner Health System, New Orleans, LA

Alpesh N. Amin, MD
University of California, Irvine

Daniel J. Brotman, MD
Johns Hopkins Hospital, Baltimore, MD

Sylvia C. McKean, MD
Brigham and Women’s Hospital, Boston, MA

Alex C. Spyropoulos, MD
Lovelace Medical Center, Albuquerque, NM

Amir K. Jaffer, MD
University of Miami, Miami, FL

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A large, well-designed, randomized clinical trial comparing aspirin to LMWH or fondaparinux remains to be conducted.

References

Deitelzweig SB, McKean SC, Amin AN, Brotman DJ, Jaffer AK, Spyropoulos AC. Prevention of venous thromboembolism in the orthopedic surgery patient. Cleve Clin J Med 2008; 75(suppl 3):S27–S36.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 suppl):338S–400S.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 suppl):132S–175S.
Zimlich RH, Fulbright BM, Friedman RJ. Current status of anticoagulation therapy after total hip and total knee arthroplasty. J Am Acad Orthop Surg 1996; 4:54–62.
PEP Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302.
Berend KR, Lombardi AV. Multimodal venous thromboembolic disease prevention for patients undergoing primary or revision total joint arthroplasty: the role of aspirin. Am J Orthop 2006; 35:24–29.
Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J Arthroplasty 2006; 21(6 suppl 2):139–143.
Lotke PA, Lonner JH. The benefit of aspirin chemoprophylaxis for thromboembolism after total knee arthroplasty. Clin Orthop Relat Res 2006; 452:175–180.
Callaghan JJ, Dorr LD, Engh GA, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians—are they appropriate for orthopaedic surgery? J Arthroplasty 2005; 20:273–274.
Dorr LD, Gendelman V, Maheshwari AV, Boutary M, Wan Z, Long WT. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 2007; 89:2648–2657.
American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty: Summary of Recommendations. http://www.aaos.org/Research/guidelines/PE_summary.pdf. Accessed April 16, 2008.
Parvizi J, Ghanem E, Joshi A, Sharkey PF, Hozack WJ, Rothman RH. Does “excessive” anticoagulation predispose to periprosthetic infection? J Arthroplasty 2007; 22(6 suppl 2):24–28.
Bern M, Deshmukh RV, Nelson R, et al. Low-dose warfarin coupled with lower leg compression is effective prophylaxis against thromboembolic disease after hip arthroplasty. J Arthroplasty 2007; 22:644–650.
Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994; 271:1780–1785.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.

References

Deitelzweig SB, McKean SC, Amin AN, Brotman DJ, Jaffer AK, Spyropoulos AC. Prevention of venous thromboembolism in the orthopedic surgery patient. Cleve Clin J Med 2008; 75(suppl 3):S27–S36.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 suppl):338S–400S.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 suppl):132S–175S.
Zimlich RH, Fulbright BM, Friedman RJ. Current status of anticoagulation therapy after total hip and total knee arthroplasty. J Am Acad Orthop Surg 1996; 4:54–62.
PEP Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302.
Berend KR, Lombardi AV. Multimodal venous thromboembolic disease prevention for patients undergoing primary or revision total joint arthroplasty: the role of aspirin. Am J Orthop 2006; 35:24–29.
Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J Arthroplasty 2006; 21(6 suppl 2):139–143.
Lotke PA, Lonner JH. The benefit of aspirin chemoprophylaxis for thromboembolism after total knee arthroplasty. Clin Orthop Relat Res 2006; 452:175–180.
Callaghan JJ, Dorr LD, Engh GA, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians—are they appropriate for orthopaedic surgery? J Arthroplasty 2005; 20:273–274.
Dorr LD, Gendelman V, Maheshwari AV, Boutary M, Wan Z, Long WT. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 2007; 89:2648–2657.
American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty: Summary of Recommendations. http://www.aaos.org/Research/guidelines/PE_summary.pdf. Accessed April 16, 2008.
Parvizi J, Ghanem E, Joshi A, Sharkey PF, Hozack WJ, Rothman RH. Does “excessive” anticoagulation predispose to periprosthetic infection? J Arthroplasty 2007; 22(6 suppl 2):24–28.
Bern M, Deshmukh RV, Nelson R, et al. Low-dose warfarin coupled with lower leg compression is effective prophylaxis against thromboembolic disease after hip arthroplasty. J Arthroplasty 2007; 22:644–650.
Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994; 271:1780–1785.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.

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Prevention of venous thromboembolism in the hospitalized medical patient

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Prevention of venous thromboembolism in the hospitalized medical patient

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The need for prophylaxis of venous thromboembolism (VTE) in hospitalized acutely ill medical patients is well established. Without prophylaxis, hospitalized medical patients develop VTE at a rate of 5% to 15%.^1–3 Moreover, pulmonary embolism (PE) occurs more frequently in hospitalized medical patients than in nonmedical patients, and is a leading cause of sudden death in hospitalized medical patients.^4,5 Without appropriate prophylaxis, 1 in 20 hospitalized medical patients may suffer a fatal PE.⁴

PROPHYLAXIS IN MEDICAL PATIENTS: UNDERUSED AND OFTEN INAPPROPRIATE

Despite these risks and the clear indications for VTE prophylaxis in hospitalized medical patients, prophylaxis of VTE is omitted more often in these patients than in hospitalized surgical patients.⁵ Even when prophylaxis is given, it is often used inappropriately in the medical population. So concludes a recent analysis of data from 196,104 patients with acute medical conditions who were discharged from 227 US hospitals from January 2002 to September 2005.⁶ Criteria for inclusion in the analysis were patient age of 40 years or older, a hospital stay of 6 days or greater, and an absence of contraindications to anticoagulation. Appropriate prophylaxis was defined in accordance with the Sixth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy.⁷

The analysis revealed an overall VTE prophylaxis rate of 61.8%, but the rate of appropriate prophylaxis was only 33.9%, meaning that two-thirds of discharged patients did not receive prophylaxis in accordance with ACCP guidelines. When temporal trends were analyzed according to groups based on patients’ diagnosis at admission (acute myocardial infarction, severe lung disease, ischemic stroke, cancer, heart failure, or trauma), the rate of appropriate prophylaxis remained essentially flat from the beginning to the end of the study period for virtually all diagnosis groups.⁶

Similar findings have emerged from the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE), an ongoing international registry of acutely ill medical patients.⁸ Data from the first 15,156 patients, enrolled from July 2002 through September 2006, reveal that 50% of patients received pharmacologic and/or mechanical VTE prophylaxis in the hospital, and only 60% of patients who met established criteria for VTE prophylaxis actually received it.

Analysis of the US portion of the IMPROVE data shows that 54% of the US patient sample received some form of VTE prophylaxis; 22% of US patients received intermittent pneumatic compression, 21% received unfractionated heparin (UFH), 14% received low-molecular-weight heparin (LMWH), and 3% wore compression stockings.⁸ Thus, despite a paucity of data supporting a benefit of intermittent pneumatic compression in this population,⁹ it was the most frequently used form of prophylaxis in US patients.

CLINICAL TRIALS OF PHARMACOLOGIC PROPHYLAXIS IN MEDICAL PATIENTS

Figure 1. Rates of venous thromboembolism (VTE) in three large double-blind, placebo-controlled studies of pharmacologic prophylaxis of VTE in high-risk hospitalized medical patients.

The evidence in support of pharmacologic prophylaxis of VTE in high-risk hospitalized medical patients is considerable. Three large double-blind, placebo-controlled trials of anticoagulants currently available in the United States have been reported in this patient population (Figure 1).^1–3

The Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial1 randomized 1,102 hospitalized patients to one of two doses of the LMWH enoxaparin (20 mg or 40 mg once daily subcutaneously) or placebo for 6 to 14 days. Compared with placebo, the 40-mg dose of enoxaparin was associated with a 63% reduction in risk of VTE over 3 months of follow-up (P < .001) (Figure 1).

The Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT)2 was a multicenter, randomized, double-blind study comparing the LMWH dalteparin (5,000 IU daily given subcutaneously for 14 days) with placebo in 3,706 acutely ill medical patients. Over 90 days of follow-up, the risk of VTE was reduced by 44% in patients assigned to dalteparin compared with those assigned to placebo (P = .0015) (Figure 1).

The Arixtra for Thromboembolism Prevention in a Medical Indications Study (ARTEMIS)3 randomized 849 medical patients 60 years or older to 6 to 14 days of therapy with the selective factor Xa inhibitor fondaparinux (2.5 mg once daily subcutaneously) or placebo. Compared with the placebo group, fondaparinux recipients had a 47% lower risk of developing VTE by day 15 (P = .029) (Figure 1).

Fewer events and fatal PEs, but no effect on all-cause mortality

A recent meta-analysis by Dentali et al¹⁰ further demonstrates the efficacy of anticoagulant therapy for preventing symptomatic VTE in hospitalized medical patients. This analysis included several other trials in addition to the three reviewed above,^1–3 for a total of nine randomized studies (seven of which were dou-ble-blind) comprising 19,958 patients. Across the nine studies, anticoagulant prophylaxis was clearly superior to placebo in preventing fatal PE (relative risk, 0.38 [95% CI, 0.21 to 0.69]). There was a strong trend toward a reduction in symptomatic deep vein thrombosis (DVT) with prophylaxis but no effect on all-cause mortality. The meta-analysis also provided reassurance that prophylaxis does not increase the rate of major bleeding.

HOW DO THE PROPHYLAXIS OPTIONS STACK UP?

What the ACCP recommends

Current ACCP guidelines recommend the use of either LMWH or low-dose UFH (5,000 U subcutaneously two or three times daily) as a Grade 1A recommendation for VTE prophylaxis in patients with medical conditions and risk factors for VTE.⁹ This represents the guidelines’ highest level of recommendation, ie, one that is based on randomized controlled trials (RCTs) without important limitations. In contrast, the 2006 International Consensus Statement, developed as a collaborative effort among expert bodies on VTE, specified a more narrow dosing recommendation for UFH in this patient population (5,000 U three times daily, not twice daily) as well as specifying 40 mg once daily as the recommended dose of enoxaparin and 5,000 IU once daily as the recommended dose of dalteparin.¹¹

For medical patients with risk factors for VTE who have a contraindication to anticoagulant prophylaxis, the ACCP guidelines recommend the use of graduated compression stockings or intermittent pneumatic compression devices as a Grade 1C+ recommendation (“no RCTs but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies”⁹).

Current ACCP guidelines do not address the use of fondaparinux in their recommendations for VTE prophylaxis in medical patients.

Getting a handle on bleeding risk

Patient characteristics that exclude pharmacologic thromboprophylaxis due to bleeding risk are generally limited to active bleeding or coagulopathy, as demonstrated by a platelet count less than 50,000 cells/µL or an international normalized ratio greater than 1.5. Additionally, bleeding risk should be carefully assessed if an invasive procedure is planned during a patient’s hospital stay.

It is worth noting that the anticoagulant doses used for VTE prophylaxis are a fraction of those used for treatment of VTE. Thus, if a patient would be treated with full-dose anticoagulation if VTE developed, then that patient should be eligible for VTE prophylaxis.

Because the use of mechanical forms of prophylaxis in medical patients is not truly evidence-based, mechanical prophylaxis should be reserved for medical patients who have a contraindication to anticoagulants, or for use in combination with anticoagulants in patients at very high risk of VTE.

UFH vs LMWH

Two meta-analyses have compared UFH with LMWH for VTE prevention in medical patients.12,13 In a recent analysis that included 10 trials directly comparing the two therapies, 14 trials comparing UFH with control, and 11 trials comparing LMWH with control, Wein et al found a lower risk of DVT with LMWH than with UFH (relative risk, 0.68 [95% CI, 0.52 to 0.88]) but no difference between the therapies in mortality or bleeding risk.¹² In an earlier and smaller analysis, Mismetti et al found no significant differences between UFH and LMWH in preventing DVT or death but did find a significant reduction in major bleeding episodes with LMWH versus three-times-daily UFH (52% relative reduction; P = .049).¹³

Randomized trials also reveal that enoxaparin 40 mg once daily is as efficacious as UFH 5,000 U three times daily for VTE prevention in medical patients.^14,15 The above analysis by Wein et al¹² and an additional meta-analysis by King and colleagues¹⁶ found that three-times-daily dosing of UFH is more efficacious than twice-daily dosing of UFH, but at the expense of more bleeding, including major bleeding.

Economic considerations

Because of differences in drug acquisition costs between UFH and the LMWH agents, several economic evaluations have compared the use of these therapies for prophylaxis in medical patients at risk of VTE.

In an analysis of hospital costs for medical patients receiving VTE prophylaxis from more than 330 US hospitals for the period 2001–2004, Burleigh et al found that mean total hospital costs were higher for patients who received UFH than for those who received LMWH ($7,615 vs $6,866) even though mean drug costs were higher for LMWH ($791 vs $569 for UFH).¹⁷ A reduction in hospital length of stay appeared to contribute to the overall savings with LMWH; other contributors may have included costs associated with heparin-induced thrombocytopenia (HIT) in UFH recipients or the extra nursing time required for administering UFH in two or three daily doses.

Leykum et al used a decision analysis model to estimate the economic effect of substituting enoxaparin for UFH in hospitalized medical patients for whom VTE prophylaxis is indicated.¹⁸ Cost data were based on Medicare reimbursement rates as well as drug and laboratory costs for a multi-institutional health system. The model assumed HIT incidence rates of 2.7% with UFH and 0.3% with enoxaparin. It also assumed the cost of a daily dose to be $4 for UFH versus $84 for enoxaparin. From the payer perspective, the model showed that substituting enoxaparin for UFH would reduce the overall cost of care by $28.61 per day on a per-patient basis, despite enoxaparin’s higher acquisition cost, and would save $4,550 per quality-adjusted life-year by reducing the incidence of HIT.

Another cost analysis confirms the association between HIT and increased hospital costs. Creekmore et al retrospectively analyzed data from 10,121 adult medical patients who received VTE prophylaxis at the University of Utah Hospital in Salt Lake City from August 2000 to November 2004.¹⁹ They found that an admission during which HIT developed incurred a mean cost of $56,364, compared with $15,231 for an admission without HIT. Because LMWH was associated with a lower incidence of HIT compared with UFH (0.084% vs 0.51%, respectively), LMWH reduced the incremental cost of VTE prophylaxis by $13.88 per patient compared with UFH.

THE EXCLAIM TRIAL: IS THERE A ROLE FOR EXTENDED PROPHYLAXIS?

Although the previously discussed studies have clearly demonstrated the benefit of in-hospital VTE prophylaxis for acutely ill medical patients, none has rigorously examined extended-duration out-of-hospital prophylaxis in these patients. This represents an important gap in the literature, since a substantial proportion of VTE develops in the outpatient setting within 3 months of a hospitalization, and most outpatient VTE episodes occur within 1 month of a preceding hospitalization.²⁰

To begin to fill this gap, the Extended Clinical Prophylaxis in Acutely Ill Medical Patients (EXCLAIM) trial was conducted to compare extended-duration LMWH prophylaxis with a standard LMWH prophylaxis regimen in acutely ill medical patients using a prospective, multicenter, randomized, double-blind, placebo-controlled design.²¹

Patients and study design

Patients were eligible for enrollment if they were aged 40 years or older and had recent immobilization (≤ 3 days), a predefined acute medical illness, and either level 1 mobility (total bed rest or sedentary state) or level 2 mobility (level 1 with bathroom privileges). The predefined acute medical illnesses consisted of New York Heart Association class III/IV heart failure, acute respiratory insufficiency, or other acute medical conditions, including post-acute ischemic stroke, acute infection without septic shock, and active cancer.

All patients received open-label enoxaparin 40 mg subcutaneously once daily for 10 ± 4 days, after which they were randomized to either enoxaparin 40 mg subcutaneously once daily or placebo for an additional 28 ± 4 days.

The primary efficacy end point was the incidence of VTE events, defined as asymptomatic DVT documented by mandatory ultrasonography at the end of the double-blind treatment period (28 ± 4 days) or as symptomatic DVT, symptomatic PE, or fatal PE at any time during the double-blind period. Symptomatic DVT was confirmed by objective tests; PE was confirmed by ventilation-perfusion scan, computed tomography, angiography, or autopsy.

Secondary efficacy end points were mortality at the end of the double-blind period, at 3 months, and at 6 months, as well as the incidence of VTE at 3 months.

The primary safety outcome measure was the incidence of major hemorrhage during the double-blind period; secondary safety measures were rates of major and minor hemorrhage, minor hemorrhage, HIT, and serious adverse events.

Population amended at planned interim analysis

After approximately half of the patients were enrolled, a planned and blinded interim analysis for futility concluded that the study was unlikely to show a statistically significant advantage of enoxaparin over placebo. The trial’s steering committee followed the suggestion of its data safety monitoring board to redefine the inclusion criteria to refocus enrollment on patients with a high risk of VTE. A blinded analysis was performed to identify this subgroup.

The resulting amended inclusion criteria were the same as above except that level 2 mobility had to be accompanied by at least one of three additional high-risk criteria: (1) age greater than 75 years, (2) history of prior VTE, or (3) diagnosis of cancer.

The trial’s main exclusion criteria were evidence of active bleeding, a contraindication to anticoagulation, receipt of prophylactic LMWH or UFH more than 72 hours prior to enrollment, treatment with an oral anticoagulant within 72 hours of enrollment, major surgery within the prior 3 months, cerebral stroke with bleeding, and persistent renal failure (creatinine clearance < 30 mL/min).

Results

The amended study population included 5,105 patients, 5,049 of whom received open-label enoxaparin. Of this group, 2,013 were randomized to active extended prophylaxis with enoxparain and 2,027 to placebo. Baseline characteristics, including level of mobility, were similar between the two groups.

Efficacy. As detailed in Table 1, VTE events occurred at a statistically significantly higher rate in the placebo arm than in the extended-duration enoxaparin arm, as did asymptomatic proximal DVT and symptomatic VTE. Rates of PE and fatal PE were also lower with enoxaparin than with placebo, but the number of events was so small that the betweengroup differences were not statistically significant.

The efficacy of extended prophylaxis with enoxaparin was enduring, as the cumulative incidence of VTE events at day 90 was significantly lower in enoxaparin recipients than in placebo recipients (3.0% vs 5.2%; relative reduction of 42%; P = .0115).

There was no difference in all-cause mortality at 6 months between the enoxaparin and placebo groups (10.1% vs 8.9%, respectively; P = .179).

Safety. Major hemorrhage was significantly more frequent in the enoxaparin arm, occurring in 0.60% of enoxaparin recipients compared with 0.15% of placebo recipients (P = .019). Minor bleeding was also more common with enoxaparin (5.20% vs 3.70%; P = .024).

Conclusions

The EXCLAIM trial found that an extended-duration (38-day) enoxaparin regimen significantly reduced the overall incidence of VTE relative to a 10-day enoxaparin regimen in acutely ill medical patients with reduced mobility. At the same time, the extended regimen was associated with a significant increase in the rate of major bleeding, although the incidence of major bleeding was low. The investigators concluded that the net clinical effect of extended-duration prophylaxis with enoxaparin is favorable, as only 46 patients would need to be treated to prevent one VTE event, whereas 224 patients would need to be treated to result in one major bleeding event.²¹

For this reason, it is reasonable to consider extended prophylaxis for hospitalized medical patients after identifying these patients’ risk factors. In keeping with the trial’s amended inclusion criteria, patients older than age 75 and those with cancer or prior VTE should receive special consideration for extended prophylaxis.

RECOMMENDED APPROACH TO VTE PREVENTION IN HOSPITALIZED MEDICAL PATIENTS

Figure 2. Algorithm for VTE prophylaxis in the hospitalized medical patient.

Given the wide gap between the evidence reviewed above and current practice worldwide,^8,22,23 we propose the algorithm presented in Figure 2 for the prevention of VTE in hospitalized medical patients. Our recommended approach is guided by the principles below:

All hospitalized medical patients should be screened at the time of admission, and patients at risk for VTE should receive prophylaxis.
All patients with reduced mobility and one or more other risk factors for VTE are candidates for prophylaxis.
Patients should be reassessed daily for the development of VTE risk factors during their hospitalization if risk factors are absent on admission.
If screening or reassessment reveals any VTE risk factors, pharmacologic prophylaxis is the mainstay of therapy. If exclusion criteria for pharmacologic prophylaxis are present, mechanical prophylaxis with graduated compression stockings and intermittent compression devices should be used. For very high-risk medical patients without a contraindication to anticoagulants, combination prophylaxis with both an anticoagulant and mechanical devices is preferred.
In this patient population, LMWH agents are preferred as pharmacologic prophylaxis over UFH and over fondaparinux (which is not currently approved by the US Food and Drug Administration for this population).
If UFH is to be used in this patient population, 5,000 U three times daily is the preferred dosage.
Extended pharmacologic prophylaxis should be considered in patients older than age 75 and in patients with a cancer diagnosis or a prior VTE episode.

DISCUSSION: ADDITIONAL PERSPECTIVES FROM THE AUTHORS

Dr. Jaffer: Dr. Spyropoulos, are there any guidelines, other than those from the ACCP, that speak to VTE prophylaxis in hospitalized medical patients? If so, what are their take-home messages and how do they differ from the ACCP guidelines?

Dr. Spyropoulos: I was part of the group that developed the International Consensus Statement (ICS) published in International Angiology in 2006,¹¹ which is more recent than the latest ACCP guidelines, which were published in 2004. The ICS drew on much of the same data that the ACCP did, but we did an updated review of clinical trials.

For VTE prophylaxis in hospitalized medical patients, the ICS recommendations are more specific with regard to the type, dose, and dosing frequency of anticoagulant agents. First, they specify doses for both LMWH agents in this patient setting: 40 mg once daily for enoxaparin, and 5,000 IU once daily for dalteparin.

The ICS document also states that if UFH is the choice for prophylaxis, a regimen of 5,000 U three times daily should be considered. In the past year alone, two analyses suggest that three-times-daily dosing of UFH in medical patients provides superior efficacy to twice-daily dosing, although perhaps at the expense of more bleeding episodes.^12,16 It is important to remember that no large placebo-controlled trial supports the efficacy of a UFH regimen of 5,000 U twice daily in this population.

Finally, the ICS document states that fondaparinux 2.5 mg once daily is a viable option for prophylaxis in medical patients, based on the ARTEMIS trial,³ even though this represents an off-label use.

Dr. Jaffer: Real-world use of VTE prophylaxis is far from optimal, especially in medical patients, and this is partly a result of system-of-care issues. I’d like to conclude by asking each of my colleagues to offer your perspectives on how your own institutions have improved their systems of care to promote better use of VTE prophylaxis and what lessons might be shared with others. Dr. McKean, you work at Brigham and Women’s Hospital, which recently reported impressive results with an electronic alert system designed to increase clinicians’ consideration of VTE risk assessment and use of prophylaxis.²⁴ Please tell us about that study and the alert system.

Dr. McKean: Despite many educational initiatives at Brigham and Women’s Hospital, there were still some patients at high risk for VTE who were not receiving appropriate prophylaxis. What Dr. Samuel Goldhaber and his colleagues wanted to determine was whether changing the system of care could result in a reduced incidence of VTE.²⁴ They devised a computer software program linked to the patient database that used eight common risk factors to determine each hospitalized patient’s risk profile for VTE. Each risk factor was weighted according to a point scale, with major risk factors (cancer, prior VTE, or hypercoagulability) assigned 3 points, the intermediate risk factor of surgery assigned 2 points, and minor risk factors (advanced age, obesity, immobility, or use of hormone replacement therapy or oral contraceptives) assigned 1 point. For patients with a total risk score of 4 or greater, the computer screen generates a color-coded VTE risk alert that requires the physician to acknowledge the alert and choose one of three options: order prophylaxis as appropriate, review a 60-page document on the computer to learn more about prophylaxis, or do nothing.

The study found that hospitalized patients who were randomized to treatment under the computer alert system were significantly more likely to receive VTE prophylaxis and significantly less likely to develop VTE than were patients randomized to a control group. The alert system reduced the risk of DVT or PE at 90 days by 41% in patients considered to be at high risk. It was particularly interesting that the incidence of VTE was lower in the intervention group even when physicians chose not to use prophylaxis, which suggests that simply having this alert system in place improved outcomes, perhaps by raising awareness of the risk of VTE.²⁴

Additional studies are needed to better understand physicians’ behavior and determine why they seem to have a disproportionate fear of the risk of bleeding relative to the risk of clotting, including fatal PE, because that is really the heart of the matter. When patients are not given prophylaxis, often it is because of fear of bleeding. It is not clear, however, why some of these patients did not receive mechanical devices as an alternative form of prophylaxis, but this seems to be the case worldwide, as shown recently by the multinational ENDORSE study.²² Meanwhile, as we await studies to better understand physician perceptions and behaviors regarding prophylaxis, we need to work hard to change the system of care.

Dr. Deitelzweig: Over the past couple of years, the Ochsner Clinic has grown from a one-hospital teaching organization to a seven-hospital system with a mix of closed and open medical staff. The challenge is how to take a process that worked well in the one center, where appropriate prophylaxis was used about 90% of the time, and transfer it to the other centers in the larger system. We have endorsed several types of performance tools, such as the change-acceleration processes used by General Electric. The aim is to share a vision of heightening awareness. To do that, we have worked to mobilize the key stakeholders, at least half of them, to build algorithms that they all will endorse. It is easier said than done, however, and we have found it essential to involve both physicians and non-physician colleagues from pharmacy and nursing who have political and organizational clout.

Dr. Brotman: At Johns Hopkins, I took a bit more draconian approach to this issue because I thought that hospitalists often knew that they should be using VTE prophylaxis but sometimes weren’t, and I am not convinced that clinicians always look at prompts. So we came up with a system that incorporates both billing and documentation simultaneously. We put a hard stop on users’ documentation so that they could not sign off on a note or bill for their care until they checked off the kind of VTE prophylaxis they were using. Since hospitalists ultimately care about billing for their work, this system has at least ensured that everybody has considered and documented VTE prophylaxis on a daily basis. There are other hard stops that can be implemented in computer order-entry systems as well, and we are considering ways to roll them out on a broader scale.

However, all of these systems can have problems because patient situations change from day to day. For instance, VTE prophylaxis is not necessarily indicated in a 38-year-old ambulatory patient who comes in with a sickle cell crisis, but you will need to reconsider if the patient ends up in acute chest syndrome in the intensive care unit. I do not yet have a good way to ensure that this is being done on a daily basis with all patients.

Dr. Amin: At the University of California, Irvine, we implemented an electronic alert system, but we locked users in so that they could not complete their admission orders until they answered questions about VTE prevention. This practice increased our VTE prophylaxis rates tremendously. Because we are a level I trauma center, we allow users to bypass the screens one time, but the next time they log in, even to get a simple lab result, they have to answer the questions about VTE prevention.

With any system you develop, you also have to continue with the education process, because clinicians sometimes get into bad habits or simply forget things.

Dr. Spyropolous: At Lovelace Medical Center, we didn’t have the sophistication of an electronic order-entry system, but we had an experienced clinical pharmacist (the director of inpatient pharmacy) who helped to develop and champion VTE prevention guidelines that have then been used throughout the system in close conjunction with our hospitalists’ rounds. This system has been used successfully for the past 7 years.

References

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Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110:874–879.
Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332:325–329.
Baglin TP, White K, Charles A. Fatal pulmonary embolism in hos-pitalised medical patients. J Clin Pathol 1997; 50:609–610.
Piazza G, Seddighzadeh A, Goldhaber SZ. Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent. Chest 2007; 132:554–561.
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Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 Suppl):132S–175S.
Tapson VF, Decousus H, Pini M, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132:936–945.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thrombo-embolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl):338S–400S.
Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146:278–288.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.
Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2007; 167:1476–1486.
Mismetti P, Laporte-Simitsidis S, Tardy B, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83:14–19.
Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The Prime Study Group. Haemostasis 1996; 26(Suppl 2):49–56.
Kleber FX, Witt C, Vogel G, et al; the PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145:614–621.
King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a meta-analysis. Chest 2007; 131:507–516.
Burleigh E, Wang C, Foster D, et al. Thromboprophylaxis in medically ill patients at risk for venous thromboembolism. Am J Health Syst Pharm 2006; 63(20 Suppl 6):S23–S29.
Leykum L, Pugh J, Diuguid D, Papadopoulos K. Cost utility of substituting enoxaparin for unfractionated heparin for prophylaxis of venous thrombosis in the hospitalized medical patient. J Hosp Med 2006; 1:168–176.
Creekmore FM, Oderda GM, Pendleton RC, Brixner DI. Incidence and economic implications of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism. Pharmacotherapy 2006; 26:1438–1445.
Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007; 167:1471–1475.
Hull RD, Schellong SM Tapson VF, et al. Extended-duration venous thromboembolism (VTE) prophylaxis in acutely ill medical patients with recent reduced mobility: the EXCLAIM study. Presentation at: International Society on Thrombosis and Haemo-stasis XXIst Congress; July 6–12, 2007; Geneva, Switzerland.
Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371:387–394.
Kahn SR, Panju A, Geerts W, et al; CURVE study investigators. Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thromb Res 2007; 119:145–155.
Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent thromboembolism among hospitalized patients. N Engl J Med 2005; 352:969–977.
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Howell MD, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol 2001; 54:810–816.
Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367:1075–1079.
Alikhan R, Cohen AT, Combe S, et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Firbinolysis 2003; 14:341–346.
Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107(23 Suppl 1):I9–I16.
Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin-induced thrombocytopenia: review and update. Thromb Res 2006; 118:165–176.
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710–2715.
Sanderink GJ, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002; 105:225–231.
Douketis J, Cook D, Zytaruk N, et al. Dalteparin thromboprophylaxis in critically ill patients with severe renal insufficiency: the DIRECT study [abstract]. J Thromb Haemost 2007; 5(Suppl 2): P-S-680.
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Author and Disclosure Information

Amir K. Jaffer, MD
Associate Professor of Medicine; Chief, Division of Hospital Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL

Alpesh N. Amin, MD, MBA
Professor and Chief, Division of General Internal Medicine; Executive Director, Hospitalist Program; Vice Chair for Clinical Affairs & Quality, Department of Medicine, University of California, Irvine, Irvine, CA

Daniel J. Brotman, MD
Director, Hospitalist Program; Associate Professor of Medicine, Johns Hopkins Hospital, Baltimore, MD

Steven B. Deitelzweig, MD
Vice President of Medical Affairs; Chairman, Department of Hospital Medicine, Ochsner Health System, New Orleans, LA

Sylvia C. McKean, MD
Medical Director, BWH/Faulkner Hospitalist Service; Associate Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA

Alex C. Spyropoulos, MD
Chair, Clinical Thrombosis Center, Lovelace Medical Center; Clinical Associate Professor of Medicine/Associate Professor of Pharmacy, University of New Mexico Health Sciences Center/College of Pharmacy, Albuquerque, NM

Correspondence: Amir K. Jaffer, MD, Chief, Division of Hospital Medicine, Leonard M. Miller School of Medicine, University of Miami, 1120 NW 14th Street, 933 CRB (C216), Miami, FL 33136; ajaffer@med.miami.edu

Dr. Jaffer reported that he has received consulting fees and honoraria for teaching/speaking from Sanofi-Aventis, consulting fees and research grant support from AstraZeneca, and consulting fees from Roche Diagnostics and Boehringer Ingelheim; he also serves on the governing board of the Society for Perioperative Assessment and Quality Improvement (SPAQI) and the board of directors of the Anticoagulation Forum.

Dr. Amin reported that he has received research funding and honoraria for speaking from Sanofi-Aventis, Eisai, and GlaxoSmithKline.

Dr. Brotman reported that he has no financial relationships with commercial interests that are relevant to this article.

Drs. Deitelzweig and McKean each reported that they have received honoraria for teaching/speaking from Sanofi-Aventis. Dr. Spyropoulos reported that he has received consulting fees from Sanofi-Aventis, Eisai, and Boehringer Ingelheim.

Each author received an honorarium for participating in the roundtable that formed the basis of this supplement. The honoraria were paid by the Cleveland Clinic Center for Continuing Education from the educational grant from Sanofi-Aventis underwriting this supplement. Sanofi-Aventis had no input on the content of the roundtable or this supplement.

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Author and Disclosure Information

Amir K. Jaffer, MD
Associate Professor of Medicine; Chief, Division of Hospital Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL

Daniel J. Brotman, MD
Director, Hospitalist Program; Associate Professor of Medicine, Johns Hopkins Hospital, Baltimore, MD

Steven B. Deitelzweig, MD
Vice President of Medical Affairs; Chairman, Department of Hospital Medicine, Ochsner Health System, New Orleans, LA

Sylvia C. McKean, MD
Medical Director, BWH/Faulkner Hospitalist Service; Associate Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA

Dr. Amin reported that he has received research funding and honoraria for speaking from Sanofi-Aventis, Eisai, and GlaxoSmithKline.

Dr. Brotman reported that he has no financial relationships with commercial interests that are relevant to this article.

Author and Disclosure Information

Amir K. Jaffer, MD
Associate Professor of Medicine; Chief, Division of Hospital Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL

Daniel J. Brotman, MD
Director, Hospitalist Program; Associate Professor of Medicine, Johns Hopkins Hospital, Baltimore, MD

Steven B. Deitelzweig, MD
Vice President of Medical Affairs; Chairman, Department of Hospital Medicine, Ochsner Health System, New Orleans, LA

Sylvia C. McKean, MD
Medical Director, BWH/Faulkner Hospitalist Service; Associate Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA

Dr. Amin reported that he has received research funding and honoraria for speaking from Sanofi-Aventis, Eisai, and GlaxoSmithKline.

Dr. Brotman reported that he has no financial relationships with commercial interests that are relevant to this article.

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PROPHYLAXIS IN MEDICAL PATIENTS: UNDERUSED AND OFTEN INAPPROPRIATE

CLINICAL TRIALS OF PHARMACOLOGIC PROPHYLAXIS IN MEDICAL PATIENTS

Fewer events and fatal PEs, but no effect on all-cause mortality

HOW DO THE PROPHYLAXIS OPTIONS STACK UP?

What the ACCP recommends

Current ACCP guidelines do not address the use of fondaparinux in their recommendations for VTE prophylaxis in medical patients.

Getting a handle on bleeding risk

UFH vs LMWH

Economic considerations

THE EXCLAIM TRIAL: IS THERE A ROLE FOR EXTENDED PROPHYLAXIS?

Patients and study design

Secondary efficacy end points were mortality at the end of the double-blind period, at 3 months, and at 6 months, as well as the incidence of VTE at 3 months.

Population amended at planned interim analysis

Results

There was no difference in all-cause mortality at 6 months between the enoxaparin and placebo groups (10.1% vs 8.9%, respectively; P = .179).

Conclusions

RECOMMENDED APPROACH TO VTE PREVENTION IN HOSPITALIZED MEDICAL PATIENTS

All hospitalized medical patients should be screened at the time of admission, and patients at risk for VTE should receive prophylaxis.
All patients with reduced mobility and one or more other risk factors for VTE are candidates for prophylaxis.
Patients should be reassessed daily for the development of VTE risk factors during their hospitalization if risk factors are absent on admission.
If screening or reassessment reveals any VTE risk factors, pharmacologic prophylaxis is the mainstay of therapy. If exclusion criteria for pharmacologic prophylaxis are present, mechanical prophylaxis with graduated compression stockings and intermittent compression devices should be used. For very high-risk medical patients without a contraindication to anticoagulants, combination prophylaxis with both an anticoagulant and mechanical devices is preferred.
In this patient population, LMWH agents are preferred as pharmacologic prophylaxis over UFH and over fondaparinux (which is not currently approved by the US Food and Drug Administration for this population).
If UFH is to be used in this patient population, 5,000 U three times daily is the preferred dosage.
Extended pharmacologic prophylaxis should be considered in patients older than age 75 and in patients with a cancer diagnosis or a prior VTE episode.

DISCUSSION: ADDITIONAL PERSPECTIVES FROM THE AUTHORS

With any system you develop, you also have to continue with the education process, because clinicians sometimes get into bad habits or simply forget things.

PROPHYLAXIS IN MEDICAL PATIENTS: UNDERUSED AND OFTEN INAPPROPRIATE

CLINICAL TRIALS OF PHARMACOLOGIC PROPHYLAXIS IN MEDICAL PATIENTS

Fewer events and fatal PEs, but no effect on all-cause mortality

HOW DO THE PROPHYLAXIS OPTIONS STACK UP?

What the ACCP recommends

Current ACCP guidelines do not address the use of fondaparinux in their recommendations for VTE prophylaxis in medical patients.

Getting a handle on bleeding risk

UFH vs LMWH

Economic considerations

THE EXCLAIM TRIAL: IS THERE A ROLE FOR EXTENDED PROPHYLAXIS?

Patients and study design

Secondary efficacy end points were mortality at the end of the double-blind period, at 3 months, and at 6 months, as well as the incidence of VTE at 3 months.

Population amended at planned interim analysis

Results

There was no difference in all-cause mortality at 6 months between the enoxaparin and placebo groups (10.1% vs 8.9%, respectively; P = .179).

Conclusions

RECOMMENDED APPROACH TO VTE PREVENTION IN HOSPITALIZED MEDICAL PATIENTS

All hospitalized medical patients should be screened at the time of admission, and patients at risk for VTE should receive prophylaxis.
All patients with reduced mobility and one or more other risk factors for VTE are candidates for prophylaxis.
Patients should be reassessed daily for the development of VTE risk factors during their hospitalization if risk factors are absent on admission.
If screening or reassessment reveals any VTE risk factors, pharmacologic prophylaxis is the mainstay of therapy. If exclusion criteria for pharmacologic prophylaxis are present, mechanical prophylaxis with graduated compression stockings and intermittent compression devices should be used. For very high-risk medical patients without a contraindication to anticoagulants, combination prophylaxis with both an anticoagulant and mechanical devices is preferred.
In this patient population, LMWH agents are preferred as pharmacologic prophylaxis over UFH and over fondaparinux (which is not currently approved by the US Food and Drug Administration for this population).
If UFH is to be used in this patient population, 5,000 U three times daily is the preferred dosage.
Extended pharmacologic prophylaxis should be considered in patients older than age 75 and in patients with a cancer diagnosis or a prior VTE episode.

DISCUSSION: ADDITIONAL PERSPECTIVES FROM THE AUTHORS

With any system you develop, you also have to continue with the education process, because clinicians sometimes get into bad habits or simply forget things.

References

Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thrombo-embolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341:793–800.
Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110:874–879.
Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332:325–329.
Baglin TP, White K, Charles A. Fatal pulmonary embolism in hos-pitalised medical patients. J Clin Pathol 1997; 50:609–610.
Piazza G, Seddighzadeh A, Goldhaber SZ. Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent. Chest 2007; 132:554–561.
Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost 2007; 5:1610–1616.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 Suppl):132S–175S.
Tapson VF, Decousus H, Pini M, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132:936–945.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thrombo-embolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl):338S–400S.
Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146:278–288.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.
Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2007; 167:1476–1486.
Mismetti P, Laporte-Simitsidis S, Tardy B, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83:14–19.
Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The Prime Study Group. Haemostasis 1996; 26(Suppl 2):49–56.
Kleber FX, Witt C, Vogel G, et al; the PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145:614–621.
King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a meta-analysis. Chest 2007; 131:507–516.
Burleigh E, Wang C, Foster D, et al. Thromboprophylaxis in medically ill patients at risk for venous thromboembolism. Am J Health Syst Pharm 2006; 63(20 Suppl 6):S23–S29.
Leykum L, Pugh J, Diuguid D, Papadopoulos K. Cost utility of substituting enoxaparin for unfractionated heparin for prophylaxis of venous thrombosis in the hospitalized medical patient. J Hosp Med 2006; 1:168–176.
Creekmore FM, Oderda GM, Pendleton RC, Brixner DI. Incidence and economic implications of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism. Pharmacotherapy 2006; 26:1438–1445.
Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007; 167:1471–1475.
Hull RD, Schellong SM Tapson VF, et al. Extended-duration venous thromboembolism (VTE) prophylaxis in acutely ill medical patients with recent reduced mobility: the EXCLAIM study. Presentation at: International Society on Thrombosis and Haemo-stasis XXIst Congress; July 6–12, 2007; Geneva, Switzerland.
Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371:387–394.
Kahn SR, Panju A, Geerts W, et al; CURVE study investigators. Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thromb Res 2007; 119:145–155.
Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent thromboembolism among hospitalized patients. N Engl J Med 2005; 352:969–977.
Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151:933–938.
Howell MD, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol 2001; 54:810–816.
Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367:1075–1079.
Alikhan R, Cohen AT, Combe S, et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Firbinolysis 2003; 14:341–346.
Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107(23 Suppl 1):I9–I16.
Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin-induced thrombocytopenia: review and update. Thromb Res 2006; 118:165–176.
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710–2715.
Sanderink GJ, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002; 105:225–231.
Douketis J, Cook D, Zytaruk N, et al. Dalteparin thromboprophylaxis in critically ill patients with severe renal insufficiency: the DIRECT study [abstract]. J Thromb Haemost 2007; 5(Suppl 2): P-S-680.
Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg 2002; 12:19–24.

References

Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thrombo-embolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341:793–800.
Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110:874–879.
Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332:325–329.
Baglin TP, White K, Charles A. Fatal pulmonary embolism in hos-pitalised medical patients. J Clin Pathol 1997; 50:609–610.
Piazza G, Seddighzadeh A, Goldhaber SZ. Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent. Chest 2007; 132:554–561.
Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost 2007; 5:1610–1616.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 Suppl):132S–175S.
Tapson VF, Decousus H, Pini M, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132:936–945.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thrombo-embolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl):338S–400S.
Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146:278–288.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.
Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2007; 167:1476–1486.
Mismetti P, Laporte-Simitsidis S, Tardy B, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83:14–19.
Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The Prime Study Group. Haemostasis 1996; 26(Suppl 2):49–56.
Kleber FX, Witt C, Vogel G, et al; the PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145:614–621.
King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a meta-analysis. Chest 2007; 131:507–516.
Burleigh E, Wang C, Foster D, et al. Thromboprophylaxis in medically ill patients at risk for venous thromboembolism. Am J Health Syst Pharm 2006; 63(20 Suppl 6):S23–S29.
Leykum L, Pugh J, Diuguid D, Papadopoulos K. Cost utility of substituting enoxaparin for unfractionated heparin for prophylaxis of venous thrombosis in the hospitalized medical patient. J Hosp Med 2006; 1:168–176.
Creekmore FM, Oderda GM, Pendleton RC, Brixner DI. Incidence and economic implications of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism. Pharmacotherapy 2006; 26:1438–1445.
Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007; 167:1471–1475.
Hull RD, Schellong SM Tapson VF, et al. Extended-duration venous thromboembolism (VTE) prophylaxis in acutely ill medical patients with recent reduced mobility: the EXCLAIM study. Presentation at: International Society on Thrombosis and Haemo-stasis XXIst Congress; July 6–12, 2007; Geneva, Switzerland.
Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371:387–394.
Kahn SR, Panju A, Geerts W, et al; CURVE study investigators. Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thromb Res 2007; 119:145–155.
Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent thromboembolism among hospitalized patients. N Engl J Med 2005; 352:969–977.
Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151:933–938.
Howell MD, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol 2001; 54:810–816.
Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367:1075–1079.
Alikhan R, Cohen AT, Combe S, et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Firbinolysis 2003; 14:341–346.
Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107(23 Suppl 1):I9–I16.
Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin-induced thrombocytopenia: review and update. Thromb Res 2006; 118:165–176.
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710–2715.
Sanderink GJ, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002; 105:225–231.
Douketis J, Cook D, Zytaruk N, et al. Dalteparin thromboprophylaxis in critically ill patients with severe renal insufficiency: the DIRECT study [abstract]. J Thromb Haemost 2007; 5(Suppl 2): P-S-680.
Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg 2002; 12:19–24.

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Venous thromboembolism (VTE) is a major complication of cancer, occurring in 4% to 20% of patients,¹ and is one of the leading causes of death in cancer patients, although these figures are believed to be underestimates, given the low autopsy rates among cancer patients.² In hospitalized cancer patients specifically, VTE is the second leading cause of death.^3,4 The risk of VTE in cancer patients undergoing surgery is three to five times greater than that in surgical patients without cancer.⁴ Moreover, cancer patients with symptomatic deep vein thrombosis (DVT) exhibit a high risk of recurrent VTE that may persist for many years after the index event.⁵

VTE PREVENTION POSES PARTICULAR CHALLENGES IN CANCER PATIENTS

Until recently, data on VTE prevention specific to cancer patients have been sparse. Cancer patients have represented only a small subset (< 20%) of participants in most of the largest clinical trials of VTE prophylaxis. Until the past 2 or 3 years, clinicians largely have had to extrapolate their approach to VTE prophylaxis in cancer patients from data in patients without cancer, bearing in mind that cancer patients are among the populations at highest risk of developing VTE.

High rates of VTE, even with prophylaxis

What has been clear is that VTE prevention is a formidable challenge in this population, even when thromboprophylaxis is used. Despite thromboprophylaxis, cancer patients undergoing surgery have twice the risk of VTE and nonfatal pulmonary embolism (PE) and three times the risk of fatal PE compared with other surgical patients (Table 1).^6,7

Further insights have come from the @RISTOS project, a Web-based prospective registry of patients undergoing general, urologic, or gynecologic surgery for cancer at multiple centers in Italy.⁸ Of the 2,372 patients tracked in this study, 82% received in-hospital VTE prophylaxis and 31% received prophylaxis following discharge. Despite this relatively high frequency of prophylaxis, however, the incidence of clinically overt VTE was 2.1% and the incidence of fatal VTE was 0.8%. Notably, most VTE events occurred after hospital discharge, and VTE was the most common cause of 30-day postoperative death in this registry.

RISK FACTORS: CANCER TYPE AND TREATMENT LOOM LARGE

Both the type and stage of a patient’s cancer are important in assessing the risk of VTE. For men, cancers of the prostate, colon, brain, and lung have been associated with an increased risk of VTE. Among women, cancers of the breast, ovary, and lung have been especially implicated as risk factors for VTE.^9,10

The type of cancer therapy also influences VTE risk:

Surgery. Among patients who undergo cancer-related surgery, the rate of proximal DVT is 10% to 20%, the rate of clinically evident PE is 4% to 10%, and the incidence of fatal PE is 0.2% to 5%.^8,11
Systemic treatments, including chemotherapy and hormone therapy, are also associated with an increased risk of VTE.^12–15
Central venous catheters. Approximately 4% of cancer patients who have central venous catheters placed develop clinically relevant VTE.^16,17

In addition to the above risks related to cancer treatments, the following have been identified as risk factors for VTE in surgical oncology patients:

Age greater than 40 years (risk also increases steeply after age 60 and again after age 75)
Cancer procoagulants
Thrombophilia
Length and complications of cancer surgery (ie, often involving tissue trauma and immobilization)
Debilitation and slow recovery.

Another risk factor worth noting is perioperative transfusion, as illustrated in a recent study of 14,104 adults undergoing colorectal cancer resection.¹⁸ The overall incidence of VTE in these patients was 1.0%, and the risk of death was nearly four times as great in patients who developed VTE as in those who did not. Notably, the need for transfusion was a marker of increased risk of VTE, particularly in women: women who received perioperative transfusions had almost double the risk of developing VTE compared with women who did not receive transfusions (P = .004).

CLINICAL TRIALS OF PROPHYLAXIS IN CANCER SURGERY PATIENTS

LMWH vs UFH for in-hospital prophylaxis

Two large randomized, double-blind trials have compared low-molecular-weight heparin (LMWH) with low-dose unfractionated heparin (UFH) for VTE prophylaxis in surgical patients with cancer—the Enoxaparin and Cancer (ENOXACAN) study¹⁹ and the Canadian Colorectal Surgery DVT Prophylaxis Trial.²⁰ Patients in these studies underwent surgery for abdominal or pelvic cancer (mostly colorectal cancer). Both studies compared 40 mg of the LMWH enoxaparin given once daily with 5,000 U of UFH given three times daily for 7 to 10 days postoperatively. Outcome measures were the presence of DVT determined by venography on day 7 to 10 and the incidence of symptomatic VTE. Rates of VTE were statistically equivalent between the two treatment arms in both ENOXACAN (14.7% with LMWH vs 18.2% with UFH) and the Canadian Colorectal Surgery study (9.4% with both therapies), as were rates of major bleeding (4.1% with LMWH vs 2.9% with UFH in ENOXACAN; 2.7% with LMWH vs 1.5% with UFH in the Canadian study).

These findings are consistent with a 2001 meta-analysis by Mismetti et al of all available randomized trials comparing LMWH with placebo or with UFH for VTE prophylaxis in general surgery.²¹ This analysis found no differences in rates of asymptomatic DVT, clinical PE, clinical thromboembolism, death, major hemorrhage, total hemorrhage, wound hematoma, or need for transfusion between LMWH and UFH in patients undergoing either cancer-related surgery or surgery not related to cancer.

Fondaparinux for in-hospital prophylaxis

Subgroup analysis of the large randomized trial known as PEGASUS²² sheds some light on the efficacy of the factor Xa inhibitor fondaparinux relative to LMWH for thromboprophylaxis in cancer surgery patients. PEGASUS compared fondaparinux 2.5 mg once daily with the LMWH dalteparin 5,000 IU once daily for 5 to 9 days in patients undergoing high-risk abdominal surgery. Among the study’s 1,408 patients undergoing surgery for cancer, rates of VTE were 4.7% in the fondaparinux group compared with 7.7% in the LMWH group, a relative risk reduction of 38.6% with fondaparinux (95% CI, 6.7% to 59.6%). In contrast, in the rest of the PEGASUS population (patients undergoing abdominal surgery for reasons other than cancer), LMWH was nonsignificantly more efficacious at preventing VTE than was fondaparinux. Rates of major bleeding in this cancer subgroup were comparable between the two treatments.

Extended prophylaxis

Two additional randomized trials have evaluated extended prophylaxis with LMWH in surgical cancer patients—ENOXACAN II²³ and the Fragmin After Major Abdominal Surgery (FAME) study.²⁴

In ENOXACAN II, patients undergoing surgery for abdominal or pelvic cancer first received 6 to 10 days of prophylaxis with enoxaparin 40 mg once daily and then were randomized in a double-blind fashion to an additional 21 days of enoxaparin or placebo.²³ Among 332 patients in the intent-to-treat analysis, the rate of VTE at the end of the double-blind phase was reduced from 12.0% with placebo to 4.8% with extended-duration enoxaparin (P = .02), an effect that was maintained at 3-month follow-up (P = .01). There was no significant difference between the two groups in rates of major bleeding events or any bleeding events.

In FAME, patients received 5,000 IU of dalteparin once daily for 1 week following major abdominal surgery and then were randomized in open-label fashion to either placebo or extended prophylaxis with dalteparin for 3 more weeks; a subanalysis examined outcomes in the 198 FAME participants whose abdominal surgery was for cancer.²⁴ Among these 198 cancer surgery patients, the rate of venography-documented VTE at 4 weeks was reduced from 19.6% with placebo to 8.8% with extended-duration dalteparin, a relative reduction of 55% (P = .03). The rate of proximal DVT was reduced from 10.4% to 2.2% with extended prophylaxis, a relative reduction of 79% (P = .02).

The number needed to treat with extended LMWH prophylaxis to prevent one VTE event was 14 in ENOXACAN II²³ and 9 in the FAME subanalysis of cancer surgery patients.²⁴

New systematic review of relevant trials

Leonardi et al recently published a systematic review of 26 randomized controlled trials of DVT prophylaxis in 7,639 cancer surgery patients.²⁵ They found the overall incidence of DVT to be 12.7% in those who received pharmacologic prophylaxis compared with 35.2% in controls. They also found high-dose LMWH therapy (> 3,400 U daily) to be associated with a significantly lower incidence of DVT than low-dose LMWH therapy (≤ 3,400 U daily) (7.9% vs 14.5%, respectively; P < .01). No differences were demonstrated between LMWH and UFH in preventing DVT, DVT location, or bleeding. Bleeding complications requiring discontinuation of pharmacologic prophylaxis occurred in 3% of patients overall.

Implications of HIT

The sequelae of heparin-induced thrombocytopenia (HIT) can have major consequences for cancer surgery patients. The incidence of HIT is markedly lower with LMWH than with UFH, as demonstrated in a nested case-control study by Creekmore et al.²⁶ These researchers also found that the average cost of an admission during which HIT developed was nearly four times as great as the average cost of an admission during which UFH or LMWH was given without development of HIT ($56,364 vs $15,231; P < .001).

EVIDENCE IN SPECIFIC ONCOLOGIC POPULATIONS

Most of the patients in the trials reviewed above underwent abdominal surgery for malignancy. Although studies of VTE prophylaxis in patients undergoing nonabdominal cancer surgery are relatively few, some data are available for a few other specific oncologic populations, as reviewed below.

Surgery for gynecologic cancer

There is a paucity of randomized controlled trials or prospective observational studies on VTE and its prevention in the gynecologic cancer surgery population. Based on small historical studies, the postoperative risk of VTE in this population varies from 12% to 35%.^27,28 Twice-daily administration of UFH 5,000 U appears to be ineffective as VTE prophylaxis in this population, but increasing the frequency to three times daily reduces VTE risk by 50% to 60% compared with placebo. Once-daily LMWH is comparable to three-times-daily UFH in efficacy and safety in this population.

A systematic Cochrane review of eight randomized controlled trials in patients undergoing major gynecologic surgery revealed that heparin prophylaxis (either UFH or LMWH) reduces the risk of DVT by 70% compared with no prophylaxis, with an identical risk reduction specifically among women with malignancy (odds ratio, 0.30; 95% CI, 0.10 to 0.89).²⁹ This review found no evidence that anticoagulation reduces the risk of PE following major gynecologic surgery. LMWH and UFH were similar in efficacy for preventing DVT and had a comparable risk of bleeding complications.

Surgery for urologic cancer

The risk of VTE and the benefits of thromboprophylaxis also are poorly studied in patients undergoing surgery for urologic cancer.

The risk of VTE varies with the type of urologic surgery and the method used to diagnose VTE. For instance, patients undergoing radical retropubic prostatectomy have been reported to develop DVT at rates of 1% to 3%, PE at rates of 1% to 3%, and fatal PE at a rate of 0.6%, whereas the incidences of these events are somewhat higher in patients undergoing cystectomy: 8% for DVT, 2% to 4% for PE, and 2% for fatal PE. Radiologic diagnosis of thromboembolism in pelvic surgery patients has yielded higher incidences, with DVT rates of 21% to 51% and PE rates of 11% to 22%.³⁰

Small studies suggest that prophylaxis with either low-dose UFH or LMWH is both effective in reducing VTE risk and safe in urologic cancer surgery patients, although pharmacologic prophylaxis poses a possible increased risk of pelvic hematoma and lymphocele formation in this population.³⁰

Neurosurgery

Most neurosurgical procedures are performed for malignancies. The risk of venography-confirmed VTE in patients undergoing neurosurgery is approximately 30% to 40%.^31,32 Likewise, the risks of intracranial or intraspinal hemorrhage in these patients are high. For this reason, mechanical methods of VTE prophylaxis are preferred in these patients. The use of anticoagulant prophylaxis remains controversial in this setting, although more recent data suggest that it might be safer than previously recognized.

A meta-analysis of studies of pharmacologic prophylaxis of VTE in neurosurgery included three randomized controlled trials that compared LMWH, with or without mechanical prophylaxis, to placebo plus mechanical prophylaxis or placebo alone in a total of 922 neurosurgery patients.³³ As detailed in Table 2, the analysis demonstrated statistically significant reductions in the risks of VTE and proximal DVT in favor of LMWH, with a statistically significant doubling in the risk of any bleeding and a nonsignificant 70% increase in the risk of major bleeding with LMWH therapy. The number needed to treat to prevent 1 proximal DVT was 16, while the number needed to treat to cause 1 major bleeding event was 115. A risk-benefit analysis showed that the use of LMWH in neurosurgery patients was associated with 1 major nonfatal bleeding event for every 7 proximal DVTs prevented. When a fourth randomized trial was included in the analysis, comparing UFH 5,000 U three times daily with no prophylaxis, rates of VTE and bleeding events remained similar to those for the LMWH trials alone.

GUIDELINES FOR VTE PROPHYLAXIS IN THE CANCER SURGERY PATIENT

American College of Chest Physicians

The American College of Chest Physicians’ Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy makes a number of recommendations regarding VTE prevention in patients undergoing surgery for cancer, as outlined in Table 3.³⁴

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) recently published clinical practice guidelines on venous thromboembolic disease in cancer patients.³⁵ The defined at-risk population for these guidelines is the adult cancer inpatient with a diagnosis of (or clinical suspicion for) cancer. The guidelines recommend prophylactic anticoagulation (category 1 recommendation) with or without a sequential compression device as initial prophylaxis, unless the patient has a relative contraindication to anticoagulation, in which case mechanical prophylaxis (sequential compression device or graduated compression stockings) is recommended. (A category 1 recommendation indicates “uniform NCCN consensus, based on high-level evidence.”)

The NCCN guidelines include a specific recommended risk-factor assessment, which includes noting the patient’s age (VTE risk increases beginning at age 40 and then steeply again at age 75), any prior VTE, the presence of familial thrombophilia or active cancer, the use of medications associated with increased VTE risk (chemotherapy, exogenous estrogen compounds, and thalidomide or lenalidomide), and a number of other risk factors for VTE as outlined in the prior two articles in this supplement. The NCCN guidelines explicitly call for assessment of modifiable risk factors for VTE (ie, smoking or other tobacco use, obesity, and a low level of activity or lack of exercise) and call for active patient education on these factors.

American Society of Clinical Oncology

The American Society of Clinical Oncology (ASCO) recently released guidelines on VTE prevention and treatment in patients with cancer;¹ their key recommendations for prevention are summarized in Table 4. Notable differences from the recommendations of the Seventh ACCP Conference are the ASCO guidelines’ inclusion of fondaparinux among recommended prophylactic options for this population and more explicit recommendations on the prophylactic use of LMWH. Also, for treatment of cancer patients with established VTE, ASCO specifies that LMWH is the preferred anticoagulant for both initial and continuing treatment.

Our recommended algorithm

Figure 1. Algorithm for VTE prophylaxis in the patient undergoing major surgery for cancer.

Drawing from the above formal society guidelines and the published literature, we recommend the algorithm in Figure 1 as a practical approach to VTE prevention in patients undergoing major surgery for cancer.

LINGERING CHALLENGE OF UNDERUTILIZATION

Despite this consensus on ways to reduce thromboembolic risk in this population and the clear evidence of the benefit of VTE prophylaxis in patients with cancer, data from several registries confirm a persistently low utilization of prophylaxis in patients with cancer.^36–38 The global Fundamental Research in Oncology and Thrombosis (FRONTLINE) study surveyed 3,891 clinicians who treat cancer patients regarding their practices with respect to VTE in those patients.36 The survey found that only 52% of respondents routinely used thromboprophylaxis for their surgical patients with cancer. More striking, however, was the finding that most respondents routinely considered thrombo-prophylaxis in only 5% of their medical oncology patients. These data are echoed by findings of other retrospective medical record reviews in patients undergoing major abdominal or abdominothoracic surgery (in many cases for cancer), with VTE prophylaxis rates ranging from 38% to 75%.^37,38

SUMMARY

Patients undergoing surgery for cancer have an increased risk of VTE and fatal PE, even when thromboprophylaxis is used. Nevertheless, prophylaxis with either LMWH or UFH does reduce venographic VTE event rates in these patients. If UFH is chosen for prophylaxis, a three-times-daily regimen should be used in this population. In specific surgical cancer populations, especially those undergoing abdominal surgery, out-of-hospital prophylaxis with once-daily LMWH is warranted. Current registries reveal that compliance with established guidelines for VTE prophylaxis in this population is low.

DISCUSSION: ADDITIONAL PERSPECTIVES FROM THE AUTHORS

Dr. Jaffer: Dr. Amin, based on your study on thrombo-prophylaxis rates in US medical centers, will you comment on rates of prophylaxis for cancer surgery patients?

Dr. Amin: The overall study included approximately 200,000 medical patients and about 80,000 surgical patients enrolled over more than a 3-year period between 2002 and 2005.^39,40 Our goal was to assess rates of prophylaxis and, when it was provided, whether it was appropriate (in terms of type, dosage, and duration) based on the ACCP guidelines. A subanalysis assessed medical cancer patients and surgical cancer patients separately. Medical cancer patients received thromboprophylaxis 56% of the time but received appropriate prophylaxis only 28% of the time. Among surgical cancer patients, appropriate prophylaxis was given only about 24% of the time for those undergoing gynecologic surgery and about 12% of the time for those undergoing neurosurgery. These percentages are consistent with data from other national registries, such as the IMPROVE registry, which documented prophylaxis rates on the order of 45% in medical patients with cancer.⁴¹ We also analyzed the data according to individual practitioners and found that medical oncologists use prophylaxis about 25% of the time, which is relatively consistent with other providers, such as internists and surgeons.

So there is a huge opportunity to improve rates of prophylaxis for this group of patients that national guidelines say are at high risk. Why is prophylaxis so underutilized in the cancer population? One factor may be a misperception about the risk of bleeding with anticoagulants. Yet several studies have shown that the rate of bleeding from prophylaxis is extremely low, whether LMWH or UFH is used, so more awareness of actual bleeding risk is needed. Another factor is the obvious focus among internists and oncologists on treating the patient, with perhaps a reduced consideration of prophylaxis and prevention. A third factor may be a concern about thrombocytopenia. However, in our study of prophylaxis rates in US medical centers, we excluded patients who had thrombocytopenia, yet rates of prophylaxis were still low. Nothing in the literature indicates that anticoagulants cannot be used in patients with platelet counts of 50,000 to 150,000 cells/µL or higher, so this suggests that we need to do more education.

Dr. Jaffer: Dr. Brotman, can you tell us more about how clinicians in practice should use prophylaxis in their neurosurgery patients, such as those undergoing craniotomy or spine surgery for cancer? What is the safest and most efficacious way to prevent DVT in these patients?

Dr. Brotman: First, it’s important to recognize that some sort of prophylaxis needs to be used. Neurosurgery patients are at an extremely high risk for thromboembolic events, and such events are often fatal in these patients. Having said that, the jury is still out on whether the prophylaxis in these patients should be compression devices or anticoagulation. This gives physicians some latitude in their decisions. They can decide not to use pharmacologic prophylaxis so long as they use pneumatic compression devices consistently, perhaps even starting during the operation and certainly throughout hospitalization when the patient is immobilized.

Certainly, the concerns about using full-dose anticoagulation in the immediate postoperative setting in neurosurgery patients are valid. Yet these patients are at very high risk for thromboembolic events, and if we take too cautious an approach to prophylaxis in the immediate perioperative setting, more patients are going to have thromboembolic events, at which point management decisions become much more difficult. The risk of intracranial bleeding with anticoagulation to treat a patient who develops a DVT at postoperative day 10 will certainly be higher than it would have been with lower-dose perioperative prophylactic anticoagulation. Plus, if you put in a filter at that point, the outcomes tend to be poor. Therefore, I believe there is some degree of risk that we should be willing to take with regard to perioperative bleeding, even in neurosurgery patients.

Dr. McKean: I’d like to make a point about combination prophylaxis. At many institutions, compression stockings and sequential compression devices are used preoperatively and intraoperatively, and then pharmacologic prophylaxis—for example, twice-daily UFH—is used postoperatively. There is concern that these patients are hypercoagulable, and most clinicians believe that mechanical prophylaxis alone, even with sequential compression devices plus compression stockings, is not aggressive enough in these high-risk patients.

Dr. Jaffer: Dr. Spyropoulos, what is the optimal duration of pharmacologic prophylaxis for cancer surgery patients?

Dr. Spyropoulos: First let’s consider in-hospital prophylaxis. The supportive data for in-hospital prophylaxis are strong, and the duration of therapy used in the major in-hospital prophylaxis trials was 7 to 10 days. With regard to extended prophylaxis, we have at least two moderately sized randomized controlled trials, ENOXACAN II²³ and the substudy of FAME,²⁴ that demonstrated that extending prophylaxis with LMWH at doses of 3,400 U once daily (5,000 IU of dalteparin; 40 mg of enoxaparin) reduces VTE risk at postoperative day 30. Also, recent data from the @RISTOS registry show that in cancer surgery patients, especially those having abdominal or pelvic procedures, the leading cause of 30-day mortality was VTE.⁸ This registry also shows that despite prophylaxis, the rate of symptomatic VTE can be as high as 2%, with the rate of fatal VTE approaching 1%. Thus, in cancer patients undergoing abdominal or pelvic surgery, physicians should strongly consider prophylaxis of up to 30 days’ duration.

Dr. Jaffer: One striking finding from the @RISTOS registry was that 40% of VTE events in these cancer surgery patients occurred after postoperative day 21. This really underscores the need to consider prophylaxis for at least 4 weeks in these patients in real-world practice.

Dr. Brotman: The other striking finding from that registry was that the in-hospital prophylaxis rate was quite high, about 80%, and the rate of extended prophylaxis approached 35%. These are rates that are rarely achieved in clinical practice. Yet despite these high levels of prophylaxis, patients in this registry still had a high incidence of morbidity and mortality from VTE. This suggests that we need to improve our out-of-hospital VTE prevention paradigms.

Dr. Jaffer: Dr. Deitelzweig, oncologists and internists are often unsure about whether their ambulatory cancer patients who are receiving chemotherapy should be on any form of prophylaxis. What is your opinion?

Dr. Deitelzweig: That question comes up regularly because these patients are encountered across many medical specialties. At this point, all of the large organizations, including ASCO and NCCN, are advocating that prophylaxis is not indicated for such patients.

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Author and Disclosure Information

Daniel J. Brotman, MD
Director, Hospitalist Program; Associate Professor of Medicine, Johns Hopkins Hospital, Baltimore, MD

Steven B. Deitelzweig, MD
Vice President of Medical Affairs; Chairman, Department of Hospital Medicine, Ochsner Health System, New Orleans, LA

Amir K. Jaffer, MD
Associate Professor of Medicine; Chief, Division of Hospital Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL

Sylvia C. McKean, MD
Medical Director, BWH/Faulkner Hospitalist Service; Associate Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA

Correspondence: Alex C. Spyropoulos, MD, Chair, Clinical Thrombosis Center, Lovelace Medical Center, 500 Walter Street NE, Suite 301, Albuquerque, NM 87108; alex.spyropoulos@lovelace.com

Dr. Spyropoulos reported that he has received consulting fees from Sanofi-Aventis, Eisai, and Boehringer Ingelheim.

Dr. Brotman reported that he has no financial relationships with commercial interests that are relevant to this article.

Dr. Amin reported that he has received research funding and honoraria for speaking from Sanofi-Aventis, Eisai, and GlaxoSmithKline.

Drs. Deitelzweig and McKean each reported that they have received honoraria for teaching/speaking from Sanofi-Aventis.

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