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What Is the Optimal Therapy for Acute DVT?
The Case
A 55-year-old female undergoes cholecystectomy. On post-operative Day 2, she develops right-lower-extremity swelling and pain; venous ultrasound detects a proximal deep venous thrombosis (DVT). The patient denies smoking or use of hormonal medications. She has no history of venous thromboembolism (VTE), although her brother had a DVT at age 60. The hospitalist team is consulted for management of acute DVT.
Overview
VTE, including lower- and upper-extremity DVT and pulmonary embolism (PE), is one of the most common and preventable hospital diseases. DVT with PE is associated with a 10% mortality rate, and DVT with post-thrombotic syndrome can be associated with significant morbidity, including pain, edema, skin/pigment change, venous dilation, and ulcer development.1,2 Recognition of clinical symptoms and risk factors for DVT (see Table 1) in conjunction with validated clinical scoring predictors (such as the Wells Prediction Rule) and a high-sensitivity D-dimer assay can help diagnose the condition and determine the need for ultrasound.3-7
Pharmacologic Treatment
Anticoagulation should be initiated in all patients with VTE, regardless of patient symptoms. Anticoagulant options include:
- Intravenous (IV) or subcutaneous (SC) unfractionated heparin (UFH);
- SC low-molecular-weight heparins (LMWH), such as enoxaparin and dalteparin; and
- Fondaparinux (as effective as LMWH for acute treatment of VTE).8
These agents can be used while transitioning to oral vitamin K antagonists (VKA), such as warfarin.3
The 2012 American College of Chest Physicians (ACCP) guidelines on antithrombotic therapy for VTE recommend initial therapy with LMWH or fondaparinux (rather than IV or SC UFH). The guidelines suggest that LMWH once-daily dosing is favored over twice-daily dosing, based mainly on patient convenience, although this is a weak recommendation (2C) based on the overall quality of the data. The recommendation applies only if the daily dosing of the LMWH, including tinzaparin, dalteparin, and nadroparin, is equivalent to the twice-daily dosing (i.e., dalteparin may be dosed at 100 units/kg BID vs. 200 units/kg daily). Of importance, enoxaparin has not been studied at a once-daily dose (2 mg/kg), which is equivalent to the twice-daily dosing regimen (1 mg/kg twice daily). Additionally, one study suggests that once-daily dosing of enoxaparin 1.5mg/kg might be inferior to 1 mg/kg twice-daily dosing; therefore, caution must be exercised in applying this recommendation to the LMWH enoxaparin at this time.3,27,28 (updated Aug. 28, 2012)
Warfarin should be started simultaneously at a usual daily dose of 5 mg for the first two days, with subsequent doses adjusted to achieve a goal international normalized ratio (INR) of 2.0 to 3.0. Parenteral agents should be given for a minimum of five days and until the INR has been >2.0 for at least 24 hours.3
The new factor-Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran are promising oral alternatives to warfarin.9-11 However, neither drug is currently FDA-approved for the treatment of VTE, nor are they recommended by current guidelines (given limited data for DVT treatment and concerns of bleeding risk).3,12,13 See Table 2 (above) for comparisons of common anticoagulants.3,14-17
Duration of anticoagulation. Anticoagulant treatment of acute DVT should continue for at least three months, as shorter durations are associated with higher recurrence rates. Longer treatment may be indicated depending on the patient’s risk of recurrence.3
The ACCP guidelines estimate risk of recurrence using primary, secondary, and additional factors (see Table 3, p. 19) and recommend the following durations:
- First episode provoked: three months (proximal or distal, provoked by surgery or a nonsurgical transient risk factor);
- First episode unprovoked distal: three months (see “Considerations for isolated distal DVT,” below);
- First episode unprovoked proximal: Indefinite if low to moderate bleeding risk, three months if high bleeding risk;
- Recurrent unprovoked: Indefinite if low to moderate bleeding risk, three months if high bleeding risk; and
- With active cancer: Indefinite with LMWH due to higher risk of recurrence.3,18
These treatment duration guidelines might need to be individualized based on other factors including patient preference, ability to obtain accurate INR monitoring (for those on warfarin), treatment cost, and comorbidities.3
Considerations for isolated distal DVT. Patients with an initial episode of distal DVT, without significant symptoms or risk factors for extension (e.g. positive D-dimer, extensive clot near proximal veins, absence of a reversible provoking factor, active cancer, inpatient status, or previous VTE) might not need anticoagulation.
The DVT can be followed with serial ultrasounds for the first two weeks; anticoagulation is recommended only if the thrombus extends during that time period. The development of significant symptoms or risk factors of extension might indicate the need for anticoagulation.3
Considerations for upper-extremity DVT (UEDVT). Anticoagulation for an UEDVT is generally consistent with the above guidelines for lower-extremity DVT, with a few caveats. If an UEDVT is associated with a central venous catheter (CVC), the CVC should be removed if possible; there are no recommendations to determine whether CVC removal should be preceded by a period of anticoagulation.
A catheter-associated UEDVT requires a minimum of three months of anticoagulation; if the CVC remains in place beyond three months, anticoagulation should be continued until the catheter is removed. Unprovoked UEDVT has a lower risk of recurrence than lower-extremity DVT and three months of anticoagulation, rather than indefinite therapy, is recommended.3
Mechanical Treatment
Non-pharmacologic therapies, such as knee-high graduated compression stockings with pressure of 30 mmHg to 40 mmHg at the ankle, can help reduce the morbidity of post-thrombotic syndrome (PTS) when combined with anticoagulation. Symptomatic patients who use compression stockings as soon as feasible and for a minimum of two years can reduce their incidence of PTS by 50%.3,19,20
Thigh-length stockings are not more effective than knee-high, and while multilayer compression bandages might relieve symptoms during the first-week post-DVT, they do not reduce the one-year incidence of PTS.21,22 Early mobilization is not associated with an increased risk of PE, extension of DVT, or death; patients should ambulate as soon as physically able.23,24
Pharmacomechanical Thrombolysis
For acute DVT, ACCP guidelines recommend anticoagulation alone over pharmacomechanical thrombolysis (either systemic or catheter-directed thrombolysis and mechanical thrombus fragmentation). The rare patient with impending venous gangrene despite anticoagulation is the only clinical scenario in which thrombolysis is clearly indicated. Patients who undergo pharmacomechanical thrombolysis still need a standard course of anticoagulation.3
Role for Inferior Vena Cava Filters
The optimal role of inferior vena cava (IVC) filters remains uncertain. Only one randomized trial found that IVC filters, in conjunction with systemic anticoagulation versus systemic anticoagulation alone, were associated with short-term reductions in the incidence of PE but long-term increases in recurrent DVT, with no differences in mortality or major bleeding. However, no trials have compared anticoagulation plus IVC filter placement with IVC filter placement alone.25,26
ACCP guidelines recommend IVC filter placement only in patients with acute, proximal DVT of the lower extremity, and a contraindication to anticoagulant therapy. If the contraindication resolves, a conventional course of anticoagulation can commence. Combining an IVC filter with an anticoagulant is not recommended. The risks and benefits of retrievable filters require further investigation.3
Back to the Case
Our patient has a provoked DVT secondary to a reversible risk factor (surgery) without additional clinical risk factors. Her family history of DVT is not significant (her brother was >age 50 when it occurred). This patient should be treated with LMWH or fondaparinux with initiation of warfarin with goal INR of 2.0 to 3.0 for at least three months. She does not need an IVC filter, and she should use compression stockings to reduce the risk of PTS.
Bottom Line
In hospitalized patients, treatment of DVT should include immediate anticoagulation with LMWH, fondaparinux, or IV heparin (in patients with renal failure) with transition to warfarin and a goal INR of 2.0 to 3.0. New oral anticoagulants could prove beneficial in acute treatment of DVT but require further testing. Duration of treatment is patient-specific, but most should be anticoagulated for at least three months; some warrant indefinite therapy based on risk factors.
Dr. Sebasky is an assistant professor and Dr. DeKorte is assistant professor of medicine in the division of hospital medicine at the University of California at San Diego.
References
- Agency for Healthcare Research and Quality. Talking Points to Attract Administration Support for Venous Thromboembolism Prevention Programs. U.S. Department of Health & Human Services website. Available at: http://www.ahrq.gov/qual/vtguide/vtguideapa.htm. Accessed Feb. 4, 2012.
- Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6:1105-1112.
- Kearon C, Akl E, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-e494S.
- Hirsh J, Hull RD, Raskob GE. Clinical features and diagnosis of venous thrombosis. J Am Coll Cardiol. 1986;8(6 Suppl B):114B-127B.
- 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 Int Med. 2007;146:454-458.
- Tapson VF, Carroll BA, Davidson BL, et al. The diagnostic approach to acute venous thromboembolism. Clinical practice guideline. American Thoracic Society. Am J Respir Crit Care Med. 1999;160:1043-1066.
- Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this patient have deep vein thrombosis? JAMA. 2006;295:199-207.
- Büller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140:867-873.
- EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-25
- Garcia, D, Libby E, Crowther M. The new oral anticoagulants. Blood. 2010;115:15-20.
- Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des. 2010;16:3436-3441.
- U.S. Food and Drug Administration. Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication—Safety Review of Post-Market Reports of Serious Bleeding Events. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/
SafetyAlertsforHumanMedicalProducts/ucm282820.htm. Accessed March 12, 2012.
- Levi M, Erenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011;9:1705.
- Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2010;8(9);CD001100.Vardi M, Zittan E, Bitterman H. Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2009;(4):CD006771.
- Hirsh J, Levine MN. Low molecular weight heparin. Blood. 1992;79:1-17.
- Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361;2342-2352.
- Bauer KA. Long-term management of venous thromboembolism. JAMA. 2011;305:1336-1345.
- Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the postthrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.
- Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:759-762.
- Prandoni P, Noventa F, Quintavalla R, et al. Thigh-length versus below-knee compression elastic stockings for prevention of the post-thrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial. Blood. 2012;119:1561-1565.
- Roumen-Klappe EM, den Heijer M, van Rossum J, et al. Multilayer compression bandaging in the acute phase of deep-vein thrombosis has no effect on the development of the post-thrombotic syndrome. J Thromb Thrombolysis. 2009;27:400-405.
- Aissaoui N, Martins E, Mouly S, Weber S, Meune C. A meta-analysis of bed rest versus early ambulation in the management of pulmonary embolism, deep venous thrombosis, or both. Int J Cardiol. 2009;137:37-41.
- Anderson CM, Overend TJ, Godwin J, Sealy C, Sunderji A. Ambulation after deep vein thrombosis: a systematic review. Physiother Can. 2009;61:133-140.
- Hann CL, Streiff MB. The role of vena caval filters in the management of venous thromboembolism. Blood Rev. 2005;19:179-202.
- Decousus H, Leizorovicz A, Page Y, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med. 1998;338:409-415.
The Case
A 55-year-old female undergoes cholecystectomy. On post-operative Day 2, she develops right-lower-extremity swelling and pain; venous ultrasound detects a proximal deep venous thrombosis (DVT). The patient denies smoking or use of hormonal medications. She has no history of venous thromboembolism (VTE), although her brother had a DVT at age 60. The hospitalist team is consulted for management of acute DVT.
Overview
VTE, including lower- and upper-extremity DVT and pulmonary embolism (PE), is one of the most common and preventable hospital diseases. DVT with PE is associated with a 10% mortality rate, and DVT with post-thrombotic syndrome can be associated with significant morbidity, including pain, edema, skin/pigment change, venous dilation, and ulcer development.1,2 Recognition of clinical symptoms and risk factors for DVT (see Table 1) in conjunction with validated clinical scoring predictors (such as the Wells Prediction Rule) and a high-sensitivity D-dimer assay can help diagnose the condition and determine the need for ultrasound.3-7
Pharmacologic Treatment
Anticoagulation should be initiated in all patients with VTE, regardless of patient symptoms. Anticoagulant options include:
- Intravenous (IV) or subcutaneous (SC) unfractionated heparin (UFH);
- SC low-molecular-weight heparins (LMWH), such as enoxaparin and dalteparin; and
- Fondaparinux (as effective as LMWH for acute treatment of VTE).8
These agents can be used while transitioning to oral vitamin K antagonists (VKA), such as warfarin.3
The 2012 American College of Chest Physicians (ACCP) guidelines on antithrombotic therapy for VTE recommend initial therapy with LMWH or fondaparinux (rather than IV or SC UFH). The guidelines suggest that LMWH once-daily dosing is favored over twice-daily dosing, based mainly on patient convenience, although this is a weak recommendation (2C) based on the overall quality of the data. The recommendation applies only if the daily dosing of the LMWH, including tinzaparin, dalteparin, and nadroparin, is equivalent to the twice-daily dosing (i.e., dalteparin may be dosed at 100 units/kg BID vs. 200 units/kg daily). Of importance, enoxaparin has not been studied at a once-daily dose (2 mg/kg), which is equivalent to the twice-daily dosing regimen (1 mg/kg twice daily). Additionally, one study suggests that once-daily dosing of enoxaparin 1.5mg/kg might be inferior to 1 mg/kg twice-daily dosing; therefore, caution must be exercised in applying this recommendation to the LMWH enoxaparin at this time.3,27,28 (updated Aug. 28, 2012)
Warfarin should be started simultaneously at a usual daily dose of 5 mg for the first two days, with subsequent doses adjusted to achieve a goal international normalized ratio (INR) of 2.0 to 3.0. Parenteral agents should be given for a minimum of five days and until the INR has been >2.0 for at least 24 hours.3
The new factor-Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran are promising oral alternatives to warfarin.9-11 However, neither drug is currently FDA-approved for the treatment of VTE, nor are they recommended by current guidelines (given limited data for DVT treatment and concerns of bleeding risk).3,12,13 See Table 2 (above) for comparisons of common anticoagulants.3,14-17
Duration of anticoagulation. Anticoagulant treatment of acute DVT should continue for at least three months, as shorter durations are associated with higher recurrence rates. Longer treatment may be indicated depending on the patient’s risk of recurrence.3
The ACCP guidelines estimate risk of recurrence using primary, secondary, and additional factors (see Table 3, p. 19) and recommend the following durations:
- First episode provoked: three months (proximal or distal, provoked by surgery or a nonsurgical transient risk factor);
- First episode unprovoked distal: three months (see “Considerations for isolated distal DVT,” below);
- First episode unprovoked proximal: Indefinite if low to moderate bleeding risk, three months if high bleeding risk;
- Recurrent unprovoked: Indefinite if low to moderate bleeding risk, three months if high bleeding risk; and
- With active cancer: Indefinite with LMWH due to higher risk of recurrence.3,18
These treatment duration guidelines might need to be individualized based on other factors including patient preference, ability to obtain accurate INR monitoring (for those on warfarin), treatment cost, and comorbidities.3
Considerations for isolated distal DVT. Patients with an initial episode of distal DVT, without significant symptoms or risk factors for extension (e.g. positive D-dimer, extensive clot near proximal veins, absence of a reversible provoking factor, active cancer, inpatient status, or previous VTE) might not need anticoagulation.
The DVT can be followed with serial ultrasounds for the first two weeks; anticoagulation is recommended only if the thrombus extends during that time period. The development of significant symptoms or risk factors of extension might indicate the need for anticoagulation.3
Considerations for upper-extremity DVT (UEDVT). Anticoagulation for an UEDVT is generally consistent with the above guidelines for lower-extremity DVT, with a few caveats. If an UEDVT is associated with a central venous catheter (CVC), the CVC should be removed if possible; there are no recommendations to determine whether CVC removal should be preceded by a period of anticoagulation.
A catheter-associated UEDVT requires a minimum of three months of anticoagulation; if the CVC remains in place beyond three months, anticoagulation should be continued until the catheter is removed. Unprovoked UEDVT has a lower risk of recurrence than lower-extremity DVT and three months of anticoagulation, rather than indefinite therapy, is recommended.3
Mechanical Treatment
Non-pharmacologic therapies, such as knee-high graduated compression stockings with pressure of 30 mmHg to 40 mmHg at the ankle, can help reduce the morbidity of post-thrombotic syndrome (PTS) when combined with anticoagulation. Symptomatic patients who use compression stockings as soon as feasible and for a minimum of two years can reduce their incidence of PTS by 50%.3,19,20
Thigh-length stockings are not more effective than knee-high, and while multilayer compression bandages might relieve symptoms during the first-week post-DVT, they do not reduce the one-year incidence of PTS.21,22 Early mobilization is not associated with an increased risk of PE, extension of DVT, or death; patients should ambulate as soon as physically able.23,24
Pharmacomechanical Thrombolysis
For acute DVT, ACCP guidelines recommend anticoagulation alone over pharmacomechanical thrombolysis (either systemic or catheter-directed thrombolysis and mechanical thrombus fragmentation). The rare patient with impending venous gangrene despite anticoagulation is the only clinical scenario in which thrombolysis is clearly indicated. Patients who undergo pharmacomechanical thrombolysis still need a standard course of anticoagulation.3
Role for Inferior Vena Cava Filters
The optimal role of inferior vena cava (IVC) filters remains uncertain. Only one randomized trial found that IVC filters, in conjunction with systemic anticoagulation versus systemic anticoagulation alone, were associated with short-term reductions in the incidence of PE but long-term increases in recurrent DVT, with no differences in mortality or major bleeding. However, no trials have compared anticoagulation plus IVC filter placement with IVC filter placement alone.25,26
ACCP guidelines recommend IVC filter placement only in patients with acute, proximal DVT of the lower extremity, and a contraindication to anticoagulant therapy. If the contraindication resolves, a conventional course of anticoagulation can commence. Combining an IVC filter with an anticoagulant is not recommended. The risks and benefits of retrievable filters require further investigation.3
Back to the Case
Our patient has a provoked DVT secondary to a reversible risk factor (surgery) without additional clinical risk factors. Her family history of DVT is not significant (her brother was >age 50 when it occurred). This patient should be treated with LMWH or fondaparinux with initiation of warfarin with goal INR of 2.0 to 3.0 for at least three months. She does not need an IVC filter, and she should use compression stockings to reduce the risk of PTS.
Bottom Line
In hospitalized patients, treatment of DVT should include immediate anticoagulation with LMWH, fondaparinux, or IV heparin (in patients with renal failure) with transition to warfarin and a goal INR of 2.0 to 3.0. New oral anticoagulants could prove beneficial in acute treatment of DVT but require further testing. Duration of treatment is patient-specific, but most should be anticoagulated for at least three months; some warrant indefinite therapy based on risk factors.
Dr. Sebasky is an assistant professor and Dr. DeKorte is assistant professor of medicine in the division of hospital medicine at the University of California at San Diego.
References
- Agency for Healthcare Research and Quality. Talking Points to Attract Administration Support for Venous Thromboembolism Prevention Programs. U.S. Department of Health & Human Services website. Available at: http://www.ahrq.gov/qual/vtguide/vtguideapa.htm. Accessed Feb. 4, 2012.
- Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6:1105-1112.
- Kearon C, Akl E, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-e494S.
- Hirsh J, Hull RD, Raskob GE. Clinical features and diagnosis of venous thrombosis. J Am Coll Cardiol. 1986;8(6 Suppl B):114B-127B.
- 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 Int Med. 2007;146:454-458.
- Tapson VF, Carroll BA, Davidson BL, et al. The diagnostic approach to acute venous thromboembolism. Clinical practice guideline. American Thoracic Society. Am J Respir Crit Care Med. 1999;160:1043-1066.
- Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this patient have deep vein thrombosis? JAMA. 2006;295:199-207.
- Büller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140:867-873.
- EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-25
- Garcia, D, Libby E, Crowther M. The new oral anticoagulants. Blood. 2010;115:15-20.
- Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des. 2010;16:3436-3441.
- U.S. Food and Drug Administration. Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication—Safety Review of Post-Market Reports of Serious Bleeding Events. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/
SafetyAlertsforHumanMedicalProducts/ucm282820.htm. Accessed March 12, 2012.
- Levi M, Erenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011;9:1705.
- Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2010;8(9);CD001100.Vardi M, Zittan E, Bitterman H. Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2009;(4):CD006771.
- Hirsh J, Levine MN. Low molecular weight heparin. Blood. 1992;79:1-17.
- Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361;2342-2352.
- Bauer KA. Long-term management of venous thromboembolism. JAMA. 2011;305:1336-1345.
- Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the postthrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.
- Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:759-762.
- Prandoni P, Noventa F, Quintavalla R, et al. Thigh-length versus below-knee compression elastic stockings for prevention of the post-thrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial. Blood. 2012;119:1561-1565.
- Roumen-Klappe EM, den Heijer M, van Rossum J, et al. Multilayer compression bandaging in the acute phase of deep-vein thrombosis has no effect on the development of the post-thrombotic syndrome. J Thromb Thrombolysis. 2009;27:400-405.
- Aissaoui N, Martins E, Mouly S, Weber S, Meune C. A meta-analysis of bed rest versus early ambulation in the management of pulmonary embolism, deep venous thrombosis, or both. Int J Cardiol. 2009;137:37-41.
- Anderson CM, Overend TJ, Godwin J, Sealy C, Sunderji A. Ambulation after deep vein thrombosis: a systematic review. Physiother Can. 2009;61:133-140.
- Hann CL, Streiff MB. The role of vena caval filters in the management of venous thromboembolism. Blood Rev. 2005;19:179-202.
- Decousus H, Leizorovicz A, Page Y, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med. 1998;338:409-415.
The Case
A 55-year-old female undergoes cholecystectomy. On post-operative Day 2, she develops right-lower-extremity swelling and pain; venous ultrasound detects a proximal deep venous thrombosis (DVT). The patient denies smoking or use of hormonal medications. She has no history of venous thromboembolism (VTE), although her brother had a DVT at age 60. The hospitalist team is consulted for management of acute DVT.
Overview
VTE, including lower- and upper-extremity DVT and pulmonary embolism (PE), is one of the most common and preventable hospital diseases. DVT with PE is associated with a 10% mortality rate, and DVT with post-thrombotic syndrome can be associated with significant morbidity, including pain, edema, skin/pigment change, venous dilation, and ulcer development.1,2 Recognition of clinical symptoms and risk factors for DVT (see Table 1) in conjunction with validated clinical scoring predictors (such as the Wells Prediction Rule) and a high-sensitivity D-dimer assay can help diagnose the condition and determine the need for ultrasound.3-7
Pharmacologic Treatment
Anticoagulation should be initiated in all patients with VTE, regardless of patient symptoms. Anticoagulant options include:
- Intravenous (IV) or subcutaneous (SC) unfractionated heparin (UFH);
- SC low-molecular-weight heparins (LMWH), such as enoxaparin and dalteparin; and
- Fondaparinux (as effective as LMWH for acute treatment of VTE).8
These agents can be used while transitioning to oral vitamin K antagonists (VKA), such as warfarin.3
The 2012 American College of Chest Physicians (ACCP) guidelines on antithrombotic therapy for VTE recommend initial therapy with LMWH or fondaparinux (rather than IV or SC UFH). The guidelines suggest that LMWH once-daily dosing is favored over twice-daily dosing, based mainly on patient convenience, although this is a weak recommendation (2C) based on the overall quality of the data. The recommendation applies only if the daily dosing of the LMWH, including tinzaparin, dalteparin, and nadroparin, is equivalent to the twice-daily dosing (i.e., dalteparin may be dosed at 100 units/kg BID vs. 200 units/kg daily). Of importance, enoxaparin has not been studied at a once-daily dose (2 mg/kg), which is equivalent to the twice-daily dosing regimen (1 mg/kg twice daily). Additionally, one study suggests that once-daily dosing of enoxaparin 1.5mg/kg might be inferior to 1 mg/kg twice-daily dosing; therefore, caution must be exercised in applying this recommendation to the LMWH enoxaparin at this time.3,27,28 (updated Aug. 28, 2012)
Warfarin should be started simultaneously at a usual daily dose of 5 mg for the first two days, with subsequent doses adjusted to achieve a goal international normalized ratio (INR) of 2.0 to 3.0. Parenteral agents should be given for a minimum of five days and until the INR has been >2.0 for at least 24 hours.3
The new factor-Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran are promising oral alternatives to warfarin.9-11 However, neither drug is currently FDA-approved for the treatment of VTE, nor are they recommended by current guidelines (given limited data for DVT treatment and concerns of bleeding risk).3,12,13 See Table 2 (above) for comparisons of common anticoagulants.3,14-17
Duration of anticoagulation. Anticoagulant treatment of acute DVT should continue for at least three months, as shorter durations are associated with higher recurrence rates. Longer treatment may be indicated depending on the patient’s risk of recurrence.3
The ACCP guidelines estimate risk of recurrence using primary, secondary, and additional factors (see Table 3, p. 19) and recommend the following durations:
- First episode provoked: three months (proximal or distal, provoked by surgery or a nonsurgical transient risk factor);
- First episode unprovoked distal: three months (see “Considerations for isolated distal DVT,” below);
- First episode unprovoked proximal: Indefinite if low to moderate bleeding risk, three months if high bleeding risk;
- Recurrent unprovoked: Indefinite if low to moderate bleeding risk, three months if high bleeding risk; and
- With active cancer: Indefinite with LMWH due to higher risk of recurrence.3,18
These treatment duration guidelines might need to be individualized based on other factors including patient preference, ability to obtain accurate INR monitoring (for those on warfarin), treatment cost, and comorbidities.3
Considerations for isolated distal DVT. Patients with an initial episode of distal DVT, without significant symptoms or risk factors for extension (e.g. positive D-dimer, extensive clot near proximal veins, absence of a reversible provoking factor, active cancer, inpatient status, or previous VTE) might not need anticoagulation.
The DVT can be followed with serial ultrasounds for the first two weeks; anticoagulation is recommended only if the thrombus extends during that time period. The development of significant symptoms or risk factors of extension might indicate the need for anticoagulation.3
Considerations for upper-extremity DVT (UEDVT). Anticoagulation for an UEDVT is generally consistent with the above guidelines for lower-extremity DVT, with a few caveats. If an UEDVT is associated with a central venous catheter (CVC), the CVC should be removed if possible; there are no recommendations to determine whether CVC removal should be preceded by a period of anticoagulation.
A catheter-associated UEDVT requires a minimum of three months of anticoagulation; if the CVC remains in place beyond three months, anticoagulation should be continued until the catheter is removed. Unprovoked UEDVT has a lower risk of recurrence than lower-extremity DVT and three months of anticoagulation, rather than indefinite therapy, is recommended.3
Mechanical Treatment
Non-pharmacologic therapies, such as knee-high graduated compression stockings with pressure of 30 mmHg to 40 mmHg at the ankle, can help reduce the morbidity of post-thrombotic syndrome (PTS) when combined with anticoagulation. Symptomatic patients who use compression stockings as soon as feasible and for a minimum of two years can reduce their incidence of PTS by 50%.3,19,20
Thigh-length stockings are not more effective than knee-high, and while multilayer compression bandages might relieve symptoms during the first-week post-DVT, they do not reduce the one-year incidence of PTS.21,22 Early mobilization is not associated with an increased risk of PE, extension of DVT, or death; patients should ambulate as soon as physically able.23,24
Pharmacomechanical Thrombolysis
For acute DVT, ACCP guidelines recommend anticoagulation alone over pharmacomechanical thrombolysis (either systemic or catheter-directed thrombolysis and mechanical thrombus fragmentation). The rare patient with impending venous gangrene despite anticoagulation is the only clinical scenario in which thrombolysis is clearly indicated. Patients who undergo pharmacomechanical thrombolysis still need a standard course of anticoagulation.3
Role for Inferior Vena Cava Filters
The optimal role of inferior vena cava (IVC) filters remains uncertain. Only one randomized trial found that IVC filters, in conjunction with systemic anticoagulation versus systemic anticoagulation alone, were associated with short-term reductions in the incidence of PE but long-term increases in recurrent DVT, with no differences in mortality or major bleeding. However, no trials have compared anticoagulation plus IVC filter placement with IVC filter placement alone.25,26
ACCP guidelines recommend IVC filter placement only in patients with acute, proximal DVT of the lower extremity, and a contraindication to anticoagulant therapy. If the contraindication resolves, a conventional course of anticoagulation can commence. Combining an IVC filter with an anticoagulant is not recommended. The risks and benefits of retrievable filters require further investigation.3
Back to the Case
Our patient has a provoked DVT secondary to a reversible risk factor (surgery) without additional clinical risk factors. Her family history of DVT is not significant (her brother was >age 50 when it occurred). This patient should be treated with LMWH or fondaparinux with initiation of warfarin with goal INR of 2.0 to 3.0 for at least three months. She does not need an IVC filter, and she should use compression stockings to reduce the risk of PTS.
Bottom Line
In hospitalized patients, treatment of DVT should include immediate anticoagulation with LMWH, fondaparinux, or IV heparin (in patients with renal failure) with transition to warfarin and a goal INR of 2.0 to 3.0. New oral anticoagulants could prove beneficial in acute treatment of DVT but require further testing. Duration of treatment is patient-specific, but most should be anticoagulated for at least three months; some warrant indefinite therapy based on risk factors.
Dr. Sebasky is an assistant professor and Dr. DeKorte is assistant professor of medicine in the division of hospital medicine at the University of California at San Diego.
References
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- Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6:1105-1112.
- Kearon C, Akl E, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-e494S.
- Hirsh J, Hull RD, Raskob GE. Clinical features and diagnosis of venous thrombosis. J Am Coll Cardiol. 1986;8(6 Suppl B):114B-127B.
- 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 Int Med. 2007;146:454-458.
- Tapson VF, Carroll BA, Davidson BL, et al. The diagnostic approach to acute venous thromboembolism. Clinical practice guideline. American Thoracic Society. Am J Respir Crit Care Med. 1999;160:1043-1066.
- Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this patient have deep vein thrombosis? JAMA. 2006;295:199-207.
- Büller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140:867-873.
- EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-25
- Garcia, D, Libby E, Crowther M. The new oral anticoagulants. Blood. 2010;115:15-20.
- Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des. 2010;16:3436-3441.
- U.S. Food and Drug Administration. Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication—Safety Review of Post-Market Reports of Serious Bleeding Events. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/
SafetyAlertsforHumanMedicalProducts/ucm282820.htm. Accessed March 12, 2012.
- Levi M, Erenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011;9:1705.
- Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2010;8(9);CD001100.Vardi M, Zittan E, Bitterman H. Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2009;(4):CD006771.
- Hirsh J, Levine MN. Low molecular weight heparin. Blood. 1992;79:1-17.
- Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361;2342-2352.
- Bauer KA. Long-term management of venous thromboembolism. JAMA. 2011;305:1336-1345.
- Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the postthrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.
- Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:759-762.
- Prandoni P, Noventa F, Quintavalla R, et al. Thigh-length versus below-knee compression elastic stockings for prevention of the post-thrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial. Blood. 2012;119:1561-1565.
- Roumen-Klappe EM, den Heijer M, van Rossum J, et al. Multilayer compression bandaging in the acute phase of deep-vein thrombosis has no effect on the development of the post-thrombotic syndrome. J Thromb Thrombolysis. 2009;27:400-405.
- Aissaoui N, Martins E, Mouly S, Weber S, Meune C. A meta-analysis of bed rest versus early ambulation in the management of pulmonary embolism, deep venous thrombosis, or both. Int J Cardiol. 2009;137:37-41.
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- Hann CL, Streiff MB. The role of vena caval filters in the management of venous thromboembolism. Blood Rev. 2005;19:179-202.
- Decousus H, Leizorovicz A, Page Y, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med. 1998;338:409-415.