Treatment of the Patient with Deep Vein Thrombosis

,

Applied Evidence

Treatment of the Patient with Deep Vein Thrombosis

J Fam Pract. 2001 February;50(2):249-256

By

David Weismantel, MD

References

1. 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;151:933-38.

2. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93.

3. 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;93:2212-45.

4. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J Med 1986;315:1109-14.

5. Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997;157:2562-68.

6. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med 1993;119:874-81.

7. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-98.

8. Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999;130:800-09.

9. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000;160:181-88.

10. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:682-87.

11. Wells PS, Kovacs MJ, Bormanis J, et al. Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection. Arch Intern Med 1998;158:1809-11.

12. Harrison L, McGinnis J, Crowther M, et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998;158:2001-03.

13. Gould MK, Dembitzer AD, Sanders GD, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a cost-effectiveness analysis. Ann Intern Med 1999;130:789-99.

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15. Institute for Clinical Systems Improvement. Health care guideline: deep vein thrombosis. Bloomington, Minn: Institute for Clinical Systems Improvement; 1999.

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17. Partsch H, Kechavarz B, Kohn H, et al. The effect of mobilisation of patients during treatment of thromboembolic disorders with low-molecular-weight heparin. Int Angiol 1997;16:189-92.

18. Schellong SM, Schwarz T, Kropp J, et al. Bed rest in deep vein thrombosis and the incidence of scintigraphic pulmonary embolism. Thromb Haemost 1999;82 (suppl):127-29.

19. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg loading doses. Arch Intern Med 1999;159:46-48.

20. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with 6 months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661-65.

21. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-07.

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Deep vein thrombosis (DVT), defined as a partial or complete occlusion of a deep vein by thrombus, is a relatively uncommon yet important diagnosis in primary care practice. Population-based studies have estimated the age-adjusted incidence of DVT at 48 per 100,000 persons per year, with age-specific rates increasing steadily as the patient grows older.^1,2 A typical family physician could expect to diagnose 1 or 2 patients with DVT each year. In addition to age, other personal risk factors for the development of DVT include previous thromboembolism, pregnancy and the postpartum period, malignancy, inherited thrombophilias, and exogenous estrogen therapy. Environmental risk factors include immobility, trauma, surgery, and intensive care. The classic Virchow triad (stasis, vascular damage, and hypercoagulability) describes the basic pathophysiologic factors that alone or more commonly in combination promote the development of thrombosis.

The previous article in this series described the evaluation of the patient with suspected DVT. In this article I will outline an evidence-based approach to treating a patient with a confirmed diagnosis of DVT Figure 1. Special attention will be given to the selection of cost-effective interventions that minimize the likelihood of acute or long-term complications.

Initial Therapy

Prompt anticoagulation with heparin is the first priority in treating the patient with DVT by preventing the local extension, embolization, and recurrence of venous thromboembolic disease. Heparin acts immediately to catalyze the inhibition of several activated coagulation factors and leads to the stabilization of the intravascular thrombus. Heparinization is typically continued for 3 to 5 days until a stable and therapeutic international normalized ratio (INR) is established with oral warfarin therapy. There are 2 approved approaches available for the acute anticoagulant treatment of DVT: intravenous unfractionated heparin (UH) and subcutaneous low-molecular-weight heparin (LMWH). In the case of a significant contraindication to anticoagulation or a recurrent thromboembolic event despite adequate anticoagulation, an inferior vena caval filter is the treatment of choice.

Unfractionated Heparin

Traditionally the initial treatment of DVT has been anticoagulation with intravenous UH; the goal of this therapy is the prompt establishment of an activated partial thromboplastin time (APTT) of 1.5 to 2.5 times the control.³ The failure to achieve a therapeutic APTT within 24 hours has been associated with an increased likelihood of recurrent thromboembolism (23% vs 5%, absolute risk reduction [ARR]=18%; number needed to treat [NNT]=5.5; level of evidence [LOE]=1b).^4,5 Several protocols for managing UH therapy have been shown to achieve therapeutic anticoagulation more rapidly than traditional approaches. Figure 2 summarizes a weight-based heparin dosing nomogram that has been proved effective, safe, and superior to standard therapy in a randomized controlled trial; this particular protocol achieved therapeutic anticoagulation in 97% of patients within 24 hours (LOE=1b).⁶ Patients treated with UH should remain hospitalized until therapeutically anticoagulated with oral warfarin.

Low-Molecular-Weight Heparin

After the approval of enoxaparin for the treatment of DVT in 1998, acute outpatient management of DVT with LMWH became possible. The advantages of LMWH include fixed dosing, a subcutaneous route of administration, and a more predictable anticoagulant response. Laboratory monitoring is unnecessary except in patients with renal insufficiency, as a result of better bioavailability, longer half-life, and dose-independent clearance. If monitoring of LMWH is necessary, an anti-Xa level of 0.4 to 0.7 U per mL is the goal of therapy.⁷ The only LMWHs currently approved and labeled by the United States Food and Drug Administration for the treatment of acute DVT are enoxaparin at a dosage of 1 mg per kg administered subcutaneously twice daily or 1.5 mg per kg once daily (inpatient therapy only) and tinzaparin at a dosage of 175 anti-Xa IU per kg administered subcutaneously once daily.

The safety and effectiveness of LMWH therapy for acute DVT were demonstrated in a recent meta-analysis of 11 randomized controlled trials with a total of 3674 patients. In comparison with unfractionated heparin, LMWH significantly reduced the risk of death over 3 to 6 months. A trend toward a reduction in recurrent thromboembolic events was also observed. It was concluded that more than 5 negative trials would have to be published in the future and included in a metaanalysis to negate this mortality advantage of LMWH. A summary of this metaanalysis is provided in Table 1 (LOE=1a).⁸ A subsequent meta-analysis of 13 randomized controlled trials with a total of 4447 patients with venous thromboembolism (DVT or pulmonary embolism) found a similar statistically significant reduction in mortality (ARR=1.6%; NNT=60) yet only a trend toward reduction in the risk of recurrent thromboembolism and major bleeding (LOE=1a).⁹ From this information it is apparent that LMWH is at least as safe and effective as UH in the treatment of DVT and that 1 death is prevented for every 60 patients treated with LMWH instead of UH.