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Treatment of the Patient with Deep Vein Thrombosis.

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.

[Figure 1 ILLUSTRATION OMITTED]

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 (APTD 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.
FIGURE 2

WEIGHT-BASED INTRAVENOUS HEPARIN NOMOGRAM

Loading dose:                       80 units/kg
Initial maintenance dose:           18 units/kg/h
Dosage adjustments by APTT level:
  <35 seconds                       80 units/kg bolus, then increase
                                      infusion rate by 4 units/kg/h
  35-45 seconds                     40 units/kg bolus, then increase
                                      infusion rate by 2 units/kg/h
  46-75 seconds                     No change
  71-90 seconds                     Decrease infusion rate by 2
                                      units/kg/h
  >90 seconds                       Hold infusion 1 hour, the decrease
                                      infusion rate by 3 units/kg/h

APTT levels are drawn 6 hours after any dosage change and should be
ordered every 24 hours until 2 consecutive APTTs therapeutic.

NOTE: Adapted from Raschke and colleagues.(6)
APTT denotes activated partial thromboplastin time.


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 metaanalysis 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 meta-analysis to negate this mortality advantage of LMWH. A summary of this meta-analysis 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.
TABLE 1

LMWH VERSUS UH IN THE TREATMENT OF DVT: SUMMARY OF
META-ANALYSIS RESULTS

Variable                Summary         Summary Absolute      Number
                       Odds Ratio       Risk Reduction %     Needed to
                        (95% CI)            (95 CI)            Treat

Major bleeding       0.57(0.33-0.99)   0.61(-0.04 to 1.26)
Recurrent RTE        0.85(0.63-1.14)   0.88(-0.48 to 2.24)
Death (overall)      0.71(0.53-0.94)     1.65(0.36-2.94)         61
Death
  Due to RTE         0.75(0.31-1.79)   0.21(-0.28 to 0.71)
  Due to major
    bleeding         0.67(0.11-4.00)   0.15(-0.20 to 0.51)
  In patients with
    cancer           0.57(0.31-1.03)     9.75(0.34-19.16)        10

NOTE: Adapted from Gould and coworkers.(3)

LMWH denotes low-molecular-weight heparin; UH, unfractionated heparin;
DVT, deep vein thrombosis; CI, confidence interval; RTE,
thromboembolism.


Several studies have demonstrated the efficacy and safety of administering LMWH at home. One study of 400 patients with DVT compared home therapy with LMWH with inpatient UH and failed to demonstrate any significant difference in risk of recurrent thromboembolism or major bleeding (LOE=1b).[10] Additionally, no difference in these clinical outcomes was found in another prospective study comparing patient self-injection with injection by home care nurse (LOE=2B).[11] Patients are both capable and willing to participate in this treatment regimen; 91% were pleased with home therapy, and 70% felt comfortable with serf-injection of LMWH (LOE=2c).[12]

A cost-effectiveness analysis published in 1999 studied the economic viability of universal treatment of acute DVT with LMWH. The cost of initial care was higher in hospitalized patients receiving LMWH, but this was partly offset by the reduced costs for early complications. Treatment with LMWH increased the quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient LMWH treatment was $7820 per additional quality-adjusted life-year. Sensitivity analysis demonstrated that LMWH was cost saving when at least 8% of the patients were treated at home or if late complications were assumed to occur 25% less frequently in patients receiving LMWH. It was concluded that LMWH is highly cost-effective and is the preferred treatment for DVT (LOE=1b).[13]

Because using LMWH to treat outpatients with DVT has the potential to reduce health care costs, several organizations have published recommendations or guidelines suggesting an outpatient alternative for uncomplicated DVT.[3,14,15] It is generally agreed that patients with an uncomplicated DVT, good cardiopulmonary reserve, no excessive bleeding risk, and normal renal function can safely be treated with LMWH at home. Those with the comorbidities or the possible contraindications to anticoagulation noted in Table 2 should typically be hospitalized for initial management. Also, the home therapy patient will require education on the correct dosage and administration of LMWH, recognition of adverse events, and available resources to address problems or questions during the treatment course. Although there is limited evidence to support these specific recommendations, current expert opinion favors a conservative approach in the selection of patients for home treatment of DVT (LOE=5).

TABLE 2

POSSIBLE CONTRAINDICATIONS TO THE OUTPATIENT MANAGEMENT OF DVT WITH LMWH
Recurrent DVT despite adequate anticoagulation
Suspected pulmonary embolism
Extensive iliofemoral disease or edema
Medical instability--lack of cardiorespiratory reserve
Renal insufficiency (creatinine clearance [is less than] 30mL/min)
History of heparin-induced thrombocytopenia
Hereditary coagulation disorder
Pregnancy
Recent trauma
Surgery
Recent cerebrovascular accident

DVT denotes deep vein thrombosis; LMWH, low-molecular-weight heparin.


Whether patients are treated in the hospital or at home, LMWH should be considered the primary standard treatment for DVT. The relative safety, tolerability, efficacy, and cost-effectiveness of LMWH make it the obvious and preferred therapeutic alternative.

VENA CAVAL FILTER PLACEMENT

Placement of an inferior vena caval filter is reserved for patients with a contraindication to anticoagulation; a serious complication of anticoagulation, or recurrent thromboembolism despite adequate anticoagulation. To date there have been no randomized or cohort studies directly comparing inferior vena caval interruption with standard anticoagulation therapy. However, a recent clinical trial of vena caval filter placement in 400 anticoagulated patients revealed a significant decrease in pulmonary embolism assessed at day 12 of therapy (ARR=3.7%; NNT=27) but a significant increase in the rate of recurrent symptomatic DVT over the next 2 years (absolute risk increase [ARI]=9.2%; number needed to harm [NNH]=11; LOE=1b).[16] The available evidence does not support the use of vena caval filters in the management of the patient with an initial and uncomplicated DVT.

ACTIVITY

Patients with acute DVT have traditionally been confined to bed rest for a period of 3 to 7 days, yet there is no evidence that this practice improves clinical outcomes. A study of 638 patients with DVT who were allowed to ambulate with compression stockings demonstrated a low incidence of pulmonary emboli documented by ventilation-perfusion scan when compared with that in the literature (LOE=4).[17] A more recent randomized trial of 126 patients with acute proximal vein thrombosis compared 8 days of strict bed rest with early mobilization; there was no statistically significant difference in the incidence of scintigraphically detectable pulmonary embolism (LOE=1b).[18] These studies do not currently support the previous recommendation of bed rest for the acute treatment of DVT.

EXTENDED THERAPY

After the initial evaluation, stabilization, and treatment of a patient with DVT, a plan is needed to minimize the risk of recurrent thromboembolism and chronic postphlebitic complications. Although unsupported by specific evidence, most recommendations include the discontinuation and avoidance of any exogenous estrogen therapy. Oral anticoagulation with warfarin decreases the incidence of recurrent thromboembolic events, while the extended use of compression stockings decreases the development of the postphlebitic syndrome.

ORAL ANTICOAGULATION WITH WARFARIN

For a patient presenting with a first DVT, oral anticoagulation with warfarin should be initiated on the first day of treatment, after heparin loading is complete. Adequacy of therapy is monitored by measurement of the INR, a standardization of the plasma thromboplastin ratio now used to correct for the variance between laboratories resulting from the use of different thromboplastin reagents. The antithrombotic effect of warfarin is best established after 3 to 5 days; it is for this reason that heparin is overlapped with warfarin during the first several days of therapy. The algorithm in Table 3 has been shown to improve the success of achieving a stable and therapeutic INR by day 5 of therapy with less initial risk of hemorrhagic complication (LOE=1b).[19] The heparin may be discontinued when the INR is within the therapeutic range of 2.0 to 3.0 for patients with DVT (LOE=5).[14]
TABLE 3

ALGORITHM FOR THE INITIATION OF
WARFARIN THERAPY

Day     INR       Dosage

1                  5.0 mg
2      <1.5        5.0 mg
      2.0-2.5      2.5 mg
       >2.5      1.0-2.5 mg
3      <1.5         0 mg
      1.5-1.9   5.0-10.0 mg
      2.0-2.4    2.5-5.0 mg
      2.5-3.0     0-2.5 mg
       >3.0       0-2.5 mg
4      <1.5         0 mg
      1.5-1.9     10.0 mg
      2.0-3.0   7.5-10.0 mg
       >3.0       0-5.0 mg
5      <1.5         0 mg
      1.5-1.9     10.0 mg
      2.0-3.0   7.5-10.0 mg
       >3.0         0 mg
6      <1.5     7.5-12.5 mg
      1.5-1.9   5.0-10.0 mg
      2.0-3.0    0.0-7.5 mg

       >3.0         0 mg

NOTE: Adapted from Crowther and colleagues.(20)

INR denotes international normalized ratio.


The optimal duration of oral anticoagulant therapy for a first episode of DVT varies and depends on whether risk factors are transient or persistent. A comparison of 6 weeks versus 6 months of oral anticoagulant therapy found an increased risk of recurrent venous thromboembolism in the 6-week group. The risk decreased from 18.1% with 6 weeks of treatment to 9.5% with 6 months; 12 patients would have to be treated for 6 months instead of 6 weeks to prevent 1 episode of recurrent venous thromboembolism (NNT=12; LOE=1b).[20] A subsequent comparison of 3 months of anticoagulation with extended oral anticoagulation for approximately 10 months found a reduction in the risk of recurrent venous thromboembolism (ARR=26%; NNT=4) but an increased risk of major bleeding (ARI=3.8%; NNH=26) in the extended therapy group over a period of 2 years (LOE=1b).[21] In general, a longer duration of oral anticoagulant therapy is not surprisingly associated with a decreased risk of venous thromboembolic recurrence and an increased risk of bleeding complications. Using the data from the previously mentioned study, for every 100 patients given extended therapy instead of the traditional 3 months there will be 4 additional major bleeds and 25 fewer episodes of recurrent venous thromboembolism. A recent Cochrane review of 1500 patients in 4 studies similarly found a decreased risk of recurrent venous thromboembolism with prolonged warfarin therapy (0.9% vs 12%, ARR=11.1; NNT=9) but an increased incidence of major bleeding (2.1% vs 0%, ARI=2.1%; NNH=48; LOE=1a).[22] In the case of recurrent DVT, lifetime anticoagulant therapy should be considered in the absence of risk factors for bleeding. The specific recommendations for duration of oral anticoagulation have been adapted from the American College of Chest Physicians (LOE=5)[15] and are included in Figure 1.

COMPRESSION STOCKINGS

The addition of compression stockings to standard oral anticoagulant therapy is supported by a study of 194 patients comparing the use of knee-high 30 to 40 mm Hg custom-fitted graded compression stockings over a 2-year period and a median follow-up of 76 months. The development of mild-moderate postphlebitic syndrome was decreased by 58% (ARR=27.1%; NNT=3.7), and the incidence of severe postphlebitic syndrome was decreased by 51% (ARR=12%; NNT=8.3). Although there was not a significant difference in the rate of recurrent venous thromboembolism, extended use of compression stockings improved the long-term clinical course and should be considered a valuable addition in the long-term management of DVT (LOE=1b).[23]

INVESTIGATION FOR POSSIBLE MALIGNANCY OR COAGULATION DEFECT

Although there is an increased incidence of cancer at the time of presentation in patients with idiopathic DVT (ie, no clear predisposing cause such as bed rest), a complete medical evaluation including history, physical examination, and basic laboratory studies has been shown to adequately detect malignancy in this setting. A retrospective study of 986 consecutive patients found no difference in cancer incidence over the next 34 months among the 142 DVT patients and 844 patients with DVT ruled out by the clinical evaluation outlined in Table 4 (LOE=4).[24] A prospective cohort study of 260 patients with DVT provided 2 years of regular follow-up visits and found that all subsequent cancers were diagnosed because the patient became symptomatic and sought care from a general practitioner (LOE=2b).[25] Beyond initial and age-appropriate cancer screening, there is no evidence that an aggressive search for an underlying malignancy is warranted.

TABLE 4

SUGGESTED MEDICAL EVALUATION OF THE PATIENT WITH DEEP VEIN THROMBOSIS
Thorough medical history and review of systems
Complete physical examination, including:
 Rectal examination
 Pelvic examination
 Breast examination
Age-appropriate cancer screening
Laboratory evaluation
 Complete blood count
 Sedimentation rate
 Renal and liver function tests
 Urinalysis
 Chest radiograph

NOTE: Adapted from Comuz and coworkers.[25]


Inherited thrombophilias are associated with an increased risk for venous thromboembolic disease, yet the diagnosis of one of these defects does not substantially change the clinical management of initial or recurrent DVT. Likewise, counseling regarding the increased risk associated with prolonged immobilization, surgery, pregnancy, and exogenous estrogen therapy would be unchanged. A sensible approach may be to screen for hereditary thrombophilias (factor V Leiden, protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, and hyperhomocysteinuria) in the case of recurrent DVT, a younger patient, or a family history of thromboembolic disease. In the event that an inherited thrombophilia is diagnosed, further screening and possible identification of other family members could lead to avoidance of known secondary risk factors and subsequent thromboembolic events. The typical patient with an initial episode of DVT will not benefit from the investigation for an inherited coagulation defect.

CONCLUSIONS

The clinical and economic outcomes associated with DVT can be improved with a simple evidence-based approach to therapy (Figure 1). Management of a first episode of DVT should begin with immediate anticoagulation with LMWH, preferably at home if there are no contraindications to outpatient management. Oral anticoagulation should be instituted at initial presentation and continued for a period of 3 to 6 months depending on individual risk factors for bleeding. The addition of compression stockings provides symptomatic relief and decreases the incidence of symptomatic postphlebitic syndrome. Extensive evaluation for malignancy or an inherited thrombophilia is not warranted in most cases of DVT.

KEY POINTS

* Low-molecular-weight heparin is the preferred treatment for initial anticoagulation of patients with deep vein thrombosis (DVT).

* Patients with extensive iliofemoral thromboembolic disease and edema, suspected pulmonary embolism, renal insufficiency, pregnancy, and contraindications to anticoagulation are best hospitalized for initial therapy.

* Oral anticoagulation with warfarin should be started immediately and continued for an optimal duration of 3 months to lifetime therapy, depending on existing risk factors.

* An extensive work-up for malignancy or thrombophilias should be based on suspicions noted in the history and physical examination and is not routinely required for all patients with DVT.

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.

[14.] Hyers TM. Antithrombotic therapy for venous thromboembolic disease. Chest 1998; 114 (suppl):561S-78S.

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

[16.] Decousus H, Leizorovicz A, Parent F, 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; 338:409-15.

[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.

[22.] Hutten BA, Prins MH. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.

[23.] Brandjes DPM, Buller HR, Heijboer H, et al. Randomized trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349:759-62.

[24.] Cornuz J, Pearson SD, Creager MA, et al. Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep vein thrombosis. Ann Intern Med 1996; 125:785-93.

[25.] Prandoni P, Lensing AWA, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992; 327:1128-33.

Submitted, revised, February 1, 2001.

From the Department of Family Practice, Michigan State University. Reprint requests should be addressed to David Weismantel, MD, Michigan State University, Department of Family Practice, East Lansing, MI 48824. E-mail: david.weismantel@ht.msu.edu.
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Author:WEISMANTEL, DAVID
Publication:Journal of Family Practice
Date:Mar 1, 2001
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