Overview

Venous thromboembolism (VTE) refers to all forms of pathologic thrombosis occurring on the venous side of the circulation, the most common of which is deep venous thrombosis (DVT) of the lower extremities. The most life-threatening manifestation of VTE is embolization of venous thrombi to the pulmonary circulation-pulmonary embolism (PE). The occurrence of VTE is generally triggered by a confluence of environmental and constitutional risk factors.

VTE and its complications are a common cause of morbidity and mortality in the United States. Researchers have estimated that the average annual incidence of isolated DVT is 50 per 100,000 people and for PE, with or without DVT, the incidence is 70 per 100,000. Others estimate the incidence as being higher and suggest that 450,000 cases of DVT (350,000 cases of non-fatal PE, and 250,000 cases of fatal PE) may occur annually in the United States.

The reference standard for VTE diagnosis remains clot visualization with contrast venography or pulmonary angiography. However, the invasiveness and the risks of these modalities have led to a steady increase in the use of non-invasive or minimally invasive VTE testing. All of these tests are optimally used after clinical examination and estimation of the pre-test likelihood of disease.

When VTE has been diagnosed, acute management usually involves anticoagulation with intravenous unfractionated heparin (UFH), or more recently, subcutaneous low molecular weight heparin (LMWH), to prevent further clot formation and allow endogenous thrombolysis to proceed. Thrombolytic therapy with intravenous tissue plasminogen activator, urokinase, or streptokinase typically has been reserved for patients with life threatening pulmonary embolism. Once adequate anticoagulation is achieved with heparin, patients switch to oral anticoagulants (e.g., warfarin) for months to years to decrease the risk of recurrent VTE. Although anticoagulants are effective in treating VTE, they are also associated with an increased risk of serious bleeding complications.

Reporting the Evidence

With recent technological advances in diagnosis of VTE and the availability of new pharmacological therapies, a number of questions require careful evaluation of the evidence to guide clinical practice and policy-making. This report addresses the following questions regarding the diagnosis and treatment of VTE.

Methodology

The Johns Hopkins University Evidence-based Practice Center (EPC) assembled a team of physicians from diverse specialties including general internal medicine, hematology, radiology, and pulmonary and critical care medicine. The EPC team then recruited 16 technical experts and peer reviewers to provide input regarding the choice of key questions and/or to review a draft of the evidence report. These included investigators active in thrombosis research, representatives of major professional organizations, experts in research methodology, an allied health professional, and representatives of private and governmental payers.

Findings

1. What are the efficacy and safety of LMWH compared with UFH for the treatment of DVT?

2. What are the efficacy and safety of LMWH compared with UFH for the treatment of PE?

• Fourteen systematic reviews have addressed these questions.
• Eleven of these 14 reviews reported either that LMWH was more efficacious than UFH at reducing thrombus recurrence within the subsequent 3 or 6 months, or that the data was trending in that direction.
• Five of six reviews reported that thrombus extension was less with LMWH than with UFH.
• Nine of ten reviews reported less major bleeding with LMWH compared with UFH.
• Nine of 11 reviews reported fewer deaths within the followup period among patients who received LMWH compared with UFH.
• The more recent reviews (from 1998 to 2000) tended to report smaller magnitudes of benefit than the older reviews (recurrence of VTE: relative risk [RR] 0.7 to 0.8; major bleeding: RR 0.6 to 0.7; mortality: RR 0.7 to 0.8).
• The evidence suggested that for treatment of DVT, LMWH is more efficacious than UFH for reducing the rate of VTE recurrence, thrombus extension, and death-and LMWH causes less major bleeding than UFH (Evidence Grade: A).
• The evidence suggested that for treatment of PE, LMWH was likely to be as effective and safe as UFH (Evidence Grade: B).

3a. What are the efficacy and safety of outpatient versus inpatient treatment of DVT with LMWH or UFH?

3b. What is the cost-effectiveness of outpatient versus inpatient treatment of DVT with LMWH or UFH?

• Eight trials compared LMWH as an outpatient to UFH as an inpatient, and two trials compared LMWH as an outpatient to LMWH as an inpatient.
• Nine studies analyzed the costs or cost-effectiveness of LMWH compared with UFH.
• The randomized trials that tested LMWH as an outpatient, or with early discharge, compared with UFH did not demonstrate a difference in adverse outcomes between groups, and showed a major reduction in duration of hospitalization and associated costs.
• The comparisons between LMWH in the hospital or at home revealed no difference in outcomes, but found a major savings in hospitalization costs.
• No study alone was adequately powered to detect small differences in rates of adverse events between groups.
• These studies primarily enrolled patients who were selected as being appropriate for outpatient therapy, and the results may not be applicable to all patients presenting with VTE.
• Overall, the evidence indicated that outpatient treatment of DVT with LMWH is likely to be efficacious and safe (Evidence Grade: B).
• The cost effectiveness studies suggested that LMWH is either cost-saving or cost-effective compared to UFH (Evidence Grade: B).

4. What is the optimal duration of treatment for DVT and PE in patients without known thrombophilic disorders and in patients with thrombophilic disorders?

• Twelve randomized trials and one cohort study addressed this question.
• For a first episode of idiopathic DVT, outcomes were best if warfarin was given for 3 to 6 months. The benefit to risk ratio declined after 6 months.
• For patients with VTE and temporary risk factors, 3 months of therapy may be sufficient.
• For symptomatic calf vein thrombosis, outcomes were best if warfarin was given for 6 weeks.
• No randomized studies focused exclusively on duration of treatment for patients with PE. For patients with any first VTE, which included some patients with PE, 6 months of therapy was superior to 6 weeks.
• Indefinite treatment was most efficacious for patients with a second episode of VTE or patients with a thrombophilic condition, although the evidence was sparse.
• The evidence regarding duration of therapy for patients with idiopathic DVT or DVT with only temporary risks was relatively consistent (Evidence Grade: B); for patients with VTE and a thrombophilic condition or a second DVT, the evidence was sparse (Evidence Grade: I). Little evidence was found on treatment duration for patients with PE (Evidence Grade: I).

5. How accurate are clinical prediction rules used for the diagnosis of DVT or PE?

• Nineteen studies addressed this topic for diagnosis of DVT, and five studies addressed this for PE diagnosis.
• The most frequently tested clinical prediction rule for diagnosing DVT was the one developed by Wells and colleagues in 1995.
• Studies were relatively consistent in showing that the Wells model is useful for identifying patients that have no more than a 10 percent chance of having a DVT, and is useful for identifying patients with a high enough risk of DVT to warrant additional testing (Evidence Grade: B).
• For detection of proximal DVT, the area under the Receiver Operating Characteristic curve (AUC) ranged from 0.79 to 0.92, whereas for distal DVT, the AUCs ranged only from 0.65 to 0.79, suggesting that the Wells model is more accurate for the diagnosis of proximal DVT than for distal DVT.
• Addition of the D-dimer assay to the model improved the diagnostic performance.
• The clinical prediction rules for diagnosing PE were tested less throughly and were less accurate than those used for diagnosing DVT. The Wells model had negative predictive values ranging from 72 percent to 98 percent when a lower score cutoff was used and from 64 percent to 89 percent when a higher score cutoff was used (Evidence Grade: C).

6a. What are the test characteristics of ultrasonography for diagnosis of DVT?

6b. Are calf vein thromboses adequately identified with ultrasound?

• Seven systematic reviews addressed this topic.
• The evidence was consistent in showing that ultrasonography has relatively high sensitivity and specificity for diagnosis of proximal lower extremity DVT in symptomatic patients (Evidence Grade: A). With a false negative rate across studies ranging from 0 percent to 6 percent, a negative ultrasound cannot absolutely exclude disease. For diagnosis of VTE in asymptomatic patients, ultrasonography retained its high specificity, but its sensitivity was markedly reduced to as low as 37 percent.
• Upper extremity DVT, even if symptomatic, was often missed with ultrasound alone, although this was evaluated in few studies (Evidence Grade: C). Recent studies suggested that its efficacy may be higher than previously thought.
• For diagnosis of calf vein thrombosis, three reviews found that ultrasound had sensitivity as low as 29 percent in both asymptomatic and symptomatic patients (Evidence Grade: B).
• In the high quality studies, duplex and color Doppler modalities offered no important advantage over compression ultrasound in diagnosing proximal DVT.

7a. What are the test characteristics of helical CT for diagnosis of PE?

7b. What are the test characteristics of MRI and MRA for diagnosis of PE?

• Six systematic reviews addressed the use of helical CT for diagnosis of PE.
• Eight original studies met strict eligibility criteria for the EPC review of use of helical CT for diagnosis of PE.
• Seven studies met eligibility criteria for the review of use of MRI/MRA for diagnosis of PE.
• In the examination of both systematic reviews and primary studies, the EPC team found a moderate amount of variation in reported sensitivity of helical CT for the diagnosis of PE, ranging from 45 to 100 percent; reported specificity ranged from 78 to 100 percent (Evidence Grade: B). Based on a focused review of the primary literature, the best overall estimate of sensitivity was 86 percent (95 percent confidence interval [CI], 80 percent to 90 percent), and the team's best overall estimate of specificity was 92 percent (95 percent CI, 88 percent to 95 percent). Interpretation of these estimates should be done with caution due to potential selection bias and heterogeneity in the reviewed studies.
• Variation in the reported sensitivity of contrast-enhanced helical CT for the diagnosis of PE cannot be entirely explained by variation in study design or by the level of pulmonary arteries (segmental or subsegmental) included in CT interpretation.
• MRA was sensitive and specific in detecting acute PE of the lobar and segmental branches of pulmonary arteries in patients presenting with clinical suspicion for PE, although the studies were small (Evidence Grade: B).
• Accuracy of detecting smaller emboli was reduced substantially for emboli distal to the lobar segment of the arteries.

8. What are the test characteristics of D-dimer for diagnosis of VTE?

• Only two systematic reviews have addressed this issue.
• One review evaluated studies of D-dimer in patients with normal ultrasonography; the other evaluated 29 studies that used D-dimer and reported on its sensitivity and specificity for diagnosing DVT.
• The major determinants for specificity of D-dimer tests were the type of assay, the cut-off values, and the spectrum of clinical characteristics of enrolled patients free of thromboembolic disease.
• The lack of standardization of the various D-dimer assays, variable cut-off levels, and specimen-type variation (whole blood or plasma) made summarizing this literature challenging (Evidence Grade: C).
• D-dimer tests generally had greater specificity than sensitivity in VTE diagnosis.
• Specificities were higher for outpatients than for inpatients, and for patients without comorbidity, for both Enzyme Linked Immunosorbent Assay and agglutination assays.

Future Research

Availability of Full Report

The full evidence report from which this summary was taken was prepared for AHRQ by the Johns Hopkins University Evidence-based Practice Center under contract number 290-97-0007. It is expected to be available in early 2003. At that time, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requestors should ask for Evidence Report/Technology Assessment No. 68, Diagnosis and Treatment of Deep Venous Thrombosis and Pulmonary Embolism. When available, Internet users will be able to access the report online through AHRQ's Web site at: www.ahrq.gov.

www.ahrq.gov

AHRQ Pub. No. 03-E012 January 2003 ISSN 1530-440X

AHRQ Pub. No. 03-E012