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 noninvasive 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.

Treatment

1. What are the efficacy and safety of LMWH

compared with UFH for the treatment of

DVT? 

The main outcomes of interest were death,

recurrent VTE, and bleeding complications.

2. What are the efficacy and safety of LMWH

compared with UFH for treatment of PE?

The outcomes of interest were the same as for

question 1.

3a. What are the efficacy and safety of

outpatient versus inpatient treatment of

DVT with LMWH or UFH? 

The clinical outcomes of interest were the

same as for question 1. 

Evidence Report/Technology Assessment

Number 68

Diagnosis and Treatment of Deep Venous

Thrombosis and Pulmonary Embolism

Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

Agency for Healthcare Research and Quality
3b. What is the cost-effectiveness of outpatient versus

inpatient treatment of DVT with LMWH or UFH?

The outcomes of interest included all costs to society in

addition to the above mentioned clinical outcomes.

4. What is the optimal duration of treatment for DVT and

PE in patients without known thrombophilic disorders

and in patients with thrombophilic disorders? 

The main outcomes of interest again were death, recurrent

VTE, and bleeding complications.

Diagnosis

5. How accurate are clinical prediction rules used for the

diagnosis of DVT or PE?

The review focused on prediction rules that were based on

at least two of the following types of clinical information:

medical history, physical examination, and blood tests.

6a. What are the test characteristics of ultrasonography for

diagnosis of DVT?

The review focused on the sensitivity, specificity, and

predictive values of ultrasonography.

6b. Are calf vein thromboses adequately identified with

ultrasound?

The review for this question also focused on the

sensitivity, specificity, and predictive values of

ultrasonography.

7a. What are the test characteristics of helical computed

tomography (CT) for diagnosis of PE relative to

ventilation/perfusion (V/Q) scanning or standard

angiography?

7b. What are the test characteristics of magnetic resonance

imaging (MRI) and magnetic resonance angiography

(MRA) for diagnosis of PE relative to V/Q scanning

and/or standard angiography? 

The review focused on the sensitivity, specificity, and

predictive values of these radiologic tests (7a and 7b).

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

of VTE?

The review focused on the sensitivity, specificity, and

predictive values of this blood test.

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.

Literature Search

The EPC team searched several literature indexing systems

to identify articles relevant to the review. These included

MEDLINE®, MICROMEDEX®, the Cochrane Controlled

Trials Register, and the Cochrane Database of Systematic

Reviews. To ensure a comprehensive literature search and

identification of all relevant articles, the EPC team also

examined the reference lists from articles identified through the

electronic searching, queried the technical experts, and reviewed

the table of contents of recent issues of relevant journals.

Two members of the EPC team independently reviewed the

abstracts identified by the search to exclude those that did not

meet the eligibility criteria. Primary studies were eligible if they

addressed one of the key questions, included original human

data, were not limited to prevention of VTE, were not case

reports, and were written in the English language. Reviews were

eligible for inclusion in the report if they used a systematic

approach to searching and synthesizing the literature on one of

the key questions. Individual key questions had additional

exclusion criteria. When two reviewers agreed that an abstract

was not eligible, it was excluded from further review.

The EPC team discovered that the primary literature had

been systematically reviewed in some detail for questions 1, 2,

6a, 6b, 7a, and 8. To avoid replication of earlier work, team

members systematically reviewed the reviews on these

questions. They extracted the results of the reviews and

reported the aggregate effect measures. For questions 3a, 3b, 4,

5, and 7b, they reviewed the primary studies found in the

literature search. Team members also reviewed selected primary

studies on question 7a, even though some systematic reviews

had addressed this question.

To focus the evidence report on the studies that would be

most valuable in addressing the key questions, they used the

following additional eligibility criteria:

• For key questions 3a and 4, they excluded studies that did

not include a comparison group.

• For key question 5, the EPC team excluded studies that

did not use an appropriate reference test to make the

diagnosis of VTE or that did not specify a priori the plans

for testing of the clinical prediction rule.

• For key question 7b, they excluded studies that did not

use pulmonary angiography or V/Q scanning as the

reference test for diagnosing PE. 

Review Process

Paired reviewers assessed the quality of each eligible article.

Differences between the paired reviewers were resolved by faceto-face discussion. The systematic reviews received points for

the adequacy of the authors’ reporting of search strategies (3

items), the description of the inclusion criteria for the primary

2
studies (3 items), the adequacy of the quality assessment of the

primary studies (2 items), the validity of the methods for

combining the results (2 items), and the degree to which

conclusions were supported by the evidence (2 items). The

primary studies received points for the degree to which they

described the patients included in the study (4 items), designed

the study to minimize bias in the results (3 items), the

description of the intervention or evaluation (2 items), the

adequacy of followup (5 items), and the reporting of

appropriate statistical methods (4 items). The cost-effectiveness

studies (question 3b) received points for nine items. The score

for each category of study quality was the percentage of the

total points available in each category for that study, and could

range from 0 to 100 percent. The overall quality score reported

was the mean of the five categorical scores. 

One reviewer in each pair was the primary reviewer who

abstracted data from the article, and the second reviewer

confirmed the accuracy of the first reviewer’s work.

Evidence Grades 

Five members of the EPC team independently graded the

strength of evidence on each key question. If the team

members disagreed about an evidence grade, the final grade

given was based on the majority opinion. They graded the

strength of evidence on each question as strong (Grade A),

moderate (Grade B), weak (Grade C), or insufficient (Grade I).

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.

3
• 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

4
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 contrastenhanced 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

Efficacy and Safety of LMWH for DVT and PE

Future research is needed to address the relative risks and

benefits of specific LMWH preparations and their efficacy in

subpopulations of patients with VTE (e.g., PE only) and

unique patient populations (e.g., patients with malignancies, or

other thrombophilic conditions).

Outpatient Versus Inpatient Treatment of DVT

Additional studies are needed to evaluate the use of

outpatient therapy among a less restricted group of patients, or

specifically in high-risk subgroups such as patients with

malignancies or known hereditary thrombophilias. Also needed

are high quality trials designed as equivalency studies to

confirm that LMWH as an outpatient is equivalently effective

and safe relative to UFH in the hospital. Additional trials are

needed of LMWH as an outpatient for stable patients with PE.

LMWH needs to be evaluated for outpatients with

symptomatic calf vein thrombosis.

Duration of Treatment for VTE

Further research is needed regarding the optimal duration of

therapy after PE. The results of ongoing randomized studies of

low dose warfarin for long duration prophylaxis will help clarify

whether prevention of VTE can be achieved with greater safety.

Additional trials regarding duration of therapy in patients with

permanent thrombotic risk factors are needed.

Clinical Prediction Rules

Further research is needed for refinement of the clinical

prediction rules to optimize their performance characteristics

and to test the addition of laboratory testing. Research is also

needed to clarify the optimal role for clinical prediction rules.

Are they to be used to aid in interpretation of radiologic tests or

can they supplant further testing? Researchers will need to

identify the most efficacious way to move these rules into

general practice.

Radiologic Tests

Future research needs to clarify the role of ultrasonography

for diagnosis of upper extremity DVT. Studies should

incorporate discussion of the importance or lack of importance

of diagnosis of calf vein thrombosis in studies that address the

sensitivity and specificity of testing modalities. Additional

systematic reviews of this topic could explore the heterogeneity

between studies and alternative ways to present the aggregate

data.

The question about the use of helical CT would benefit

from more high quality prospective studies in which helical CT

is compared to pulmonary arteriography for detecting PE.

Future studies of MRI/MRA need to be standardized in terms

of speed, image acquisition, number of breath holds, presence

or absence of cardiac gating, and dose of contrast to yield

precise estimates of test characteristics. The feasibility of

MRI/MRA in patients with symptomatic PE (with tachypnea

and tachycardia) needs to be studied.

D-dimer

Future research is needed with attention to the clinical

spectrum of the patients, the duration of symptoms, the clinical

setting, age, and comorbid conditions of the patients. Another

5
important point not addressed adequately in the literature is the

role of abnormal D-dimer levels in patients with calf vein

thrombosis. 

Overall Areas of Future Research

Clinicians need to know the role of newer agents (including

lepirudin, argatroban, or fondaparinux) in the treatment of

VTE. Studies should examine the role of systemic

thrombolytics in the treatment of PE and DVT for patients

without a life-threatening burden of clot. Additional work also

needs to be done in clarifying the optimal treatment of patients

with thrombophilias such as malignancies and prothrombotic

mutations, including duration of treatment, prothrombin time

requirements, and prophylactic regimens. 

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