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Simplification of the Diagnostic Management of Suspected Deep Vein Thrombosis
Roderik A. Kraaijenhagen, MD, PhD;
Franco Piovella, MD, PhD;
Enrico Bernardi, MD, PhD;
Fabio Verlato, MD;
Erik A. M. Beckers, MD;
Maria M. W. Koopman, MD, PhD;
Marisa Barone, MD;
Giuseppe Camporese, MD;
Bert Jan Potter van Loon, MD, PhD;
Martin H. Prins, MD, PhD;
Paolo Prandoni, MD, PhD;
Harry R. Büller, MD, PhD
Arch Intern Med. 2002;162:907-911.
ABSTRACT
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Background The standard diagnostic approach in patients with suspected deep vein
thrombosis is to repeat the compression ultrasonography after 1 week in all
patients with an initial normal result. We hypothesized that a normal finding
of a D-dimer assay safely obviates the need for repeated ultrasonography.
In addition, we evaluated the potential value of a pretest probability assessment
for this purpose.
Methods At presentation, consecutive outpatients with suspected thrombosis underwent
independent assessment by means of ultrasonography of the proximal veins,
a whole-blood D-dimer assay, and a pretest clinical model. Patients with normal
ultrasonographic findings and an abnormal D-dimer assay result were scheduled
for repeated ultrasonography. We evaluated the incidence of symptomatic venous
thromboembolic complications during a 3-month follow-up, and the value of
clinical pretest probability with ultrasonography or D-dimer assay in scenario
analyses.
Results We studied 1756 patients with prevalence of thrombosis of 22%. At entry,
results of the D-dimer assay and ultrasonography were normal in 828 patients
(47%). Of these, 6 returned with confirmed symptomatic venous thromboembolism
(complication rate, 0.7%; 95% confidence interval [CI], 0.3%-1.6%). Repeated
ultrasonography was avoided in 61% of the patients with an initial normal
test result. Scenario analyses disclosed that the complication rate was 1.6%
(95% CI, 0.8%-2.6%) in those with a low clinical pretest probability and a
normal result of ultrasonography at referral, whereas this figure was 1.8%
(95% CI, 0.9%-3.3%) in patients with a low clinical probability result and
a normal result of the D-dimer assay at referral.
Conclusions It is safe to withhold repeated ultrasonography in patients with suspected
deep vein thrombosis who have normal results of ultrasonograpy and the SimpliRED
D-dimer assay at presentation. The combination of a low clinical pretest probability
with a normal result of compression ultrasonography or the D-dimer assay appears
to be equally safe in refuting the diagnosis of deep vein thrombosis.
INTRODUCTION
DURING THE past 2 decades, the diagnostic management of clinically suspected
deep vein thrombosis of the lower extremity has considerably improved.1 Invasive diagnostic procedures such as contrast venography
have gradually been replaced by noninvasive methods, most notably impedance
plethysmography and compression ultrasonography. Results of both methods have
shown a high accuracy for the diagnosis of symptomatic proximal vein thrombosis,
but the sensitivity for nonocclusive or calf vein thrombi is much lower.2 Because these smaller thrombi may extend and give
rise to pulmonary embolism, the concept of serial testing with repeated investigation
during a 7- to 14-day period was introduced to rule out the disease.3-6 In 2
prospective studies, compression ultrasonography was shown to be superior
to impedance plethysmography in detecting proximal venous thrombosis and in
managing clinically suspected disease.6-7
Compression ultrasonography with an extended evaluation of the distal popliteal
vein has recently been shown to safely reduce the number of investigations
to 2 tests with an interval of 1 week.8-9
Although repeated testing remains mandatory to detect extending thrombi, the
major disadvantage of this approach is that all patients with an initial normal
ultrasonographic result need to undergo reinvestigation. Therefore, it has
become desirable to develop new strategies that obviate the need for repeated
testing in those patients at very low risk for thrombosis. For this purpose,
D-dimer assays and clinical pretest probability scores have been advocated.10-12 At present, only
a limited number of prospective studies have evaluated the usefulness of these
novel methods in the actual treatment of symptomatic patients,13-16
and it is unknown which approach is most useful and suitable for daily medical
practice.1
Therefore, we studied a large cohort of patients with clinically suspected
deep vein thrombosis and tested the hypothesis that the combination of normal
results of compression ultrasonography and rapid whole-blood bedside D-dimer
assay at referral can safely exclude the presence of thrombosis and obviate
the need for serial testing. In addition, we assessed the potential value
of a pretest clinical probability score in this setting.
PATIENTS AND METHODS
PATIENTS
From November 1, 1995, to January 31, 1999, consecutive outpatients
with clinically suspected deep leg vein thrombosis, who were referred by their
family physicians to the thrombosis units of the participating centers, were
eligible for the study. The referral patterns and the diagnostic processes
in these centers were comparable.3, 9
The protocol was approved by the institutional review boards.
Patients were excluded if they were younger than 18 years, had experienced
a previous episode of deep vein thrombosis in the same leg without documented
normalization of the ultrasonographic findings, had concurrent signs or symptoms
suggestive of pulmonary embolism, had received anticoagulant treatment for
more than 24 hours before referral, or were unable to return to the study
center for follow-up because of geographic inaccessibility. Eligible patients
had to give written informed consent.
DIAGNOSTIC TESTS
Compression ultrasonography was performed and the results were interpreted
as described previously.9 The outcomes were
categorized as normal or abnormal, ie, noncompressible.
For purposes of this study, we used the SimpliRED rapid whole-blood
bedside D-dimer assay (AGEN Biomedical Ltd Brisbane, Queensland).17 The test is performed on capillary blood samples
drawn by means of a fingerstick method or on citrated venous blood samples.
Agglutination occurs at D-dimer concentrations of above 200 mg/L. The outcomes
of the test were categorized as normal or abnormal.
The clinical pretest probability was assessed by means of the clinical
score model described by Wells et al.12 This
quantitative clinical model stratifies patients with suspected deep vein thrombosis
into high, moderate, or low probability for having deep vein thrombosis.
STUDY DESIGN
At the day of referral, compression ultrasonography of the proximal
leg veins, the D-dimer assay, and the clinical pretest probability assessment
were performed in all patients by 3 independent operators. Patients with an
abnormal ultrasonographic result were considered to have deep vein thrombosis.
Subsequent management decisions in patients with a normal ultrasonographic
finding were based on the outcome of the D-dimer assay, whereas information
about the pretest clinical probability was used for a scenario analysis. In
case of a normal D-dimer assay result, ultrasonography was not repeated, whereas
patients with an abnormal D-dimer assay result were scheduled for repeated
ultrasonography after 1 week. Patients with a normal D-dimer assay finding
at presentation were considered not to have venous thrombosis, as were those
with an abnormal D-dimer assay result and repeated normal results of ultrasonography.
All patients were scheduled for a visit after 3 months and were instructed
to contact the study center immediately if signs or symptoms of venous thromboembolism
occurred before this visit. Objective testing was performed in these patients
to confirm or refute the disease. Anticoagulant therapy was given only to
patients with an abnormal ultrasound.
All deaths and suspected venous thromboembolic complications were reviewed
by an independent blinded adjudication committee. Venous thromboembolism was
considered present if (1) symptomatic deep vein thrombosis was confirmed by
new abnormal findings on compression ultrasonography or an intraluminal filling
defect on results of ascending phlebography; (2) symptomatic pulmonary embolism
was confirmed by a high-probability finding on a ventilation-perfusion lung
scan or an abnormal angiographic finding; or (3) in case of death, pulmonary
embolism was confirmed by autopsy findings or could not be ruled out confidently.
STATISTICAL ANALYSIS
We hypothesized that a normal D-dimer assay result in combination with
a normal initial ultrasound outcome would safely exclude the presence of deep
vein thrombosis in symptomatic outpatients at referral and would obviate the
need for repeated testing. Based on data from previous clinical studies that
evaluated other noninvasive strategies, our new diagnostic strategy would
be considered comparably safe if the upper limit of the 95% upper confidence
interval (CI) of the total cumulative rate of symptomatic venous thromboembolic
complications for 3 months was 2.0% or less.1
Assuming an expected prevalence of 30% for deep vein thrombosis, we calculated
that approximately 1500 consecutive symptomatic patients should be included
to yield sufficiently narrow CIs around the expected total complication rate
of 1%. A venous thromboembolic complication was defined as a pulmonary embolism
between referral and repeated ultrasonography or as a pulmonary embolism or
deep vein thrombosis during the 3-month follow-up that was confirmed by objective
test results. We calculated the complication rate using the Kaplan-Meier survival
analysis. The exact 95% CIs around the complication rates were calculated
using StatXact (Version 3.0; Cytel Software Corporation, Cambridge, Mass).
In addition, we performed a scenario analysis on the safety of other
potential diagnostic strategies to exclude deep vein thrombosis at referral
(ie, a low pretest clinical probability with a normal ultrasonographic finding;
a low pretest clinical probability with a normal D-dimer assay finding, or
each of these diagnostic methods alone) using the approach described in the
previous paragraph.
Finally, for all strategies, we determined the efficiency by calculating
the proportion of patients from the initial cohort in whom initial and/or
repeated ultrasonography could be avoided.
If results of the D-dimer assay or the pretest probability were obtained
with knowledge of the results of compression ultrasonography, the patient
was excluded for the respective analyses.
RESULTS
PATIENTS
During the study period, 1899 consecutive outpatients with clinically
suspected acute deep vein thrombosis of the lower extremity were referred.
Of these, 143 (8%) were excluded for the following reasons: preexisting anticoagulant
treatment for more than 24 hours (43%), a previous venous thrombosis in the
same leg without normalization of ultrasonographic findings (53%), geographic
inaccessibility for follow-up (2%), and refusal of informed consent (2%).
Therefore, 1756 patients entered the study. Their mean age was 60 years (range,
18-96 years), and 1099 (63%) were female. Mean time since onset of symptoms
was 7 days. The underlying disorders are shown in the following tabulation:
COMBINED COMPRESSION ULTRASONOGRAPHY AND D-DIMER ASSAY STRATEGY
Of the 1756 patients who entered the study, 17 were excluded from this
analysis because the D-dimer assay was not performed or was performed with
knowledge of the ultrasonographic results. Ultrasonographic findings were
abnormal in 391 patients (22%). Of the remaining 1348 patients with a normal
compression ultrasonographic test result, the D-dimer assay finding was normal
in 828 (61%). Of these patients, 19 returned during the 3-month follow-up
with new or increased signs and symptoms of venous thromboembolism. In 6 of
them, the venous thromboembolic event was confirmed by results of objective
tests (2 had nonfatal pulmonary embolism and deep vein thrombosis developed
in 4), whereas it was refuted in the other 13 patients, who did not receive
anticoagulation therapy and had an uneventful follow-up. Therefore, the cumulative
incidence of venous thromboembolic complications in this patient group was
0.7% (95% CI, 0.3%-1.6%). Of the 520 patients with an abnormal D-dimer assay
finding and a normal compression ultrasonographic finding at presentation,
symptomatic pulmonary embolism developed in 2 (0.4%) (fatal in 1) before repeated
testing. Of the remaining 518 patients, the results of repeated ultrasonography
after 1 week were abnormal in 17 patients (3%). In the 501 patients with a
normal result of serial ultrasonography, new or increased signs and symptoms
of venous thromboembolism occurred in 21 dur ing the 3-month follow-up. The
disease was objectively confirmed in 9 of these patients (2 had pulmonary
embolism [fatal in 1], and 7 had deep vein thrombosis), whereas it was refuted
in the other 12, who did not receive anticoagulation therapy and had an uneventful
follow-up. Hence, the incidence of symptomatic venous thromboembolic complications
in patients with an abnormal D-dimer assay result at presentation and a normal
result of repeated ultrasonography was 2.1% (95% CI, 1.1%-3.8%; Table 1). Overall, the strategy of combined ultrasonography and
the D-dimer assay to limit repeated ultrasonography to patients with an abnormal
D-dimer assay result was associated with an incidence of symptomatic venous
thromboembolic complications of 1.3% (95% CI, 0.7%-2.0%).
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Table 1. Clinical Outcomes of the Combined D-Dimer and Compression
Ultrasonography Strategy in Patients With Suspected Deep Vein Thrombosis
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With this strategy, repeated ultrasonography could be avoided in 61%
of the patients with an initial normal test result.
SCENARIO ANALYSIS
Since the pretest probability score was also independently obtained
in all patients at presentation, the potential value of various strategies
combining clinical pretest probability with D-dimer and/or ultrasonographic
testing results could be assessed.
Combined Compression Ultrasonography and Clinical Pretest Probability
Strategy
Of the 1756 patients who entered the study, 30 were excluded from this
analysis because the pretest probability was not performed or was determined
with knowledge of the ultrasonography result. The distribution of the clinical
pretest probability in the remaining 1726 patients is presented in Table 2, as well as the combined prevalence
of venous thromboembolism at presentation or during follow-up. In 896 patients
(51%), the pretest probability was scored as low. In 62 of these patients,
the results of ultrasonography disclosed deep vein thrombosis at referral.
During the 3-month follow-up of the remaining 834 patients, venous thromboembolism
was diagnosed in 13 (3 pulmonary emboli [fatal in 1] and 10 deep vein thrombi;
in 7 of the latter patients, deep vein thrombosis was detected by routine
ultrasonography after 1 week, which was scheduled because the D-dimer assay
result was abnormal at presentation). Hence, the cumulative incidence of venous
thromboembolism in patients with a low clinical pretest probability and a
normal ultrasound result was 1.6% (95% CI, 0.8%-2.6%).
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Table 2. Distribution of Clinical Pretest Probability in 1726 Patients
With Suspected Venous Thrombosis and the Prevalence of Venous Thromboembolism*
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This strategy would obviate the need for repeated ultrasonography in
62% of symptomatic patients with a normal ultrasonographic finding at presentation.
Combined D-Dimer Assay and Clinical Pretest Probability Strategy
At presentation, 561 patients had a low pretest clinical probability
and a normal D-dimer assay finding. Symptomatic venous thromboembolism was
objectively confirmed in 10 of these patients, by either abnormal ultrasonographic
results at referral (7 patients) or recurrent signs and symptoms during the
3-month follow-up (3 patients: 1 with a nonfatal pulmonary embolism and 2
with deep vein thrombosis). The cumulative incidence of symptomatic venous
thromboembolism in this subset of patients was 1.8% (95% CI, 0.9%-3.3%). This
strategy, in which deep vein thrombosis is excluded by the combination of
a normal D-dimer and a low pretest probability, would obviate the need for
initial ultrasonography in one third of referred patients.
Other Strategies
A strategy in which deep vein thrombosis is excluded on the basis of
a low pretest probability alone is associated with a cumulative incidence
of symptomatic venous thromboembolism of 8.4% (95% CI, 6.6%-10.4%), whereas
if we used the D-dimer assay alone, this rate would be 2.8% (95% CI, 1.8%-4.2%).
Finally, a strategy in which none of the patients with a normal ultrasonographic
finding at referral undergo repeated testing is associated with a cumulative
incidence of venous thromboembolism of 2.5% (95% CI, 1.8%-3.5%) during a 3-month
follow-up.
COMMENT
At present, the standard diagnostic approach for patients presenting
with clinically suspected deep vein thrombosis of the lower limbs consists
of compression ultrasonography at referral and a repeated test after 1 week
in those patients with a normal initial ultrasonographic finding to detect
extending thrombi initially limited to the calf veins. This strategy is safe,
since it is associated with a low venous thromboembolic complication rate
of approximately 1% during 3 months of follow-up.8-9
However, the need for repeated testing makes this approach highly inefficient,
since the ultrasonographic finding will convert to abnormal in only a low
percentage of patients.8-9
The present study clearly shows that the need for repeated ultrasonography
can be reduced by about 60% without a decrease in safety by using the SimpliRED
D-dimer assay. The total venous thromboembolic complication rate for this
novel strategy was 1.3% (95% CI, 0.7%-2.0%; Table 1), which is fully comparable to the present standard diagnostic
approach.
To evaluate the potential safety and efficiency of other diagnostic
strategies in their capacity to reduce the need for (repeated) ultrasonography,
we independently and prospectively collected information about the clinical
pretest probability at presentation, in addition to the ultrasound and D-dimer
investigations. Scenario analysis shows that deep vein thrombosis cannot be
safely refuted on the basis of a low clinical pretest probability or a normal
SimpliRED D-dimer assay finding alone. The venous thromboembolic complication
rate for a 3-month period in these patients was found to be as high as 8.4%
(upper 95% confidence limit, 10.4%) and 2.8% (upper 95% confidence limit,
4.2%), respectively. Despite the frequent assumption that the finding of a
single compression ultrasonography is sufficient, our analysis shows clearly
that a single ultrasound test of the upper leg to the proximal part of the
deep calf veins is less safe than the strategy of combined ultrasonography
and the D-dimer assay. The total venous thromboembolic complication rate during
a 3-month follow-up in patients with a normal ultrasonographic result and
no further investigation was found to be 2.5% (upper 95% confidence limit,
3.5%), which is approximately twice the complication rate of the strategy
of combined ultrasonography and the D-dimer assay (2.5% vs 1.3%; P = .048).
Diagnostic strategies in which the D-dimer assay is combined with the
clinical pretest probability or the clinical pretest probability is combined
with compression ultrasonography appear to be as safe and efficient as the
combination of the D-dimer assay and ultrasonography, particularly if one
considers that approximately half of the venous thromboembolic complications
in these strategies were diagnosed by routine initial or repeated ultrasonography
as dictated by the primary strategy evaluated in this study. Some of these
thrombi might have regressed spontaneously. In our analysis, the venous thromboembolic
complication rate in the subgroup of patients in which the D-dimer assay was
combined with the clinical pretest probability was 1.8% (95% CI, 0.9%-3.3%).
In these patients, ultrasonography can be completely avoided (approximately
30% of initial cohort). Therefore, in terms of reduction of ultrasonography,
this strategy compares favorably with the strategy in which a D-dimer assay
is combined with ultrasonography. Although this approach is very tempting,
the safety and efficiency require further clinical confirmation before daily
use in clinical practice can be advocated. Recently, Wells and colleagues13 evaluated the safety of withholding treatment in
patients with a normal ultrasonographic finding and a low pretest probability
at presentation and observed a very low venous thromboembolic complication
rate of 0.3% (95% CI, 0%-1.7%) during the 3-month follow-up. In the present
analysis, this figure was slightly higher, at 1.6% (95% CI, 0.8%-2.6%). This
strategy should be considered safe, although it has the potential disadvantage
that the clinical pretest probability may become less accurate when used in
routine clinical care.18 The high reproducibility
of D-dimer assays may therefore have an advantage in this respect.19
In our study, we made use of the SimpliRED D-dimer assay. Because this
assay can be performed at the bedside on whole-blood samples, it is very convenient
for daily clinical care, in particular in the emergency department. The drawback
of this assay, however, is that without proper experience, interpretation
of the result may be difficult.20 Therefore,
some institutions may be reluctant to use this specific D-dimer assay. In
these institutions, implementation of this strategy with use of a quantitative
D-dimer assay could be considered, since the various D-dimer assays have recently
been shown to be interchangeable, due to the fact that the sensitivity-specificity
ratio of each assay can be adapted to their intended role in clinical practice
by varying their critical cutoff value.10
CONCLUSIONS
The findings of this management study show that, for patients presenting
with clinically suspected deep leg vein thrombosis, the diagnostic management
strategy in which compression ultrasonography is combined with a D-dimer assay
is a safe and more efficient alternative to the present standard approach
of repeated ultrasonography. Two other diagnostic management strategies (the
clinical model combined with compression ultrasonography and the D-dimer assay
combined with the clinical model) appear to be equally safe and efficient
in the exclusion of deep vein thrombosis at referral. However, further evaluation
of these latter strategies is required before their use in daily clinical
practice can be advocated.
AUTHOR INFORMATION
Accepted for publication August 29, 2001.
We thank Ton W. A. Lensing, MD, for his suggestions.
Corresponding author: Roderik A. Kraaijenhagen, MD, PhD, Department
of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam,
the Netherlands.
From the Departments of Vascular Medicine (Drs Kraaijenhagen, Koopman,
and Büller) and Clinical Epidemiology (Dr Prins), Academic Medical Center,
University of Amsterdam, the Netherlands; the Thromboembolism Unit, IRCCS
Policlinico San Matteo, Pavia, Italy (Drs Piovella and Barone); Clinica Medica
II (Drs Bernardi and Prandoni) and Service of Angiology (Drs Verlato and Camporese),
University Hospital of Padua, Padua, Italy; and the Department of Internal
Medicine, Sint Lucas Andreas Hospital, Amsterdam, the Netherlands (Drs Beckers
and Potter van Loon).
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Diagnosis of Lower-Extremity Deep Vein Thrombosis in Outpatients
Riddle and Wells
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D-Dimer Testing for Deep Venous Thrombosis: A Metaanalysis
Heim et al.
Clin. Chem. 2004;50:1136-1147.
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Withholding Anticoagulation after a Negative Result on Duplex Ultrasonography for Suspected Symptomatic Deep Venous Thrombosis
Stevens et al.
ANN INTERN MED 2004;140:985-991.
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One-Time Comprehensive Ultrasonography To Diagnose Deep Venous Thrombosis: Is That the Solution?
El Kheir and Buller
ANN INTERN MED 2004;140:1052-1053.
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D-Dimer for the Exclusion of Acute Venous Thrombosis and Pulmonary Embolism: A Systematic Review
Stein et al.
ANN INTERN MED 2004;140:589-602.
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Evaluation of D-Dimer in the Diagnosis of Suspected Deep-Vein Thrombosis
Wells et al.
NEJM 2003;349:1227-1235.
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A Clinical Probability Assessment and D-dimer Measurement Should Be the Initial Step in the Investigation of Suspected Venous Thromboembolism
Kelly and Hunt
Chest 2003;124:1116-1119.
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A Diagnostic Strategy Involving a Quantitative Latex D-Dimer Assay Reliably Excludes Deep Venous Thrombosis
Bates et al.
ANN INTERN MED 2003;138:787-794.
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Combination of a Normal D-Dimer Concentration and a Non-High Pretest Clinical Probability Score Is a Safe Strategy to Exclude Deep Venous Thrombosis
Schutgens et al.
Circulation 2003;107:593-597.
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Potency of Inhaled Corticosteroid Fails to Predict Reduced Emergency Department Visits
Williams
Arch Intern Med 2003;163:247-248.
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The Clinical Usefulness of D-Dimer Testing in Cancer Patients With Suspected Deep Venous Thrombosis
ten Wolde et al.
Arch Intern Med 2002;162:1880-1884.
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