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The Clinical Usefulness of D-Dimer Testing in Cancer Patients With Suspected Deep Venous Thrombosis
Marije ten Wolde, MD;
Roderik A. Kraaijenhagen, MD;
Martin H. Prins, MD;
Harry R. Büller, MD
Arch Intern Med. 2002;162:1880-1884.
ABSTRACT
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Background Little is known about the diagnostic value of a D-dimer test in cancer
patients with clinically suspected deep venous thrombosis (DVT).
Objective To evaluate the clinical utility of a whole blood rapid D-dimer test
(SimpliRED) in cancer patients compared with noncancer patients.
Methods In consecutive patients with suspected lower limb DVT, a D-dimer test
and ultrasonogram were performed. Cancer status was recorded at presentation.
If the D-dimer test and ultrasonogram results were normal, DVT was considered
absent. If the D-dimer result was abnormal, ultrasonography was performed
again 1 week later. Anticoagulant therapy was only instituted in those patients
with an abnormal ultrasonography result. All patients were followed up for
3 months to record subsequent thromboembolic events. The accuracy of the D-dimer
test was assessed, and the efficiency and safety of withholding additional
ultrasonography in cancer patients with normal results on both D-dimer and
ultrasonography was compared with noncancer patients.
Results A total of 1739 consecutive patients were studied, 217 (12%) of whom
had cancer. The negative predictive value of the D-dimer test was 97% in both
cancer and noncancer patients. In 63 (29%) of all 217 cancer patients, the
D-dimer and ultrasonography results were normal at referral; therefore, the
diagnosis of DVT was refuted and anticoagulant treatment was withheld. In
these 63 patients, one thromboembolic event occurred during follow-up (1.6%;
95% confidence interval, 0.04%-8.53%).
Conclusions The negative predictive value of a whole blood D-dimer test in cancer
patients seems as high as in noncancer patients. In a substantial proportion
of cancer patients, the diagnosis can likely be refuted at referral, based
on normal D-dimer test and ultrasonogram results. Furthermore, it seems safe
to withhold anticoagulant therapy in these patients.
INTRODUCTION
MAJOR IMPROVEMENTS in the diagnostic management of patients with suspected
deep venous thrombosis (DVT) have been achieved in the last decades. At first,
the invasive procedure of venography was replaced by noninvasive tests, such
as impedance plethysmography and compression ultrasonography. However, additional
tests performed during a 2-week period were required to rule out adequately
the diagnosis. Subsequently, it was shown for compression ultrasonography
that the number of follow-up tests could be safely reduced to a single follow-up
test with a 1-week interval.1-2
Recently, further improvements have been attained by the introduction of the
D-dimer test. A D-dimer test represents the level of plasma D-dimers, which
are degradation products of cross-linked fibrin. Numerous studies3-4 have investigated the accuracy of this
test for the diagnosis of DVT. Since the sensitivity of the test is approximately
90% to 95% and the specificity is only 55%, the test is best suited for ruling
out DVT instead of proving the presence of the disease. However, the test
cannot be used as the sole test to exclude DVT, since given a sensitivity
of approximately 90% to 95%, still 5% to 10% of DVTs will be missed. Therefore,
the test should be used as an adjunct to other diagnostic methods. Management
studies have shown that if a rapid D-dimer test is performed with ultrasonography
in patients suspected of having DVT, the diagnosis can be ruled out if both
test results are normal. Two large studies5-6
have recently demonstrated that, using this strategy, the follow-up ultrasonogram
and thus an extra hospital visit can be safely omitted in more than 45% of
patients. A follow-up ultrasonogram is necessary to exclude an extending (calf)
vein thrombosis only in the remaining patients with an abnormal D-dimer test
result at referral.
Although it is well documented that the D-dimer test is useful in the
diagnostic workup of patients with suspected DVT, it is thought that the D-dimer
test is of less value in patients with underlying cancer. Since D-dimer levels
are likely higher in cancer patients,7-8
more of these patients will have an abnormal test result, making the test
less efficient in this population to exclude DVT at referral. Lee and colleagues9 found that the D-dimer test is of less value in cancer
patients because the negative predictive value (NPV) of the test in these
patients is lower than in noncancer patients as a consequence of the higher
prevalence of DVT among cancer patients. The high prevalence of DVT among
cancer patients and the relatively low specificity of the D-dimer test in
these patients will result in a decreased NPV. On the other hand, the expected
lower NPV could theoretically be counterbalanced by an increased sensitivity.
The aim of this article is to examine the clinical utility of a whole blood
D-dimer test in cancer patients suspected of having DVT compared with noncancer
patients suspected of having DVT. We assessed the sensitivity, specificity,
and predictive values of the D-dimer test. In addition, the safety and efficiency
of withholding additional ultrasonography in patients with normal results
on both the D-dimer test and ultrasonogram were evaluated.
PATIENTS AND METHODS
Consecutive outpatients with clinically suspected DVT of the leg treated
from November 1, 1995, to January 31, 1999, were eligible for the study. Patients
were referred by their family physician to the thrombosis unit. Patients were
excluded if they were pregnant, were younger than 18 years, had experienced
a previous episode of DVT in the same leg without documented normalization,
had concurrent signs or symptoms suggestive of pulmonary embolism, had received
anticoagulant treatment for more than 24 hours, or were unable to return to
the study center for follow-up because of geographic inaccessibility. Cancer
status was recorded at presentation. Patients were considered to have active
cancer if they were receiving (palliative) treatment for cancer or if they
had received treatment for cancer in the past 6 months.
STUDY DESIGN
Patients were investigated according to the following diagnostic strategy.6 All patients underwent compression ultrasonography
of the proximal veins and D-dimer testing at the day of referral. Both tests
were performed by 2 independent investigators, who were both unaware of the
cancer status of each patient. If the D-dimer and ultrasonography results
were normal, the patient was considered not to have DVT and no further testing
was performed. If the ultrasonography result was normal and the D-dimer test
result abnormal, ultrasonography was performed again 1 week later. If this
second ultrasonogram result was also normal, DVT was again ruled out. Anticoagulant
therapy was only instituted in those patients with an abnormal ultrasonogram
result. All patients were followed up for 3 months to record possible subsequent
thromboembolic events. 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. In the case
of suspected DVT, ultrasonography and venography were performed; in the case
of suspected pulmonary embolism, ventilation perfusion scintigraphy was performed,
followed by angiography if a nondiagnostic result was obtained.
For the analysis, patients were divided into 2 groups: patients with
cancer and patients without cancer. In both groups, clinical utility was determined
by assessing the accuracy indexes, venous thromboembolic complication rates,
and the efficiency of D-dimer testing.
Accuracy Indexes
The sensitivity, specificity, NPVs, and positive predictive values were
calculated using the 3-month follow-up as the reference standard (ie, DVT
was considered absent if no venous thromboembolic event could be detected
from referral through 3 months of follow-up, and DVT was considered present
when venous thrombosis was shown by objective testing).
Venous Thromboembolic Complication Rate
The safety of withholding additional ultrasonography was determined
in both patient groups by calculating the number of subsequent venous thromboembolic
complications during the 3-month follow-up period (ie, complication rate).
Efficiency
The efficiency of using the D-dimer test as an adjunct to ultrasonography
was defined as the proportion of patients in whom additional ultrasonography
could be avoided (which is the proportion of patients in whom the diagnosis
could be refuted on the day of referral).
DIAGNOSTIC TESTS
A rapid, whole blood, bedside D-dimer assay (SimpliRED D-dimer assay;
Agen Biomedical Ltd, Brisbane, Australia) was used. The test can be performed
by using 10 µL of whole blood obtained from a capillary or venipuncture
sample. This autologous red blood cell agglutination assay uses as an active
agent a chemical conjugate of a monoclonal antibody specific to human D-dimer
(DD-3B6/22) linked to a monoclonal antibody that binds to the surface of human
red blood cells (RAT-IC3/86).10 Agglutination
occurs at D-dimer concentrations greater than 200 µg/L within 2 minutes.
The outcomes of the test were categorized as normal or abnormal.
Compression ultrasonography was performed and interpreted as described
previously.2 Briefly, the common femoral vein
and the popliteal vein down to the trifurcation of the calf veins were examined.
The compressibility of these veins was assessed in the transverse plane. The
outcomes were categorized as normal or abnormal (ie, noncompressible).
STATISTICAL ANALYSIS
Sensitivity, specificity, predictive values, and venous thromboembolic
complication rates in both patients groups were calculated. Their exact 95%
confidence intervals (CIs) were calculated using Confidence Interval Analysis
(Version 1.0).11
RESULTS
During the study period, 1899 consecutive patients with suspected DVT
were screened. Of these, 143 patients (8%) were excluded for the following
reasons: a previous episode of DVT in the same leg without documented ultrasonographic
normalization (53%), anticoagulant treatment for more than 24 hours (43%),
geographic inaccessibility for follow-up (2%), and refusal of informed consent
(2%). In 17 patients, the D-dimer was not performed or performed with knowledge
of the ultrasonogram test result, and these patients were excluded from further
analysis. Thus, 1739 patients were included in the present analysis. Of these
patients, 217 (12%) were known to have cancer at presentation. Twenty-one
percent of the cancer patients were bedridden or underwent surgery in the
past 4 weeks; 54% of the cancer patients were hospitalized in the past 6 months;
and the 3-month mortality rate in the cancer group was 3%. Table 1 summarizes the characteristics of the patients with and
without cancer. Both groups were comparable with respect to age, sex, and
median time since onset of symptoms. However, more cancer patients had been
immobilized or had undergone surgery. A recent trauma had occurred in a higher
percentage of the patients without cancer.
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Table 1. Baseline Characteristics of 1739 Patients Suspected of Having
Deep Venous Thrombosis With and Without Cancer
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CANCER PATIENTS
Of the 217 cancer patients, 64 (29%) had a normal D-dimer test result
and 153 (71%) an abnormal D-dimer test result. The ultrasonogram result was
abnormal in 1 patient with a normal D-dimer test result, whereas it was abnormal
in 79 patients with an abnormal D-dimer test result. Of those 63 patients
(29%; 95% CI, 23%-35%) with both normal D-dimer and normal ultrasonogram results,
1 patient developed a thromboembolic event during follow-up. Those patients
with an abnormal D-dimer test result and a normal ultrasonogram result underwent
additional ultrasonography, the results of which were abnormal in 3 patients.
In 3 of the other patients (with an abnormal D-dimer test result and normal
serial ultrasonography result), a thromboembolic complication occurred during
follow-up. Thus, overall, in 87 cancer patients venous thromboembolism was
present (prevalence, 40%). Figure 1,
A, shows an overview of the diagnostic strategy arms with the corresponding
patient numbers.
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Overview of the diagnostic strategy arms of the study. CUS indicates
compression ultrasonography; VTE, venous thromboembolism; and DVT, deep venous
thrombosis.
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PATIENTS WITHOUT CANCER
In 782 (51%) of the 1522 noncancer patients, a normal D-dimer test result
was obtained. Of these patients, 17 had an abnormal ultrasonogram result.
Of the 765 remaining patients with both normal D-dimer test and ultrasound
results (50%; 95% CI, 48%-53%), 5 developed a venous thromboembolic event
during follow-up. In those patients with an abnormal D-dimer test result,
DVT was detected by an abnormal ultrasonogram result in 294 patients. The
other 446 patients had a normal ultrasonogram result and underwent follow-up
ultrasonography 1 week later, the results of which were abnormal in 14 patients.
In the remaining 432 patients (with an abnormal D-dimer test result and normal
serial ultrasonography result), a thromboembolic event occurred in 8 patients.
Hence, venous thromboembolism was present in 338 noncancer patients (prevalence,
22%; 95% CI, 20%-24%). Figure 1, B, outlines the distribution of patients throughout the different strategy
arms.
ACCURACY INDEXES
Of the 87 cancer patients with venous thromboembolism, 2 patients had
a false-negative D-dimer test result (sensitivity, 98%; 95% CI, 92%-100%;
specificity, 48%; 95% CI, 39%-56%). In 22 of the 338 noncancer patients with
venous thromboembolism, a false-negative D-dimer test result was present (sensitivity,
93%; 95% CI, 90%-96%; specificity, 64%; 95% CI, 62%-67%). Of the 64 cancer
patients with a negative D-dimer test result, 62 did not have venous thromboembolism,
resulting in an NPV of 97% (95% CI, 89%-100%). Of all 782 noncancer patients
with a normal D-dimer test result, 760 seemed not to have venous thromboembolism
(NPV, 97%; 95% CI, 96%-98%). Table 2
gives the accuracy indexes for both patient categories.
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Table 2. Accuracy of the SimpliRED D-Dimer Test in Patients Suspected
of Having Deep Venous Thrombosis With and Without Cancer*
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VENOUS THROMBOEMBOLIC COMPLICATION RATE
In 63 (29%) of the 217 cancer patients, the D-dimer and ultrasonography
results were normal at the day of referral; DVT was considered to be excluded,
and anticoagulant therapy was withheld. In these 63 patients, only one thromboembolic
event occurred during follow-up (complication rate, 1.6%; 95% CI, 0.04%-8.5%).
Of those 71 cancer patients who had normal serial ultrasonogram results, 3
thromboembolic events occurred (complication rate, 4.2%; 95% CI, 0.9%-11.9%).
The complication rate of withholding additional ultrasonography in cases
of both normal D-dimer and ultrasonogram results in patients without cancer
was 0.9% (95% CI, 0.4%-1.9%). In 8 of 432 noncancer patients with normal serial
ultrasonography results, thromboembolic complications occurred (complication
rate, 1.9%; 95% CI, 0.8%-3.6%).
EFFICIENCY
The need for additional ultrasonography and therefore an extra hospital
visit could be avoided in 63 of all 217 cancer patients. The efficiency of
using a D-dimer test as an adjunct to ultrasonography is therefore 29% (95%
CI, 23%-35%) compared with 50% (95% CI, 48%-53%) in the noncancer patients.
COMMENT
Our results indicate that the use of the D-dimer test, as measured in
this study, does seem useful in cancer patients who have suspected DVT. This
conclusion is supported in 3 ways. First, we found that the NPV of a whole
blood D-dimer test (SimpliRED D-dimer) in cancer patients is as high as in
patients who do not have cancer. Second, the low complication rate after withholding
anticoagulant therapy indicates that it seems safe to reject the diagnosis
in cancer patients with suspected DVT who have normal results on both ultrasonogram
and D-dimer test. Third, 29% of cancer patients clinically suspected of having
DVT have a normal D-dimer test result in combination with a normal ultrasonogram
result (and considering the 95% CI, this proportion is unlikely to be lower
than 23%). Therefore, using the D-dimer test, the need for an additional ultrasonogram
can potentially be avoided in approximately 25% of the cancer patients with
clinically suspected DVT. However, although the D-dimer test could be used
as an exclusionary test to rule out DVT when a normal D-dimer test result
is obtained, the test is not helpful in cancer patients (which is not different
from noncancer patients) to prove DVT in case of a positive or abnormal test
result, given the low positive predictive value of 56% (95% CI, 48%-63%).
(In noncancer patients, the positive predictive value is 43% [95% CI, 39%-46%].)
The predictive values of a test are influenced by the prevalence of
the disease in the studied population and the accuracy parameters (ie, the
sensitivity and specificity of the test itself).12
A higher prevalence of the disease and a lower specificity of the test tend
to decrease the NPV, whereas a higher sensitivity would tend to increase the
NPV. This balancing effect is nicely illustrated by our study results. The
prevalence of DVT in cancer patients was almost twice as high as in noncancer
patients, and the specificity of the D-dimer test was decreased by 25%, which
could have resulted in a lower NPV of the D-dimer test in the cancer group.
However, because high D-dimer levels often are present in cancer patients
(also in the absence of DVT), it is expected that the D-dimer test will have
a higher sensitivity in this subset of patients. Indeed, the sensitivity of
the D-dimer test was 98% in cancer patients compared with 93% in noncancer
patients. The decreasing effect of the higher prevalence and the lower specificity
on the NPV of the test is therefore compensated by the higher sensitivity
of the D-dimer test in cancer patients, resulting in an equally high NPV of
97% for both cancer and noncancer patients.
It could be argued that the high sensitivity and NPV found in the cancer
patients were partly owing to the relatively high percentage of cancer patients
who recently underwent surgery, which can also lead to high D-dimer levels.
However, when the same analysis was performed after excluding those cancer
patients who recently underwent surgery, a sensitivity of 97% (95% CI, 89%-100%),
a prevalence of DVT of 37% (95% CI, 30%-44%), and an NPV of 97% (95% CI, 89%-100%)
were observed. Hence, it is unlikely that the relatively high proportion (21%)
of patients who were immobilized or underwent surgery has influenced our findings.
Our results are different from the findings of Lee et al,9
who observed a significantly lower NPV of 79% in cancer patients compared
with an NPV of 97% in noncancer patients. Using the same D-dimer assay, they
reported a sensitivity of 83% in noncancer patients and a sensitivity of 86%
in cancer patients, which are low values compared with the sensitivities in
our study but also compared with sensitivities of the SimpliRED D-dimer assay
reported in other studies.13-17
The prevalence of DVT in their cancer patients (49%) was higher than in our
cancer patients (40%; 95% CI, 34%-47%). This high prevalence might be due
to the fact that their patients suspected of having DVT were partly referred
from a regional cancer center. These patients are possibly more sick compared
with cancer patients referred from a general practitioner, as was the case
in our study. The low sensitivity of their D-dimer test and the high prevalence
of DVT probably resulted in the low NPV.
Apart from assessing the NPV of the D-dimer test, we prospectively demonstrated
that it seems safe to reject the diagnosis of DVT in patients suspected of
having DVT with concomitant cancer when both normal D-dimer test and ultrasonogram
results are obtained. Regarding the complication rate of 4.2% (95% CI, 0.9%-11.9%)
for serial ultrasonography (the current diagnostic standard), the observed
complication rate of 1.6% (95% CI, 0.04%-8.5%) of withholding anticoagulants
after normal D-dimer and ultrasonogram results is acceptable in this particular
high-risk group of cancer patients. However, ideally more patients need to
be studied to increase the confidence of this observation.
Some issues of our study require comment. Although the results of this
study indicate the clinical usefulness of D-dimer testing for the diagnosis
of DVT, the CIs are still too wide to draw definite conclusions. Therefore,
and also because our study concerns a post hoc analysis, further investigation
is necessary before these results can be implemented in daily practice. Moreover,
the available D-dimer assays are not interchangeable. Accuracy variables of
different D-dimer assays could vary among different populations and should
be tested in each patient population before clinical introduction.
In conclusion, our results indicate that D-dimer testing is helpful
in cancer patients. When a D-dimer test is used as an adjunct to ultrasonography,
a subsequent ultrasonogram can be avoided in about one quarter of all cancer
patients referred for clinically suspected DVT.
AUTHOR INFORMATION
Accepted for publication January 17, 2002.
We thank Paolo Prandoni, MD, and Franco Piovella, MD, from Padua and
Pavia, Italy, and Bert Jan Potter van Loon, MD, Saint Lucas Andreas Hospital,
Amsterdam, the Netherlands, for their contributions to this study.
Corresponding author and reprints: Marije ten Wolde, MD, Department
of Vascular Medicine, Room F4-138, Academic Medical Center, Meibergdreef 9,
1105 AZ Amsterdam, the Netherlands (e-mail: M.tenwolde{at}amc.uva.nl).
From the Department of Vascular Medicine, Academic Medical Center,
Amsterdam (Drs ten Wolde, Kraaijenhagen, and Büller), and Department
of Clinical Epidemiology and Medical Technology Assessment, Academic Hospital
Maastricht, Maastricht (Dr Prins), the Netherlands. None of the authors has
a financial or proprietary interest in the subject matter or materials discussed
in the article.
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