The Clinical Usefulness of D-Dimer Testing in Cancer Patients With Suspected
Deep Venous Thrombosis


Author Information
<http://archinte.ama-assn.org/issues/v162n16/rfull/#aainfo>   Marije ten
Wolde, MD; Roderik A. Kraaijenhagen, MD; Martin H. Prins, MD; Harry R.
Büller, MD
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.
Arch Intern Med. 2002;162:1880-1884
IOI10551
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
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r1> , 2
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r2>  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 studies 3
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r3> , 4
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r4>  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 studies 5 <http://archinte.ama-assn.org/issues/v162n16/rfull/#r5>
, 6 <http://archinte.ama-assn.org/issues/v162n16/rfull/#r6>  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
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r7> , 8
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r8>  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 colleagues 9
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r9>  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
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r6>  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
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r10>  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 <http://archinte.ama-assn.org/issues/v162n16/rfull/#r2>
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
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r11>



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
<http://archinte.ama-assn.org/issues/v162n16/fig_tab/ioi10551_t1.html>
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.
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 <http://archinte.ama-assn.org/issues/v162n16/fig_tab/ioi10551_f1.html> ,
A, shows an overview of the diagnostic strategy arms with the corresponding
patient numbers.
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
<http://archinte.ama-assn.org/issues/v162n16/fig_tab/ioi10551_f1.html> , 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
<http://archinte.ama-assn.org/issues/v162n16/fig_tab/ioi10551_t2.html>
gives the accuracy indexes for both patient categories.
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
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r12>  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
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r9>  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
<http://archinte.ama-assn.org/issues/v162n16/rfull/#r13>  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/Article Information


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.

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: [log in to unmask]
<mailto:[log in to unmask]> ).
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.




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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.