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
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
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.
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
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.
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.
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.
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.
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/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]).
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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Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.