Clinical Chemistry 56:11 1758–1766 (2010)
Point-of-Care Testing
Diagnostic Accuracy and User-Friendliness of 5 Point-of-Care D-Dimer Tests for the Exclusion of Deep Vein Thrombosis Geert-Jan Geersing,1 Diane B. Toll,1 Kristel J.M. Janssen,1 Ruud Oudega,1 Marloes J.C. Blikman,1 Rene´ Wijland,1 Karen M.K. de Vooght,2 Arno W. Hoes,1 and Karel G.M. Moons1*
BACKGROUND: Point-of-care D-dimer tests have recently been introduced to enable rapid exclusion of deep venous thrombosis (DVT) without the need to refer a patient for conventional laboratory-based D-dimer testing. Before implementation in practice, however, the diagnostic accuracy of each test should be validated. METHODS:
We analyzed data of 577 prospectively identified consecutive primary care patients suspected to have DVT, who underwent 5 point-of-care D-dimer tests— 4 quantitative (Vidas®, Pathfast™, Cardiac®, and Triage®) and 1 qualitative (Clearview Simplify®)—and ultrasonography as the reference method. We evaluated the tests for the accuracy of their measurements and submitted a questionnaire to 20 users to assess the user-friendliness of each test.
RESULTS:
All D-dimer tests showed negative predictive values higher than 98%. Sensitivity was high for all point-of-care tests, with a range of 0.91 (Clearview Simplify) to 0.99 (Vidas). Specificity varied between 0.39 (Pathfast) and 0.64 (Clearview Simplify). The quantitative point-of-care tests showed similar and high discriminative power for DVT, according to calculated areas under the ROC curves (range 0.88 – 0.89). The quantitative Vidas and Pathfast devices showed limited user-friendliness for primary care, owing to a laborious calibration process and long analyzer warm-up time compared to the Cardiac and Triage. For the qualitative Clearview Simplify assay, no analyzer or calibration was needed, but interpretation of a test result was sometimes difficult because of poor color contrast.
CONCLUSIONS: Point-of-care D-dimer assays show good and similar diagnostic accuracy. The quantitative Cardiac and Triage and the qualitative Clearview Simplify
1
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; 2 Department for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands. * Address correspondence to this author at: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. Fax ⫹31-88-75-68-099; e-mail
1758
D-dimer seem most user-friendly for excluding DVT in the doctor’s office. © 2010 American Association for Clinical Chemistry
More than 75% of the patients in whom deep vein thrombosis (DVT)3 is suspected and who are referred for objective testing— commonly performed with legcompression ultrasonography– do not have DVT (1, 2 ). D-dimer testing for DVT has been introduced to improve the diagnostic process and, in particular, to reduce the number of unnecessary referrals for leg-compression ultrasonography. Concentrations of D-dimer are increased in patients with DVT, but may also be increased in other conditions such as cancer, infections, pregnancy, and recent surgery. Hence, D-dimer tests are typically used as rule-out tests (3, 4 ). Although D-dimer testing is readily available to many hospital physicians within their central laboratories, this is often not the case for primary care physicians. Most patients with suspected DVT, however, are first seen in primary care settings, and for such cases referral to central laboratories for D-dimer testing is not always a practical solution. Therefore, to enable exclusion of DVT in the doctor’s office, several point-of-care D-dimer tests have been developed (5–14 ). These tests yield results within 10 –15 min and in many cases may eliminate the need for referrals to central laboratories or diagnostic services. Indeed, a recent study demonstrated that the use of a qualitative point-of-care D-dimer test was both safe and cost-effective in primary care (15, 16 ). Consequently, the introduction of point-of-care D-dimer tests for use in primary care settings is eagerly awaited. As with all new therapies, however, diagnostic devices, including biomarker tests, must undergo
[email protected]. Received April 1, 2010; accepted August 16, 2010. Previously published online at DOI: 10.1373/clinchem.2010.147892 3 Nonstandard abbreviations: DVT, deep vein thrombosis; D-DU, D-dimer units; FEU, fibrinogen equivalent units; AUC, area under the ROC curve.
Comparison of 5 Point-of-Care D-Dimer Tests
rigorous and phased evaluation before they are introduced in daily practice. Well-tested, conventional, laboratory-based D-dimer assays can be safely substituted with point-of-care tests only if the new tests show high negative predictive value and sensitivity. As with any D-dimer test, point-of-care tests will be used only in combination with a clinical assessment (e.g., with a validated clinical-decision rule), and their added value beyond such clinical assessment must be evaluated. As a first step in the evaluation of novel diagnostic techniques, a single-test approach is advocated in which the results of the new test are compared with the current reference standard (17–20 ). In the present study of 4 quantitative point-of-care D-dimer tests and 1 qualitative point-of-care D-dimer test, we aimed to quantify and compare the diagnostic accuracy of these tests by direct comparison with legcompression ultrasonography as a reference method in primary care patients with suspected DVT. Furthermore, the user-friendliness of each assay was assessed to provide information to assist physicians in choosing a point-of-care test, particularly when multiple pointof-care tests show similar diagnostic accuracy. Material and Methods PATIENTS
We prospectively identified 577 consecutive primary care patients with suspected DVT in 3 regions of the Netherlands (inclusion period November 2006 to September 2008). Suspicion of DVT was based on pain, swelling, or redness of the leg. Patients were excluded from the study if they were younger than 18 years; undergoing treatment with anticoagulant therapy with vitamin K antagonists or low molecular weight heparin, or were unable or unwilling to give informed consent. All study participants were subsequently referred by their general practitioner for compression ultrasonography, which was performed at 3 participating primary care diagnostic centers (Deventer Hospital, STAR Medical Diagnostic Centre Rotterdam, and Medical Diagnostic Centre LabNoord Groningen). The study protocol was approved by the medical ethics committees of the participating centers. BLOOD COLLECTION
In all patients, venous whole blood was drawn from the anterior cubital vein. Depending on the assay, venous blood was collected into tubes containing 105 mmol/L citrate, K2 EDTA (1.8 g/L whole blood), or lithium heparin (15 000 USP units/L whole blood). Immediately after venous blood collection, capillary blood was collected via a finger prick.
POINT-OF-CARE D-DIMER TESTS (INDEX TESTS)
The 5 point-of-care D-dimer tests were performed on each patient’s blood sample, according to the manufacturer’s instructions. Each test was performed by laboratory workers unfamiliar with point-of-care testing. Hence, all laboratory workers received brief instructions on how to perform the respective point-of-care tests. Laboratory workers were unaware of the result of the compression ultrasonography, and blinded for the outcome of the other D-dimer tests. QUANTITATIVE D-DIMER TESTS
D-dimer measurements were based on assay-specific reference curves. The quantitative test results were reported either as D-dimer units (D-DU), which were based on calibration with purified fibrin fragment D-dimer, or as fibrinogen equivalent units (FEU), which were based on the amount of purified fibrinogen used for the preparation of a cross-linked fibrin clot, which was then degraded by plasmin and used as calibrator. A test outcome given in FEU can be converted to D-DU by using a conversion factor of 1.8 (21 ). Consequently, 1 g/L FEU corresponds with 1.8 g/L D-DU. All D-dimer measurement units were converted into FEU (g/L). We included 4 quantitative assays in our study. Vidas D-dimer exclusion. The Vidas D-dimer test (bioMe´rieux) was performed with 200 L of citrated plasma, by using the Vidas mini analyzer. This test combines a 2-step enzyme immunoassay sandwich method with fluorescent detection. It uses an alkalinephosphatase–labeled anti-FbDP monoclonal mural antibody (P2C5A10). The Vidas analyzer displays a quantitative result within a range of 45–10.000 g/L FEU, with a cutoff value of 500 g/L FEU. Pathfast D-dimer. The Pathfast D-dimer test (Mitsubishi Cagaku Iatron) was performed with 100 L citrated plasma, by using the Pathfast in vitro diagnostic system. This chemiluminescent enzyme immunoassay contains 2 D-dimer monoclonal antibodies, one labeled with alkaline phosphatase and the other coated with magnetic particles. The analyzer displays a quantitative result within a range of 5–5000 g/L FEU, with a cutoff value of 570 g/L FEU. Cardiac D-dimer. The Cardiac D-dimer test (Roche Diagnostics) was performed with 150 L whole blood anticoagulated with Li-heparin, by using the Cobas h 232 reader instrument. The test is based on a dual monoclonal antibody sandwich comprising a poly(streptadivin)-biotin capture system with a gold particle label. The Cardiac D-dimer displays a quantitative result within a range of 100 – 4000 g/L FEU, with a cutoff value of 500 g/L FEU. Clinical Chemistry 56:11 (2010) 1759
Triage D-dimer. The Triage D-dimer test (Biosite) was performed with 250 L of EDTA whole blood by using the Triage Meter Plus. This single-marker fluorescence sandwich immunoassay uses the 3B6 D-Dimer antibody. The Triage Meter Plus displays a quantitative result within a range of 56 –2800 g/L FEU (or 100 – 5000 g/L D-DU), with a cutoff value of 196 g/L FEU (or 350 g/L D-DU). QUALITATIVE D-DIMER TEST
Clearview Simplify D-dimer. The Clearview Simplify D-dimer test (Inverness Medical) was performed with 35 L of capillary whole blood. The principle is based on immunochromatography, and the test uses 2 Ddimer–specific murine monoclonal antibodies, 1 of which (DD3B6/224) is conjugated to colloidal gold particles. A visible pink-purple colored line is formed at the test zone (T) when D-dimer concentrations exceed 80 g/L (positive test result). Test results are valid if a pink-purple line is present at the control zone (PC). REFERENCE STANDARD (COMPRESSION ULTRASONOGRAPHY)
After venous and capillary blood was drawn, each patient underwent real-time compression ultrasonography of the symptomatic leg. DVT was considered present if 1 of the proximal veins including the popliteal vein was not fully compressible. The physician who judged the result of the compression ultrasonography was blinded to the outcome of the D-dimer assays. Compression ultrasonography was repeated within 1 week in patients whose ultrasound results showed no evidence of DVT. USER-FRIENDLINESS OF THE POINT-OF-CARE D-DIMER TESTS
To evaluate the user-friendliness of the 5 point-of-care D-dimer tests, 20 nurses from a thrombosis service, who were unfamiliar with laboratory testing, received in-depth instruction by the manufacturers on the use of the assays. Subsequently they practiced each test twice to gain familiarity with the measurements. Directly after performing each test, in a random order, for the third time, the nurses completed in a questionnaire concerning the user-friendliness of the 5 tests. DATA ANALYSIS
Estimates of diagnostic accuracy for the point-of-care D-dimer tests, including sensitivity, specificity, negative likelihood ratio, and negative predictive value (with their corresponding 95% CIs) were calculated at the manufacturers’ provided thresholds. In addition, the area under the ROC curve (AUC or c-statistic) was determined for each quantitative point-of-care D-dimer test as a measure of discriminative ability in distinguishing between patients with and without 1760 Clinical Chemistry 56:11 (2010)
Table 1. Patient characteristics of 577 patients with suspected DVT. Characteristic
Female sex Age, mean (SD), years Symptom duration, median (interquartile range), days
Value
63 58 (16) 9 (5–21)
Previous deep venous thrombosis, %
16
Females using oral contraceptives, %
15
Treatment of any malignancy ⬍6 months, %
2
Surgery ⬍4 weeks, %
2
Leg trauma ⬍4 weeks, %
4
Vein distension, %
7
Calf swelling ⱖ3 cm, %
12
DVT, %
12
DVT. An AUC of 0.5 reflects no discriminating ability, whereas a perfect diagnostic tool has an AUC of 1.0 (22 ). Missing data rates for study variables ranged from 0% for results of the compression ultrasonography (used to establish DVT prevalence) to 11.4% for presence of vein distension. Because missing data seldom occur randomly, it is widely acknowledged that excluding the data obtained from study participants who have a missing value leads not only to a loss of statistical power but also to biased results. To decrease bias and increase statistical efficiency, it is better to impute missing values rather than perform a complete case analysis (23–26 ). Accordingly, before conducting the above analysis, we imputed our missing data using multiple regression imputation techniques available in R2.8 software (R foundation for Statistical Computing, www.R-project.org). Results The study included 577 primary care patients with suspected DVT. In 71 patients (12.3%) compression ultrasonography showed a proximal DVT. The mean age of the study population was 58 years, and 63% of participants were women. Additional patient characteristics are presented in Table 1. ACCURACY MEASURES
All accuracy measures of the point-of-care D-dimer tests are presented in Table 2. At the thresholds provided by the manufacturers, all point-of-care D-dimer tests showed negative predictive values higher than 98%. Sensitivities of the Vidas, Pathfast, Triage, Cardiac, and Clearview Simplify D-dimer tests were 0.99, 0.98, 0.97, 0.94, and 0.91, respectively, with corre-
Comparison of 5 Point-of-Care D-Dimer Tests
Table 2. Diagnostic accuracy measures of the 5 point-of-care D-dimer tests for the exclusion of DVT (N ⴝ 577). Cutoff value
Sensitivity (95% CI)
Specificity (95% CI)
LRⴚa (95% CI)
NPV (95% CI)
AUC (95% CI)
Vidas
500 g/L FEU
0.99 (0.96–1.0)
0.42 (0.37–0.46)
0.03 (0.01–0.24)
99.5 (98–100)
0.89 (0.82–0.97)
Pathfast
570 g/L FEU
0.98 (0.94–1.0)
0.39 (0.35–0.44)
0.06 (0.02–0.29)
99.2 (98–100)
0.89 (0.81–0.97)
Triage
196 g/L FEU
0.97 (0.93–1.0)
0.48 (0.44–0.53)
0.06 (0.03–0.23)
99.2 (98–100)
0.88 (0.80–0.97)
Cardiac
500 g/L FEU
0.94 (0.88–0.99)
0.62 (0.58–0.67)
0.10 (0.07–0.25)
98.6 (97–100)
0.88 (0.80–0.96)
0.91 (0.85–0.98)
0.64 (0.60–0.69)
0.14 (0.09–0.29)
98.1 (97–100)
NA
D-dimer assay
Clearview Simplify a
80 g/L
LR⫺, likelihood ratio negative; NPV, negative predictive value; NA, not applicable because it is a qualitative assay.
sponding specificities of 0.42, 0.39, 0.48, 0.62, and 0.64. All quantitative point-of-care tests showed similar and good discriminative power in distinguishing between patients with and without DVT (range AUC 0.88 – 0.89). USER-FRIENDLINESS
The ease of operation of the D-dimer tests and the risk of errors in the procedure were comparable among the 4 quantitative point-of-care D-dimer tests (Table 3). The qualitative Clearview Simplify test differs from the other tests because no analyzer is needed; this test can be performed on capillary whole blood, and no calibration is necessary. In addition, interpretation of the Clearview Simplify test requires subjective color reading, which was judged as moderately difficult by 25% of participants compared to 0%–5% for the quantitative tests. The time needed to perform a single analysis varied from 10 min for the Clearview Simplify test to 38 min for the Vidas test. The time needed for calibration (excluding time for preparation of calibration liquids) varied from 0 min (no calibration required) for the Clearview Simplify, or ⬍1 min for the Cardiac and Triage tests to 21 and 38 min for the Pathfast and Vidas tests, respectively. In addition, calibration of the Vidas and Pathfast tests may require some laboratory skills. The retail prices of analyzers varied from ⬍5000 euros (Cardiac and Triage) to between 5000 and 15 000 euros (Vidas and Pathfast), whereas for the Clearview Simplify D-dimer no analyzer is required. Prices for 1 disposable test kit were approximately the same for all point-of-care D-Dimer tests (between 5 and 10 euros for 1 test kit). The analyzers for all quantitative assays were able to test multiple other biomarkers, ranging from 5 other biomarkers for the Cardiac to 84 other biomarkers for the Vidas analyzer. Discussion We determined, in a direct assay comparison, the relative user-friendliness and the diagnostic accuracy of 5 point-of-care D-dimer tests for aiding in the exclusion
of clinically suspected DVT. Negative predictive values of all tests were high (⬎98%), whereas sensitivities varied from 0.91 (Clearview Simplify D-dimer test) to 0.99 (Vidas D-dimer test). Specificity varied from 0.39 for the Pathfast to 0.64 for the Clearview Simplify D-Dimer test. Both the quantitative Cardiac and Triage and the qualitative Clearview Simplify D-dimer tests were rated as user-friendly for primary care, but reading test results for the quantitative tests was judged to be easier than for the qualitative test. The initial presentation of DVT often occurs in the primary care setting, where the accessibility of additional testing (conventional D-dimer or compression ultrasonography) is relatively poor compared to a hospital setting. Availability of sensitive point-of-care D-dimer tests is therefore highly valuable in the primary care setting. However, to the best of our knowledge, this study was the first to explore the diagnostic accuracy of different point-of-care D-dimer tests for DVT in primary care patients. The results of this study can therefore be compared only to studies performed in the hospital setting. The differences found may be difficult to interpret because they may be attributable to spectrum bias (i.e., diagnostic accuracy of a test may differ in different subgroups of patients or domain) and variation in DVT prevalence (27 ). However, the results of this study are largely in accordance with other studies in the hospital setting performed to evaluate the accuracy of a point-of-care D-dimer test for the exclusion of DVT. We recently performed a diagnostic metaanalysis on 4 currently available point-of-care D-dimer tests (8 ). In this metaanalysis the pooled sensitivity for the Clearview Simplify was 0.87 vs 0.91 in this study; for the Cardiac 0.96 vs 0.94, and for the Triage point-of-care D-dimer 0.93 vs 0.97 with corresponding pooled specificities of 0.62 vs 0.64, 0.57 vs 0.62, and 0.48 vs 0.48. Hence, our study showed slightly lower sensitivity for the Cardiac and slightly higher sensitivity for the Triage point-of-care D-dimer test. Although few studies have been performed for these new point-of-care assays, our results still fall within the (relatively wide) 95% CIs of the pooled analysis of the Clinical Chemistry 56:11 (2010) 1761
1762 Clinical Chemistry 56:11 (2010) Venipuncture
Yes
95/0/5
Operation of analyzer
95/0/5
Test strip placement in analyzer
12 months at 2–8 °C
5–8/test strip
Test kit, euros
Maximum storage time for test strips
€€
Analyzer
Retail pricef
6
NA
Buffer application on test strip
Simultaneous analyses, n
75/20/5
Blood application on test strip
Liability to flaws in procedure, small/moderate/ large, %
95/5/0
Reading test result
Ease of performance, easy/moderate/difficult, %
Calibration by experienced personnel, yes/no
21
Calibration
1/day, 1/lot
17
Control assay
Calibration frequency
17
Preparation of calibration or control liquids
NA
15–17
Analysis
Control optic system device frequency
1
Preparation for analysis
2/day
0
Test strip equilibration
QC assay frequency
30
Analyzer warm-up
Time required, min
Type of blood sampling
Pathfast
Venous whole blood, plasma (heparin-Li, heparin-Na, citrate-Na), capillary blood
Aspects of user-friendliness
Types of blood samples (anticoagulant)
Vidas
Clearview simplify
10–12 months at 2–8 °C
5–8/test strip
€€
12
70/20/10
NA
60/35/5
95/5/0
100/0/0
Yes
1/2 weeks, 1/lot
NA
1/2 weeks, 1/lot
44
35
21 months at room temperature
9–10/test strip
NA (no analyzer required)
NA
NA
80/20/0
80/20/0
NA
75/25/0
NA
NA
NA
NA
NA
NA
1/lote
NAd
?g at 2–8 °C
9–10/test strip
€
1
90/10/0
NA
90/10/0
90/10/0
100/0/0
no
1/lotc
Continued on page 1763
8 months at 2–8 °C
10/test strip
€
1
100/0/0
NA
85/15/0
85/15/0
95/5/0
no
1/lot
c
e
20 ⬍1c
16
10
1
0
⬍1
Venipuncture
⬍1c 1/day
Cardiac
Venous whole blood (heparin)
NA
NA
10–15
ⱕ10
38b NA
1
⬍1
1b
⬍1
Venipuncture
15
24
Triage
Venous whole blood, plasma (EDTA)
0
NAa
Fingerprick or venipuncture
Capillary blood, venous whole blood, plasma (citrate-Na, heparin, EDTA)
0
30
Venipuncture
Plasma (citrate-Na)
Point-of-care D-dimer assay
Table 3. Detailed information on user-friendliness of the 5 point-of-care D-dimer tests.
Yes No 4 h at room temperature LIS, HIS
Print function, yes/no
Device portable, yes/no
Time and temperature after blood sample collection
Connectivityh LIS
24 h at 2–8 °C
No
Yes
Yes, 84 single markers
Vidas
NA
24 h at 2–8 °C
Yes
No
No
Clearview simplify
LIS, HIS, PHCIS
24 h at room temperature
Yes
Yes
Yes, 7 multi and 3 single markers
Triage
LIS, HIS
8 h at room temperature
Yes
No
Yes, 5 single markers
Cardiac
b
NA, figure not applicable for this aspect of the assay. Excluding time needed to centrifuge whole blood. c Calibration data transferred by lot-specific code chip. d Low and high QCs are built in the test-strip. e Manufacturer does not recommend a fixed frequency; 1/lot: once per change of lot number. f Retail price in euros (excluding value-added tax) for 1 analyzer in the Netherlands, 2007; €:⬍5000; €€:5000 –15 000. g ?: Data not provided by the manufacturer. h Connectivity refers to the possibility of the analyzer to directly transfer test results to electronic patient files, such as an (LIS, laboratory information system; HIS, hospital information system; or PHCIS, primary health care information system.
a
Yes, 7 single markers
Pathfast
Multiple marker, yes/no, n
Aspects of user-friendliness
Point-of-care D-dimer assay
Table 3. Detailed information on user-friendliness of the 5 point-of-care D-dimer tests. (Continued from page 1762)
Comparison of 5 Point-of-Care D-Dimer Tests
Clinical Chemistry 56:11 (2010) 1763
metaanalysis. In particular, more studies are needed of the quantitative assays in the domain of primary care. A previous study of the diagnostic accuracy of the Pathfast assay showed a higher sensitivity (1.0 vs 0.98) and much higher specificity (0.63 vs 0.39) compared to our study (7 ). Many studies have evaluated the diagnostic accuracy of the Vidas D-dimer test, which showed, as did our study, high sensitivity and only moderate specificity for excluding DVT (4 ). Because all point-of-care D-dimer tests seemed to show good diagnostic accuracy to aid in the exclusion of DVT, the decision of which test to use will likely depend on their user-friendliness. For example, the user-friendliness of the Vidas and Pathfast tests may be limited for primary care owing to the size of the devices and because of the need for a relatively difficult and time-consuming calibration and analyzer warm-up time. In addition, the Vidas test has to be performed with citrated plasma. On the basis of user-friendliness the Cardiac and Triage devices may be preferred for use in an emergency department setting or small primary care clinics. In addition, these tests produce a D-dimer test result within 15 min and can provide measurements of other (cardiovascular) biomarkers, such as brain natriuretic peptide, troponin, and C-reactive protein. The Clearview Simplify test is also userfriendly for primary care, because it is easily portable, requires no analyzer, can be performed on capillary whole blood, and requires no calibration. LIMITATIONS
For our results to be fully understood, we must discuss a few issues. In this study all point-of-care testing was performed by laboratory workers. Sometimes pointof-care equipment may seem to be easy to use and robust in the hands of laboratory staff, but it may cause significant problems for nonlaboratory users within their own environment (28 ). For example, problems with the reproducibility of the technique may arise when it is used only infrequently by an isolated general practitioner. The laboratory workers in our study were unfamiliar with point-of-care testing and therefore received instruction from the manufacturers on how to use the point-of-care devices. We also sought opinions on the user-friendliness of the point-of-care D-dimer tests from nurses without laboratory experience who learned to perform the tests. More than 90% of these nurses judged the quantitative assays as easy to use. Given that posttraining surveillance is assured, we therefore believe that it is feasible for point-of-care testing to be performed in primary care settings by either trained nurses or general practitioners. Another issue is that a multivariable approach may be preferable to quantify the added value of a new diagnostic test beyond existing test results (17–20 ). Accord1764 Clinical Chemistry 56:11 (2010)
ingly, a D-dimer test cannot be used as a stand-alone test (4 ) but is typically combined with other patient information such as sex, calf swelling, and vein distension, commonly summarized in a formal clinical decision rule. Our study clearly did not use such a multivariable approach. Point-of-care D-dimer tests have only recently been introduced and—as an initial step—we first aimed to compare the diagnostic performance of these tests by themselves. For the quantitative Pathfast, Cardiac, and Triage point-of-care D-dimer tests our study is the largest to date, and for the qualitative Clearview Simplify only 1 previous study in the domain of primary care has been performed, for which patient management was guided by a clinical decision rule and the result of the D-dimer test (15 ). This study demonstrated that the use by general practitioners of the Clearview Simplify D-dimer test— combined with a clinical decision rule—prevented almost 50% of referrals and missed only 1.4% of DVT cases during follow-up. Hence, point-of-care D-dimer testing safely prevented unnecessary referral of patients for additional testing. Not surprisingly, the use of point-of-care D-dimer testing also was found to improve the costeffectiveness of health care use (16 ). In the current study, quantitative point-of-care D-dimer tests showed even higher sensitivity and negative predictive value to rule out DVT compared with the qualitative Clearview Simplify. This higher sensitivity and negative predictive value, however, comes at the cost of slightly lower specificity of these quantitative tests, and accordingly may result in more false-positive tests (i.e., referrals for ultrasonography). Therefore more studies are needed to assess the true or added value of point-of-care tests (particularly quantitative tests) to pretest information that is commonly applicable in these patients. Nevertheless, the present results are promising for the use of point-of-care D-dimer tests to exclude DVT in the primary care setting. To provide additional insight into the possible results of such future management studies based on the existing data, we plotted a Fagan nomogram. In such a nomogram, the posttest probabilities (i.e., probability of missing DVT) are calculated using the accuracy measure (i.e., negative likelihood ratio) of the point-of-care D-dimer test, depending on a chosen pretest probability. If, for example, a patient has a pretest probability of only 5% with the use of 1 of the available diagnostic prediction rules for DVT (2, 15 ), a negative Cardiac D-dimer result yields a posttest probability of (only) 0.5%. A Fagan nomogram is presented in Fig. 1 for 2 different point-of-care D-dimer tests (Cardiac and Vidas D-dimer). Different posttest probabilities can be calculated for different pretest probabilities by drawing a line from these pretest probabilities and the likelihood ratio. A third consideration is that we used compression ultrasonography as the reference standard for deep venous thrombosis. In a metaanalysis, Goodacre and col-
Comparison of 5 Point-of-Care D-Dimer Tests
Fig. 1. Fagan nomogram for Cardiac D-dimer (upper lines) and Vidas D-dimer (lower lines) for different pretest probabilities. Solid lines are for 5% and dashed lines for 30% pretest probability. Accordingly, the posttest probabilities were 0.2% and 1.3% for the Vidas D-dimer and 0.5% and 4.1% for the Cardiac D-dimer. For other pretest probabilities, the posttest probability can be calculated by simply drawing a line through the negative likelihood ratio of the respective point-of-care D-dimer test and the chosen pretest probability.
leagues found a pooled sensitivity of compression ultrasonography for detection of proximal DVT of 0.94, compared with venography as reference standard (29 ). This finding implies that even compression ultrasonography might miss a small proportion of DVT cases. Moreover, we do not have follow-up data for our patients. Hence, some DVT cases may have been missed, which may have led to a small overestimation of the sensitivity of the point-of-care D-dimer tests. However, as with many reference standards, compression ultrasonography is not perfect, but is now the accepted reference standard in daily clinical practice. For our study compression ultrasonograms were repeated
if the initial result was negative. This resulted in only 3 extra cases of DVT. So we believe that the possible overestimation of the sensitivity could not have been very large. Conclusions In a direct assay comparison, all point-of-care D-dimer tests showed similar high sensitivities. Specificities varied and were highest for the Cardiac and Clearview Simplify. Although future diagnostic studies are needed in the primary care setting to evaluate patient management in daily practice guided by both a clinical Clinical Chemistry 56:11 (2010) 1765
decision rule and a point-of-care D-dimer test, our results indicate that point-of-care D-dimer tests have good diagnostic accuracy to aid in safe and costeffective exclusion of DVT in the doctor’s office. Because the quantitative Cardiac and Triage and the qualitative Clearview Simplify were rated the most user-friendly for primary care, these tests may be the preferred tests in such future management studies.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures of Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest: Employment or Leadership: None declared.
Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: The Netherlands Organisation for Scientific Research (ZonMW 945-04-009) and the Netherlands Heart Foundation (project number 2006B236) gave funding to the study. K.G.M. Moons, the Netherlands Organisation for Scientific Research (ZonMW 9120.8004 and 918.10.615). Expert Testimony: None declared. Other: Manufacturers of the point-of-care D-dimer assays provided test kits free of charge for study purposes. However, they had no influence on any aspect relevant to this study. Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript. Acknowledgments: We gratefully acknowledge the support provided by the Netherlands Organisation for Scientific Research and the Netherlands Heart Foundation. We thank the staff of the laboratories of the Deventer Hospital and the medical diagnostic center of Rotterdam (STAR Medical Diagnostic Centre) and Groningen (LabNoord) for performing the D-dimer analyses for this evaluation.
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