Potential impact of adjusting the threshold of the quantitative D-dimer based on pretest probability of acute pulmonary embolism.

Abstract

The utility of D-dimer testing for suspected pulmonary embolism (PE) can be limited by test specificity. The authors tested if the threshold of the quantitative D-dimer can be varied according to pretest probability (PTP) of PE to increase specificity while maintaining a negative predictive value (NPV) of >99%.
This was a prospective, observational multicenter study of emergency department (ED) patients in the United States. Eligible patients had a diagnostic study ordered to evaluate possible PE. PTP was determined by the clinician's unstructured estimate and the Wells score. Five different D-dimer assays were used. D-dimer test performance was measured using 1) standard thresholds and 2) variable threshold values: twice (for low PTP patients), equal (intermediate PTP patients), or half (high PTP patients) of standard threshold. Venous thromboembolism (VTE) within 45 days required positive imaging plus decision to treat.
The authors enrolled 7,940 patients tested for PE, and clinicians ordered a quantitative D-dimer for 4,357 (55%) patients who had PTPs distributed as follows: low (74%), moderate (21%), or high (4%). At standard cutoffs, across all PTP strata, quantitative D-dimer testing had a test sensitivity of 94% (95% confidence interval [CI] = 91% to 97%), specificity of 58% (95% CI = 56% to 60%), and NPV of 99.5% (95% CI = 99.1% to 99.7%). If variable cutoffs had been used the overall sensitivity would have been 88% (95% CI = 83% to 92%), specificity 75% (95% CI = 74% to 76%), and NPV 99.1% (95% CI = 98.7% to 99.4%).
This large multicenter observational sample demonstrates that emergency medicine clinicians currently order a D-dimer in the majority of patients tested for PE, including a large proportion with intermediate PTP and high PTP. Varying the D-dimer's cutoff according to PTP can increase specificity with no measurable decrease in NPV.

Full text

Page 1

CLINICAL PRACTICE
Potential Impact of Adjusting the Threshold of
the Quantitative D-dimer Based on Pretest
Probability of Acute Pulmonary Embolism
Christopher Kabrhel, MD, MPH, D. Mark Courtney, MD, Carlos A. Camargo Jr., MD, DrPH, Christo-
pher L. Moore, MD, Peter B. Richman, MD, MBA, Michael C. Plewa, MD, Kristen E. Nordenholtz, MD,
Howard A Smithline, MD, Daren M. Beam, MD, Michael D. Brown, MD, and Jeffrey A. Kline, MD
Abstract
Objectives: The utility of D-dimer testing for suspected pulmonary embolism (PE) can be limited by test
specificity. The authors tested if the threshold of the quantitative D-dimer can be varied according to
pretest probability (PTP) of PE to increase specificity while maintaining a negative predictive value (NPV)
of >99%.
Methods: This was a prospective, observational multicenter study of emergency department (ED)
patients in the United States. Eligible patients had a diagnostic study ordered to evaluate possible PE.
PTP was determined by the clinician’s unstructured estimate and the Wells score. Five different D-dimer
assays were used. D-dimer test performance was measured using 1) standard thresholds and 2) variable
threshold values: twice (for low PTP patients), equal (intermediate PTP patients), or half (high PTP
patients) of standard threshold. Venous thromboembolism (VTE) within 45 days required positive
imaging plus decision to treat.
Results: The authors enrolled 7,940 patients tested for PE, and clinicians ordered a quantitative D-dimer
for 4,357 (55%) patients who had PTPs distributed as follows: low (74%), moderate (21%), or high (4%). At
standard cutoffs, across all PTP strata, quantitative D-dimer testing had a test sensitivity of 94% (95% confi-
dence interval [CI] = 91% to 97%), specificity of 58% (95% CI = 56% to 60%), and NPV of 99.5% (95%
CI = 99.1% to 99.7%). If variable cutoffs had been used the overall sensitivity would have been 88% (95%
CI = 83% to 92%), specificity 75% (95% CI = 74% to 76%), and NPV 99.1% (95% CI = 98.7% to 99.4%).
Conclusions: This large multicenter observational sample demonstrates that emergency medicine clini-
cians currently order a D-dimer in the majority of patients tested for PE, including a large proportion
with intermediate PTP and high PTP. Varying the D-dimer’s cutoff according to PTP can increase
specificity with no measurable decrease in NPV.
ACADEMIC EMERGENCY MEDICINE 2009; 16:325–332 ª 2009 by the Society for Academic Emergency
Medicine
Keywords: D-dimer, emergency department, venous thromboembolism, decision-making
Q
have found it to be highly sensitive for PE, but limited to
uantitative D-dimer testing is commonly used
to rule out acute pulmonary embolism (PE). Pre-
vious analyses of the quantitative D-dimer test
some degree by low specificity. Independent meta-analy-
ses have demonstrated that automated quantitative
D-dimer assays, including immunoturbidimetric and
enzyme-linked immunosorbent assays, have approximate
ª 2009 by the Society for Academic Emergency Medicine
doi: 10.1111/j.1553-2712.2009.00368.x
ISSN 1069-6563
PII ISSN 1069-6563583
325
From the Department of Emergency Services, Massachusetts General Hospital, Harvard Medical School (CK, CAC), Boston, MA;
the Department of Emergency Medicine, Northwestern University Medical Center (DMC), Chicago, IL; the Department of Emer-
gency Medicine, Yale University Medical Center (CLM), New Haven, CT; the Department of Emergency Medicine, Mayo Clinic
Arizona (PBR), Scottsdale, AZ; the Department of Surgery, St. Vincent Mercy Medical Center, Medical College of Ohio (MCP),
Toledo, OH; the Division of Emergency Medicine, Department of Surgery, University of Colorado (KEN), Denver, CO; the Depart-
ment of Emergency Medicine, Baystate Medical Center (HAS), Springfield, MA; the Pitt County Memorial Hospital, East Carolina
University School of Medicine (DMB), Greenville, NC; the Department of Emergency Medicine, Michigan State University (MDB),
Grand Rapids, MI; and the Department of Emergency Medicine, Carolinas Medical Center (JAK), Charlotte, NC.
Presented at the Society for Academic Emergency Medicine (SAEM) Annual Meeting, Washington, DC, 2008.
Received October 14, 2008; revision received December 10, 2008; accepted December 10, 2008.
Jeffrey Kline owns stock in CP Diagnostics LLC.
Address for correspondence and reprints: Jeffrey A. Kline, MD; e-mail: Jeffery.kline@carolinashealthcare.org.

Page 2

sensitivity of 95% and specificity of 45% at thresholds
that correspond to 1,000 fibrinogen equivalent units,
leading to a negative likelihood ratio of approximately
0.1.1–4
Published clinical guidelines and Food and Drug
Administration labeling recommend the use of pretest
probability (PTP) assessment in combination with a sin-
gular D-dimer threshold to arrive at an acceptably low
posttest probability as a method to rule out PE.5,6Avail-
able data support using a negative D-dimer to rule out
PE in patients with low PTP. Data from European stud-
ies suggest that D-dimer testing may also be appropri-
ate for intermediate PTP patients, but data from high
PTP patients are sparse.7–10
The practice of limiting D-dimer use to low PTP
patients assumes that the D-dimer has the same diag-
nostic performance across the spectrum of patients
tested. Adjusting the positive⁄negative threshold of
the D-dimer level according to the patient’s PTP could
allow the D-dimer to safely exclude PE in a larger
number of patients, including those with higher PTP.
This would increase the fraction of patients with a
low PTP who could have PE excluded without ioniz-
ing radiation. This adjustment strategy was evaluated
by Linkins et al.,11who showed in a retrospective
analysis that adjusting the D-dimer’s threshold could
increase theD-dimer’s specificity
compromising sensitivity (95%), or negative predictive
value (NPV; >98%).11A similar strategy was also ana-
lyzed retrospectively by Righini et al.,12who demon-
strateda marginalincrease
usefulness.
The aim of this study was to evaluate the quantitative
D-dimer in patients using data obtained from a large
multicenter study ofemergency
patients evaluated for PE. We hypothesized that an
approach using a variable positive⁄negative threshold
would increase the specificity of quantitative D-dimer
testing while maintaining the high NPV of the test.
to 60% without
in theD-dimer’s
department(ED)
METHODS
Study Design
Data for this article were collected as part of a prospec-
tive, multicenter, observational study of ED patients
undergoing testing for possible PE from May 1, 2003,
to March 31, 2007. The institutional review board of
each participating institution approved the protocol for
the enrollment of patients.
Study Setting and Population
This study analyzed final data from participating centers
in the United States, comprising 10 academic medical
centers and two community hospitals. Patients were eli-
gible for enrollment if the treating clinician had suffi-
cient suspicion to order any of the following tests to
diagnose possible PE: D-dimer, computed tomography
(CT) pulmonary angiography, ventilation⁄perfusion lung
scan(V⁄Q), orextremity
required that the treating physician confirm that the
diagnostic test was ordered as part of an evaluation for
acute PE, so that studies ordered to evaluate deep vein
thrombosis (DVT) without PE, or for other reasons, did
venousultrasound. We
not trigger enrollment. Sites enrolled patients either 1)
during randomly selected ED shifts representative of all
day, evening, night, weekday, and weekend shifts at the
institution or 2) consecutively, defined as a minimum of
85% capture of eligible patients. Details of study enroll-
ment are described elsewhere.13
Study Protocol
After a diagnostic test for PE was ordered, but before
results were known, data were collected based upon
knowledge of the clinician who ordered the qualifying
diagnostic study for PE. To enhance generalizability, we
characterized PTP using both an unstructured approach
and the more structured scoring system developed by
Wells et al.14–17When using the unstructured estimate,
we defined low PTP as <15%, intermediate PTP as
15%–40%, and high PTP as >40%. When using the Wells
score, we defined low PTP as <2 points, intermediate PTP
as 2–6 points, and high PTP as >6 points.14,18Both the
unstructured estimate and data for the Wells score were
collected prospectively at the time of enrollment.
For the purpose of follow-up, patients were also
asked whether they would return to the enrolling insti-
tution after discharge if their symptoms returned or
worsened or if they required additional care. Either the
treating clinician or a study coordinator uploaded data
into a Web-based, secure, electronic data collection
form, accessible from any computer in the ED that had
Internet access.19
The decision to order a D-dimer was at the discretion
of the evaluating physician. D-dimer assays were those
used for routine clinical care at participating institu-
tions. We analyzed patients who had one of the follow-
ing quantitative D-dimer assays ordered in the ED,
prior to pulmonary vascular imaging: VIDAS (bio-
Merieux SA, Marcy-Etoile, France), Liatest (Diagnostica
Stago, Asnières sur Seine, France), Hemosil (Dade
Behring, Marburg, Germany), Advanced D-dimer (Dade
Behring), Biopool Minutex (diaPharma, West Chester,
OH), or MDA (Organon Teknika Corporation, Durham,
NC). Using the standard definitions of negative, Liatest,
VIDAS, and MDA D-dimers were considered negative
at concentrations of <500 ng⁄ml, Biopool Minutex at
<250 ng⁄mL, Hemosil at <244 ng⁄mL, and the Advanced
D-dimer at <1.6 lg⁄mL.
When using variable D-dimer cutoffs, we defined a
negative D-dimer as either twice (for low PTP patients)
or half (for high PTP patients) the standard definition
and no change for patients with intermediate PTP. We
chose to use twice⁄half the standard values, rather than
the values used by Linkins et al.,11for two main rea-
sons: 1) we favored a simple system that clinicians
could remember, even at the expense of statistical
efficiency, and 2) it was unclear whether the cutoffs
Linkins et al. used (0.2, 0.5, and 2.1 lg FEU mL)1, MDA
D-dimer [bioMerieux, Inc., Durham, NC]) should be
appliedproportionatelyacross
assays. We preferred to confirm the usefulness of pre-
defined cutoffs rather than reestablish novel cutoffs
(e.g., using receiver operating characteristic [ROC]
curves), which would then need to be validated. The
levels we chose were decided a priori, and no other
levels were tested.
differentD-dimer
326
Kabrhel et al.•EFFECT OF VARYING D-DIMER CUTOFF

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Outcome Measures
The outcome of interest was a diagnosis of acute PE
during the ED visit or within 45 days of the patient’s
ED evaluation. We considered patients to have PE if
they were evaluated for possible PE in the ED, if they
had radiologic confirmation of the diagnosis of either
PE or DVT during the index visit or within 45 days of
the index visit, or if they died of PE during the 45-day
follow-up period. Confirmatory imaging included CT
angiography or conventional angiography showing a
pulmonary arterial or deep venous filling defect inter-
preted as positive for PE or DVT, high-probability V⁄Q
scan, or positive venous ultrasound consistent with
DVT in the proximal or distal vasculature of the upper
or lower extremities. All imaging results were based on
the dictated report of board-certified attending radiolo-
gists not affiliated with the study. We followed patients
for 45 days using a previously validated, published
methodology that included chart review and telephone
follow-up.13,19
Data Analysis
We used SAS v 9.l, (SAS Institute, Cary, NC) for all
statisticalcalculations.Baseline
reported as simple proportions, means with standard
deviations(±SD),and medians
ranges (IQR). Differences between groups were tested
using chi-squared analysis. Test characteristics were
calculated from 2 · 2 tables using standard techniques
characteristics are
withinterquartile
and are reported with exact 95% confidence intervals
(CI).
RESULTS
We prospectively enrolled 7,940 patients (Figure 1), of
whom 545 (6.9%) had PE and 4,357 (55%) had a quan-
titative D-dimer performed. The Liatest was the most
commonly performed assay (34%), followed by the VI-
DAS (29%). There were 10 patients for whom the type
of D-dimer assay performed could not be ascertained.
These were included in the total number of patients,
but excluded from all analyses related to D-dimer.
Among patients who had a quantitative D-dimer per-
formed, 8 had unexpected electronic data transfer
errors that precluded analysis of clinician’s unstruc-
tured assessment of PTP. All patients had the data
necessary to calculate the Wells score. The D-dimer
concentrations were normal in the majority of patients
tested(n = 2,454;56%).
(5.4%) patients who had a quantitative D-dimer per-
formed were diagnosed with PE. Table 1 shows the
baseline characteristicsof
patients who had a D-dimer as part of their diagnostic
evaluation.
We compared patients who had a D-dimer ordered
to patientswho hadpulmonary
ordered as the first test in centers where a quantitative
D-dimer was available. Patients with a D-dimer done
Two-hundredthirty-four
enrolledpatientsand
vascular imaging
Figure 1. Patients evaluated for possible PE. PE = pulmonary embolism; PTP = pretest probability. *Eight patients had unexpected
electronic errors that precluded clinician’s unstructured assessment of PTP. §Using standard cutoffs.
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had slightly lower mean age (48 years vs. 51 years,
p < 0.0001), were similarly likely to be female (67% vs.
66%, p = 0.35), and had similar racial background,
although the overall distribution was slightly different
across groups (57% vs. 57% white; 34% vs. 35% Afri-
can American; 5% vs. 6% Hispanic; p = 0.006). The
median Wells score was similar in patients undergoing
D-dimer testing when compared with patients who did
not (1.5 [IQR 0.0–2.5] vs. 1.5 [IQR 0.0–3.0]). Patients who
underwent D-dimer testing were less likely to have had
prior PE (9% vs. 14%, p < 0.0001), a history of cancer
(4% vs. 10%, p < 0.0001), or recent surgery (4% vs.
10%, p < 0.0001). Compared with patients who had pul-
monary vascular imaging without a preceding D-dimer,
patients who underwent D-dimer testing were less
likely to be diagnosed with venous thromboembolism
(VTE; 5% vs. 9%, p < 0.0001).
Overall, the imaging test most frequently performed
to evaluate for PE was CT angiography, which was per-
formed in 4,237 (53%) patients. Venous ultrasound was
performed in 987 (12%) patients, and V⁄Q scanning
was performed for 468 (6%) patients. Conventional pul-
monary angiography was performed in 180 (2.2%)
enrolled patients. Among 4,357 patients who had quan-
titative D-dimer testing, CT angiography was per-
formed in2,068(47%),
performed in 458 (11%), V⁄Q scanning was performed
in 210 (5%), and conventional pulmonary angiography
was performed in 47 (1%).
In general, unstructured PTP assessment and the
Wells score categorized patients as low, intermediate,
and high PTP in similar proportions (Table 2). Within
these groups, the outcome rates of PE were similar. In
both low and intermediate PTP groups, the prevalence
of PE was £13%.
venousultrasound was
Among patients who had a quantitative D-dimer per-
formed, 191 (4%) patients had an unstructured clinician
estimate of PTP > 40%, and 58 (30%) of these had PE
(Table 3). The D-dimer had a sensitivity of 93% and
NPV of 93%. Ninety-five (2%) patients had a Wells
score of >6, and 32 (34%) of these patients had PE. The
D-dimer had a sensitivity of 94% and NPV of 91%.
However, in both subgroups of high PTP patients, CIs
were wide due to small sample size. There were two
deaths among patients with negative D-dimer results
(using standard cutoffs). Neither of these patients had
PE. These patients were both categorized as intermedi-
ate PTP by unstructured estimate and both had Wells
scores between 2 and 6.
Using the standard cutoffs across all levels of PTP,
the quantitative D-dimer had a sensitivity of 94%,
specificity of 58%, and NPV of 99.5% (Table 3). In a
Table 1
Baseline Characteristics of Enrolled Patients
Entire Cohort
Quantitative D-dimer Available
DoneNot Done
Quantitative D-dimer
Not Available
Enrolled
Age, years (mean ±SD)
Female, n (%)
Race⁄ethnicity, n (%)
White
African American
Hispanic
Asian
Native American
Other
Primary insurance, n (%)
Private
Medicare
Medicaid
Self-pay
Military
Unknown
Medical history, n (%)
Malignancy
PE
Surgery (within 1 month)
7,940
49 ± 17
5,328 (67)
4,367
48 ± 17
2,937 (67)
3,029
51 ± 18
2,006 (66)
544
49 ± 18
385 (70.8)
4,541 (57)
2,704 (34)
482 (6)
74 (1)
8 (<1)
131 (2)
2,507 (57)
1,478 (34)
238 (5)
53 (1)
6 (<1)
85 (2)
1,722 (57)
1,081 (35)
170 (6)
17 (1)
2 (<1)
37 (1)
312 (57)
145 (27)
74 (14)
4 (1%)
0
9 (2)
3,482 (44)
1,128 (14)
906 (11)
693 (9)
68 (1)
1,528 (19)
2,063 (47)
548 (13)
459 (11)
376 (9)
36 (1)
755 (17)
1,137 (38)
453 (15)
377 (12)
256 (9)
32 (1)
769 (25)
282 (52)
127 (23)
70 (13)
61 (11)
0
4 (1)
489 (6)
858 (11)
520 (7)
161 (4)
378 (9)
193 (4)
302 (10)
416 (14)
294 (10)
26 (5)
64 (12)
33 (6)
PE = pulmonary embolism.
Table 2
Prevalence of PE According to PTP
PTP*Patients in CategoryPatients with PE
Low
<15%
Wells score <2
Intermediate
15%–40%
Wells score 2–6
High
>40%
Wells score >6
5357 (68)
5482 (69)
167 (3)
173 (3)
2087 (26)
2201 (28)
215 (10)
280 (13)
488 (6)
257 (3)
163 (33)
92 (36)
All values expressed as n (%).
PE = pulmonary embolism; PTP = pretest probability.
*Assessed using unstructured clinical estimates (for percent-
age values) or using the system described by Wells et al.18
328
Kabrhel et al.•EFFECT OF VARYING D-DIMER CUTOFF

Page 5

hypothetical analysis, had the proposed variable D-dimer
cutoffs been used, the overall sensitivity would have
decreased to 88% (using PTP) and 85% (using Wells),
but the specificity would have increased to 75% (using
either Wells or PTP). As would be expected in each PTP
subgroup, when variable cutoffs resulted in decreased
sensitivity, there was an associated increase in specific-
ity (and vice versa). The hypothetical decrease in sensi-
tivity was most significant for patients with low PTP,
such that using the D-dimer at twice threshold would
have yielded a sensitivity of 72% in patients with
unstructured PTP of <15% and 68% in patients with a
Wells score of <2. Simultaneously, however, the speci-
ficity would have increased to 86%, for unstructured
PTP or Wells score. When coupled with the 3% preva-
lence of PE in this subgroup, the NPV would remain
high (99%), with the lower limit of the 95% CI if >98%.
We performed subgroup analyses to assess whether
this strategy could be applied to patients in whom
D-dimer testing tends to be less useful due to low speci-
ficity: patients who have malignancy, are older, or are
pregnant. In 161 patients with cancer, standard and
variable cutoffs had similar sensitivity (92% vs. 92%)
and NPV (95% vs. 96%), but the specificity using vari-
able cutoffs was 39% compared to 30% using standard
cutoffs. In 972 patients more than 60 years old, variable
cutoffs resulted in sensitivity of only 86%, compared to
97% using standard cutoffs, although NPV remained
high for both (98% vs. 99%). Using variable cutoffs,
specificity was 56%, compared to only 36% using stan-
dard cutoffs. In 75 pregnant patients, sensitivity (86%
vs. 86%) and NPV (100% vs. 100%) were again similar,
but variable cutoffs yielded specificity of 53%, com-
pared to only 24% with standard cutoffs.
In Table 4, we combined raw numbers from 2 · 2
tables to estimate the potential effect of changing to a
variable D-dimer cutoff on testing. We undertook this
analysis with these assumptions: that no patient with a
negative D-dimer undergoes diagnostic imaging, all
patients with a positive D-dimer undergo diagnostic
imaging, and imaging results in no false-positive or
false-negative diagnoses. In this scenario, we estimate
that using variable cutoffs would result in an additional
12–18 false-negative D-dimers, or ‘‘missed PE’’ diagnoses
(depending on whether the Wells score or unstructured
PTP estimate is used). This corresponds to 2.7–4.1 per
Table 3
Test Characteristics of Quantitative D-dimer using Standard and Variable Cutoffs
PTP
Sensitivity,
% (95% CI)
Specificity,
% (95% CI)LR(–)
Prevalence
of PE,* % NPV, % (95% CI)
Unstructured PTP Score
All, n = 4,349
Standard cutoff?
Variable cutoff?
<15%, n = 3,224
Standard cutoff?
Variable cutoff§
15%–40%, n = 934
Standard cutoff?
Variable cutoff||
>40%, n = 191
Standard cutoff?
Variable cutoff–
Wells Score
All, n = 4,357
Standard cutoff?
Variable cutoff**
<2, n = 3,228
Standard cutoff?
Variable cutoff§
2–6, n = 1,034
Standard cutoff?
Variable cutoff||
>6, n = 95
Standard cutoff?
Variable cutoff–
5.4
94 (91, 97)
88 (83, 92)
58 (56, 60)
75 (74, 76)
0.10 (0.06–0.16)
0.17 (0.12–0.23)
99.5 (99.1, 99.7)
99.1 (98.7, 99.4)
2.7
94 (87, 98)
72 (61, 81)
63 (61, 65)
86 (85, 88)
0.09 (0.04–0.22)
0.32 (0.23–0.45)
99.7 (99.4, 99.9)
99.1 (98.7, 99.4)
9.7
96 (89, 99)
96 (89, 99)
42 (39, 46)
42 (39, 46)
0.11 (0.04–0.28)
0.11 (0.04–0.28)
98.9 (97.2, 99.7)
98.9 (97.2, 99.7)
30.4
93 (83, 98)
98 (91, 100)
38 (29, 46)
13 (8, 20)
0.18 (0.07–0.48)
0.14 (0.02–0.99)
92.6 (82.1, 97.9)
94.4 (72.7, 99.9)
5.4
94 (91, 97)
85 (80, 89)
58 (56, 60)
75 (74, 77)
0.10 (0.06–0.16)
0.20 (0.15–0.27)
99.5 (99.1, 99.7)
98.9 (98.5, 99.2)
2.9
93 (85, 97)
68 (58, 78)
63 (61, 65)
86 (85, 87)
0.12 (0.06–0.24)
0.37 (0.27–0.49)
99.6 (99.3, 99.9)
98.9 (98.4, 99.3)
10.4
96 (91, 99)
96 (91, 99)
43 (40, 46)
43 (40, 46)
0.09 (0.03–0.23)
0.09 (0.03–0.23)
99.0 (97.5, 99.7)
99.0 (97.5, 99.7)
33.4
94 (79, 99)
97 (84, 100)
33 (22, 46)
14 (7, 25)
0.19 (0.05–0.75)
0.22 (0.03–1.65)
91.3 (72.0, 98.9)
90.0 (55.5, 99.7)
LR(–) = negative likelihood ratio, defined as (1 – sensitivity)⁄(specificity); NPV = negative predictive value; PE = pulmonary
embolism.
*Prevalence of PE in patients who underwent quantitative D-dimer testing.
?Standard cutoff defined as: D-dimer considered negative if <500 ng⁄mL for VIDAS and Liatest and <1.6 lg⁄mL for Advanced
D-dimer.
?D-dimer cutoff at twice standard value when PTP < 15%, standard value when PTP 15%–40%, and twice standard value when
PTP > 40%
§D-dimer cutoff at twice standard value.
||D-dimer cutoff at standard value.
–D-dimer cutoff at half standard value.
**D-dimer cutoff at twice standard value when Wells score <2, standard value when Wells score 2–6, and twice standard value
when Wells score >6.
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1,000 patients evaluated for PE. The vast majority of
these false-negative D-dimers would occur in low-PTP
patients. We combined the total number of negative
D-dimers to estimate the number of imaging tests that
could be avoided and determined that using a variable
cutoff would obviate 662–690 imaging tests, or 152–158
per 1,000 patients evaluated for PE. Thus, using our
assumptions, variable cutoff would obviate 38–55 imag-
ing tests for each missed PE diagnosis.
DISCUSSION
The current analysis was undertaken to determine the
current standard of practice regarding the use of the
quantitative D-dimer in a large representative sample of
ED patients and to determine if D-dimer efficiency
could be safely increased by varying the numeric cutoff
defining a negative test according to PTP.
We submit that the present standard of care supports
using a negative D-dimer to rule out PE in patients with
low PTP. Our analysis confirms the low prevalence (3%)
of PE in patients with low PTP evaluated in the United
States. Previous analyses of European data suggest that
the sensitivity of the quantitative D-dimer may be suffi-
ciently high to rule out PE in patients with intermediate
PTP as well.8–10In our sample, we found that in patients
with intermediate PTP, the prevalence of PE was <13%.
Thus, conservatively assuming that the quantitative
D-dimer in use at a given institution has a negative like-
lihood ratio of 0.13 (consistent with our study and prior
meta-analyses),1,2,4our analysis implies that a negative
quantitative D-dimer can exclude PE with a posttest
probability of <2% in intermediate PTP patients. This
result compares favorably to other criterion standards
used to exclude PE, including the Prospective Investiga-
tion of Pulmonary Embolism Diagnosis (PIOPED-II)
study20(low clinical probability and negative CT angio-
gram: NPV = 96%). To our knowledge, this is the larg-
est prospective study to date that has examined actual
clinical practice and shown that D-dimer is often used
to rule out PE in intermediate PTP patients.
Baseduponour previous
surprisedthatlow and
work,we were
patients
not
intermediatePTP
comprised the vast majority of all patients tested for
PE, regardless of the first test ordered (i.e., D-dimer or
CT angiography).21Clinicians did order a D-dimer on
approximately 40% of patients with a high PTP, result-
ing in about 3%–6% of all patients with a D-dimer
ordered having a high PTP. Our data suggest that the
D-dimer at standard cutoff yielded an unacceptably low
NPV (approximately 90%–92%), and this was not signif-
icantly improved at the half-standard cutoff. Taken
together, our data do not support the use of D-dimer at
any threshold to rule out PE in high-PTP patients.
A key objective of this work was to assess the con-
cept proposed in a previous work that showed that
varying the positive⁄negative cutoff of the quantitative
D-dimer according to the patient’s PTP increased speci-
ficity with little decrease in sensitivity or NPV.11,12We
believed that the cutoff Linkins et al. proposed for low
PTP patients (more than four times the standard cutoff,
based on ROC curve analysis) would represent a sharp
change from current practice, so we decided by con-
sensus to test the effect of a simple doubling the thresh-
old low PTP patients. This adjustment would have
allowed the NPV of the quantitative D-dimer to remain
99%. It must be emphasized that the hypothetical
increase in D-dimer cutoff for low-PTP patients would
have substantially decreased the test’s sensitivity and
that the observed high overall NPV is dependent on a
low prevalence of disease in low-PTP patients. We esti-
mate that using a variable cutoff would result in
approximately 3–4 additional missed PEs per 1,000
patients, although it would have afforded a 15%
decrease in the rate of pulmonary vascular imaging.
LIMITATIONS
The results of this study must be interpreted within the
context of its design. This was a large, multicenter
study, performed in academic and community centers,
resulting in a heterogeneous population with a variety
of D-dimer assays used, although all were quantitative
and automated in format. We did not explore differ-
ences between specific assays. Our study was observa-
tional and noninterventional, such that we believe the
Table 4
Estimated Number of False and True Negatives Using Standard and Variable D-dimer Cutoffs
Standard Cutoff Variable Cutoff
False
Negatives
True
Negatives
Total
Negatives
False
Negatives
True
Negatives
Total
Negatives
Wells score
<2
2–6
>6
Total
PTP
<15%
15%–40%
>40%
Total
8
7
2
2,004
410
2,012
417
30
4
1
35
2,701
399
2,731
403
23259 10
17 2,4372,4543,1093,144
5
6
6
2,012
368
2,017
374
24
4
1
29
2,711
355
2,735
359
53 591718
17 2,4332,4503,0833,112
Estimates are based on raw numbers from 2 · 2 tables, assuming no additional workup after a negative D-dimer, complete diag-
nostic imaging after a positive D-dimer, and no false-negative or false-positive imaging results.
PTP = pretest probability.
330
Kabrhel et al.•EFFECT OF VARYING D-DIMER CUTOFF

Page 7

results represent the real world and probably should
not be compared or contrasted to studies that purport
to follow a rigid study protocol. The diagnostic crite-
rion standard for this study was clinically significant PE
(or DVT) within 45 days of the index visit that was
detected by standard care processes. We did not have
resources to perform radiologic testing to monitor
asymptomatic patients for VTE. It remains possible that
a few patients had a PE or DVT and went undiagnosed
during the follow-up period, and these patients were
incorrectly classified as true-negatives.
Our observational design may also have engendered
some selection bias. We attempted to minimize this
issue by enrolling either from a random sample of ED
shifts or consecutively and by collecting PTP data con-
temporaneously with the ED workup. There were small
differences in the baseline characteristics of patients
who underwent D-dimer testing and the overall study
population. The rate of PE was also lower in patients
undergoing D-dimer testing than the overall study pop-
ulation. This may be because high-PTP patients who
went directly to imaging have a higher prevalence of
PE than those for whom the clinician sent a D-dimer.
Clinicians may have also avoided D-dimer testing on
patients known to have conditions that elevate the D-
dimer (e.g., malignancy). However, the data we present
describing the prevalence of PE across levels of PTP
apply to all patients enrolled, including those who did
not undergo D-dimer testing. Furthermore, our PTP
estimates were collected prospectively, so while there
may have been selection bias in terms of which patients
underwent D-dimer testing, the relationship between
PTP and D-dimer results should still be accurate.
Our population of ED patients had a lower preva-
lence of PE than some previously published studies.
While we feel that this percentage is consistent with
clinical practice in U.S. EDs, our results may not trans-
late to other countries and would likely not apply to
inpatient populations. Despite the fact that we enrolled
a large number of patients, we found relatively few
patients with high PTP. This is consistent with observa-
tions from our prior work.21Unfortunately, the rela-
tively small number of high PTP patients limited our
ability to confidently assess the test characteristics of
the quantitative D-dimer in high-PTP patients. A sub-
stantially larger data set will be required to accumulate
an unbiased sample of high-PTP patients sufficiently
large to have narrow CIs. Finally, we did not assess
whether clinicians would actually be willing to use vari-
able cutoffs in their practice. Studying the implementa-
tion of variable cutoffs, or a study that allows clinicians
to choose cutoffs based on their own comfort level,
may be worthwhile.
CONCLUSIONS
We found a sufficiently low prevalence of PE in a large,
multicenter sample of ED patients with both low and
intermediate PTP to conclude that all patients with a
PTP less than high are appropriate for quantitative D-
dimer testing. Varying the D-dimer’s positive⁄negative
cutoff according to the patient’s PTP could decrease
sensitivity, increase specificity, and maintain a NPV of
‡99%. Future work is needed to better quantify the
potential health risks and benefits that would occur
if different D-dimer thresholds were adopted in a
management protocol.
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