J R Soc Med 2005;98:54-58
doi:10.1258/jrsm.98.2.54
© 2005 Royal Society of Medicine
Screening for pulmonary embolism with a D-dimer assay: do we still need to assess clinical probability as well?
Christopher J Hammond BM MRCS
Tajek B Hassan MD FFAEM
Department of Accident and Emergency, Leeds General Infirmary, Great
George Street, Leeds LS1 3EX, UK
Correspondence to: C J HammondE-mail:
doctorhammond{at}ntlworld.com
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SUMMARY
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Clinical risk stratification and D-dimer assay can be of use
in excluding
pulmonary embolism in patients presenting to emergency
departments but many
D-dimer assays exist and their accuracy
varies. We used clinical risk
stratification combined with a
quantitative latex-agglutination D-dimer assay
to screen patients
before arranging further imaging if required. Retrospective
analysis
of a sequential series of 376 patients revealed that no patient
with
a D-dimer of <275 ng/mL was diagnosed with pulmonary
embolism, irrespective
of clinical probability. We conclude
that a latex-agglutination assay could be
used to exclude pulmonary
embolism without the necessity for clinical risk
stratification.
If these findings are borne out by further work, D-dimer
strategies
to exclude pulmonary embolism could substantially reduce imaging
workload.
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INTRODUCTION
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The annual incidence of pulmonary embolism (PE) in the community
is about
30 per 100 000.
1
Patients commonly present to accident
and emergency departments with symptoms
and signs that could
be due to PE, but clinical examination and routine
investigation
is of limited value for confirmation or exclusion of this
diagnosis.
The British Thoracic Society guidelines for the investigation
and
management of suspected acute
PE
2 emphasize the
roles of
clinical risk stratification and D-dimer assay to exclude PE,
followed
by further investigation if required. However, there are numerous
D-dimer
assays on the market and each has its own sensitivity and
specificity.
3,4
Moreover
there is a heterogeneity of results with individual assays;
5,6
no
clear consensus exists about what constitutes a positive or
negative
result, since the numerous macromolecular complexes
containing D-dimer
epitopes are measured in different
ways.
4 In addition,
some non-quantitative assays require subjective
interpretation of the test
result and are prone to inter-observer
variability.
5 The
British Thoracic Society guidelines incorporate the most
investigated
assays—a whole-blood red cell agglutination
assay (SimpliRed
TM AGEN
Biomedical, Brisbane, Australia), and
a rapid enzyme-linked immunosorbent
assay (Vidas).
Quantitative latex agglutination D-dimer assays have been shown to be
effective in excluding deep venous thrombosis and PE in some patient
subgroups.3,7,8
Older non-quantitative or semi-quantitative manual latex agglutination assays
are of limited use in excluding PE since they lack sufficient
sensitivity.4,9,10
In our institution, junior doctors in the emergency department use a simple
clinical risk assessment model to classify patients into low, intermediate or
high clinical probability, followed by an automated quantitative latex
microsphere agglutination D-dimer assay. Patients are then either discharged
or referred for further investigation. To validate the use of this D-dimer
assay in day-to-day practice we retrospectively audited its accuracy by
relating the results to final clinical diagnosis.
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MATERIALS AND METHODS
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Patients presenting to the Leeds General Infirmary emergency
department
with a potential diagnosis of pulmonary embolism
were assessed and
investigated in the emergency department and
on a twelve-bedded observation
and investigation facility called
the clinical decisions unit (CDU). They were
managed according
to the care pathway outlined in
Figure 1. History, examination
findings,
risk factors, assessment of likelihood of PE, results of
investigations
and progress on CDU were recorded on a multidisciplinary
document
(the ‘protocol document’). The protocol documents
of all
patients with a possible diagnosis of PE passing through
the clinical
decisions unit between November 2001 and March
2003 were reviewed. A new
D-dimer assay (Instrumentation Laboratory
quantitative automated latex
agglutination immunoassay) had
been introduced in November 2001.
Data abstracted from the protocol documents were: assessment of clinical
probability of PE (Box 1);
D-dimer result; imaging results; and discharge diagnosis from CDU (PE/PE
excluded). Any missing data were obtained from the pathology and radiology
department computers. The emergency department notes and hospital inpatient
notes were not reviewed except to obtain test results where these were
unavailable from other sources. Long-term outcome was not assessed.
The presence or absence of PE at discharge from CDU was decided on the
basis of test results and clinical review of the patient by either a
peri-fellowship CDU fellow or an accident and emergency consultant. If there
was felt to be any uncertainty about diagnosis, further investigations were
ordered. Patients who had discordant symptoms, signs or results were
investigated further. The validity of the discharge diagnosis was reviewed on
the basis of the test results and clinical information in the protocol
documents. Receiver operator characteristic curves were then produced for the
D-dimer result versus discharge diagnosis (PE/PE excluded).
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RESULTS
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412 patients with a potential diagnosis of PE passed through
the clinical
decisions unit and protocol documents were available
for 395 (96%). 19 of
these patients were excluded from further
analysis as they were
inappropriately entered onto the protocol
(see
Table 1) leaving 376 patients.
Of these, 168 (45%) were
classified as low clinical probability, 135 (36%)
intermediate
and 73 (19%) high.
Patients with PE confirmed
PE was diagnosed in 31 patients (8.2%). The criteria for finally assigning
a patient a diagnosis of PE are given below (some patients had more than one
test):
- CT pulmonary angiogram showing PE (12 patients)
- Ventilation-perfusion (V/Q) scan high probability and high
clinical probability (4 patients) intermediate clinical probability (6
patients)
- V/Q scan intermediate probability and continuing signs and symptoms on
review (2 patients)
- Doppler ultrasound or CT pulmonary angiogram showing deep venous thrombosis
and continuing symptoms and signs of PE on review (7 patients).
Patients with PE excluded
PE was excluded in 345 patients (92%). The criteria for final exclusion of
PE were as follows:
- CT pulmonary angiogram normal (49 patients)
- V/Q scan normal (147 patients)
- V/Q scan low probability and at least one of... low clinical probability
(12 patients) intermediate clinical probability (21 patients) and pain gone on
review (6 patients)
- D-dimer result normal (<275 ng/mL) and at least one of... clinical
probability low (91 patients) clinical probability intermediate and on review
pain gone (4 patients)
- Clinical probability low and on review pain gone (4 patients)
- Clear alternative diagnosis becoming apparent whilst on CDU (10
patients).
A single patient had an intermediate probability V/Q scan and a subsequent
CT pulmonary angiogram reported non-normal but unlikely to reflect PE. This
patient had improved on review and was discharged with PE excluded.
Incidence of PE by clinical risk
2 patients of 167 (1.2%) with low clinical risk were diagnosed with
pulmonary embolism after investigation. Both these patients had D-dimer
>700 ng/mL. 11 patients of 133 (8.3%) with intermediate clinical risk were
diagnosed with PE. None of these had a normal value (<275 ng/mL) for
D-dimer. 17 patients of 71 (23.9%) with high clinical risk were diagnosed with
PE. None of these had a normal D-dimer.
Figure 2 summarizes the
incidence of PE by clinical risk.
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DISCUSSION
|
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Our data are consistent with the findings of others that a normal
D-dimer
result in combination with a clinical assessment of
low probability of PE
reliably excludes pulmonary
embolism.
7,11
Intriguingly,
our study suggests that the D-dimer may also be of use in
excluding
PE in intermediate and high clinical probability groups. None
of the
28 patients in these groups who were eventually diagnosed
with PE had a
D-dimer of less than 275 ng/mL. Other investigators
have made similar
suggestions: Bates
et al.,
3 using a different
automated
quantitative latex agglutination assay, found that a normal
D-dimer
(<500 ng/mL) could potentially exclude deep venous
thrombosis in high
clinical risk
groups
3 and the
Vidas ELISA
D-dimer assay has been shown to exclude PE on its own without
the
need for clinical risk
stratification.
12,13
Nevertheless,
current recommendations are that a normal D-dimer alone does
not
adequately exclude
PE.
2
329 imaging studies were conducted on the patient group as a whole. Use of
a D-dimer cut-off (to exclude PE) of 700 ng/mL for low clinical probability
patients and 275 ng/mL for intermediate and high probability patients has the
potential to reduce imaging workload by 208 studies (63%).
Our findings emphasize the role of D-dimer as a test of exclusion. Whilst
the test has high sensitivity, it has poor specificity and is not reliable for
diagnosis. Moreover, the patient population we studied was an outpatient
population. The D-dimer is likely to be of less use in an inpatient population
where the incidence of PE is
higher14 and the
D-dimer is less likely to be
normal.8,15
Strengths and weaknesses of the study
It is unlikely that all low clinical probability patients were captured
into the study, since certain patients were discharged directly from the
emergency department on the basis of a low clinical probability assessment and
a normal D-dimer, without a protocol document being filled out. However, it
was a prerequisite that a protocol document be completed before the patient
could be transferred to CDU for further investigation and therefore the
capture of intermediate and high clinical probability patients, and of low
clinical probability patients with a D-dimer >275 ng/mL, is likely to be
near complete. Rarely, a patient may have been admitted directly to inpatient
medical teams (bypassing CDU) if the unit was full or if the patient was
deemed unsuitable for a specific reason (e.g. confusion, social circumstances
precluding rapid discharge, pregnancy or haemodynamic instability).
Our rates of diagnosis of PE overall and by clinical risk group are lower
than those reported by other investigators. The published rates of PE overall
and for low, intermediate and high clinical risk groups are in the regions of
17–23%, 3–9%, 16–30% and 40–78%,
respectively.11,12,16
Our low PE rates may reflect differences in study populations, our population
having a larger number of patients in whom PE was excluded relative to other
studies. This interpretation is supported by the high proportion of
‘normal’ V/Q results: of 230 V/Q scans performed, 150 (65%) were
‘normal’, compared with 16–39% in the other
studies.11,12,16
The only explanation we can offer for this difference is that the threshold
for investigation for potential PE was lower in our series than in others.
Departmental ethos encouraged a low threshold to avoid inappropriate
discharge; moreover, further diagnostic investigation was readily arranged via
CDU without the need for referral to an admitting inpatient team. Therefore,
despite the low rate of diagnosis of PE, we feel the study should be
generalisable to similar populations of patients presenting to emergency
departments.
A potential source of bias was the lack of a gold standard test with which
to compare the D-dimer result. A CT pulmonary angiogram reliably diagnoses or
excludes
PE.17,18
A normal V/Q scan reliably excludes
PE.18 The
likelihood of PE with high, intermediate and low probability V/Q scans depends
on the clinical (pretest) probability but a high probability scan in
association with high clinical probability is associated with a 96% risk of PE
when compared with pulmonary
angiography.19 A
low probability scan in association with low clinical probability is
associated with a 4% risk of
PE.19 A normal
D-dimer with other assays excludes PE,
12 especially when
associated with a low clinical
probability.11 On
this basis, 83.5% (314) of our sample had PE excluded or diagnosed on the
basis of established diagnostic criteria.
The other 62 patients had PE excluded or diagnosed after reassessment
and/or further imaging as deemed clinically necessary, but definitive
diagnosis (on the basis of established diagnostic criteria) was not achieved
for these patients, nor was formal follow-up arranged to assess long-term
(e.g. three-month) outcome. This lack of definitive diagnosis and absence of
formal follow-up could introduce bias and represents a weakness of the study.
Nevertheless, the results are representative of our day-to-day practice, where
patients are assessed and investigated as appropriate and not simply for the
sake of completeness. In clinical management terms, the diagnostic certainty
in these 62 patients was sufficient to allow discharge or admission for
treatment. We therefore believe their discharge diagnoses to be acceptably
reliable.
Conclusion
Our study suggests that the Instrumentation Laboratories automated
quantitative latex microsphere agglutination assay of D-dimer is able to
exclude PE at a level of 275 ng/dL without the need for clinical risk
assessment. A more rigorous study design is required to confirm this. If these
findings are borne out by further work, use of D-dimer could substantially
reduce imaging workload.
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SUMMARY
INTRODUCTION
