Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02601846 |
| Other study ID # |
Geneva 15-010 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
November 2015 |
| Est. completion date |
June 2019 |
Study information
| Verified date |
May 2021 |
| Source |
University Hospital, Geneva |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
A multicentre multinational prospective management outcome study has recently proven the
safety of a diagnostic strategy combining clinical probability assessment with an
age-adjusted D-dimer cut-off, defined as a value of (age x 10) in patients > 50 years, for
ruling out PE in outpatients, with a very low likelihood of subsequent symptomatic VTE.
Moreover, this study showed that such a strategy increased the diagnostic yield of D-dimers,
as it allowed ruling out PE without further investigation in a significantly higher
proportion of patients than when using standard cut-off, particularly so in patients 75 years
or older.
The objective of the present study is to confirm in a prospective cohort of "real life"
patients the usefulness of the age-adjusted D-dimer cut-off to rule out PE in patients
presenting to the emergency department with suspected PE.
Description:
BACKGROUND
PE diagnostic strategies Pulmonary embolism (PE) is a frequently suspected diagnosis in the
emergency room (ER) in patients presenting with shortness of breath and/or chest pain without
any obvious cause identified. Historically, PE diagnosis required a pulmonary angiography, a
costly and invasive procedure with associated morbidity and even mortality. Over the last 25
years, evolving diagnostic strategies have been developed and widely validated in prospective
multicentre management outcome studies, with the aim of confirming or excluding the diagnosis
of PE safely enough to avoid realising pulmonary angiography. Nowadays, PE diagnosis
therefore relies on diagnostic strategies, including sequential evaluation of clinical
probability, measurement of plasma D-dimer levels and most often CT pulmonary angiogram
(CTPA), rather than a standalone test.
The initial and essential step is the assessment of pre-test clinical probability, either by
gestalt or by validated clinical prediction rules (Wells rule of Geneva score). This initial
evaluation separates patients into different groups of PE prevalence, and thus directly
influences the negative and positive predictive values of the diagnostic tests used in these
patients.
D-dimer measurement Plasma D-dimer measurement has been extensively evaluated for the
exclusion of PE in outpatients. The diagnostic usefulness of D-dimers lies in their high
sensitivity and hence their capacity to exclude PE when below a certain cut-off ("negative
D-dimers") without further investigations. Indeed, in patients with "non-high" clinical
probability (low and intermediate groups in a three category score or unlikely group in a
dichotomic score), a highly sensitive negative D-dimer test safely excludes PE without
additional investigations. Sensitive D-dimer tests include those performed by the ELISA
technique (median sensitivity 99%; Vidas®, Stratus®, AxSYM®) and by quantitative latex
methods (median sensitivity 96%; STA Liatest®, Tinaquant®). In patients with high clinical
probability or likely PE, the negative predictive value of even a highly sensitive D-dimer
test will be insufficient to exclude PE. D-dimer measurement is thus not used in these
patients.
Performance of D-dimers in elderly patients The specificity of the ELISA and quantitative
latex D-dimer tests for venous thromboembolism (VTE) is limited, ranging from 35 to 40%.
Indeed, D-dimers increase in various clinical situations, including cancer, infectious or
inflammatory states, pregnancy or during post-operative periods, but also with age, leading
to reduced specificity of the test in elderly patients. In other words, the probability of
having a negative test result is reduced, so that the number of patients needed to test (NNT)
to exclude one PE without further investigations is higher. Indeed, whereas PE can be ruled
out in presence of non-high clinical probability and negative D-dimers in one out of 3
outpatients presenting to the emergency room with suspected PE, it can be excluded in only
one out of 20 patients > 80 years. As current diagnostic strategies for PE include imaging
(most often CTPA) in patients with positive D-dimers, lack of specificity of D-dimers in the
elderly leads to a high proportion of these patients undergoing CTPA.
Age-adjusted D-dimer cut-off The question of a higher D-dimer cut-off in elderly patients was
raised a decade ago, but studies confirming the potential security of such a strategy by
retrospectively applying age-adjusted cut-offs to large prospective cohorts of consecutive
patients with suspected VTE were published between 2010 and 2012 and confirmed the safety of
using age-adjusted cut-offs on an overall population of several thousands of patients.
A progressive age-adjusted D-dimer cut-off (agex10 microg/L in patients > 50 years) was
retrospectively derived and validated in a sample of 1712 patients with suspected PE. The
retrospective validation study showed that the age-adjusted cut-off could increase by around
20% the number of patients in whom the D-dimer test was considered negative, without
increasing the proportion of false-negative results when compared to the standard cut-off
(<500 microg/L). The increase in the diagnostic yield of D-dimers was particularly pronounced
in patients over 80 years, as the age-adjusted cut-off allowed an increase in the proportion
of "negative" D-dimers from 9% to 21%, without any false negative result.
This progressive age-adjusted D-dimer cut-off has been prospectively validated in the
ADJUST-PE study, a large multicentre multinational (19 centres in Belgium, France, the
Netherlands, and Switzerland) management outcome study published at the beginning of this
year. All consecutive patients who presented to the emergency department with clinically
suspected PE were assessed by a sequential diagnostic work-up using clinical probability
assessment (by one of the two following scores: simplified, revised Geneva score or the
two-level Wells score for PE), highly sensitive D-dimer measurement (ELISA or
immuno-turbidimetric assays), and CTPA. Patients with a D-dimer level below their
age-adjusted cut-off did not undergo further investigations and were thus left without
anticoagulant treatment and followed-up for a period of 3 months.
The ADJUST-PE study included a total of 3346 patients with suspected PE, from whom 22 were
excluded (D-dimers not performed in 21 and 1 consent withdrawal), leaving 3324 patients
included for the analysis. The subgroup of particular interest was of course patients having
D-dimer levels between 500 microg/L and their age-adjusted cut-off (n=337). None of these
patients was lost to follow-up and 6 patients received therapeutic anticoagulation for
another indication than VTE. Of the remaining 331, 7 died and 7 had suspected VTE. Only one
of these 14 events was adjudicated as confirmed VTE (nonfatal PE). The so-called
"failure-rate" of the age-adjusted cut-off was thus very low at 1 / 331 (0.3%; 95% CI
0.1%-1.7%), so that this strategy can be considered as very safe.
In the ADJUSt-PE study, the overall number of patients ≥ 75 years was 766, of whom 673 had
non-high clinical probability (87.9%). Among these 673 patients, the proportion of patients
with D-dimer levels <500 microg/L was 43/673 (6.4%; 95% CI 4.8%-8.5%). Additional 157/673
patients (23.3%) had D-dimer levels below their age-adjusted cut-off. This means that among
the patients ≥ 75 years with suspected PE and non-high clinical probability, 200/673 (29.7%;
95% CI 26.4%-33.3%) had a "negative" D-dimer result when age-adjusted cut-off was used. After
excluding 5 of these patients who received anticoagulation for another indication, none of
the remaining 195 patients experienced confirmed VTE during the 3 month follow-up (0.0%; 95%
CI 0.0%-1.9%). The diagnostic yield of D-dimers was thus particularly increased by using an
age-adjusted cut-off in patients ≥ 75 years, as the number of patients needed to test to
exclude one PE diminished from 16 with conventional cut-off to 3.4 with age-adjusted cut-off,
a figure that corresponds to the NNT in the general population in previous studies.
Increasing the proportion of patients in whom PE can be ruled out based on clinical
probability assessment and D-dimer measurement without further testing is particularly
interesting in older patients. Indeed, the higher prevalence of renal failure in this
population increases the potential risk of contrast-induced nephropathy related to CTPA or
even contra-indicates this test, and ventilation-perfusion lung scan (which can be performed
in patients with severe renal failure) provides a high proportion of inconclusive results in
older patients. Moreover, ruling out PE based on clinical probability and a simple blood test
could contribute to reduce the time spent in the emergency department and the costs related
to PE diagnostic work-up. Indeed, a previous study had shown that D-dimer measurement with
conventional cut-off was highly cost-saving in patients less than 80 years, but not in
patients over 80 years. Using an age-adjusted D-dimer cut-off dramatically increases the
proportion of patients in whom PE can be ruled out and is thus highly likely to reduce the
costs of PE diagnosis in the emergency department.
