Supplementary Material - Role of D-Dimer testing in venous thromboembolism with concomitant renal insufficiency in critical care
Summary of take home messages
In the present study on almost 10,000 emergency department patients with suspected venous thromboembolism (VTE) we could show that D-Dimer levels are increased in patients without VTE. D-Dimer levels correlate with degree of renal dysfunction. While sensitivity of D-Dimer remains high with worsening renal function, specificity declines markedly. We were able to define safe renal function adjusted D-Dimer levels to rule out VTE in addition to clinical prediction rules that yield a post-test probability for VTE < 1%.
Background
Clinical prediction rules such as the Wells score or the revised Geneva score are well established tools in the diagnosis of pulmonary embolism (1). In patients with low or intermediate risk it is recommended to perform D-Dimer testing to rule out pulmonary embolism prior to performance of a computertomography (CT) angiography or a ventilation perfusion scan, since a negative D-Dimer result can safely be used to rule out the presence of pulmonary embolism (1-4). However, recently there has been controversy about several patient populations in whom D-Dimer level well above the current threshold of 500 µg/l can be considered normal: In 2007 Harper and coworkers first described that D-Dimer levels appeared to be age dependent (5), which was confirmed in a large following study where age adjusted D-Dimer levels were used safely in addition to the revised Geneva score to rule out pulmonary embolism (6). But also renal insufficiency can lead to D-Dimer elevations despite absence of venous thromboembolism: Recently, our group found that D-Dimer levels were mostly elevated in patients with an estimated glomerular filtration rate (eGFR) below 60 ml/min despite absence of pulmonary embolism as proven by CT angiography (7). A second study by a different group confirmed these results later (8). However, so far only data from patients suspected of having pulmonary embolism in comparably small patient collectives are available. No “safe” eGFR adapted D-Dimer threshold has been proposed so far on basis of a large patient collective. This would be interesting to know since renal function adapted D-Dimer cutoffs could result in less performance of unnecessary CT angiographies and consequent radiation exposition and potential adverse events such as allergic reactions to contrast medium.
We therefore wanted to A.) evaluate the relationship between D-Dimer levels and renal function in a large collective of patients presenting to the emergency department of a large university hospital with suspected venous thromboembolism and B.) find renal function adapted D-Dimer cutoffs to safely rule out venous thromboembolism in patients with renal insufficiency.
Methods
Study subjects & Design
In this retrospective study, performed from a prospectively updated database, all patients presenting to the Department of Emergency Medicine of the Inselspital, University Hospital Bern, between 01 January 2009 and 01 November 2013 (58 months) with suspected venous thromboembolism and measurement of D-Dimer levels were included. Patients undergoing dialysis were excluded from the study.
Methods
All data were gathered in a prospective fashion and saved in the research registry of the Department of Emergency Medicine. In case of multiple visits of patients only the first visit was considered for the analysis. Of all patients included in the study the following parameters were extracted for analysis: age; sex; current thrombosis or thromboembolism; history of thrombosis or thromboembolism; known hemostaseologic diagnosis; recent trauma, surgery, bleeding, myocardial infarction, vascular dissection, infection, ischemia, cardiac arrhythmia and type of arrhythmia, cirrhosis of the liver, seizure, chronic inflammatory diseases, neoplasia (solid or hematologic), history of organ transplantation, heart failure, pregnancy, renal insufficiency. Additionally, we obtained data on the following current medications: vitamin K antagonists, heparin and heparin derivates, aspirin, clopidogrel and new anticoagulants (e.g. rivaroxaban). The following data on laboratory examinations were extracted for analysis: D-Dimer, serum creatinine (on day of admission, day 1 and 2 after admission) and international normalized ratio. In patients with elevated creatinine levels at admission the level was compared to prior creatinine levels in our laboratory system as well as matched with previous clinical data and physician reports to assess whether the renal insuffiency was acute, acute on chronic or chronic. D-Dimer was measured by the hemostaseologic laboratory of the University Hospital Bern by use of the VIDAS D-Dimer Exclusion II (BioMérieux SA, Marcy l'Etoile, France; reference range: < 500 µg/l; sensitivity > 99%, specificity 35.7%, negative predictive value > 99%). Serum creatinine was determined at the Center of Laboratory Medicine of the University Hospital Bern by use of the Roche Modular P800 (F. Hofmann-La Roche Ltd., Basel, Switzerland; reference range: male 59 – 104 µmol/l; female 45 – 84 µmol/l). Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration Formula (CKD-EPI) (9):
GFR = 141 X min(Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age X 1.018 [if female] X 1.159 [if black] *
(* Where Scr is serum creatinine (mg/dl), κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1)
All data were obtained by the same person (GL) who also created the study database using Microsoft Excel, MS Office 2007 (Microsoft Corp, WA, USA).
Analysis
Distribution of interval variables were assessed using normal plots and logarithm transformation was used as required. Normally- distributed interval variables are given as means and standard deviation (SD), while non-normally distributed interval variables and ordinal variables are given as median and first to third quartile. Correlations between renal function parameters and D-Dimer were calculated using Kendall’s tau coefficient. Standard linear regression was used to determine associations of various risk factors with D-Dimer. For all tests a two-sided p-value of ≤ 0.05 was considered statistically significant.
Sensitivity, specificity, predictive values and likelihood ratios were calculated using standard equations (10). It is an accepted primary benchmark for a safe diagnostic protocol for 1 to 2% of patients with a negative result to actually have VTE (11). Hence, in order to define cut-offs values for D-Dimer for the three stages of chronic renal failure, we aimed to obtain a post-test probability of 1%. In a group of patients with a low pre-test probability, the prevalence of VTE is approximately 5% (12). Therefore, in order to obtain a post-test probability of 1%, the cut-off values of D-Dimer in all three groups must have a negative likelihood ratio of 0.2:
0.05 (pretest odds) x 0.2 (negative likelihood ratio of cut-off value) = 0.01 (post-test odds)
Statistics were calculated using SPSS for Windows release 20.0, Chicago, IL.
The study was approved by the local institutional review board, the Ethics Committee of the Canton of Bern, Switzerland and due to the retrospective design the need for informed consent was waived.
Additional results
On admission to the emergency department 278 patients (2.9%) were on vitamin K antagonists, 91 patients (0.9%) used low molecular weight heparins and 39 (0.4%) took new oral anticoagulants. 162 patients (48.6% of VTE had pulmonary embolism, 70 patients (21%) had deep venous thrombosis of the leg, 60 patients (18%) had sinus venous thrombosis, 38 patients (11.4%) had superficial phlebitis and 3 patients (0.9%) had portal venous thrombosis.
Table 1 gives an overview on prevalence of negative D-Dimer results and presence of a thromboembolic event stratified for eGFR.
Declining eGFR correlated significantly with the absolute value of D-Dimer and so did age of patients (Figure 1, 2). Table 3 shows the diagnostic test characteristics of D-Dimer at a standard cut-off value of 500 µg/L for detection and exclusion of venous thromboembolism.
In the multivariable regression analysis age, C-reactive protein, presence of venous thromboembolism, active bleeding, presence of a vascular dissection and eGFR presented a strong relation to D-Dimer levels (see Table 2).
Tables
eGFR / Patients (n and % of all patients) / D-Dimer < 500 µg/L / Thromboembolic event< 30 ml/min / 518 (5.3%) / 36 (6.9%) / 21 (4.1%)
30 to 60 ml/min / 1,759 (18.1%) / 335 (19%) / 49 (2.8%)
> 60 ml/min / 7,439 (76.6%) / 3,973 (53,4%) / 263 (3.5%)
Table 1. Prevalence of negative D-Dimer results and presence of venous thromboembolism stratified for eGFR.
Regression coefficient / Standard error / Standardized regression coefficient / p-valueAge / 0.021 / 0.001 / 0.345 / < 0.0001
eGFR ln / -,161 / ,020 / -,083 / < 0.0001
CRP ln / 0.298253782 / 0.006810704 / 0.354 / < 0.0001
Male Sex / -0.152 / 0.017 / -0.068 / < 0.0001
Venous thrombembolism / 1.093 / 0.048 / 0.175 / < 0.0001
Hemostasiologic disorder / 0.259 / 0.114 / 0.017 / 0.023
Trauma / 0.835 / 0.085 / 0.074 / < 0.0001
Surgery / 1.207 / 0.289 / 0.032 / < 0.0001
Active bleeding / 0.626 / 0.037 / 0.135 / < 0.0001
Myocardial infarction / 0.199 / 0.051 / 0.030 / < 0.0001
Dissection / 1.148 / 0.080 / 0.108 / < 0.0001
Ischemia / 0.218 / 0.021 / 0.090 / < 0.0001
Cardiac arrhythmia / 0.177 / 0.038 / 0.036 / < 0.0001
Cirrhosis of the liver / 0.462 / 0.147 / 0.024 / 0.002
Seizure / 0.408 / 0.042 / 0.074 / < 0.0001
Malignancy / 0.264 / 0.038 / 0.053 / < 0.0001
Pregnancy / 0.971 / 0.171 / 0.043 / < 0.0001
Vitamin K Antagonisten / -0.284 / 0.051 / -0.043 / < 0.0001
Aspirin / 0.106 / 0.032 / 0.025 / 0.001
Table 2. Results of the multivariable regression analysis.
Sensitivity / 0,88 / 0,85 to 0,92 / 0,86 / 0,82 to 0,90 / 0,98 / 0,94 to 1,02 / 0,95 / 0,86 to 1,04
Specificity / 0,46 / 0,45 to 0,47 / 0,55 / 0,54 to 0,56 / 0,20 / 0,18 to 0,21 / 0,07 / 0,05 to 0,09
Positive Predictive Value / 0,05 / 0,05 to 0,06 / 0,07 / 0,06 to 0,07 / 0,03 / 0,02 to 0,04 / 0,04 / 0,02 to 0,06
Negative Predictive Value / 0,99 / 0,99 to 0,99 / 0,99 / 0,99 to 0,99 / 0,99 / 0,99 to 1,00 / 0,97 / 0,92 to 1,03
Test Efficiency / 0,47 / 0,56 / 0,22 / 0,11
Likelihood Ratio positive / 1,63 / 1,56 to 1,70 / 1,9 / 1,80 to 2,01 / 1,22 / 1,16 to 1,28 / 1,02 / 0,93 to 1,13
Likelihood Ratio negative / 0,26 / 0,19 to 0,34 / 0,26 / 0,19 to 0,35 / 0,10 / 0,01 to 0,73 / 0,68 / 0,10 to 4,70
Table 3. Diagnostic test characteristics of D-Dimer at a standard cut-off value of 500 µg/L for detection and exclusion of venous thromboembolism.
Figure legends
Figure 1. Correlation of eGFR and D-Dimer (both logarithm transformed).
Figure 2. Correlation of age and D-Dimer (logarithm transformed).
Reference List
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