Citation for published version (APA): Mac Gillavry, M. R. (2001). Some understanding of diagnostic tests for pulmonary embolism

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1 UvA-DARE (Digital Academic Repository) Some understanding of diagnostic tests for pulmonary embolism Mac Gillavry, M.R. Link to publication Citation for published version (APA): Mac Gillavry, M. R. (2001). Some understanding of diagnostic tests for pulmonary embolism General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 20 Sep 2018

2 CHAPTER 9 Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism Wouter de Monyé 1,2, Bernd-Jan Sanson 3, Melvin R. Mac Gillavry 4, Peter M. T. Pattynama 2 ' 5, Harry R. Biiller 5, Annette A. van den Berg-Huysmans 2, Menno V. Huisman 1, on behalf of the ANTELOPE-Study Group 'Department of General Internal Medicine, department of Radiology, Leiden University Medical Centre, Leiden; 'Department of Vascular Medicine, Academic Medical Center, Amsterdam; 4 Department of Internal Medicine, Slotervaart Hospital; Amsterdam; 'Department of Radiology, Erasmus University Medical Centre, Rotterdam, The Netherlands submitted for publication

3 88 Chapter 9 Abstract Background D-dimer blood tests have been suggested to rule out pulmonary embolism. Despite evidence of the safety of withholding anticoagulant treatment in patients with suspected PE and a normal D-dimer assay result, clinicians remain reluctant to use a D-dimer assay as the first and sole diagnostic test. Objective To investigate the relation between D-dimer plasma concentration and pulmonary embolus location and its influence on the diagnostic accuracy of D-dimer plasma concentration measurements in the diagnosis of PE. Design- Plasma D-dimer levels were measured using a quantitative immunoturbidimetric method. A strict protocol of ventilation-perfusion scintigraphy, pulmonary angiography and spiral computed tomography (CT) was used to arrive at a final diagnosis. Independent readers assessed the largest pulmonary artery in which embolus was visible using both spiral CT and pulmonary angiograms. Setting Prospective multicentre study in six Dutch referral centres. Patients A total of 314 consecutive in- and outpatients with clinically suspected pulmonary embolism. Measurements Diagnostic accuracy indices were calculated and the influence of embolus location on the diagnostic accuracy was evaluated using the Kruskal-Wallis test and receiver operated characteristics (ROC) analysis. Results There was a strong correlation between plasma D-dimer concentration and embolus location (Kruskal-Wallis, p<0.001). The assay showed greater accuracy in excluding segmental or larger emboli (sensitivity=93%) than sub-segmental emboli (sensitivity=50%). Conclusions D-dimer concentration and the accuracy of D-dimer assays are clearly dependent on embolus location and smaller, sub-segmental, PE may be missed when D-dimer assays are used as a sole test to exclude pulmonary embolism.

4 Embolus location affects the sensitivity of a rapid quantitative D-dimer assay 89 Introduction The clinical diagnosis of pulmonary embolism (PE) is neither sensitive nor specific and clinical signs or symptoms can only suggest the diagnosis. Therefore objective diagnostic tests are necessary to establish the diagnosis of PE (1-4). Ideally, such a test would be able to rule in or rule out the diagnosis of PE with a high degree of certainty and would be rapid and widely available (5). This is clinically relevant because patients with clinically suspected PE are often being evaluated at the first aid department and a normal test result would imply that a patient is sent home without anticoagulant treatment. A suitable non-invasive test is the measurement of the plasma concentration of D-dimer, a specific degradation product of cross-linked fibrin that is released when the endogenous fibrinolytic system attacks the fibrin matrix of thromboemboli. The plasma level of D-dimer is almost always increased in patients with acute PE or deep venous thrombosis (DVT). Since raised concentrations of D-dimer can be found in many conditions, a positive value should be interpreted in conjunction with more specific tests for PE. It has been suggested that a normal level of D-dimer measured with an enzyme-linked immunosorbent assay (ELISA) may accurately exclude PE (6, 7). In a recent study by Perrier et al, a non-invasive diagnostic strategy was evaluated in patients with suspected PE and DVT. In their study, 159 patients with suspected PE presenting at the emergency ward were left untreated on the basis of a normal D-dimer assay result, without any recurrent venous thromboembolism during 3 month follow-up (8). However, despite this evidence of the safety of withholding anticoagulant treatment in patients with suspected PE and a normal D-dimer assay result, clinicians remain reluctant to use a D-dimer assay as the first and sole diagnostic test. In view of the above, we postulate that clinicians require further understanding on which emboli are accurately detected by D-dimer testing only. A recent retrospective study by Sijens et al. in selected patients with proven PE suggested a relation between thrombusload and D-dimer assay accuracy and found the accuracy in the detection of PE in sub-segmental arteries to be significantly lower (9). The aim of our study was to prospectively assess the relation between levels of D-dimer and the location of PE and to evaluate its influence on the diagnostic performance of the D-dimer assay in consecutive patients with suspected PE. Materials and Methods Patients This study was conducted from June 1997 through March 1998 as part of a large prospective multicentre study in six Dutch hospitals. Consecutive in- and out-

5 90 Chapter 9 patients with clinically suspected PE were eligible. Patients who had already undergone objective diagnostic examinations for their current symptoms were excluded, as were patients in whom the diagnostic work-up could not be initiated within 24 hours. Further exclusion criteria were pregnancy, age less than 18 years and the immediate need for thrombolytic therapy. The study was approved by the Institutional Review Boards of all participating centres and informed consent was obtained from all participating patients. Plasma collection and D-dimer assays Prior to or within 24 hours after the start of heparin therapy, venous blood was drawn using standard 4.5-ml citrate Vacutainer tubes (Becton Dickinson, Franklin Lakes NJ, United States). These were centrifugated at 4 Celsius for 15 minutes at 2500 G. Plasma was then aliquoted into 2 ml. tubes, snapfrozen and stored at -80" Celcius. Quantitative D-dimer measurements were performed on samples, which had been thawed only once, using the Tinaquant assay (Boehringer Mannheim GmbH, Mannheim, Germany) according to the manufacturer's instructions. Tinaquant D-dimer, an immunoturbidimetric assay for quantitative in vitro determination of fibrin degradation products (D-dimer and X-Oligomers) was carried out on a Hitachi system (Hitachi Ltd., Tokyo, Japan). The manufacturers advised cut-off value for the Tinaquant assay is 0.5 ug/ml. Technicians responsible for performing the assay were not aware of patient identity and diagnostic test results. Conversely, the D-dimer measurements were not made known to the interpreters of the diagnostic tests in this study. Diagnostic work-up for PE All patients underwent lung perfusion scintigraphy and extensive bilateral B- mode compression ultrasonography of the leg veins. A normal perfusion scintigram excluded PE, and no further examinations were performed. Ventilation scintigraphy and a spiral CT scan were performed following an abnormal perfusion result. Ventilation-perfusion results were classified either as high probability for pulmonary embolism (defined as one or more segmental perfusion defect with locally normal ventilation) or as non-diagnostic (10). Pulmonary angiography was performed in patients with a non-diagnostic VQ-scan and in patients with a high-probability VQ-scan and a discordant normal spiral CT scan. The maximum time span between examinations was 24 hours. A panel of independent experts interpreted all diagnostic tests. The final diagnosis of PE was thus established by a high-probability VQ scan with a concurrent abnormal spiral CT scan or by an abnormal pulmonary angiogram. PE was excluded on the basis of a normal perfusion scan or a normal pulmonary angiogram. To ascertain the largest involved branch of the pulmonary artery, three experienced radiologists reviewed the pulmonary angiograms and the spiral CT scans

6 Embolus location affects the sensitivity of a rapid quantitative D-dimer assay 91 of patients with the final diagnosis PE. Patients were categorised according to the largest pulmonary vessel in which PE was visible: central (main pulmonary trunk, left or right pulmonary artery, lobar artery), segmental or sub-segmental artery. Lung perfusion scintigraphy was performed using Technetium-99m macroaggregated albumin particles and images were obtained from six directions. Ventilation scintigraphy was performed using Krypton-81m gas. Pulmonary angiography was performed using a digital subtraction technique, with a catheter positioned selectively in the left and right pulmonary artery. Spiral CT angiography was performed during a 32 seconds single breath hold. If patients were very dyspneic, scanning was performed during shallow breathing. Statistical analysis The correlation between D-dimer concentration and embolus location was tested using the non-parametric Kruskal-Wallis test. Receiver operated characteristics (ROC) analysis and the area under the ROC-curve (AUC) were constructed to assess the influence of embolus location on the accuracy of the assay for PE irrespective of the manufacturer supplied cut-off value. An AUC of 1 would signify a perfect test and an AUC of 0.5 would be found if the test results would be completely random. The sensitivity and specificity of the D-dimer assay was calculated at the cut-off value advised by the manufacturer. Results Patients During the course of this study, 440 eligible patients gave informed consent and were included in the study. In 70 of the 440 patients no final diagnosis regarding the presence of absence of PE could be made according to our strict study criteria (Table 9.1). Plasma was obtained within 24 hours and processed according to protocol in 314 of the remaining 370 patients. The mean age of the studied population was 50 years (S.D. 18 years) and 188 (60%) of the 314 patients were female. Of the 314 patients, 251 (80%) were initially seen on an outpatient basis while the remaining 63 (20%) developed symptoms of PE during hospital stay for other reasons. The clinical characteristics of the included and excluded patients were comparable (data not shown). The prevalence of PE was 32%.

7 92 Chapter 9 Table 9.1 Consecutive patients screened Patients screened 807 Excluded Age < 18 years 11 Pregnancy 7 Indication for immediate thrombolytic therapy 4 Objective diagnostic work-up already started elsewhere 24 Logistic* or technical reasons (weekend, holidays) 84 Eligible patients 677 Informed consent 440 Diagnosis according to study protocol 370 Number of patients from whom plasma was obtained 314 * Precluding completion of the diagnostic protocol within 48 hours of presentation Accuracy ofd-dimer assay Using the manufacturers advised cut-off value of 0.5 ug/ml, the overall sensitivity of the assay was 81% and the specificity was 63% (Table 9.2). Thus, the assay returned a false negative result in 19 PE positive patients. B-mode compression ultrasound of the leg veins was performed in all of these patients and revealed no DVT. The area under the ROC curve (AUC), a measure of the accuracy irrespective of the cut-off value, was 0.78 (95% CI , Figure 9.1). Table 9.2 Accuracy values of the D-dimer assay using the manufacturer's advised cut-off value for all 314 patients with suspected pulmonary embolism PE absent PE present D-dimer 'normal' D-dimer 'positive' Levels of D-dimer and extent ofpe. Figure 9.2 depicts the D-dimer concentrations measured in the subgroups categorised according to the largest involved pulmonary artery branch. The concentration of plasma D-dimer was shown to be dependent on the location of the largest embolus visible (P<0.001), being highest in patients with emboli in the pulmonary trunc and lowest in the sub-segmental group. Influence of embolus location on assay performance The influence of embolus localion on the accuracy of the D-dimer assays is shown in figures 9.3a and 9.3b. These figures show the ROC-curve of the D- dimer assay in patients with PE in segmental or larger arteries (AUC=0.86, 95%

8 Embolus location affects the sensitivity of a rapid quantitative D-dimer assay 93 1,00 Figure 9.1 Receiver Operated Characteristics curve of the performance of the D-dimer assay in all 314 patients with suspected pulmonary embolism 0.00 ' 1, specificity CI ) and the curve in patients with PE in a sub-segmental artery (AUC=0.59, 95% CI ). Using the manufacturers advised cut-off value of 0,5 ug/ml, the corresponding sensitivity for segmental and larger PE was 93% (95% CI 90-96%). In contrast, the sensitivity for sub-segmental PE was 50% (95% CI 44-56%). Figure 9.2 "ob Box and Whisker plot of D-dimer concentration depicting quartiles, stratified according to largest involved pulmonary artery i : i V//7//A V/////A trunc lobar artery sub-segmental left/right branch segmental Largest pulmonary artery involved

9 94 Chapter 9 A 1,00 JS - r J~ / 1,50- c o 0,00,25,25 - r^ 0, specificity 1 - specificity Figure 9.3 A: Receiver Operated Characteristics curve of the performance of the D-dimer assay for segmental or larger emboli. B: Receiver Operated Characteristics curve of the performance of the D-dimer assay for sub-segmental emboli. Discussion The main finding of our study is that there is indeed a strong correlation between plasma D-dimer concentration and embolus location. Furthermore, our data indicate that the accuracy of D-dimer measurement to exclude PE depends strongly on embolus location. At the manufacturer's advised cut-off value, sensitivity was raised from 81% overall, to 93% for segmental and larger PE. The accuracy for smaller sub-segmental emboli, however, was shown to be only 50%. In our series 20% of all patients had emboli confined to sub-segmental arteries only, which is well in the range found in previous studies (6%, 20% and 30%) (11-13). It should be noted that none of the 19 PE positive patients with a negative D-dimer assay had concomitant DVT as assessed with bilateral B-mode compression ultrasonography. This study provides important knowledge about the consequence of a negative D-dimer result when used as a first and sole test in patients with suspected PE. A negative D-dimer result rules out virtually all large PE and half of sub-segmental PE. Although no studies are available in which patients with proven (subsegmental) PE are left untreated, indirect evidence suggests that this might indeed be safe (9, 14, 15). It has been suggested that patients with smaller emboli and good cardiorespiratory reserve could suffice with follow up, using screening tests for DVT as a possible source of new emboli. Hull et al. obtained six-month follow-up in 627 patients with a non-diagnostic lungscan (14). These patients

10 Embolus location affects the sensitivity of a rapid quantitative D-dimer assay 95 were serially tested for the presence of DVT and, if none was detected, were not treated with anticoagulants. Venous thromboembolism during follow-up occurred in only 12 patients (1.9%). Similarly, in a study by Wells et al 665 patients with a non-diagnostic lungscan and no DVT upon serial testing with ultrasonography were left untreated (15). Only 3 patients (0.5%) had recurrent venous thromboembolism during 3 month follow-up. Of note, in the latter two studies a non-diagnostic lungscan could easily be obtained in the presence of larger than sub-segmental PE (11, 12) and in these studies only testing for the presence of DVT in the leg veins as a possible source of recurrent PE was performed. In contrast, a negative D-dimer assay result, using a carefully chosen cut-off value, could exclude DVT not only from the leg veins, but also from elsewhere in the body and would thus be a more extensive test than ultrasound of the leg veins. Although D-dimer testing does not detect all PE, the missed emboli are small and their clinical relevance is unclear. It should be noted that the accuracy of other diagnostic modalities with respect to these small emboli is similarly unclear. Ventilation-perfusion scintigraphy requires at least a segmental mismatch for it to be 'high probabililty' for PE. Smaller defects need further investigation with other techniques and only a normal perfusion scintigram rules out PE (10). Spiral computed tomography of the pulmonary arteries, a highly propagated new test in the diagnosis of PE, fails to detect sub-segmental emboli as well (16-18). Finally, the interobserver variability of pulmonary angiography - the gold standard diagnostic modality for PE - is much higher when it comes to these small sub-segmental emboli than it is for larger PE (19, 20). A few methodological points should be considered. The rigid protocol and the later independent blinded adjudication of the reference tests reduced the number of patients in which a final diagnosis could be established. However, it is unlikely that this has biased our study since this did not lead to differences in clinical characteristics between the included and the excluded patients (data not shown) and the prevalence of PE is similar to that reported in previous studies. In conclusion, D-dimer plasma concentration is clearly correlated with the location of PE. Thus, the accuracy of D-dimer measurement in patients with suspected PE depends on the embolus present in the largest pulmonary artery. Although highly accurate for segmental and larger PE, D-dimer measurement can miss sub-segmental PE. It is however uncertain whether these small emboli really need anticoagulant treatment. Our data could support physicians to take management decisions in patients who present at the first aid department with clinically suspected pulmonary embolism and have a normal D-dimer bloodtest.

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