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Evaluation of a Quantitative D-Dimer Latex Immunoassay for Acute Pulmonary Embolism Diagnosed by Computed Tomographic Angiography
ORIGINAL ARTICLE DIAGNOSTIC D-DIMER IMMUNOASSAY
Evaluation of a Quantitative D-Dimer Latex Immunoassay for Acute Pulmonary Embolism Diagnosed by Computed Tomographic Angiography DAVID A. FROEHLING, MD; PAUL R. DANIELS, MD; STEPHEN J. SWENSEN, MD; JOHN A. HEIT, MD; JAYAWANT N. MANDREKAR, PHD; JAY H. RYU, MD; AND PETER L. ELKIN, MD OBJECTIVE: To determine the sensitivity and specificity of a quantitative plasma fibrin D-dimer latex immunoassay (LIA) for the diagnosis of acute pulmonary embolism. SUBJECTS AND METHODS: Study subjects were Mayo Clinic Rochester inpatients and outpatients with suspected acute pulmonary embolism; all had undergone quantitative D-dimer LIA testing and multidetector-row computed tomographic (CT) angiography between August 3, 2001, and November 10, 2003. Multidetectorrow CT angiography was the diagnostic reference standard. RESULTS: Of 1355 CT studies, 208 (15%) were positive for acute pulmonary embolism. Median D-dimer levels were significantly higher for patients with acute pulmonary embolism (1425 ng/mL) than for patients without (500 ng/mL) (P<.001). The highest specificity that optimizes sensitivity for acute pulmonary embolism was achieved by using a discriminant value of 300 ng/mL, which yielded a sensitivity of 0.94 (95% confidence interval [CI], 0.89-0.97), a specificity of 0.27 (95% CI, 0.25-0.30), and a negative predictive value of 0.96 (95% CI, 0.93-0.98). CONCLUSION: The quantitative D-dimer LIA with a discriminant value of 300 ng/mL had high sensitivity and high negative predictive value but low specificity for the diagnosis of acute pulmonary embolism. On the basis of these results, we believe that a negative quantitative D-dimer LIA result and a low pretest probability of thromboembolism together are sufficient to exclude acute pulmonary embolism.
Mayo Clin Proc. 2007;82(5):556-560 ANTELOPE = Advances in New Technologies Evaluating the Localisation of Pulmonary Embolism; CI = confidence interval; CT = computed tomographic; ELISA = enzyme-linked immunosorbent assay; LIA = latex immunoassay; PIOPED = Prospective Investigation of Pulmonary Embolism Diagnosis
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n the United States, acute pulmonary embolism develops in approximately 200,000 patients each year and is the primary cause of death in about 30% of these patients.1,2 Early diagnosis and anticoagulation therapy reduce the mortality rate from 30% to 3%,3 but acute pulmonary embolism is difficult to diagnose; it is often an unexpected finding at autopsy.4,5 Historically, radionuclide (ventilation-perfusion) lung scans and pulmonary angiography were the most common methods of diagnosing acute pulmonary embolism.6,7 Both tests have drawbacks. Only 28% of patients in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study had diagnostic lung scans, which necessitated further evaluation.8 Although pulmonary angiogra556
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phy has been considered the diagnostic reference standard, this invasive test is limited by diagnostic inaccuracy, interreader variability, and incomplete studies.9-12 In the past 5 years, computed tomographic (CT) angiography has replaced the radionuclide lung scan (and pulmonary angiography to a large degree) as the primary imaging modality for the diagnosis of acute pulmonary embolism.13 Single-detector helical CT angiography has a sensitivity range of 0.64 to 1.00 and a specificity range of 0.89 to 1.00 for diagnosing acute pulmonary embolism.14-16 Singledetector helical CT angiography is less accurate than pulmonary angiography for detecting isolated subsegmental pulmonary emboli.12 However, patients with negative CT angiography findings have a good prognosis and a low rate of thromboembolism at 3-month follow-up.17-19 Improvements in CT technology have resulted in better detection of small peripheral pulmonary emboli. Multidetector-row CT scanners have markedly improved the visualization of segmental and subsegmental pulmonary arteries.20,21 The accuracy of multidetector-row CT angiography for the diagnosis of acute pulmonary embolism is probably equivalent to and in some cases may be superior to pulmonary angiography.22 Plasma fibrin D-dimer is a cross-linked fibrin degradation product; its levels in peripheral blood may increase up to 8-fold with thromboembolic disease.23,24 Because of the low specificity of all D-dimer assays for acute deep venous thrombosis and acute pulmonary embolism, the primary value of this test is to exclude these diagnoses in patients with a low pretest probability of thromboembolism.25,26 From the Division of General Internal Medicine (D.A.F., P.R.D., P.L.E.), Department of Radiology (S.J.S.), Division of Cardiovascular Diseases (J.A.H.), Division of Biostatistics (J.N.M.), and Division of Pulmonary and Critical Care Medicine (J.H.R.), College of Medicine, Mayo Clinic, Rochester, Minn. Portions of this manuscript have been published in abstract form in Journal of General Internal Medicine, 2006. This study was supported in part by the Mayo Foundation (D.A.F.) and grant LM06918-03 from the National Library of Medicine and grant PH000022-01 from the Centers for Disease Control and Prevention (P.L.E.). Address reprint requests and correspondence to David A. Froehling, MD, Division of General Internal Medicine, College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2007 Mayo Foundation for Medical Education and Research
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DIAGNOSTIC D-DIMER IMMUNOASSAY
In a retrospective study using electron-beam CT angiography as the diagnostic reference standard, we found that the semiquantitative latex agglutination D-dimer assay had a sensitivity of 0.83 for the diagnosis of acute pulmonary embolism.27 Previous studies have suggested that the quantitative D-dimer latex immunoassay (LIA) has greater sensitivity than the semiquantitative latex agglutination assay for the diagnosis of acute pulmonary embolism.28,29 Because of the small number of patients in previous studies, some uncertainty remains about the sensitivity and specificity of the quantitative D-dimer LIA for the diagnosis of acute pulmonary embolism. The appropriate discriminant value for defining a negative study is also unclear. To address these issues, we retrospectively evaluated the ability of a quantitative D-dimer LIA to diagnose acute pulmonary embolism using multidetector-row CT angiography as the diagnostic reference standard. SUBJECTS AND METHODS We electronically queried the Radiology Research database at the Mayo Clinic in Rochester, Minn, and identified all inpatients and outpatients who were referred for multidetector-row CT pulmonary angiography because of a clinical suspicion of acute pulmonary embolism between August 3, 2001, and November 10, 2003. The study start date was chosen to coincide with the change from singledetector to multidetector-row CT angiography, and the study end date was chosen to ensure an adequate sample size. We electronically queried the Laboratory Information Services database for eligible patients and collected the CT angiography date and plasma fibrin D-dimer LIA values if assays were performed within 3 days (before or after) of the CT pulmonary angiography. This time restriction was based on data that suggested that the sensitivity of the Ddimer LIA decreased when tests were performed 4 or more days after onset of symptoms.30 The study was approved by the Mayo Clinic Institutional Review Board. All patients were examined using a multidetector-row helical CT scanner as previously described.31,32 Three CT scanners were used in this study: a 16-slice scanner (Siemens Sensation 16, Siemens Medical Solutions, Forchheim, Germany), an 8-slice scanner (GE Lightspeed/QXl Ultra, General Electric, Milwaukee, Wis), and a 4-slice scanner (GE Lightspeed/QXl Plus, General Electric). Radiologic criteria from the PIOPED II study were used to establish the diagnosis of acute and chronic pulmonary emboli.32 All CT pulmonary embolism examinations were reviewed by a boardcertified, fellowship-trained staff radiologist with experience in vascular CT. Contrast media was injected at a rate of 4 mL/second. Contrast media dosage and concentration were determined by a sliding-scale algorithm that was based on Mayo Clin Proc.
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patient weight. Images were constructed with a slice thickness of 2.5 mm. All radiology reports were independently reviewed by one of the authors (D.A.F., P.R.D., or P.L.E.) and without knowledge of the D-dimer results. Reports were assigned 1 of the following interpretations: positive for acute pulmonary embolism, positive for chronic pulmonary embolism, negative for pulmonary embolism, or inadequate (or indeterminate) study. The 29 ambiguous CT reports and films were reviewed by a board-certified, fellowship-trained staff radiologist with experience in vascular CT (S.J.S.). Plasma fibrin D-dimer LIAs were performed using the MDA 180 automated coagulometer (bioMérieux, Inc, Durham, NC) and a commercial immunoassay kit (MDA D-dimer, bioMérieux, Inc). Assays were performed according to the manufacturer’s instructions.29 The reportable D-dimer LIA values ranged from less than 100 ng/mL to more than 2000 ng/mL; reported values were rounded to the nearest 50 ng/mL to yield 41 possible outcomes. During the study period, 1630 patients underwent CT angiography for suspected acute pulmonary embolism and were tested with a quantitative plasma fibrin D-dimer LIA. Patients were excluded if D-dimer tests were performed more than 3 days before or after CT angiography (n=184) or if the CT angiogram was interpreted as chronic pulmonary embolism (n=14) or as an inadequate or indeterminate study (n=15). Patients who denied access to their medical records for research purposes also were excluded (n=62). We used data from our prior study27 for sample size determination. We assumed an 18% prevalence of disease and a D-dimer LIA sensitivity of 0.83 for acute pulmonary embolism. We anticipated that 96 patients would be positive for acute pulmonary embolism using the reference standard of CT angiography. These assumptions led to a maximum 10% half-width of the 95% confidence interval (CI) for sensitivity (0.74-0.90) and an estimated sample size of at least 534 patients. We used the Wilcoxon rank sum test to compare D-dimer values of patients with and without acute pulmonary embolism because the 2 groups had nonnormal distributions. Sensitivity, specificity, and negative predictive values of the Ddimer LIA were estimated using all 41 possible discriminant values, and binomial 95% CIs were calculated. Threshold values used in the calculation of sensitivity and specificity were explored using receiver operating characteristic curve analysis.33 Statistical analyses were performed with SAS software (version 8.0, SAS Institute Inc, Cary, NC). P<.05 was considered statistically significant. RESULTS Of the 1355 patients in the study, the mean age was 59±19 years (range, 13 to 98 years), and 837 patients (62%) were
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TABLE 1. Discriminant Value–Dependent True and False D-Dimer Immunoassay Findings (N=1355)
1.0
No. of results
Sensitivity
0.8
True
False
True
False
250 300 350 500 2001
197 195 192 178 76
899 837 785 604 203
248 310 362 543 944
11 13 16 30 132
0.4
0.0 0.0
0.2
0.4
0.6
0.8
1.0
1 – Specificity
FIGURE 1. Receiver operating characteristic curve for the quantitative D-dimer latex immunoassay used to diagnose acute pulmonary embolism.
female. The prevalence of acute pulmonary embolism was 15% (208 patients). Of the 208 patients with acute pulmonary embolism, the median D-dimer concentration was 1425 ng/mL. Of the 1147 patients without acute pulmonary embolism, the median D-dimer concentration was 500 ng/mL. The difference between these median values was significant (P<.001). The range of D-dimer concentrations was the same for both groups (<100 ng/mL to >2000 ng/mL). The 41 possible discriminant (threshold) values were analyzed. A negative assay result would include any Ddimer concentration lower than the discriminant value. The trade-off between sensitivity and specificity is shown by the receiver operating characteristic curve (Figure 1). The area under the curve was 0.71 with an SE of 0.02. The best discriminant value was 300 ng/mL; assays with D-dimer values less than 300 ng/mL had the highest specificity that optimized sensitivity for the diagnosis of acute pulmonary embolism. With a discriminant value of 300 ng/mL, the sensitivity of the quantitative D-dimer LIA for
Negative
Discriminant value (D-dimer, ng/mL)
0.6
0.2
Positive
the diagnosis of acute pulmonary embolism was 0.94 (95% CI, 0.89-0.97), and the negative predictive value was 0.96 (95% CI, 0.93-0.98). However, specificity was 0.27 (95% CI, 0.25-0.30). At this discriminant value, 76% of assays (1032/1355) had positive results, and the false-positive rate was 62% (837/1355). We also investigated the discriminant values used in other studies and specifically considered 250 ng/mL,29 350 ng/mL,28 500 ng/mL,34 and 2001 ng/mL (the maximum value for the assay). The number of true- and false-positive results and true- and false-negative results for these discriminant values is shown in Table 1. The sensitivity, specificity, positive and negative predictive values and positive and negative likelihood ratios are shown in Table 2. Even a strongly positive D-dimer assay (>2000 ng/mL) yielded a positive likelihood ratio of only 2.06. DISCUSSION In a prior study of a semiquantitative latex agglutination Ddimer assay (using a discriminant value of 250 ng/mL), we determined that assay sensitivity was 0.83 (95% CI, 0.760.88) and specificity was 0.39 (95% CI, 0.36-0.43) for the diagnosis of acute pulmonary embolism.27 The quantitative D-dimer LIA (using a discriminant value of 300 ng/mL) had superior sensitivity (P<.05) but inferior specificity (P<.05). By using a discriminant value of 300 ng/mL, sensitivity of the quantitative D-dimer LIA for the diagnosis of acute pulmonary embolism was similar to that found by Heit et
TABLE 2. Discriminant Value–Dependent Sensitivity, Specificity, Predictive Value, and Likelihood Ratio* Likelihood ratio
Predictive value
Discriminant value (D-dimer, ng/mL)
Sensitivity
Specificity
Positive
Negative
Positive
Negative
250 300 350 500 2001
0.95 (0.90-0.97) 0.94 (0.89-0.97) 0.92 (0.88-0.95) 0.86 (0.80-0.90) 0.37 (0.30-0.44)
0.22 (0.19-0.24) 0.27 (0.25-0.30) 0.32 (0.29-0.34) 0.47 (0.44-0.50) 0.82 (0.80-0.84)
0.18 (0.16-0.20) 0.19 (0.17-0.21) 0.20 (0.17-0.22) 0.23 (0.20-0.26) 0.27 (0.22-0.33)
0.96 (0.92-0.98) 0.96 (0.93-0.98) 0.96 (0.93-0.97) 0.95 (0.93-0.96) 0.88 (0.86-0.90)
1.21 (1.16-1.26) 1.28 (1.22-1.35) 1.35 (1.28-1.43) 1.63 (1.50-1.76) 2.06 (1.66-2.57)
0.24 (0.14-0.44) 0.23 (0.14-0.39) 0.24 (0.15-0.39) 0.30 (0.22-0.43) 0.77 (0.70-0.86)
*Parenthetical data are 95% confidence intervals.
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TABLE 3. Efficacy of Quantitative D-Dimer Latex Immunoassays for the Diagnosis of Acute Pulmonary Embolism Study
No. of patients
Discriminant value (D-dimer, ng/mL)
Sensitivity
Specificity
Diagnostic reference standard
Heit et al,28 2000 Bates et al,29 2001 Current
105 278 1355
350 250 300
0.95 0.94 0.94
Data not shown 0.42 0.27
Pulmonary angiography Explicit algorithm Computed tomographic angiography
al28 and Bates et al29; all studies involved the same quantitative D-dimer LIA but had different discriminant values. Our specificity was significantly less than that found by Bates et al29 (P<.05), which may be attributable to the inclusion of inpatient data in the analysis; the D-dimer assay has low specificity (0.07) for patients hospitalized for more than 24 hours.35 A comparison of sensitivity and specificity from these studies is shown in Table 3. Stein et al34 recently published a systematic review of Ddimer testing for the exclusion of venous thromboembolic disease. They indicated that the quantitative rapid enzymelinked immunosorbent assays (ELISAs) were clinically superior to all other D-dimer assays for excluding acute pulmonary embolism. The ELISA had an overall sensitivity of 0.95 (95% CI, 0.83-1.00) and an overall specificity of 0.39 (95% CI, 0.28-0.51) when a discriminant value of 500 ng/mL was used.34 The sensitivity of our quantitative LIA (using a discriminant value of 300 ng/mL) was similar to that of the quantitative rapid ELISA; our specificity was less than the ELISA specificity. In the systematic review,34 the largest prospective study of a quantitative rapid D-dimer ELISA for the diagnosis of acute pulmonary embolism was the Dutch study by the Advances in New Technologies Evaluating the Localisation of Pulmonary Embolism (ANTELOPE) group.36 In the ANTELOPE study, ELISA sensitivity was 0.88 when a discriminant value of 500 ng/mL was used, and sensitivity was 0.96 when a discriminant value of 250 ng/mL was used; the corresponding specificities were 0.52 and 0.29. If we used the ANTELOPE discriminant values, sensitivity of our LIA was similar, but specificity was slightly lower. For patients with low or moderate pretest probability of acute pulmonary embolism, quantitative D-dimer LIAs with a discriminant value of 250 ng/mL and quantitative rapid D-dimer ELISAs with a discriminant value of 500 ng/mL have negative predictive values of 0.99.29,34 Clinicians probably should not order D-dimer tests for a patient with a high pretest probability of acute pulmonary embolism because D-dimer LIA results are unlikely to be negative in such patients and because of concerns about patient safety. In one study, the 95% CI of the 3-month venous thromboembolic risk for patients with negative quantitative rapid D-dimer ELISA findings and a high pretest probabilMayo Clin Proc.
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ity of pulmonary embolism was 0% to 23%.37 Further study is required to determine whether a quantitative D-dimer LIA with a discriminant value of 300 ng/mL and a low or moderate pretest probability for acute pulmonary embolism can effectively exclude this disorder. Our study has several strengths and limitations. To our knowledge, it is the largest study to date of a quantitative D-dimer LIA for the diagnosis of acute pulmonary embolism. Although CT angiography has not replaced pulmonary angiography as the diagnostic reference standard, patients with negative CT angiographic findings for pulmonary embolism have a good prognosis, similar to that of patients with negative pulmonary angiographic findings.17-19 Overall, the clinical validity is similar for CT angiographic findings and pulmonary angiographic findings.19 In addition, multidetector-row CT angiography represents state-of-the-art imaging for acute pulmonary embolism38; it is the imaging modality of choice for the diagnosis of this disorder at our institution and many others. Despite these strengths, our study was limited by its performance at only 1 institution and by its retrospective nature. Furthermore, pretest probability of acute pulmonary embolism could not be calculated retrospectively. CONCLUSION The quantitative D-dimer LIA with a discriminant value of 300 ng/mL had high sensitivity and high negative predictive value for excluding acute pulmonary embolism. However, specificity was low; only about one fourth of patients had a negative and clinically useful D-dimer assay result. Nevertheless, sensitivity of the quantitative D-dimer LIA for the diagnosis of acute pulmonary embolism was superior to that of the semiquantitative latex agglutination assay and similar to that of the quantitative rapid ELISA (using different discriminant values). By itself, the quantitative Ddimer LIA was insufficient to exclude acute pulmonary embolism. On the basis of these results, we believe that a negative quantitative D-dimer LIA result and a low pretest probability of thromboembolism together are sufficient to exclude acute pulmonary embolism. Unless specific contraindications exist, patients with a high pretest probability of acute pulmonary embolism should undergo CT angiography directly.
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REFERENCES 1. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton JL III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158:585593. 2. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med. 1999;159:445453. 3. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet. 1960;1:1309-1312. 4. Morgenthaler TI, Ryu JH. Clinical characteristics of fatal pulmonary embolism in a referral hospital. Mayo Clin Proc. 1995;70:417-424. 5. Spiliopoulou C, Papadodima S, Kotakidis N, Koutselinis A. Clinical diagnoses and autopsy findings: a retrospective analysis of 252 cases in Greece. Arch Pathol Lab Med. 2005;129:210-214. 6. Ginsberg JS. Management of venous thromboembolism. N Engl J Med. 1996;335:1816-1828. 7. Goldhaber SZ. Pulmonary embolism. N Engl J Med. 1998;339:93-104. 8. PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990;263:2753-2759. 9. Novelline RA, Baltarowich OH, Athanasoulis CA, Waltman AC, Greenfield AJ. The clinical course of patients with suspected pulmonary embolism and a negative pulmonary arteriogram. Radiology. 1978;126:561-567. 10. Mills SR, Jackson DC, Older RA, Heaston DK, Moore AV. The incidence, etiologies, and avoidance of complications of pulmonary angiography in a large series. Radiology. 1980;136:295-299. 11. Stein PD, Athanasoulis C, Alavi A, et al. Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation. 1992;85: 462-468. 12. Ryu JH, Swensen SJ, Olson EJ, Pellikka PA. Diagnosis of pulmonary embolism with use of computed tomographic angiography. Mayo Clin Proc. 2001;76:59-65. 13. Stein PD, Kayali F, Olson RE. Trends in the use of diagnostic imaging in patients hospitalized with acute pulmonary embolism. Am J Cardiol. 2004; 93:1316-1317. 14. Rathbun SW, Raskob GE, Whitsett TL. Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a systematic review. Ann Intern Med. 2000;132:227-232. 15. Mullins MD, Becker DM, Hagspiel KD, Philbrick JT. The role of spiral volumetric computed tomography in the diagnosis of pulmonary embolism. Arch Intern Med. 2000;160:293-298. 16. de Monye W, Pattynama PM. Contrast-enhanced spiral computed tomography of the pulmonary arteries: an overview. Semin Thromb Hemost. 2001;27:33-39. 17. Swensen SJ, Sheedy PF II, Ryu JH, et al. Outcomes after withholding anticoagulation from patients with suspected acute pulmonary embolism and negative computed tomographic findings: a cohort study. Mayo Clin Proc. 2002; 77:130-138. 18. Moores LK, Jackson WL Jr, Shorr AF, Jackson JL. Meta-analysis: outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography. Ann Intern Med. 2004;141:866874. 19. Quiroz R, Kucher N, Zou KH, et al. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: a systematic review. JAMA. 2005;293:2012-2017.
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20. Ghaye B, Szapiro D, Mastora I, et al. Peripheral pulmonary arteries: how far in the lung does multi-detector row spiral CT allow analysis? Radiology. 2001;219:629-636. 21. Schoepf UJ, Goldhaber SZ, Costello P. Spiral computed tomography for acute pulmonary embolism. Circulation. 2004;109:2160-2167. 22. Winer-Muram HT, Rydberg J, Johnson MS, et al. Suspected acute pulmonary embolism: evaluation with multi-detector row CT versus digital subtraction pulmonary arteriography. Radiology. 2004;233:806-815. 23. Kelly J, Rudd A, Lewis RR, Hunt BJ. Plasma D-dimers in the diagnosis of venous thromboembolism. Arch Intern Med. 2002;162:747-756. 24. D’Angelo A, D’Alessandro G, Tomassini L, Pittet JL, Dupuy G, Crippa L. Evaluation of a new rapid quantitative D-dimer assay in patients with clinically suspected deep vein thrombosis. Thromb Haemost. 1996;75:412416. 25. Bates SM, Kearon C, Crowther M, et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med. 2003;138:787-794. 26. Kruip MJ, Leclercq MG, van der Heul C, Prins MH, Buller HR. Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies: a systematic review. Ann Intern Med. 2003;138:941-951. 27. Froehling DA, Elkin PL, Swensen SJ, Heit JA, Pankratz VS, Ryu JH. Sensitivity and specificity of the semiquantitative latex agglutination D-dimer assay for the diagnosis of acute pulmonary embolism as defined by computed tomographic angiography. Mayo Clin Proc. 2004;79:164-168. 28. Heit JA, Meyers BJ, Plumhoff EA, Larson DR, Nichols WL. Operating characteristics of automated latex immunoassay fibrin D-dimer tests in the diagnosis of angiographically-defined acute pulmonary embolism. Thromb Haemost. 2000;83:970. 29. Bates SM, Grand’Maison A, Johnston M, Naguit I, Kovacs MJ, Ginsberg JS. A latex D-dimer reliably excludes venous thromboembolism. Arch Intern Med. 2001;161:447-453. 30. Heit JA, Minor TA, Andrews JC, Larson DR, Li H, Nichols WL. Determinants of plasma fibrin D-dimer sensitivity for acute pulmonary embolism as defined by pulmonary angiography. Arch Pathol Lab Med. 1999;123:235240. 31. Remy-Jardin M, Remy J. Spiral CT angiography of the pulmonary circulation. Radiology. 1999;212:615-636. 32. Gottschalk A, Stein PD, Goodman LR, Sostman HD. Overview of Prospective Investigation of Pulmonary Embolism Diagnosis II. Semin Nucl Med. 2002;32:173-182. 33. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143:29-36. 34. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004;140:589-602. 35. Miron MJ, Perrier A, Bounameaux H, et al. Contribution of noninvasive evaluation to the diagnosis of pulmonary embolism in hospitalized patients. Eur Respir J. 1999;13:1365-1370. 36. de Monye W, Sanson BJ, Buller HR, Pattynama PM, Huisman MV, ANTELOPE Study Group. The performance of two rapid quantitative D-dimer assays in 287 patients with clinically suspected pulmonary embolism. Thromb Res. 2002;107:283-286. 37. Righini M, Aujesky D, Roy PM, et al. Clinical usefulness of D-dimer depending on clinical probability and cutoff value in outpatients with suspected pulmonary embolism. Arch Intern Med. 2004;164:2483-2487. 38. Goldhaber SZ. Multislice computed tomography for pulmonary embolism: a technological marvel. N Engl J Med. 2005;352:1812-1814.
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Evaluation of a Quantitative D-Dimer Latex Immunoassay for Acute Pulmonary Embolism Diagnosed by Computed Tomographic Angiography DAVID A. FROEHLING, MD; PAUL R. DANIELS, MD; STEPHEN J. SWENSEN, MD; JOHN A. HEIT, MD; JAYAWANT N. MANDREKAR, PHD; JAY H. RYU, MD; AND PETER L. ELKIN, MD OBJECTIVE: To determine the sensitivity and specificity of a quantitative plasma fibrin D-dimer latex immunoassay (LIA) for the diagnosis of acute pulmonary embolism. SUBJECTS AND METHODS: Study subjects were Mayo Clinic Rochester inpatients and outpatients with suspected acute pulmonary embolism; all had undergone quantitative D-dimer LIA testing and multidetector-row computed tomographic (CT) angiography between August 3, 2001, and November 10, 2003. Multidetectorrow CT angiography was the diagnostic reference standard. RESULTS: Of 1355 CT studies, 208 (15%) were positive for acute pulmonary embolism. Median D-dimer levels were significantly higher for patients with acute pulmonary embolism (1425 ng/mL) than for patients without (500 ng/mL) (P<.001). The highest specificity that optimizes sensitivity for acute pulmonary embolism was achieved by using a discriminant value of 300 ng/mL, which yielded a sensitivity of 0.94 (95% confidence interval [CI], 0.89-0.97), a specificity of 0.27 (95% CI, 0.25-0.30), and a negative predictive value of 0.96 (95% CI, 0.93-0.98). CONCLUSION: The quantitative D-dimer LIA with a discriminant value of 300 ng/mL had high sensitivity and high negative predictive value but low specificity for the diagnosis of acute pulmonary embolism. On the basis of these results, we believe that a negative quantitative D-dimer LIA result and a low pretest probability of thromboembolism together are sufficient to exclude acute pulmonary embolism.
Mayo Clin Proc. 2007;82(5):556-560 ANTELOPE = Advances in New Technologies Evaluating the Localisation of Pulmonary Embolism; CI = confidence interval; CT = computed tomographic; ELISA = enzyme-linked immunosorbent assay; LIA = latex immunoassay; PIOPED = Prospective Investigation of Pulmonary Embolism Diagnosis
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n the United States, acute pulmonary embolism develops in approximately 200,000 patients each year and is the primary cause of death in about 30% of these patients.1,2 Early diagnosis and anticoagulation therapy reduce the mortality rate from 30% to 3%,3 but acute pulmonary embolism is difficult to diagnose; it is often an unexpected finding at autopsy.4,5 Historically, radionuclide (ventilation-perfusion) lung scans and pulmonary angiography were the most common methods of diagnosing acute pulmonary embolism.6,7 Both tests have drawbacks. Only 28% of patients in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study had diagnostic lung scans, which necessitated further evaluation.8 Although pulmonary angiogra556
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phy has been considered the diagnostic reference standard, this invasive test is limited by diagnostic inaccuracy, interreader variability, and incomplete studies.9-12 In the past 5 years, computed tomographic (CT) angiography has replaced the radionuclide lung scan (and pulmonary angiography to a large degree) as the primary imaging modality for the diagnosis of acute pulmonary embolism.13 Single-detector helical CT angiography has a sensitivity range of 0.64 to 1.00 and a specificity range of 0.89 to 1.00 for diagnosing acute pulmonary embolism.14-16 Singledetector helical CT angiography is less accurate than pulmonary angiography for detecting isolated subsegmental pulmonary emboli.12 However, patients with negative CT angiography findings have a good prognosis and a low rate of thromboembolism at 3-month follow-up.17-19 Improvements in CT technology have resulted in better detection of small peripheral pulmonary emboli. Multidetector-row CT scanners have markedly improved the visualization of segmental and subsegmental pulmonary arteries.20,21 The accuracy of multidetector-row CT angiography for the diagnosis of acute pulmonary embolism is probably equivalent to and in some cases may be superior to pulmonary angiography.22 Plasma fibrin D-dimer is a cross-linked fibrin degradation product; its levels in peripheral blood may increase up to 8-fold with thromboembolic disease.23,24 Because of the low specificity of all D-dimer assays for acute deep venous thrombosis and acute pulmonary embolism, the primary value of this test is to exclude these diagnoses in patients with a low pretest probability of thromboembolism.25,26 From the Division of General Internal Medicine (D.A.F., P.R.D., P.L.E.), Department of Radiology (S.J.S.), Division of Cardiovascular Diseases (J.A.H.), Division of Biostatistics (J.N.M.), and Division of Pulmonary and Critical Care Medicine (J.H.R.), College of Medicine, Mayo Clinic, Rochester, Minn. Portions of this manuscript have been published in abstract form in Journal of General Internal Medicine, 2006. This study was supported in part by the Mayo Foundation (D.A.F.) and grant LM06918-03 from the National Library of Medicine and grant PH000022-01 from the Centers for Disease Control and Prevention (P.L.E.). Address reprint requests and correspondence to David A. Froehling, MD, Division of General Internal Medicine, College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2007 Mayo Foundation for Medical Education and Research
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DIAGNOSTIC D-DIMER IMMUNOASSAY
In a retrospective study using electron-beam CT angiography as the diagnostic reference standard, we found that the semiquantitative latex agglutination D-dimer assay had a sensitivity of 0.83 for the diagnosis of acute pulmonary embolism.27 Previous studies have suggested that the quantitative D-dimer latex immunoassay (LIA) has greater sensitivity than the semiquantitative latex agglutination assay for the diagnosis of acute pulmonary embolism.28,29 Because of the small number of patients in previous studies, some uncertainty remains about the sensitivity and specificity of the quantitative D-dimer LIA for the diagnosis of acute pulmonary embolism. The appropriate discriminant value for defining a negative study is also unclear. To address these issues, we retrospectively evaluated the ability of a quantitative D-dimer LIA to diagnose acute pulmonary embolism using multidetector-row CT angiography as the diagnostic reference standard. SUBJECTS AND METHODS We electronically queried the Radiology Research database at the Mayo Clinic in Rochester, Minn, and identified all inpatients and outpatients who were referred for multidetector-row CT pulmonary angiography because of a clinical suspicion of acute pulmonary embolism between August 3, 2001, and November 10, 2003. The study start date was chosen to coincide with the change from singledetector to multidetector-row CT angiography, and the study end date was chosen to ensure an adequate sample size. We electronically queried the Laboratory Information Services database for eligible patients and collected the CT angiography date and plasma fibrin D-dimer LIA values if assays were performed within 3 days (before or after) of the CT pulmonary angiography. This time restriction was based on data that suggested that the sensitivity of the Ddimer LIA decreased when tests were performed 4 or more days after onset of symptoms.30 The study was approved by the Mayo Clinic Institutional Review Board. All patients were examined using a multidetector-row helical CT scanner as previously described.31,32 Three CT scanners were used in this study: a 16-slice scanner (Siemens Sensation 16, Siemens Medical Solutions, Forchheim, Germany), an 8-slice scanner (GE Lightspeed/QXl Ultra, General Electric, Milwaukee, Wis), and a 4-slice scanner (GE Lightspeed/QXl Plus, General Electric). Radiologic criteria from the PIOPED II study were used to establish the diagnosis of acute and chronic pulmonary emboli.32 All CT pulmonary embolism examinations were reviewed by a boardcertified, fellowship-trained staff radiologist with experience in vascular CT. Contrast media was injected at a rate of 4 mL/second. Contrast media dosage and concentration were determined by a sliding-scale algorithm that was based on Mayo Clin Proc.
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patient weight. Images were constructed with a slice thickness of 2.5 mm. All radiology reports were independently reviewed by one of the authors (D.A.F., P.R.D., or P.L.E.) and without knowledge of the D-dimer results. Reports were assigned 1 of the following interpretations: positive for acute pulmonary embolism, positive for chronic pulmonary embolism, negative for pulmonary embolism, or inadequate (or indeterminate) study. The 29 ambiguous CT reports and films were reviewed by a board-certified, fellowship-trained staff radiologist with experience in vascular CT (S.J.S.). Plasma fibrin D-dimer LIAs were performed using the MDA 180 automated coagulometer (bioMérieux, Inc, Durham, NC) and a commercial immunoassay kit (MDA D-dimer, bioMérieux, Inc). Assays were performed according to the manufacturer’s instructions.29 The reportable D-dimer LIA values ranged from less than 100 ng/mL to more than 2000 ng/mL; reported values were rounded to the nearest 50 ng/mL to yield 41 possible outcomes. During the study period, 1630 patients underwent CT angiography for suspected acute pulmonary embolism and were tested with a quantitative plasma fibrin D-dimer LIA. Patients were excluded if D-dimer tests were performed more than 3 days before or after CT angiography (n=184) or if the CT angiogram was interpreted as chronic pulmonary embolism (n=14) or as an inadequate or indeterminate study (n=15). Patients who denied access to their medical records for research purposes also were excluded (n=62). We used data from our prior study27 for sample size determination. We assumed an 18% prevalence of disease and a D-dimer LIA sensitivity of 0.83 for acute pulmonary embolism. We anticipated that 96 patients would be positive for acute pulmonary embolism using the reference standard of CT angiography. These assumptions led to a maximum 10% half-width of the 95% confidence interval (CI) for sensitivity (0.74-0.90) and an estimated sample size of at least 534 patients. We used the Wilcoxon rank sum test to compare D-dimer values of patients with and without acute pulmonary embolism because the 2 groups had nonnormal distributions. Sensitivity, specificity, and negative predictive values of the Ddimer LIA were estimated using all 41 possible discriminant values, and binomial 95% CIs were calculated. Threshold values used in the calculation of sensitivity and specificity were explored using receiver operating characteristic curve analysis.33 Statistical analyses were performed with SAS software (version 8.0, SAS Institute Inc, Cary, NC). P<.05 was considered statistically significant. RESULTS Of the 1355 patients in the study, the mean age was 59±19 years (range, 13 to 98 years), and 837 patients (62%) were
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TABLE 1. Discriminant Value–Dependent True and False D-Dimer Immunoassay Findings (N=1355)
1.0
No. of results
Sensitivity
0.8
True
False
True
False
250 300 350 500 2001
197 195 192 178 76
899 837 785 604 203
248 310 362 543 944
11 13 16 30 132
0.4
0.0 0.0
0.2
0.4
0.6
0.8
1.0
1 – Specificity
FIGURE 1. Receiver operating characteristic curve for the quantitative D-dimer latex immunoassay used to diagnose acute pulmonary embolism.
female. The prevalence of acute pulmonary embolism was 15% (208 patients). Of the 208 patients with acute pulmonary embolism, the median D-dimer concentration was 1425 ng/mL. Of the 1147 patients without acute pulmonary embolism, the median D-dimer concentration was 500 ng/mL. The difference between these median values was significant (P<.001). The range of D-dimer concentrations was the same for both groups (<100 ng/mL to >2000 ng/mL). The 41 possible discriminant (threshold) values were analyzed. A negative assay result would include any Ddimer concentration lower than the discriminant value. The trade-off between sensitivity and specificity is shown by the receiver operating characteristic curve (Figure 1). The area under the curve was 0.71 with an SE of 0.02. The best discriminant value was 300 ng/mL; assays with D-dimer values less than 300 ng/mL had the highest specificity that optimized sensitivity for the diagnosis of acute pulmonary embolism. With a discriminant value of 300 ng/mL, the sensitivity of the quantitative D-dimer LIA for
Negative
Discriminant value (D-dimer, ng/mL)
0.6
0.2
Positive
the diagnosis of acute pulmonary embolism was 0.94 (95% CI, 0.89-0.97), and the negative predictive value was 0.96 (95% CI, 0.93-0.98). However, specificity was 0.27 (95% CI, 0.25-0.30). At this discriminant value, 76% of assays (1032/1355) had positive results, and the false-positive rate was 62% (837/1355). We also investigated the discriminant values used in other studies and specifically considered 250 ng/mL,29 350 ng/mL,28 500 ng/mL,34 and 2001 ng/mL (the maximum value for the assay). The number of true- and false-positive results and true- and false-negative results for these discriminant values is shown in Table 1. The sensitivity, specificity, positive and negative predictive values and positive and negative likelihood ratios are shown in Table 2. Even a strongly positive D-dimer assay (>2000 ng/mL) yielded a positive likelihood ratio of only 2.06. DISCUSSION In a prior study of a semiquantitative latex agglutination Ddimer assay (using a discriminant value of 250 ng/mL), we determined that assay sensitivity was 0.83 (95% CI, 0.760.88) and specificity was 0.39 (95% CI, 0.36-0.43) for the diagnosis of acute pulmonary embolism.27 The quantitative D-dimer LIA (using a discriminant value of 300 ng/mL) had superior sensitivity (P<.05) but inferior specificity (P<.05). By using a discriminant value of 300 ng/mL, sensitivity of the quantitative D-dimer LIA for the diagnosis of acute pulmonary embolism was similar to that found by Heit et
TABLE 2. Discriminant Value–Dependent Sensitivity, Specificity, Predictive Value, and Likelihood Ratio* Likelihood ratio
Predictive value
Discriminant value (D-dimer, ng/mL)
Sensitivity
Specificity
Positive
Negative
Positive
Negative
250 300 350 500 2001
0.95 (0.90-0.97) 0.94 (0.89-0.97) 0.92 (0.88-0.95) 0.86 (0.80-0.90) 0.37 (0.30-0.44)
0.22 (0.19-0.24) 0.27 (0.25-0.30) 0.32 (0.29-0.34) 0.47 (0.44-0.50) 0.82 (0.80-0.84)
0.18 (0.16-0.20) 0.19 (0.17-0.21) 0.20 (0.17-0.22) 0.23 (0.20-0.26) 0.27 (0.22-0.33)
0.96 (0.92-0.98) 0.96 (0.93-0.98) 0.96 (0.93-0.97) 0.95 (0.93-0.96) 0.88 (0.86-0.90)
1.21 (1.16-1.26) 1.28 (1.22-1.35) 1.35 (1.28-1.43) 1.63 (1.50-1.76) 2.06 (1.66-2.57)
0.24 (0.14-0.44) 0.23 (0.14-0.39) 0.24 (0.15-0.39) 0.30 (0.22-0.43) 0.77 (0.70-0.86)
*Parenthetical data are 95% confidence intervals.
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DIAGNOSTIC D-DIMER IMMUNOASSAY
TABLE 3. Efficacy of Quantitative D-Dimer Latex Immunoassays for the Diagnosis of Acute Pulmonary Embolism Study
No. of patients
Discriminant value (D-dimer, ng/mL)
Sensitivity
Specificity
Diagnostic reference standard
Heit et al,28 2000 Bates et al,29 2001 Current
105 278 1355
350 250 300
0.95 0.94 0.94
Data not shown 0.42 0.27
Pulmonary angiography Explicit algorithm Computed tomographic angiography
al28 and Bates et al29; all studies involved the same quantitative D-dimer LIA but had different discriminant values. Our specificity was significantly less than that found by Bates et al29 (P<.05), which may be attributable to the inclusion of inpatient data in the analysis; the D-dimer assay has low specificity (0.07) for patients hospitalized for more than 24 hours.35 A comparison of sensitivity and specificity from these studies is shown in Table 3. Stein et al34 recently published a systematic review of Ddimer testing for the exclusion of venous thromboembolic disease. They indicated that the quantitative rapid enzymelinked immunosorbent assays (ELISAs) were clinically superior to all other D-dimer assays for excluding acute pulmonary embolism. The ELISA had an overall sensitivity of 0.95 (95% CI, 0.83-1.00) and an overall specificity of 0.39 (95% CI, 0.28-0.51) when a discriminant value of 500 ng/mL was used.34 The sensitivity of our quantitative LIA (using a discriminant value of 300 ng/mL) was similar to that of the quantitative rapid ELISA; our specificity was less than the ELISA specificity. In the systematic review,34 the largest prospective study of a quantitative rapid D-dimer ELISA for the diagnosis of acute pulmonary embolism was the Dutch study by the Advances in New Technologies Evaluating the Localisation of Pulmonary Embolism (ANTELOPE) group.36 In the ANTELOPE study, ELISA sensitivity was 0.88 when a discriminant value of 500 ng/mL was used, and sensitivity was 0.96 when a discriminant value of 250 ng/mL was used; the corresponding specificities were 0.52 and 0.29. If we used the ANTELOPE discriminant values, sensitivity of our LIA was similar, but specificity was slightly lower. For patients with low or moderate pretest probability of acute pulmonary embolism, quantitative D-dimer LIAs with a discriminant value of 250 ng/mL and quantitative rapid D-dimer ELISAs with a discriminant value of 500 ng/mL have negative predictive values of 0.99.29,34 Clinicians probably should not order D-dimer tests for a patient with a high pretest probability of acute pulmonary embolism because D-dimer LIA results are unlikely to be negative in such patients and because of concerns about patient safety. In one study, the 95% CI of the 3-month venous thromboembolic risk for patients with negative quantitative rapid D-dimer ELISA findings and a high pretest probabilMayo Clin Proc.
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ity of pulmonary embolism was 0% to 23%.37 Further study is required to determine whether a quantitative D-dimer LIA with a discriminant value of 300 ng/mL and a low or moderate pretest probability for acute pulmonary embolism can effectively exclude this disorder. Our study has several strengths and limitations. To our knowledge, it is the largest study to date of a quantitative D-dimer LIA for the diagnosis of acute pulmonary embolism. Although CT angiography has not replaced pulmonary angiography as the diagnostic reference standard, patients with negative CT angiographic findings for pulmonary embolism have a good prognosis, similar to that of patients with negative pulmonary angiographic findings.17-19 Overall, the clinical validity is similar for CT angiographic findings and pulmonary angiographic findings.19 In addition, multidetector-row CT angiography represents state-of-the-art imaging for acute pulmonary embolism38; it is the imaging modality of choice for the diagnosis of this disorder at our institution and many others. Despite these strengths, our study was limited by its performance at only 1 institution and by its retrospective nature. Furthermore, pretest probability of acute pulmonary embolism could not be calculated retrospectively. CONCLUSION The quantitative D-dimer LIA with a discriminant value of 300 ng/mL had high sensitivity and high negative predictive value for excluding acute pulmonary embolism. However, specificity was low; only about one fourth of patients had a negative and clinically useful D-dimer assay result. Nevertheless, sensitivity of the quantitative D-dimer LIA for the diagnosis of acute pulmonary embolism was superior to that of the semiquantitative latex agglutination assay and similar to that of the quantitative rapid ELISA (using different discriminant values). By itself, the quantitative Ddimer LIA was insufficient to exclude acute pulmonary embolism. On the basis of these results, we believe that a negative quantitative D-dimer LIA result and a low pretest probability of thromboembolism together are sufficient to exclude acute pulmonary embolism. Unless specific contraindications exist, patients with a high pretest probability of acute pulmonary embolism should undergo CT angiography directly.
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20. Ghaye B, Szapiro D, Mastora I, et al. Peripheral pulmonary arteries: how far in the lung does multi-detector row spiral CT allow analysis? Radiology. 2001;219:629-636. 21. Schoepf UJ, Goldhaber SZ, Costello P. Spiral computed tomography for acute pulmonary embolism. Circulation. 2004;109:2160-2167. 22. Winer-Muram HT, Rydberg J, Johnson MS, et al. Suspected acute pulmonary embolism: evaluation with multi-detector row CT versus digital subtraction pulmonary arteriography. Radiology. 2004;233:806-815. 23. Kelly J, Rudd A, Lewis RR, Hunt BJ. Plasma D-dimers in the diagnosis of venous thromboembolism. Arch Intern Med. 2002;162:747-756. 24. D’Angelo A, D’Alessandro G, Tomassini L, Pittet JL, Dupuy G, Crippa L. Evaluation of a new rapid quantitative D-dimer assay in patients with clinically suspected deep vein thrombosis. Thromb Haemost. 1996;75:412416. 25. Bates SM, Kearon C, Crowther M, et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med. 2003;138:787-794. 26. Kruip MJ, Leclercq MG, van der Heul C, Prins MH, Buller HR. Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies: a systematic review. Ann Intern Med. 2003;138:941-951. 27. Froehling DA, Elkin PL, Swensen SJ, Heit JA, Pankratz VS, Ryu JH. Sensitivity and specificity of the semiquantitative latex agglutination D-dimer assay for the diagnosis of acute pulmonary embolism as defined by computed tomographic angiography. Mayo Clin Proc. 2004;79:164-168. 28. Heit JA, Meyers BJ, Plumhoff EA, Larson DR, Nichols WL. Operating characteristics of automated latex immunoassay fibrin D-dimer tests in the diagnosis of angiographically-defined acute pulmonary embolism. Thromb Haemost. 2000;83:970. 29. Bates SM, Grand’Maison A, Johnston M, Naguit I, Kovacs MJ, Ginsberg JS. A latex D-dimer reliably excludes venous thromboembolism. Arch Intern Med. 2001;161:447-453. 30. Heit JA, Minor TA, Andrews JC, Larson DR, Li H, Nichols WL. Determinants of plasma fibrin D-dimer sensitivity for acute pulmonary embolism as defined by pulmonary angiography. Arch Pathol Lab Med. 1999;123:235240. 31. Remy-Jardin M, Remy J. Spiral CT angiography of the pulmonary circulation. Radiology. 1999;212:615-636. 32. Gottschalk A, Stein PD, Goodman LR, Sostman HD. Overview of Prospective Investigation of Pulmonary Embolism Diagnosis II. Semin Nucl Med. 2002;32:173-182. 33. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143:29-36. 34. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004;140:589-602. 35. Miron MJ, Perrier A, Bounameaux H, et al. Contribution of noninvasive evaluation to the diagnosis of pulmonary embolism in hospitalized patients. Eur Respir J. 1999;13:1365-1370. 36. de Monye W, Sanson BJ, Buller HR, Pattynama PM, Huisman MV, ANTELOPE Study Group. The performance of two rapid quantitative D-dimer assays in 287 patients with clinically suspected pulmonary embolism. Thromb Res. 2002;107:283-286. 37. Righini M, Aujesky D, Roy PM, et al. Clinical usefulness of D-dimer depending on clinical probability and cutoff value in outpatients with suspected pulmonary embolism. Arch Intern Med. 2004;164:2483-2487. 38. Goldhaber SZ. Multislice computed tomography for pulmonary embolism: a technological marvel. N Engl J Med. 2005;352:1812-1814.
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