Published online before print March 28, 2006, 10.1148/radiol.2392050118
(Radiology 2006;239:563-575.)
© RSNA, 2006
Pulmonary Embolism at Multi–Detector Row CT of Chest: One-year Survival of Treated and Untreated Patients1
Christoph Engelke, MD,
Ernst J. Rummeny, MD and
Katharina Marten, MD
1 From the Department of Radiology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany. Received January 24, 2005; revision requested April 1; revision received April 19; accepted May 23; final version accepted July 7.
Address correspondence to C.E. (e-mail: cengelke{at}roe.med.tum.de).
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ABSTRACT
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Purpose: To retrospectively assess outcome in patients with clinically unsuspected pulmonary embolism (PE) at chest multi–detector row computed tomography (CT).
Materials and Methods: Institutional review board approval and informed consent were not required. PE was assessed in consecutive CT scans in 1966 patients (mean age, 60 years; range, 15–96 years; male-female ratio, 1.79) and graded with severity score. Studies with true-positive and false-negative radiologic diagnoses were determined. Coexisting morbidity, anticoagulant therapy (ACT), complications, and 1-year outcome were reviewed. Statistical evaluation included Mann-Whitney U test, 
2 test, Poisson regression, and Kaplan-Meier statistics.
Results: Scans were PE positive in 117 patients. Clinical data review was complete in 96 patients; 63 of 96 patients had malignancy; in 58, PE was not suspected. In 38 of these 58 patients, radiology report findings were false-negative (mean severity score, 20.21 ± 17.88 [standard deviation] and 9.55 ± 7.12 for those with true-positive and false-negative findings, respectively; P = .012). Forty-nine patients received therapeutic ACT; 21, prophylactic ACT; and 26, no treatment. PE severity was higher in patients with therapeutic ACT versus those without (P < .001). Bleeding complications were more frequent with therapeutic ACT (two early deaths, five major nonfatal hemorrhages) than without (one minor hemorrhage; P = .037). There were eight early deaths (therapeutic ACT, seven; without ACT, one; P = .037). Positive predictors of early death included severity score >28, use of systemic thrombolytic therapy, occurrence of major hemorrhage, and new-onset cardiac or renal failure (P = .001–.043). Negative predictors were report with false-negative findings and no therapeutic ACT (P = .007–.037). Predictors of late death (n = 25) were older age, malignancy, and renal failure (P = .001–.043).
Conclusion: Clinically unsuspected PE may remain undetected at routine chest CT; these patients have favorable short-term outcome without therapeutic ACT.
© RSNA, 2006
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INTRODUCTION
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Patients who are referred for diagnostic imaging to confirm the clinical suspicion of a pulmonary embolism (PE) are a preselected population (1). The overall mortality from acute PE has been reported to be in the range of 10%–30% (1,2). More than 80% of fatalities from PE occur within the first 30 minutes, more than 90% occur within 2.5 hours of the event (1,2), and most patients who die of PE have advanced chronic coexisting morbidity. Therefore, patients who survive long enough to be referred for imaging have a relatively favorable prognosis (1,3–6). In patients with an established diagnosis of PE, however, a potential life-saving benefit of anticoagulant therapy (ACT) may be offset by morbidity and mortality due to complications of treatment or advanced coexisting disease (7,8). On the other hand, patients in whom clinical symptoms are unrecognized or are attributed to other causes may undergo chest computed tomography (CT) with the use of protocols that are not tailored for detection of pulmonary emboli, and use of such protocols leaves an uncertain number of patients who actually have a PE without a diagnosis and untreated and with a potential for increased mortality (1,2,9,10).
To date, to our knowledge there are no published data about undetected acute PE in patients who undergo multi–detector row CT of the chest, and it is unknown how the severity of PE in combination with other morbidity factors influences the natural course of the disease in patients treated for PE in comparison with those who are accidentally left untreated. Researchers in two previous studies (11,12) who investigated the prospective or retrospective CT detection of PE that was not clinically suspected did not reexamine cohorts with negative findings in CT reports for false-negative radiologic diagnoses and failure to treat the patients and, therefore, findings in these studies do not allow the study of the natural course of PE.
Thus, the purpose of this study was to retrospectively assess the outcome of patients in whom PE was not clinically suspected at chest multi–detector row CT.
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MATERIALS AND METHODS
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Study Design and Reference Standard
Our institutional review board does not require its approval or patient informed consent for a retrospective study such as ours. This retrospective study involved all patients who underwent multi–detector row CT of the chest in our department within a 1-year period (October 2001 to September 2002) in the setting of a tertiary referral cancer center with a subspecialization in esophageal cancer treatment. All patients had clinical indications for chest CT and gave informed consent to perform the CT examination. In an emergency setting, when no patient consent could be obtained, consent was obtained from relatives, if at all possible, instead. All CT scans were retrospectively assessed for the presence of a PE by a chest radiologist (C.E.) who had 10 years of experience in clinical chest CT. All scans positive for PE were reassessed in consensus with a second chest radiologist (K.M.) who had 5 years of experience in chest CT to confirm the diagnosis and assess the severity of the PE. Cases of disagreement between the two reviewers were resolved with the review of a third radiologist (E.J.R.) who had 20 years of experience in clinical chest CT. This CT review served as the standard of reference to identify patients with presence of PE that was undetected at the initial radiologic assessment (radiology reports with false-negative findings). This assessment was followed by review of patient clinical records by one reviewer (C.E.) for concurrent morbidity factors, PE risk factors, symptoms consistent with PE, whether the referring clinician indicated a suspicion of PE, PE-related morbidity factors, whether ACT was administered and its complications, and the 30-day and 1-year patient outcomes. The study end point was 1-year follow-up after initial CT or death.
Study Population and Multi–Detector Row CT Scans
The study included 2536 CT scans obtained in 1966 consecutive patients (1261 male patients, 705 female patients; mean age, 60 years; range, 15–96 years; male-female ratio, 1.79) who underwent contrast material–enhanced multi–detector row CT of the chest at our institution between October 2001 and September 2002. Three hundred forty-one (13.4%) of 2536 scans were obtained for cancer staging and response assessment for esophageal cancer. The remaining 2195 (86.6%) scans were obtained in patients who were suspected of having PE (156 [6.2%] of 2536 scans), in those who were suspected of having aortic disease (105 [4.1%] of 2536 scans), and in those who had other indications for imaging (1934 [76.3%] of 2536 scans). Between October 2001 and May 2002, the multi–detector row CT scanner used was a four–detector row system (Volume Zoom; Siemens Medical Solutions, Erlangen, Germany), which was then upgraded to a 16–detector row scanner (Sensation 16; Siemens Medical Solutions) for the remaining study period.
Scan acquisition parameters were standardized in four protocols, which included pulmonary CT angiography, CT angiography of the thoracic aorta (hereafter, aortic CT angiography), thin-collimation CT of the mediastinum for esophageal disease (hereafter, mediastinal CT), and standard CT of the chest (hereafter, other chest CT). Anatomic tube current modulation was available with the 16–detector row scanner only. Chest CT was performed with the four–detector row scanner and the following parameters: 120 kV; 90–200 mAs; and four detector rows and 1.0-mm section thickness (4 x 1.0 mm) and 4 x 2.5 mm for mediastinal CT and other chest CT, respectively. With the 16–detector row scanner, imaging was performed with 16 x 0.75 mm. The table feed was 5–15 mm per rotation. Reconstruction section thickness for mediastinal CT was 1.25 mm with the four–detector row scanner and 0.70 mm with the 16–detector row scanner; for other chest CT, it was 3.00–5.00 mm. A contrast agent bolus of 120 mL, 300 mg of iodine per milliliter (Imeron 300; Bracco-Byk Gulden, Konstanz, Germany), was injected into a peripheral antecubital artery or a central vein with a power injector (Stellant; Medrad, Volkach, Germany) at flow rates of 4 or 5 mL/sec for CT angiography and at a flow rate of 3 mL/sec for the other techniques. This injection was followed by a 30-mL normal saline chaser injected at a flow rate of 3–4 mL/sec. The scan delay was 50–60 seconds for mediastinal CT and other chest CT. This scan delay has been used in our department for scans other than CT angiographic scans because a previous audit showed that it provided increased enhancement of mediastinal tumor tissues with better correspondence with positron emission tomographic results. With these scans, the 40-second contrast material bolus injection was succeeded by a 10-second normal saline chaser to augment vessel enhancement. An automatic scan delay trigger of 15–25 seconds was chosen for CT angiographic techniques.
At the time of the study, no picture archiving and communication system was available at our department, and findings on scans other than CT angiographic scans were interpreted from hard-copy film images and were reported in consensus by two radiologists. One of them was board certified with at least 10 years of clinical CT experience, and the other was a resident or board-certified radiologist with at least 2 years of experience. CT angiographic scans were interpreted at a CT postprocessing workstation (Leonardo; Siemens Medical Solutions) by using thin reconstructed image data sets.
Image Review
All retrospective multi–detector row CT scan reviews were performed with a dedicated workstation by two radiologists (C.E. and K.M.) in consensus by using interactive transverse cine-mode and multiplanar reformatted images at individual window settings, according to previously published standards (13,14). They did not have a priori knowledge of clinical or radiologic report information. Unenhanced scans and examinations with corrupted image data were excluded from the current study. The presence of respiration- or pulsation-related movement artifacts was recorded. Mean pulmonary arterial attenuation was measured at three levels (bifurcation of main pulmonary artery at the level of the carina, upper lobe segmental arteries at the level of the aortic arch, and lower lobe segmental arteries at the level of the left atrium). Each scan was assessed for analyzability of main, lobar, segmental, and subsegmental arteries. Nonanalyzable scans obtained at the level of segmental pulmonary arteries were excluded. The criterion for diagnosis of a PE was presence of low-attenuation material within the pulmonary arterial tree (13,14). The distribution of emboli and the degree of luminal obliteration by embolic material served for assignment of a PE severity score as published by Mastora and co-workers (15), which is expressed as a global severity score and can be converted to a percentage pulmonary arterial bed obstruction index by dividing it by 155. This obstruction score correlates well with the presence of hemodynamic compromise at echocardiography. Patients with concurrent chronic pulmonary arterial hypertension according to established criteria (16,17) and a PE were excluded from this study. The presence of lung disease for diagnosis of substantial contributing morbidity factors (eg, pulmonary consolidation, atelectasis, multiple metastases, emphysema, interstitial lung disease) and evidence of peripheral deep venous thrombosis from additional imaging were recorded.
Clinical Data Review and Follow-up
The clinical data assessment included data from clinical in- and outpatient files and local clinical and pathology departmental databases (C.E.). Data that were recorded included risk factors for venous thromboembolic disease, a history of venous thromboembolic disease, substantial coexisting cardiac (New York Heart Association class III or higher) or respiratory (PaCO2 
42 mm Hg) disease, systemic hypertension, myocardial infarction, stroke, renal failure (creatinine level 1.5 mg/dL [59 µmol/L]), and septicemia. Risk factors for venous thromboembolic disease were obesity, malignancy, thrombophilia, recent trauma, recent surgery, or immobilization for more than 7 days before CT. Evidence of thrombophilia was recorded and included various coagulation disorders, such as protein C or protein S deficiencies, factor V (Leyden) mutations, factor XII deficiency, antithrombin III deficiency, prothrombin 20210 A mutation, antiphospholipid antibody syndrome, and type II heparin-induced thrombocytopenia. The following were recorded: the presence of symptoms consistent with PE (eg, sudden-onset dyspnea, cough, tachypnea, chest pain, hemoptysis, collapse); the documented clinical suspicion of PE; and the results of clinical diagnostic tests that included D-dimer assay, electrocardiography, echocardiography, and further imaging (duplex ultrasonography, venography, ventilation-perfusion scintigraphy, and pulmonary arteriography).
Data assessment after occurrence of PE included the inpatient period and subsequent 1-year outpatient follow-up (eg, systemic anticoagulant treatment; inferior vena cava filter placement; interventional PE fragmentation; surgical embolectomy and complications; PE-induced morbidity conditions, which included cardiac or renal failure; occurrence of pulmonary arterial hypertension; recurrence of PE; and death). Therapeutic ACT was defined as therapy with intravenous administration of heparin (prothrombin time, 60 seconds), which was later replaced with oral administration of phenprocoumon (international normalized ratio, 2.0). Prophylactic ACT was defined as body weight–adapted subcutaneous therapy with various types of heparin, with a prothrombin time within the normal range. Systemic thrombolytic therapy was defined according to the definition published by Goldhaber and co-workers (18). The clinical follow-up data were complemented by information from telephone interviews of general practitioners and from standardized questionnaires sent to all referring general practitioners, data from a review of death certificates and postmortem pathology reports, and information from telephone interviews of all surviving patients (C.E.).
Statistical Analysis
The use of several tests in our study has been described in a similar setting (19). We used spreadsheet-based statistical software (StatsDirect, release 2.3.8; CamCode, Herts, England). Nonnormality of PE severity score distribution was tested by using the Shapiro-Wilk method. Differences in contrast material enhancement at the three anatomic levels were analyzed by using one-way analysis of variance with multiple pairwise Tukey-Kramer comparisons (20). Differences in PE severity between true-positive and false-negative diagnoses and between treatment groups were assessed by using the Mann-Whitney U test. Univariate analyses (2 test, two-tailed Fisher exact probability, univariate Poisson regression analysis) were used to correlate PE severity with clinical factors and to determine predictors of morbidity and death within 30 days of PE occurrence (early morbidity and early death). Multivariate analysis was performed by using backward stepwise Poisson regression analysis, which selects the best predictors until all remaining variables of the tested model are significant. The spreadsheet-based statistical software fits the multiplicative Poisson regression model as a log-linear regression, with an offset equal to the natural logarithm of person-time specified (21–23) in which the coefficient exponents are equal to the incidence rate ratio (relative risk). Predictors of late death were tested by using cumulative Kaplan-Meier survival analysis with the corresponding log-rank test. A P value of less than .05 was considered to indicate a significant difference.
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RESULTS
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Presence of PE
Of the 2536 contrast-enhanced chest multi–detector row CT scans in 1966 patients, 570 were repeat scans obtained during the study period. Fifty-four scans were excluded from further analysis because of poor quality. No scan had to be excluded because of the presence of chronic pulmonary arterial hypertension. Of the remaining 1912 multi–detector row CT scans (1912 patients; the number of scans is the same as the number of patients), 117 (6.12%) were identified as positive for PE (PE presence): In 109 of these, consensus about whether a scan was positive was reached by the first reviewers (C.E., K.M.); the third radiologist (E.J.R.) diagnosed PE on the eight remaining scans. The contrast enhancement was homogeneous and did not differ significantly among the upper, middle, or lower arterial levels (P = .25; Tukey-Kramer comparisons, P > .05). The average individual median attenuation values were 310.8 HU ± 140.8 (standard deviation), 267.3 HU ± 89.9, 243.3 HU ± 100.3, and 218.4 HU ± 93.0 for pulmonary CT angiograms, aortic CT angiograms, mediastinal CT scans, and other chest CT scans, respectively. The average median attenuation values did not differ significantly between scans with reports with true-positive diagnoses (287.3 HU ± 138.5) and scans with reports with false-negative diagnoses (233.0 HU ± 91.3), with a P value of more than .05. Arterial attenuation was not a univariate predictor of true-positive diagnosis (P > .05). Contrast enhancement for PE analysis was classified as adequate by the reviewers down to segmental arteries (n = 117) and to subsegmental branches (n = 55).
PE occurred most frequently in patients who were referred for pulmonary CT angiography and mediastinal CT (37.3%, 8.2%, 5.1%, and 3.3% for pulmonary CT angiography, mediastinal CT, aortic CT angiography, and other chest CT, respectively [Table 1]). Ancillary pulmonary CT findings included consolidation (n = 24), atelectasis (n = 44), metastases (n = 17), emphysema (n = 11), and evidence of interstitial lung disease (n = 7), which, however, occupied only a minor average part of the entire lung volume (0.7%–2.7%).
The clinical data review was complete in 96 of 117 patients with scans positive for PE (59 men, 37 women; mean age, 64 years; range, 23–83 years), which made up the final study population (36, three, 19, and 38 patients in whom pulmonary CT angiograms, aortic CT angiograms, mediastinal CT scans, and other chest CT scans, respectively, were obtained [Tables 1, 2]). Sixty-three of these 96 patients had active malignancy (Table 1). Thirty-five of these 96 patients had more than one morbidity factor that, apart from malignancy, included obesity (n = 16); chronic cardiorespiratory failure (n = 27); previous myocardial infarction (n = 10); stroke (n = 8); systemic hypertension (n = 51); chronic renal failure (n = 20); thrombophilia (n = 3), with type II heparin-induced thrombocytopenia in one patient, factor V (Leyden) heterozygotic mutation in one patient, and prothrombin 20210 A mutation in one patient; and previous septicemia (n = 4). Recent trauma, surgery, or immobilization was frequent (14, 23, and 14 patients, respectively) and was associated with clinical suspicion of PE (27 of 38 patients in whom there was a clinical suspicion of PE vs 25 of 58 patients in whom there was no clinical suspicion of PE, P = .025). Twelve of 96 patients had a diagnosis of deep venous thrombosis and were treated with therapeutic ACT (n = 5) or low–molecular weight heparin (n = 2) at the time of multi–detector row CT. The five remaining patients had malignant disease with contraindications to ACT. Of the 96 patients with scans positive for PE, six underwent additional imaging for PE (ventilation-perfusion scintigraphy in five and conventional angiography for interventional PE fragmentation in one).
Diagnosis of PE and Therapeutic Interventions
In 51 of 96 study patients, evidence of symptoms consistent with PE was present, whereas in only 40 of these, including 36 patients referred for pulmonary CT angiography, was a clinical suspicion of PE documented (Fig 1, Table 1). In the remaining 44 patients without evidence of symptoms, there were no pathologic clinical test results or imaging results suggestive of PE. There were 43 scans positive for PE with radiology reports that included false-negative diagnoses (five pulmonary CT angiograms, two aortic CT angiograms, 17 mediastinal CT scans, and 19 other chest CT scans) (Figs 2–4, Table 2). These false-negative diagnoses were most frequent in patients referred for esophageal cancer staging (17 of 19 patients) and standard chest multi–detector row CT (19 of 38 patients). The mean PE severity score on all 96 scans was 22.07 ± 22.35 (mean pulmonary artery obstruction index, 14.5%; range, 1.9%–56.8%; median, 7.7%). The PE severity score was significantly lower on scans with reports that included false-negative diagnoses (mean PE severity score, 9.56 ± 7.14) compared with those with reports that included a correct initial diagnosis (mean PE severity score, 33.15 ± 25.24) (P < .001). This difference was particularly evident on pulmonary CT angiograms (Table 2). A low PE severity score was a univariate predictor of failure to clinically suspect PE (P = .003) and, as a result, was predictive of a false-negative diagnosis on a CT report (P < .001).
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Figure 1a: Transverse pulmonary CT angiographic images. (a) Image depicted PE (severity score, 15) in right lower lobar and segmental arteries 8–10 (arrows) in 47-year-old woman with ovarian cancer after laparotomy. Radiologic diagnosis was true-positive at the time. The patient received ACT in therapeutic dosage and was alive after 10 months of follow-up. (b) Image depicted PE (severity score, 24) in right lower lobe segmental artery 10 (arrow) in 54-year-old immobilized woman with advanced non–small cell lung cancer (stage IIIb) and cerebral metastasis in whom there was no clinical suspicion of PE. Radiologic diagnosis was true-positive at the time. The patient was treated with anticoagulants in prophylactic dosage and died of the malignancy 16 months later.
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Figure 1b: Transverse pulmonary CT angiographic images. (a) Image depicted PE (severity score, 15) in right lower lobar and segmental arteries 8–10 (arrows) in 47-year-old woman with ovarian cancer after laparotomy. Radiologic diagnosis was true-positive at the time. The patient received ACT in therapeutic dosage and was alive after 10 months of follow-up. (b) Image depicted PE (severity score, 24) in right lower lobe segmental artery 10 (arrow) in 54-year-old immobilized woman with advanced non–small cell lung cancer (stage IIIb) and cerebral metastasis in whom there was no clinical suspicion of PE. Radiologic diagnosis was true-positive at the time. The patient was treated with anticoagulants in prophylactic dosage and died of the malignancy 16 months later.
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Figure 2: Transverse pulmonary CT angiographic image in 68-year-old immobilized woman with inguinal recurrence of malignant melanoma in whom there was no clinical suspicion of PE. PE (severity score, 3) depicted in left upper lobe segmental artery 1 (arrow) was undetected at routine assessment. The patient was treated with anticoagulants in prophylactic doses and died of metastatic disease 4 months later.
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Figure 3: Transverse pulmonary angiographic images in 51-year-old man with pulmonary metastatic disease from esophageal cancer in whom there was no clinical suspicion of PE. A–F, PE (severity score, 3) depicted in right lower lobe segmental artery at a subsegmental artery origin (segment 9, arrow) was undetected at routine assessment. The patient did not receive ACT and was alive after 12 months of follow-up.
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Figure 4: Pulmonary angiographic transverse images obtained 7 days after esophageal cancer surgery in 56-year-old woman in whom there was no clinical suspicion of PE. A–F, PE (severity score, 3) depicted at first subsegmental junction of anterobasal segment (segment 8, arrow) was undetected at routine assessment. The patient did not receive treatment and was alive 11 months later.
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Treatment in 70 of 96 patients was as follows: systemic thrombolytic therapy, in five; therapeutic ACT, in 44; and prophylactic ACT, in 21. Twenty-six patients in whom there was no clinical suspicion of PE did not receive ACT (21 patients had CT reports with a false-negative diagnosis; of five patients with a correct initial diagnosis, three had advanced-stage malignancies and two had other contraindications for therapeutic ACT). Of the 47 patients who did not receive therapeutic anticoagulant doses, 16 had previous negative findings at leg studies. Patients who received systemic thrombolytic therapy or those who received therapeutic anticoagulant dosages had significantly higher PE severity scores than did those who did not receive therapeutic anticoagulant doses (P = .001–.014) (Table 3). At Poisson regression analysis, increasing PE severity was positively correlated with therapeutic ACT (P = .007) and was negatively correlated with no treatment (P = .007). Further, increasing PE severity was a predictor of hemorrhage within 30 days after CT (P = .049) but was not a predictor of development of cardiac or renal failure, PE recurrence, or pulmonary hypertension.
Morbidity and Outcome
Among 96 patients, there were a total of 33 deaths (eight deaths occurred within 30 days and 25 deaths occurred after 30 days; average, 5.9 months; range, 1.5–20.0 months). The mean overall follow-up time was 8.9 months (range, 3 days to 29.5 months). Of the eight patients who died early (mean follow-up, 14.8 days ± 11.0), none had a CT report with a false-negative diagnosis. In four, a clinical suspicion of PE was present because of previous collapse (n = 2) or cardiac resuscitation (n = 2). One patient in whom a clinical suspicion was not present had cerebral metastatic disease from small cell lung cancer and a low PE severity score of 12 and was excluded from ACT. He died of acute renal and cardiac failure 6 days after the diagnosis of PE was established at multi–detector row CT. The other seven patients (three in whom there was no clinical suspicion of PE) received ACT (three with systemic thrombolytic therapy and four with therapeutic ACT). PE was confirmed at autopsy in one patient. PE was diagnosed clinically as the major cause of early death in five patients, whereas intracranial hemorrhage was the cause in two patients. Overall, early complications accounted for acute cardiorespiratory failure in five patients, acute renal failure in seven patients, acute hemorrhage in eight patients (seven [14.3%] of 49 patients receiving systemic thrombolytic therapy or therapeutic anticoagulation), septicemia in three patients, and stroke in two patients. In patients who died within 30 days, cardiorespiratory failure was encountered in three; acute rental failure, in six; and acute hemorrhage, in two. Of the eight patients with hemorrhage, five had major hemorrhages (one diffuse alveolar hemorrhage, one case of epistaxis, two intracerebral hemorrhages, one diffuse mucosal hemorrhage), and three of them occurred while the patients were receiving systemic thrombolytic therapy. Two patients with low PE severity scores of 7 and 15 had recurrent PE; in one of them, the PE was major (PE severity score, 67), but the patient survived. Patients who received prophylactic ACT or no anticoagulant treatment (one of 47 deaths) had a significantly better 30-day outcome than did those who received therapeutic ACT (seven of 49 deaths), with P = .037 (relative risk, 0.14; 95% confidence interval: 0.02, 0.87).
Predictors of early death (Tables 4 and 5) included previous cardiorespiratory or renal failure, a PE severity score higher than 28, systemic thrombolytic therapy, complications attributable to PE or ACT such as a major hemorrhage and acute cardiorespiratory or renal failure. The failure to clinically or radiologically diagnose PE or to initiate ACT did not increase the risk of a PE-related or other major new-onset morbidity factor or have an adverse effect on patient survival. Of the 43 patients with false-negative diagnoses in CT reports, none died within 30 days (P = .007). Patients in whom there was no clinical suspicion of PE and in whom false-negative diagnoses were included in CT reports had a significantly decreased rate of hemorrhage and early death (P = .015–.017). In patients in whom there was a clinical suspicion of PE and a false-negative diagnosis on the CT report, PE recurrence was more frequent (n = 2, P = .002). Patients who received no treatment had a significantly lower rate of acute hemorrhage, acute renal failure, and early death than did those who underwent systemic thrombolytic therapy (P = .001–.009).
The cumulative 1-year patient survival was significantly influenced by a patient age older than 65 years; the presence of an active malignancy; the use of systemic thrombolytic therapy; and the occurrence of a major hemorrhage, cardiac failure, and renal failure (Figs 5, 6, Tables 4, 5). All other factors, including previous cardiac failure, previous renal failure, clinically unsuspected PE, false-negative diagnosis in a CT report, increased PE severity, and the lack of treatment of PE did not significantly influence 1-year survival (Table 4). Backward stepwise multivariate analysis of significant univariate predictors was used to calculate three sets of predictors for 30-day mortality, full follow-up (the time from the occurrence of PE to the end of the study), and death after 30 days (Table 5). The strongest predictor in all sets was new-onset renal failure (P < .001). Previous cardiac failure was a predictor of early death (P = .046), whereas systemic thrombolytic therapy was predictive of early (P = .027) and, less strongly, of overall death (P = .028). Older age and active malignancy as parameters of contributing morbidity were predictive only for long-term outcome and not for occurrence of death at 30 days (P < .05) (Table 5).
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Figure 5a: Cumulative Kaplan-Meier survival plots with 95% confidence intervals indicated by bars. (a) Survival of elderly patients. (b) Survival of patients with underlying malignancy. (c) Survival of patients with false-negative CT report. (d) Survival of patients receiving no treatment. The cumulative 1-year patient survival was significantly influenced by patient age older than 65 years and presence of active malignancy but not by a false-negative CT report or absence of treatment.
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Figure 5b: Cumulative Kaplan-Meier survival plots with 95% confidence intervals indicated by bars. (a) Survival of elderly patients. (b) Survival of patients with underlying malignancy. (c) Survival of patients with false-negative CT report. (d) Survival of patients receiving no treatment. The cumulative 1-year patient survival was significantly influenced by patient age older than 65 years and presence of active malignancy but not by a false-negative CT report or absence of treatment.
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Figure 5c: Cumulative Kaplan-Meier survival plots with 95% confidence intervals indicated by bars. (a) Survival of elderly patients. (b) Survival of patients with underlying malignancy. (c) Survival of patients with false-negative CT report. (d) Survival of patients receiving no treatment. The cumulative 1-year patient survival was significantly influenced by patient age older than 65 years and presence of active malignancy but not by a false-negative CT report or absence of treatment.
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Figure 5d: Cumulative Kaplan-Meier survival plots with 95% confidence intervals indicated by bars. (a) Survival of elderly patients. (b) Survival of patients with underlying malignancy. (c) Survival of patients with false-negative CT report. (d) Survival of patients receiving no treatment. The cumulative 1-year patient survival was significantly influenced by patient age older than 65 years and presence of active malignancy but not by a false-negative CT report or absence of treatment.
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Figure 6a: Cumulative Kaplan-Meier survival plots with 95% confidence intervals indicated by bars. (a) Survival of patients receiving systemic thrombolytic therapy. (b) Survival of patients with major hemorrhage. (c) Survival of patients with new-onset renal failure. (d) Survival of patients with new-onset cardiac failure. The cumulative 1-year patient survival was significantly influenced by systemic thrombolytic therapy, occurrence of major hemorrhage, and new-onset cardiac failure and renal failure.
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Figure 6b: Cumulative Kaplan-Meier survival plots with 95% confidence intervals indicated by bars. (a) Survival of patients receiving systemic thrombolytic therapy. (b) Survival of patients with major hemorrhage. (c) Survival of patients with new-onset renal failure. (d) Survival of patients with new-onset cardiac failure. The cumulative 1-year patient survival was significantly influenced by systemic thrombolytic therapy, occurrence of major hemorrhage, and new-onset cardiac failure and renal failure.
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Figure 6c: Cumulative Kaplan-Meier survival plots with 95% confidence intervals indicated by bars. (a) Survival of patients receiving systemic thrombolytic therapy. (b) Survival of patients with major hemorrhage. (c) Survival of patients with new-onset renal failure. (d) Survival of patients with new-onset cardiac failure. The cumulative 1-year patient survival was significantly influenced by systemic thrombolytic therapy, occurrence of major hemorrhage, and new-onset cardiac failure and renal failure.
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Figure 6d: Cumulative Kaplan-Meier survival plots with 95% confidence intervals indicated by bars. (a) Survival of patients receiving systemic thrombolytic therapy. (b) Survival of patients with major hemorrhage. (c) Survival of patients with new-onset renal failure. (d) Survival of patients with new-onset cardiac failure. The cumulative 1-year patient survival was significantly influenced by systemic thrombolytic therapy, occurrence of major hemorrhage, and new-onset cardiac failure and renal failure.
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DISCUSSION
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The natural course of PE is known primarily from investigations of clinically obvious severe PE that was diagnosed in the era before imaging and the universal use of anticoagulants for treatment of this disorder (9,24). In a randomized controlled trial, Nielsen and co-workers (25) compared subjects treated with standard therapeutic ACT (heparin and phenprocoumon) and untreated control subjects with deep venous thrombosis. The results indicated that one of 48 patients in the treatment group died of PE, whereas none of the 42 control subjects experienced a fatal PE. In the frequently referenced partly randomized trial of Barritt and Jordan (9), only 19 untreated patients were enrolled. Both studies have to be regarded as underpowered by current standards and do not provide "level 1" evidence (26) of the effectiveness of ACT in patients with venous thromboembolism. There are only relatively few studies (2,25,27) of outcome with regard to patients with deep venous thrombosis or PE, including untreated patients, and in none of these studies were control subjects enrolled who were prospectively left untreated.
In 1995, Stein and co-workers (2) questioned the high mortality of untreated PE by showing that only one of 20 accidentally untreated patients from the Prospective Investigation of Pulmonary Embolism Diagnosis, or PIOPED, trial died. The authors stated that their untreated patients had "mild" PE, but the clinical findings were comparable to those of PIOPED patients treated for PE. Therefore, withholding ACT is currently considered safe only in patients with normal imaging findings or those in whom there is a low clinical suspicion for PE and in whom results of D-dimer assay are negative (28–30). Some groups have demonstrated the potential long-term safety of withholding ACT in certain subgroups of patients who are suspected of having PE and who have indeterminate findings on lung scintigrams (2,31,32). This result suggests that the mortality of patients with untreated PE is substantially lower than the widely quoted 30% (1–3,9,33), although this finding actually has never been proved in patients with clear CT evidence of PE (1,2).
In this study, we used multi–detector row CT to retrospectively identify patients with a PE that was initially undetected and who, consequently, did not receive ACT. Although a PE was present in 117 (6.1%) of 1912 patients overall, it was undetected at a relatively low overall CT false-negative rate of 2.2% (43 of 1912 patients). Among the 96 patients retrospectively identified as having findings positive for PE, however, unrecognized diagnoses were frequent (56 [58.3%] patients clinically were not suspected of having a PE, and diagnosis of a PE at radiologic evaluation was missed in 43 [44.8%] patients). As a result, more than one quarter (26 [27.1%] patients) of patients with findings positive for PE did not receive any treatment and an additional 21 (21.9%) patients received prophylactic ACT only. These results do not differ from those in the study of Goodman and co-workers (29), who discovered a PE in only 1% of cases after negative CT studies and in 3.1% of cases after low-probability ventilation-perfusion scintigraphy. The high proportion of false-negative CT reports in our cohort in which there were few patients who were clinically suspected of having a PE, with the majority of patients undergoing non-CT angiographic examinations, suggests that one must question whether withholding ACT after CT with negative findings can be regarded as safe (11,12,34–36): Results of our outcome analyses indicated that an incidentally diagnosed, as well as an undetected, PE at CT had a significantly lower intrapulmonary clot burden, and, despite the failure to treat a majority of the patients with such a PE, a relatively benign prognosis. These findings agree with the results of Schultz and co-workers (27) in 17 untreated trauma patients with a minor PE. There was only one death within 30 days among patients who did not receive therapeutic anticoagulant dosages. This patient was not clinically suspected of having PE, had a true-positive CT diagnosis of a lower lobe segmental PE, but had a clinical contraindication to treatment. The significantly worse short-term prognosis in patients receiving therapeutic anticoagulant doses, in major part, was caused by complications (complications that were substantially more frequent than indicated in the meta-analysis of Landefeld and Beyth [8]) of systemic thrombolytic treatment in patients with underlying malignancy and, in minor part, was caused by the higher clot burden in treated patients. We observed a similar trend in the 43 patients with false-negative CT reports who had no fatalities within 30 days (P = .007). The finding of a benign short-term course of PE in the group of patients who had a false-negative diagnosis and in the group of patients who did not receive therapeutic ACT is supported by the results of univariate and multivariate predictor analyses. These results indicate a replacement of the early PE-related predictors for 30-day mortality with the late predictors that include age and tumor disease as contributory factors for deaths occurring after 30 days.
Limitations of our study included, first, the lack of independent imaging proof of PE. Digital subtraction angiography, traditionally considered the imaging reference standard, however, has low interobserver agreement of 13%–66% in regard to subsegmental emboli (4,37). Therefore, CT angiography with good interobserver agreement and with specificity of 89%–100% is accepted by various authors as the sole reference standard for imaging down to fifth-generation vessels (27,38).
Second, the timing of the injection of contrast agent bolus and slice collimation were suboptimal in some patients. Despite long scan delays, however, CT scanning started at 0–10 seconds after the end of the bolus injection. As a result, pulmonary arterial contrast enhancement was homogeneous, well above 200 HU, and adequate to allow for PE analysis in all segmental arteries and, in many cases, in subsegmental branches. There was no influence of contrast enhancement on reports with true-positive or false-negative findings. For diagnosis of PE, all scans were regarded as equivalent to reference quality by the three reviewers. This renders a systematic influence of enhancement on PE diagnosis unlikely. A section thickness that is greater than the standard multi–detector row CT angiographic settings, which decreases reader accuracy, was present in only 38 (39.5%) of 96 multi–detector row CT scans. The majority of false-negative reports, however, were observed with scans obtained with thin sections (0.75–1.25-mm thickness), which makes a strong case against the idea that section thickness systematically caused false-positive diagnoses at scan reanalysis. Besides, the artifact assessment did not preclude these CT scans from analysis.
Further limitations of our study were the relatively small number of patients and the retrospective study design. Despite preliminary evidence of a mild natural course of minor PE from these data and those of the study of Schultz and co-workers (27), it is uncertain whether outcome results can be extrapolated to other patient populations, and this mild natural course should be addressed in future trials. Therefore, we do not regard the current evidence from our data as ample to recommend withholding ACT in all patients with low intrapulmonary clot burden. Also, we do not advocate disregarding concerns about false-negative CT diagnoses. At this point, we need to better define which subgroups of patients might need no treatment, and it appears reasonable to concentrate on high-risk patients (27).
In conclusion, we observed false-negative diagnoses and inadequate or absent treatment among patients who retrospectively received a diagnosis that was positive for PE in a 1-year cohort of patients undergoing multi–detector row CT of the chest. The pulmonary clot burden was relatively low and the clinical short-term outcome, however, was favorable in these patients. The 1-year prognosis of our patient collective was not associated with factors secondary to PE or complications of treatment but was linked to coexisting morbidity factors and older age. There may be evidence that patients with a high degree of coexisting morbidity factors and a PE of minor severity may have a better short-term prognosis when they are not treated or when they receive prophylactic ACT instead of therapeutic ACT.
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ACKNOWLEDGMENTS
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We thank Olli S. Miettinen, MD, MPH, MSc, PhD, Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada, for his invaluable advice and help with the statistical analysis. We are indebted to Peter Manstein from our institution for his assistance in the clinical data acquisition.
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FOOTNOTES
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Abbreviations: ACT = anticoagulant therapy • PE = pulmonary embolism
Authors stated no financial relationship to disclose.
Author contributions: Guarantor of integrity of entire study, C.E.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, C.E.; clinical studies, C.E., K.M.; statistical analysis, C.E., K.M.; and manuscript editing, C.E., K.M.
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ABSTRACT
INTRODUCTION
