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1 Deep Venous Thrombosis in Patients With Acute Pulmonary Embolism: Prevalence, Risk Factors, and Clinical Significance Philippe Girard, Olivier Sanchez, Christophe Leroyer, Dominique Musset, Guy Meyer, Jean-Baptiste Stern, Florence Parent and for the Evaluation du Scanner Spiralé dans l Embolie Pulmonaire Study Group Chest 2005;128; DOI: /chest This information is current as of September 15, 2005 The online version of this article, along with updated information and services, is located on the World Wide Web at: CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since Copyright 2005 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook IL All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. ISSN:

2 Deep Venous Thrombosis in Patients With Acute Pulmonary Embolism* Prevalence, Risk Factors, and Clinical Significance Philippe Girard, MD, FCCP; Olivier Sanchez, MD; Christophe Leroyer, MD; Dominique Musset, MD; Guy Meyer, MD; Jean-Baptiste Stern, MD; and Florence Parent, MD; for the Evaluation du Scanner Spiralé dans l Embolie Pulmonaire Study Group Study objectives: To determine the prevalence of lower-limb deep venous thrombosis (DVT) that can be detected by compression ultrasonography (CUS) in patients with symptomatic pulmonary embolism (PE) diagnosed with spiral CT pulmonary angiography (CTPA); and to explore the risk factors for positive CUS results and the prognostic significance of such findings. Design: Post hoc analysis of data from a prospective multicenter outcome study of 1,041 patients with clinically suspected nonsevere PE. All patients underwent CTPA and CUS within 24 h of enrollment and were followed up for 3 months. Patients: Among the 290 patients with positive CT findings, CUS was diagnostic in 281 patients who constitute the study population. Results: Mean age SD was years; 128 patients (44.8%) were men. DVT signs or symptoms were present in 90 patients (32%). CUS detected DVT in 169 patients (60.1%; 95% confidence interval [CI], 54.1 to 65.9%), including 127 patients (45.2%; 95% CI, 39.3 to 51.2%) with proximal DVT. Sensitivity and specificity of DVT symptoms for CUS-detectable DVT were 43% and 85%, respectively. Multivariate analysis showed that an age > 70 years (odds ratio [OR], 1.90; 95% CI, 1.14 to 3.17) and the presence of DVT signs or symptoms (OR, 4.12; 95% CI, 2.24 to 7.55) were independent risk factors for positive CUS results. DVT symptoms (OR, 4.78; 95% CI, 2.75 to 8.33) and a history of venous thromboembolism (OR, 2.59; 95% CI, 1.46 to 4.62) were independent risk factors for proximal DVT. The 3-month risk of recurrent thromboembolic event or death was not significantly different among patients with and without DVT (6.5% vs 2.7%, p 0.15). Conclusion: These results do not support screening for DVT in patients with CTPA-proven symptomatic PE; however, they suggest that CUS might prove especially efficient and safe as a frontline test in elderly patients with suspected PE. Further studies are needed before these conclusions can be translated into clinical recommendations. (CHEST 2005; 128: ) Key words: deep venous thrombosis; diagnosis; Doppler; duplex; prognosis; pulmonary embolism; spiral CT; ultrasonography Abbreviations: CI confidence interval; CTPA spiral CT pulmonary angiography; CUS venous compression ultrasonography; DVT deep venous thrombosis; ESSEP Evaluation du Scanner Spiralé dans l Embolie Pulmonaire; NS not statistically significant; OR odds ratio; PE pulmonary embolism; V /Q ventilation/perfusion; VTE venous thromboembolism Pulmonary embolism (PE) and deep venous thrombosis (DVT) are thought to represent two clinical manifestations of the same disease, and it is *From the Institut Mutualiste Montsouris (Dr. Girard), Paris; Hôpital Européen Georges Pompidou (Drs. Sanchez and Meyer), Paris; Hôpital de la Cavale Blanche (Dr. Leroyer), Brest; Hôpital Antoine Béclère (Dr. Parent), Clamart; and Hôpital Beaujon (Dr. Stern), Clichy, France. The ESSEP study was supported by grants from Programme Hospitalier de Recherche Clinique, Ministry of Health, Paris, France, and was promoted by la Délégation de la Recherche Clinique (Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, France). widely admitted that approximately 90% of symptomatic pulmonary emboli arise from thrombi located in the leg veins. 1 3 However, relatively little is known on the epidemiology of DVT at the time of Manuscript received January 25, 2005; revision accepted March 30, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Philippe Girard, MD, FCCP, Département thoracique, Institut Mutualiste Montsouris, 42 Boulevard Jourdan, 75014, Paris, France; CHEST / 128 / 3/ SEPTEMBER,

3 PE diagnosis. In patients with symptomatic PE, systematic assessment of lower-limb deep veins has provided a wide range of DVT prevalence rates, from 10 to 93%, depending on the methodology used to diagnose DVT and on the type and size of the population samples Incidentally, spiral CT pulmonary angiography (CTPA) and venous compression ultrasonography (CUS), currently the frontline morphologic tests for PE and DVT, have not been used in previous descriptive studies of DVT at the time of PE diagnosis. Further, the risk factors for detectable DVT as well as the possible prognostic significance of detectable DVT in patients with symptomatic PE are virtually unexplored. The Evaluation du Scanner Spiralé dans l Embolie Pulmonaire (ESSEP) study, a prospective multicenter outcome study of 1,041 patients with clinically suspected nonsevere PE, tested a diagnostic strategy in which all patients underwent both CTPA and bilateral lower-limb CUS within 24 h of enrollment into the study, and all patients were then followed up for 3 months. 11 Therefore, the data from the ESSEP study offer a unique opportunity to reliably estimate the prevalence of CUS-detectable DVT in patients with CTPA-proven PE. Also, this large prospective database would allow investigating the risk factors for positive CUS results as well as the prognostic significance of such findings in patients with symptomatic, nonsevere PE. Materials and Methods Selection of the Study Population The ESSEP study is a prospective multicenter outcome study that included 1,041 patients with suspected acute nonsevere PE between September 1999 and December 2000 at 14 centers in France. 11 The main objective of the study was to assess the safety of withholding anticoagulant therapy in patients with low or intermediate clinical probability of PE and negative findings on CTPA and leg CUS. To achieve that goal, a diagnostic strategy was applied. Inclusion criteria were clinical suspicion of PE and age 18 years. The main exclusion criteria included pregnancy, PE with hemodynamic instability (defining severe PE) or unequivocal need for thrombolytic therapy, life expectancy of 3 months, impossibility of follow-up, and anticoagulant treatment for 48 h before inclusion. 11 The protocol was approved by the Ethics Committee of Paris XI University, and written informed consent was obtained from all participants before entry into the study. All patients had an evaluation of the clinical probability of PE rated empirically as low, intermediate, or high and then underwent CTPA pulmonary angiography and bilateral lower-limb CUS within 24 h of enrollment. All patients, whether treated or untreated, were followed up for 3 months. Regarding signs and symptoms of DVT, the investigators were only asked to record whether any signs or symptoms were present. No clinical details, ie, what specific signs and symptoms were present or absent, were collected. The presence or absence of signs and/or symptoms of DVT was recorded before any morphologic test was performed. Active malignancy was defined as any malignancy that deserved specific treatment within the previous 6 months. CTPA was performed in 1,039 patients, with normal results in 650 patients and nondiagnostic findings in 99 patients. CTPA showed PE in 290 patients, who constitute the eligible population for the present study. CTPA Technique and Interpretation Guidelines for CTPA were implemented at each center to standardize methods. Over the study period, single-row detector spiral CTs were used at all participating centers. A total volume of 100 to 140 ml contrast medium with a minimum concentration of 200 g/l iodine was injected at a rate of 4 to 5 ml/s through a large peripheral IV line. Scans were done with a 2- to 3-mm collimation with 120 kilovolts, 150 ma, and a pitch of 1.5 to 2.0. The images were reconstructed with intervals of 2mm and read by the local radiologist on a workstation on films with mediastinal and lung window settings, or both. PE was diagnosed if a central filling defect outlined by contrast material or complete occlusion was seen in a segmental or more proximal pulmonary artery. CTPA was judged negative for the diagnosis of PE when pulmonary arteries, including all segmental branches, were visualized and free of thrombus. CTPA was judged nondiagnostic when poor opacification or major motion artifacts were observed, precluding the visualization of at least one segmental arterial branch. It must be noticed that isolated subsegmental thrombi were considered nondiagnostic in the ESSEP study. Such thrombi accounted for 12 of the 99 patients with nondiagnostic CTPA results, and all 12 patients had negative CUS findings. 11 Interestingly, according to the ESSEP protocol, these 12 patients underwent pulmonary angiography and/or ventilation/perfusion (V /Q ) lung scanning, which confirmed PE in only 3 of them. 11 Ultrasonography of the Lower Limbs Bilateral venous CUS of the legs was done in all patients from the common femoral vein to the trifurcation of the calf veins, inclusively. Lack of vein compressibility was taken as diagnostic of DVT. In the calf, only thrombi located in the peroneal or tibial veins were taken into account. When the femoral or popliteal veins could not be examined, ultrasonography was classified as nondiagnostic. Follow-up All patients, with or without PE or DVT, and whether treated or untreated, were followed up for 3 months. According to the ESSEP protocol, follow-up consisted of telephone interviews 1 month and 2 months after inclusion, and patients were seen in an outpatient clinic at 3 months. For patients who could not be traced, death registries were systematically consulted after checking with the family physician. Critical events recorded by the investigator during follow-up were death, bleeding complications that prompted medical attention, and symptomatic venous thromboembolism (VTE). All critical events were assessed by a central adjudication committee, the members of which were independent of the study centers. In addition, the adjudication committee classified the deaths during follow-up on the basis of all available information as certainly related to PE, possibly related to PE (if the cause of death could not be clearly established), or definitely not related to PE. Statistical Analysis The 2 test was used to compare observed percentages. To identify independent risk factors for positive CUS findings, a 1594 Clinical Investigations

4 Table 1 Main Clinical Characteristics of the 281 Patients With CTPA-Proven PE and Diagnostic Lower-Limb CUS* multivariate analysis (logistic regression) was performed using statistical software (SPSS 10.1; SPSS; Chicago, IL). Patients Characteristics Results Data Age, yr Male/female gender, No. 126/155 Underlying cardiac or pulmonary disease 54 (19.2) History of VTE 75 (26.7) Recent surgery or trauma, immobilization 71 (25.3) Status at inclusion Outpatient 238 (84.7) Hospitalized 43 (15.3) Evolving cancer 25 (8.9) Miscellaneous risk factors 67 (23.8) Pretest clinical probability of PE High 160 (56.9) Intermediate 102 (36.3) Low 19 (6.7) Presence of DVT signs or symptoms 90 (32.0) *Data are presented as mean SD or No. (%) unless otherwise indicated. Includes known thrombophilia, recent delivery, recent long journey, family history of VTE, contraceptive or hormone replacement therapy, chronic venous insufficiency. CTPA showed PE in 290 patients and CUS results were available in 288 patients, but CTPA proved nondiagnostic in 7 patients (2.4%). The 281 patients with positive CTPA results and diagnostic CUS findings constitute the study population. Their main clinical characteristics are displayed in Table 1. Symptoms and Prevalence of DVT CUS diagnosed DVT in 169 patients of the 281 patients (60.1%; 95% confidence interval [CI], 54.1 to 65.9%), and it proved normal in 112 patients (39.9%) [Table 2]. Among patients with positive CUS findings, 127 patients (75.1%) had proximal (ie, popliteal and/or femoral) DVT. Therefore, the prevalence of proximal DVT in the study population was 45.2% (95% CI, 39.3 to 51.2%). Signs and/or symptoms of DVT, rated globally and empirically as absent or present, were present in 73 of the 169 patients with DVT (43.2%), and in 17 of the 112 patients with negative CUS results (15.2%). The sensitivity, specificity, and positive and negative predictive values of the presence of DVT signs or symptoms for diagnosing DVT and proximal DVT in patients with CTPA-proven PE are shown in Table 3. Risk Factors for Positive CUS Findings No statistically significant center effect was found among the 14 centers regarding the prevalence of proximal and/or distal DVT. Eight potential risk factors for positive CUS findings were tested in the univariate analysis (Table 4). Other potential risk factors such as recent delivery, known thrombophilia, hormone replacement therapy, contraceptive use, or recent long journey could not be tested because of the small numbers of patients in these subgroups. Advanced age ( 70 years), a history of VTE, cardiac or respiratory disease, current hospitalization, and the presence of signs or symptoms of DVT were statistically significant predictors for positive CUS findings in the univariate analysis and were tested in the multivariate analysis (Table 4). Only age and the presence of signs or symptoms of DVT proved to be independent risk factors in the multivariate analysis (odds ratio [OR], 1.90; 95% CI, 1.14 to 3.17 [p 0.014]; and OR, 4.12; 95% CI, 2.24 to 7.55 [p 0.001], respectively) [Table 4]. Among 47 patients with both risk factors (DVT signs or symptoms and age 70 years), 36 patients (76.6%) had CUS-detectable DVT. The univariate and multivariate analyses were Table 2 Prevalence of CUS-Detectable DVT and Prevalence of DVT Signs or Symptoms in 281 Patients With CTPA-Proven PE* Variables All Patients (n 281) No DVT (n 112) All DVT (n 169) Proximal DVT (n 127) Prevalence of CUS-detectable DVT No. (%) 169 (60.1) 95% CI Prevalence of CUS-detectable proximal DVT No. (%) 127 (45.2) 95% CI Presence of DVT signs or symptoms, No. (%) Yes 90 (32) 17 (15) 73 (41) 63 (50) No 191 (68) 95 (85) 96 (59) 64 (50) CHEST / 128 / 3/ SEPTEMBER,

5 Table 3 Diagnostic Value of the Presence of DVT Signs or Symptoms for CUS-detectable DVT in 281 Patients With CTPA-Proven PE* Variables All DVT Proximal DVT Sensitivity of DVT signs or symptoms for CUS detectable DVT Specificity Positive predictive value Negative predictive value *Data are presented as %. repeated on the same population of 281 patients to identify independent risk factors for the presence of proximal DVT (Table 5). The presence of signs or symptoms of DVT remained a highly significant independent risk factor (OR, 4.78; 95% CI, 2.75 to 8.33 [p 0.001]), whereas age was no longer a significant risk factor. However, a history of VTE was a strong independent risk factor for the presence of proximal DVT (OR, 2.59; 95% CI, 1.46 to 4.62 [p 0.001]). Among 26 patients with both risk factors (history of VTE and DVT signs or symptoms), 24 patients (92%) had CUS-detectable proximal DVT. Follow-up During the 3-month follow-up, one patient was unavailable for follow-up after 1 month, but he was alive at 3 months, as attested by consultation of his birthplace death registry. Follow-up was complete in all other patients. Eleven of the 281 patients (3.9%) with diagnostic CUS findings died, including 8 of 169 patients (4.7%) and 3 of 112 patients (2.7%) with positive and negative CUS findings, respectively (p 0.6) [Table 6]. Similarly, 6 of the 281 patients (2.1%) had a recurrent thromboembolic event during the 3-month follow-up, including 5 of 169 patients (3.0%) and 1 of 112 patients (0.9%) with positive and negative CUS findings, respectively (p 0.4). Finally, using a combined end point (recurrent VTE or death within 3 months of enrolment), the difference between patients with DVT (11 of 169 patients, 6.5%) and without DVT (3 of 112 patients, 2.7%) was not statistically significant (NS) [p 0.15; Table 6]. Discussion Improving our knowledge on the epidemiology of detectable DVT in patients with symptomatic PE can prove clinically useful from diagnostic, prognostic, and therapeutic standpoints. For example, diagnosing DVT in patients with suspected PE may obviate the need for further testing because the treatment of DVT with and without associated PE is essentially the same. 12 Therefore, identifying risk Table 4 Univariate and Multivariate Analysis of Risk Factors for Positive CUS Findings in 281 Patients With CTPA-Proven PE* Risk Factors All Patients (n 281) Positive CUS (n 169) p Value (Univariate) p Value (Multivariate) OR (95% CI) Gender Male Female Age, yr ( ) Status Outpatients NS Hospitalized Cardiac and/or respiratory disease Yes NS No History of VTE Yes NS No Recent surgery ( 30 d), immobilization Yes No Active malignancy Yes No DVT signs or symptoms Yes ( ) No *Data are presented as No. unless otherwise indicated Clinical Investigations

6 Table 5 Univariate and Multivariate Analysis of Risk Factors for the Presence of Proximal DVT on Lower-Limb CUS in 281 Patients With CTPA-Proven PE* Risk Factors All Patients (n 281) Proximal DVT (n 127) p Value (Univariate) p Value (Multivariate) OR (95% CI) Gender Male NS Female Age, yr NS Status Outpatient NS Hospitalized Cardiac and/or respiratory disease Yes No History of VTE Yes ( ) No Recent surgery ( 30 d), immobilization Yes No Active malignancy Yes No DVT signs or symptoms Yes ( ) No *Data are presented as No. unless otherwise indicated. factors for detectable DVT in patients with PE may help to define subpopulations with suspected PE in whom screening for DVT as a frontline test might prove especially effective. Also, from a prognostic and therapeutic standpoint, if the presence of detectable DVT proves to be associated with an increased risk of recurrent PE despite anticoagulant therapy, such a finding would lead to considering searching for DVT in all patients with PE, and to consider modifying therapy for patients with symptomatic PE and detectable DVT. The prevalence of detectable DVT in patients with symptomatic PE has not been widely investigated and varies greatly among studies (Table 7). The present study finds a prevalence of 60% with a narrow CI (54 to 66%). In the largest previous study 6 that assessed the prevalence of DVT in patients with PE, 82% of 213 patients with angiography-proven PE had venography-proven DVT, with a similarly narrow CI (76 to 87%). Besides the retrospective character of that series, three main factors may explain the significant difference between these prevalence rates. First, whereas sensitivity and specificity of CUS compared with venography exceed 95% for symptomatic proximal DVT, the sensitivity of CUS for detecting asymptomatic and/or distal Table 6 Three-Month Risk of Recurrent VTE Event and/or Death in Patients With and Without DVT Among 281 Patients With CTPA-Proven PE* Variables Patients With CUS-Detectable DVT (n 169) Patients Without CUS-Detectable DVT (n 112) p Value Three-month risk of death 8 (4.7) 3 (2.7) 0.6 Three-month risk of recurrent 5 (3.0) 1 (0.9) 0.4 VTE event Three-month risk of recurrent VTE event or death 11 (6.5) 3 (2.7) 0.15 *Data are presented as No. (%). VTE event symptomatic PE and/or DVT. Including two patients who died of recurrent PE (day 7 and day 72 after inclusion, respectively). Including one patient who died of recurrent PE (day 19 after inclusion). Yates correction for small samples. CHEST / 128 / 3/ SEPTEMBER,

7 Table 7 Prevalence of DVT in Patients With Proven PE in a Selection of Published Studies Source Collection of Data Diagnosis of PE Patients With PE, No. Diagnosis of DVT Prevalence of DVT, % Prevalence of Proximal DVT, % Turkstra et al Prospective Pulmonary angiography or V /Q lung scan* 149 CUS 29 van Rossum et al Metaanalysis (seven studies) Pulmonary angiography 147 (range, 10 to 37) Venography or CUS 36 (range, 10 to 93) van Rossum et al 5 Prospective V /Q lung scan* 53 CUS Girard et al Retrospective Pulmonary 213 Venography angiography Cham et al Prospective CTPA 91 CT venography 32 Loud et al Retrospective CTPA 85 CT venography 68 Elias et al Prospective Pulmonary 74 Extended CUS angiography or V /Q lung scan Present study Prospective CTPA 281 CUS *Only patients with high-probability V /Q lung scans are considered as having PE. CUS was limited to the femoral and popliteal veins. An unspecified number of patients had distal (calf) DVT diagnosed by CT venography. Extended CUS examination included the calf muscle veins, the common iliac veins, and the inferior vena cava; isolated thrombi were found at these levels in 10, 3, and 2 patients, respectively. DVT is much lower The relatively low proportion of patients with distal DVT in this study (25%, as compared with 40% in the venography study 6 ) further supports this interpretation. Second, CUS did not examine the pelvic veins and the vena cava. It has been reported that a small proportion (2 to 7%) of thrombi that can be diagnosed by venography, MRI, or CT venography are limited to the pelvic veins or vena cava and may therefore remain undetected by CUS. 6,8,17 Finally, only patients with suspected nonsevere PE were included in this study. Given the definition of severe PE in this study (ie, hemodynamic instability), our study population is likely to be representative of approximately 90% of all patients with symptomatic PE. 18 Nevertheless, the exclusion of patients with severe PE might also explain in part the lower prevalence of DVT in this study because a significant positive correlation has been demonstrated between the severity of PE and the prevalence of DVT. 6 This study confirms the poor sensitivity ( 50%) of DVT signs and/or symptoms for CUS detectable thrombi, even in patients with detectable PE, which mirrors the poor sensitivity of PE symptoms in patients with proven proximal DVT. 19 The specificity values proved significantly better, between 80% and 85% for both DVT and proximal DVT. Such figures are consistent with the finding that the presence of DVT signs or symptoms proved to be the strongest independent predictor of CUS-detectable DVT. In patients with suspected PE, diagnosing DVT may obviate the need for further testing because the treatment of DVT with and without nonsevere PE is essentially the same. 12 In this study, DVT and proximal DVT were found in 60% and 45% of patients with proven PE, respectively. Further, age 70 years and a history of VTE were found to be independent risk factors for CUS-detectable DVT and proximal DVT, respectively. This could suggest that lower-limb CUS may be efficient as a frontline test in patients with suspected PE because such an approach might spare spiral CT in as many as 68% of elderly patients with the disease and, even if only proximal DVTs are considered, up to 61% of patients with a history of VTE. Both figures, however, have their downsides, as they can lead to overtreatment. Indeed, treating patients with asymptomatic distal DVT without objectively confirming the diagnosis of PE carries the risk of treating clinically insignificant thrombi in patients without PE. Similarly, treating patients with proximal DVT and a history of VTE without objectively documenting PE carries the risk of treating patients with residual proximal thrombi without PE because approximately 30% of patients still have residual thrombi 2 years after an episode of proximal DVT, and distinguishing between acute (recent) DVT and older thrombi from a previous episode may be difficult if a baseline CUS is unavailable. 20,21 Thus, this study provides reliable prevalence and risk factor data but also raises concerns that should be taken into account in the design of safe and cost-effective diagnostic algorithms for patients with suspected PE. Finding a DVT was not found to have a significant 1598 Clinical Investigations

8 impact on the risk of recurrent VTE events or death within 3 months in this study. It must be noticed, however, that the incidence rates of such events were low (6.5% and 2.7% for patients with and without DVT, respectively) and that the nonsignificant difference might just reflect a lack of statistical power. The risk of PE, both within the first 3 months of anticoagulation and after discontinuation of therapy, has been found to be significantly higher in patients with symptomatic PE than in patients with DVT who are asymptomatic for PE However, the subpopulations of PE patients with and without DVT typically could not be individualized in these studies. Whether the presence of detectable DVT, especially proximal DVT, constitutes an independent risk factor for fatal PE during and after discontinuation of anticoagulant therapy in patients with symptomatic PE should be investigated in future prospective studies. The risk of postthrombotic syndrome might support DVT screening in patients with proven PE. Indeed, the use of elastic stockings is effective for preventing the occurrence of postthrombotic syndrome in patients with symptomatic proximal DVT. 25,26 However, it is unclear whether similar results can be expected in patients with asymptomatic and/or distal DVT, and this question also should be addressed in specific clinical and cost-effectiveness studies. Although all the data used for this study were collected prospectively, the post hoc nature of this study is a theoretical weakness. For example, details such as what specific signs and symptoms of DVT were present or absent in the study patients were not collected and therefore could not be analyzed. Also, the fact that 14 centers participated in the study may have induced some technical and clinical heterogeneities. However, data from multicenter studies are likely to reflect real-world figures better than data obtained from a single or a few highly specialized centers with potentially biased recruitments and outcomes. Further, all important clinical events that occurred during follow-up were classified by an independent central adjudication committee. In any case, both the size of this study and its methodology compare favorably with the available literature on the same subject. Finally, the technique of spiral CT (single-row detector) that was used over the study period may appear as suboptimal. It has been suggested that the use of multidetector spiral CTs might increase the sensitivity of this test because the visualization of subsegmental pulmonary arteries is improved, and isolated subsegmental thrombi have been said to represent up to 30% of detectable PEs. 30 However, this 30% figure is derived from a small retrospective series, and a more reliable value of only 6% has been reported in 375 patients with PE from the Prospective Investigation of Pulmonary Embolism Diagnosis study. 31 Further, in a recent multicenter outcome study, 32 isolated subsegmental thrombi were found in only 0.3% of the 593 patients who underwent CTPA (1.6% of the 124 patients with PE), even though multidetector spiral CTs were used in 60% of patients. Therefore, it appears unlikely that the availability of multidetector spiral CTs would have had a major impact on the main results of this study. Conclusion Sixty percent of patients with CTPA-proven symptomatic PE have CUS-detectable lower-limb DVT, mostly asymptomatic, but the presence of DVT had no detectable prognostic impact. Such results do not support screening for DVT in patients with CTPAproven symptomatic PE. However, CUS might prove especially efficient and safe as a frontline test in elderly patients with suspected PE, provided that such diagnostic strategies do not result in overtreatment. Further outcome and cost-effectiveness studies are needed before these conclusions can be translated into clinical recommendations. ACKNOWLEDGMENT: The authors wish to thank Fabrice Larrazet, MD, who performed the multivariate analysis for this study, and all the participants in the ESSEP study. A complete list of participants appears in the original report of the ESSEP study. 11 References 1 Kearon C. Natural history of venous thromboembolism. Circulation 2003; 107:I22 I30 2 Hyers TM. Venous thromboembolism. 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9 9 Coche EE, Hamoir XL, Hammer FD, et al. Using dualdetector helical CT angiography to detect deep venous thrombosis in patients with suspicion of pulmonary embolism: diagnostic value and additional findings. AJR Am J Roentgenol 2001; 176: Elias A, Colombier D, Victor G, et al. Diagnostic performance of complete lower limb venous ultrasound in patients with clinically suspected acute pulmonary embolism. Thromb Haemost 2004; 91: Musset D, Parent F, Meyer G, et al. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre outcome study. Lancet 2002; 360: Buller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(suppl):401S 428S 13 Wells PS, Lensing AW, Davidson BL, et al. Accuracy of ultrasound for the diagnosis of deep venous thrombosis in asymptomatic patients after orthopedic surgery: a metaanalysis. Ann Intern Med 1995; 122: Lensing AW, Doris CI, McGrath FP, et al. A comparison of compression ultrasound with color Doppler ultrasound for the diagnosis of symptomless postoperative deep vein thrombosis. Arch Intern Med 1997; 157: Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med 1998; 129: Kassai B, Boissel JP, Cucherat M, et al. A systematic review of the accuracy of ultrasound in the diagnosis of deep venous thrombosis in asymptomatic patients. Thromb Haemost 2004; 91: Stern JB, Abehsera M, Grenet D, et al. Detection of pelvic vein thrombosis by magnetic resonance angiography in patients with acute pulmonary embolism and normal lower limb compression ultrasonography. Chest 2002; 122: Stein PD, Henry JW. Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes. Chest 1997; 112: Girard P, Decousus M, Laporte S, et al. Diagnosis of pulmonary embolism in patients with proximal deep vein thrombosis: specificity of symptoms and perfusion defects at baseline and during anticoagulant therapy. Am J Respir Crit Care Med 2001; 164: Prandoni P, Cogo A, Bernardi E, et al. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation 1993; 88: Prandoni P, Lensing AW, Prins MH, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: Douketis JD, Kearon C, Bates S, et al. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279: Douketis JD, Foster GA, Crowther MA, et al. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000; 160: Eichinger S, Weltermann A, Minar E, et al. Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med 2004; 164: Brandjes DP, Buller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141: Patel S, Kazerooni EA, Cascade PN. Pulmonary embolism: optimization of small pulmonary artery visualization at multidetector row CT. Radiology 2003; 227: Raptopoulos V, Boiselle PM. Multi-detector row spiral CT pulmonary angiography: comparison with single-detector row spiral CT. Radiology 2001; 221: Schoepf UJ, Holzknecht N, Helmberger TK, et al. Subsegmental pulmonary emboli: improved detection with thincollimation multi-detector row spiral CT. Radiology 2002; 222: Oser RF, Zuckerman DA, Gutierrez FR, et al. Anatomic distribution of pulmonary emboli at pulmonary angiography: implications for cross-sectional imaging. Radiology 1996; 199: Stein PD, Henry JW, Gottschalk A. Reassessment of pulmonary angiography for the diagnosis of pulmonary embolism: relation of interpreter agreement to the order of the involved pulmonary arterial branch. Radiology 1999; 210: Perrier A, Roy PM, Aujesky D, et al. Diagnosing pulmonary embolism in outpatients with clinical assessment, D-dimer measurement, venous ultrasound, and helical computed tomography: a multicenter management study. Am J Med 2004; 116: Clinical Investigations

10 Deep Venous Thrombosis in Patients With Acute Pulmonary Embolism: Prevalence, Risk Factors, and Clinical Significance Philippe Girard, Olivier Sanchez, Christophe Leroyer, Dominique Musset, Guy Meyer, Jean-Baptiste Stern, Florence Parent and for the Evaluation du Scanner Spiralé dans l Embolie Pulmonaire Study Group Chest 2005;128; DOI: /chest This information is current as of September 15, 2005 Updated Information & Services References Permissions & Licensing Reprints alerting service Images in PowerPoint format Updated information and services, including high-resolution figures, can be found at: This article cites 32 articles, 25 of which you can access for free at: L Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: Receive free alerts when new articles cite this article sign up in the box at the top right corner of the online article. Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online article figure for directions.

Cover Page. The handle holds various files of this Leiden University dissertation.

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