multidetector computed tomographic pulmonary angiography in patients with a high clinical probability of pulmonary embolism

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1 Journal of Thrombosis and Haemostasis, 14: DOI: /jth ORIGINAL ARTICLE Multidetector computed tomographic pulmonary angiography in patients with a high clinical probability of pulmonary embolism L. MOORES,* J. KLINE, A. K. PORTILLO, S. RESANO, A. VICENTE, P. ARRIETA, J. CORRES,** V. TAPSON, R. D. YUSEN and D. J I M EN E Z *F. Edward Hebert School of Medicine, Uniformed Services University, Bethesda, MD; Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Internal Medicine, Instituto Ramon y Cajal de Investigacion Sanitaria IRYCIS, Ramon y Cajal Hospital; Radiology Department, Instituto Ramon y Cajal de Investigacion Sanitaria IRYCIS, Ramon y Cajal Hospital; Respiratory Department, Instituto Ramon y Cajal de Investigacion Sanitaria IRYCIS, Ramon y Cajal Hospital, Alcala de Henares University; **Emergency Department, Instituto Ramon y Cajal de Investigacion Sanitaria IRYCIS, Ramon y Cajal Hospital, Madrid, Spain; Divisions of Pulmonary and Critical Care Medicine, Cedars-Sinai, Los Angeles, CA; and Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences, Washington University School of Medicine, St Louis, MO, USA To cite this article: Moores L, Kline J, Portillo AK, Resano S, Vicente A, Arrieta P, Corres J, Tapson V, Yusen RD, Jimenez D. Multidetector computed tomographic pulmonary angiography in patients with a high clinical probability of pulmonary embolism. J Thromb Haemost 216; 14: Essentials When high probability of pulmonary embolism (PE), sensitivity of computed tomography (CT) is unclear. We investigated the sensitivity of multidetector CT among 134 patients with a high probability of PE. A normal CT alone may not safely exclude PE in patients with a high clinical pretest probability. In patients with no clear alternative diagnosis after CTPA, further testing should be strongly considered. Summary. Background: Whether patients with a negative multidetector computed tomographic pulmonary angiography (CTPA) result and a high clinical pretest probability of pulmonary embolism (PE) should be further investigated is controversial. Methods: This was a prospective investigation of the sensitivity of multidetector CTPA among patients with a priori clinical assessment of a high probability of PE according to the Wells criteria. Among patients with a negative CTPA result, the diagnosis of PE required at least one of the following conditions: ventilation/perfusion lung scan showing a high probability of PE in a patient with no history of PE, abnormal findings on venous ultrasonography in a patient without previous deep vein thrombosis at that site, or the occurrence of venous thromboembolism (VTE) in a 3-month follow-up period after anticoagulation was withheld because of a negative multidetector CTPA result. Results: We identified 498 patients with a priori clinical assessment of a high probability of PE and a completed CTPA study. CTPA excluded PE in 134 patients; in these patients, the pooled incidence of VTE was 5.2% (seven of 134 patients; 95% confidence interval [CI] ). Five patients had VTEs that were confirmed by an additional imaging test despite a negative CTPA result (five of 48 patients; 1.4%; 95% CI ), and two patients had objectively confirmed VTEs that occurred during clinical follow-up of at least 3 months (two of 86 patients; 2.3%; 95% CI 5.5). None of the patients had a fatal PE during follow-up. Conclusions: A normal multidetector CTPA result alone may not safely exclude PE in patients with a high clinical pretest probability. Keywords: diagnosis; diagnostic imaging; multidetector computed tomography; probability; pulmonary embolism. Correspondence: David Jimenez, Respiratory Department, Ramon y Cajal Hospital, 2834 Madrid, Spain. Tel.: ; fax: djimenez.hrc@gmail.com Received 6 August 215 Manuscript handled by: M. Cushman Final decision: F. R. Rosendaal, 1 November 215 Introduction Despite the existence of detailed European and North American consensus guidelines, challenges continue to exist regarding the efficient, appropriate and safe evaluation for suspected acute pulmonary embolism (PE) [1 3]. Multidetector computed tomographic pulmonary angiography (CTPA) has emerged as a prominent imaging technique for 215 International Society on Thrombosis and Haemostasis

2 Multidetector CTPA and high probability of PE 115 the exclusion or confirmation of PE, and for the detection of alternative diagnoses [4 8]. In a prospective management study that enrolled 756 consecutive patients referred to the emergency department (ED) with a clinical suspicion of PE, patients with either a high clinical probability or a non-high clinical probability and a positive ELISA D-dimer test result underwent both proximal lower limb compression ultrasonography (CUS) and multidetector CTPA [9]. CUS detected deep vein thrombosis (DVT) in only three of the 32 (.9%; 95% confidence interval [CI].3 2.7) patients who had a negative multidetector CTPA result. In another study, patients classified as having a high probability of PE by the dichotomized Wells rule and patients with a positive D-dimer test result underwent multidetector CTPA [1]. The 3-month thromboembolic risk in the patients left untreated because of a negative CTPA result was low (1.1%; 95% CI.6 1.9). The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II trial showed a sensitivity of 83% and a specificity of 96% for multidetector CTPA [11]. PIOPED II highlighted the influence of clinical probability on the predictive value of multidetector CTPA. In patients with a low or intermediate clinical probability of PE as assessed by the Wells rule, a negative CTPA result had a high negative predictive value for PE (96% and 89%, respectively), whereas this was only 6% in those with a high pretest probability. Therefore, we conducted a prospective study to assess whether a negative multidetector CTPA result might safely rule out PE in patients admitted to the ED with a high pretest probability of PE. Methods Study design We conducted a prospective non-interventional study that evaluated the sensitivity and negative predictive value of 64-slice multidetector CTPA in a cohort of consecutive adult patients who presented to an academic urban ED with a high pretest probability of PE. Setting The study was performed in the ED of Ramon y Cajal Hospital, an academic urban hospital in Madrid, Spain. Patients The inclusion criteria were patient presentation to the ED, and ED clinician suspicion of acute symptomatic PE (e.g. sudden onset of dyspnea, sudden deterioration of existing dyspnea, or sudden onset of pleuritic chest pain without another apparent cause). Patients were recruited between January 28 and December 213. Exclusion criteria included a non-high clinical probability of PE according to the Wells criteria [12], treatment with therapeutic doses of anticoagulants for > 24 h, lifeexpectancy of < 3 months, documented pregnancy, geographic inaccessibility precluding follow-up, age < 18 years, allergy to intravenous contrast agents, renal insufficiency (creatinine clearance of < 3 ml min 1 ), logistic problems (e.g. unavailability of CTPA, or patient too ill to undergo CTPA), and hemodynamic instability. The institutional review board approved the study protocol, and written or oral informed consent was obtained from all participants. Clinical decision rule All patients who were enrolled in the study underwent a clinical assessment of the probability of PE, including a Wells score (Table 1) [12]. Patients were classified as high probability with a clinical decision rule score of 7 points. Radiologic evaluation Patients were examined during suspended inspiration. Sixty-four slice multidetector-row CTPA parameters were a slice thickness of 1.25 mm with a 1.2-mm reconstruction interval at 12 kv/12 mas, 8 1 ml of nonionic contrast material containing 35 mg of iodine per milliliter with an injection speed of 4. ml s 1, and bolus tracking in the common pulmonary artery to obtain optimal contrast opacification of the pulmonary arteries. The pulmonary arteries were evaluated up to and including the subsegmental vessels from the level of the aortic arch to the lowest hemidiaphragm. PE was diagnosed if contrast material outlined an intraluminal defect or if a vessel was totally occluded by low-attenuation material on at least two adjacent slices. In patients without PE, the presence or absence of an alternative Table 1 Clinical decision rule* Variable Points Clinical signs and symptoms of deep vein thrombosis 3. (minimum of leg swelling and pain with palpation of the deep veins) Alternative diagnosis less likely than pulmonary embolism 3. Heart rate of > 1 min Immobilization (> 3 days) or surgery in the previous weeks Previous pulmonary embolism or deep vein thrombosis 1.5 Hemoptysis 1. Malignancy (receiving treatment, treated in the last 1. 6 months or palliative) *Clinical probability of pulmonary embolism low: 1 points. Clinical probability of pulmonary embolism intermediate: 2 6 points. Clinical probability of pulmonary embolism high: 7 points [12]. 215 International Society on Thrombosis and Haemostasis

3 116 L. Moores et al. diagnosis was recorded, and anticoagulant treatment was withheld. The CTPA was considered to be inconclusive if the images could not be interpreted because of motion artefacts resulting from movements of the patient or the heart, or if there was insufficient contrast enhancement of the pulmonary arteries. The decision on the presence or absence of PE was made by trained attending radiologists who were blinded to any specific patient clinical information. The diagnostic management of patients who had a negative CTPA result was left to the discretion of the attending physician. Outcomes The main outcome was the sensitivity of multidetector CTPA among patients with a priori clinical assessment of a high probability of PE according to the Wells criteria. Among patients with a negative CTPA result, the diagnosis of PE required at least one of the following conditions: ventilation/perfusion (V/Q) lung scan showing a high probability of PE in a patient with no history of PE [13], abnormal findings (i.e. non-compressibility) on venous ultrasonography in a patient without previous DVT at that site [14], or the occurrence of symptomatic (fatal and non-fatal) venous thromboembolism (VTE) in a 3-month follow-up period after anticoagulation was withheld because of a negative multidetector CTPA result. For the main outcome, investigators excluded from follow-up those patients in whom a decision was made by the physicians in charge to prescribe anticoagulants. Two independent experts (D.J. and A.K.P.), who were blinded to the initial diagnostic testing performed, adjudicated all adverse events. Fatal PE was classified as definitely present if PE was confirmed by autopsy, or if death followed a clinically severe PE. Fatal PE was classified as possibly present in patients who died suddenly or unexpectedly. risk (failure rate) in high-probability patients left untreated on the basis of a negative CTPA result not higher than 8%. We calculated that ~ 13 patients with a high clinical probability of PE and a negative CTPA result would have to be included, with a two-sided type I error of.5 and a type II error of.2. As we expected that ~ 65% of patients with a high clinical probability of PE would have a definite diagnosis of PE, a total study population of 4 patients with a high clinical probability of PE was needed. We used standard methods to calculate the sensitivity, negative predictive value, and negative likelihood ratio [15]. Patients for whom CTPA results were inconclusive were excluded from these calculations. We calculated exact 95% CIs for sensitivity and unadjusted negative predictive values from the binomial distribution by use of CONFIDENCE INTERVAL ANALYSIS software. Results Study sample Study staff screened 3237 consecutive patients with suspected acute PE for eligibility, of whom 2736 were excluded (Fig. 1). Non-high clinical probability of PE resulted in the exclusion of 2588 (8%) patients. Other reasons for exclusion included the use of therapeutic doses of anticoagulants for > 24 h (n = 83; 3.1%), renal insufficiency (n = 37; 1.3%), and shock or hypotension (n = 12;.4%). Unspecified reasons resulted in the exclusion of 16 patients (.6%). As 364 patients had positive findings for PE on CTPA and three patients had inconclusive CTPA results, the study enrolled the remaining 134 patients with a high clinical probability of PE and a negative CTPA result (Fig. 1). Three-month follow-up 3237 patients had suspected PE Follow-up consisted of a scheduled outpatient visit or telephone interview at 3 months. Patients were instructed to contact the study investigators immediately in the event of symptoms suggestive of DVT or PE. In cases of clinically suspected DVT or PE, the protocol requested objective diagnostic testing. At each visit, information was obtained on complaints suggestive of VTE, including acute onset of dyspnea, acute worsening of existing dyspnea, acute onset of chest pain, unilateral leg swelling and leg pain, and interval initiation of anticoagulants. In cases of death, information was obtained from the hospital records, or from autopsies. 51 were eligible 2736 were not eligible 2588 had low or intermediate clinical probability 83 had history of anticoagulant use 37 had abnormal creatinine levels 16 had unspecified reasons 12 had shock or hypotension 367 were not enrolled 364 had PE (on CTPA) 3 had inconclusive CTPA Statistical analysis 134 were enrolled The sample size was based on an assumption of an upper limit of the 95% CI around the 3-month thromboembolic Fig. 1. Patient flow diagram. CTPA, computed tomographic pulmonary angiography; PE, pulmonary embolism. 215 International Society on Thrombosis and Haemostasis

4 Multidetector CTPA and high probability of PE 117 Table 2 Baseline demographic and clinical characteristics of the study population (n = 134) Characteristic Value Clinical characteristics Age (years), mean (SD) 65.5 (16.8) Male gender, n (%) 68 (51) Risk factors for VTE, n (%) History of VTE 27 (2) Cancer 24 (18) Recent surgery 18 (13) Immobilization for 4 days 31 (23) Comorbid diseases, n (%) Chronic lung disease 6 (4.5) Chronic heart disease 2 (1.5) Clinical symptoms and signs at presentation Symptom duration (days) mean (SD) 3.8 (4.3) Dyspnea, n (%) 19 (81) Chest pain, n (%) 38 (28) Syncope, n (%) 12 (8.9) Hemoptysis, n (%) 3 (2.2) Clinical symptoms of DVT, n (%) 8 (6.) Heart rate (beats min 1 ) mean (SD) 1 (19.5) Heart rate > 1 min 1, n (%) 69 (51) Arterial oxygen saturation (%), mean (SD) 135 (26.5) Systolic blood pressure (mmhg) mean (SD) 92 (6.2) DVT, deep vein thrombosis; SD, standard deviation; VTE, venous thromboembolism. Patient demographics The mean age of our patient population was 65.5 years (standard deviation, 16.8 years; range, 2 95 years). The baseline demographic and clinical characteristics of the 134 study patients are shown in Table 2. VTE indicated by initial diagnostic workup In 26 patients (19%), CTPA showed no PE, but an alternative diagnosis that sufficiently explained the presenting symptoms (pneumonia, 13; emphysema, 6; cancer, 3; heart failure, 3; pneumothorax, 1) could be made (Fig. 2). None of these 26 patients received anticoagulant therapy. Forty-eight (36%; 95% CI 28 44) of the 134 patients underwent additional testing. No statistically significant differences were observed between patients who underwent or did not undergo additional testing regarding demographics, medical history, and clinical presentation, although a greater proportion of patients who underwent additional testing than of those who did not undergo additional testing had dyspnea, clinical signs and symptoms of DVT, and previous immobilization. Thirty-nine patients proceeded to venous ultrasonography. Four patients with negative CTPA results who underwent CUS Negative CTPA (n = 134) Alternative diagnosis (n = 26) CUS (n = 39*) Additional testing (n = 48) V/Q scan (n = 13*) No evidence of PE or an alternative diagnosis (n = 6) DVT (n = 4 ) No DVT (n = 35 ) PE (n = 2 ) No PE (n = 11 ) Follow-up at 3 months (n =129), no Symptoms VTE Deaths Deaths attributable to VTE 1 3 * Four patients proceeded to CUS and V/Q scan. One patient was diagnosed with DVT and PE. Three patient had negative CUS and V/Q scan test results Fig. 2. Outcomes at 3 months in 134 patients with a high clinical probability of pulmonary embolism (PE) and a negative computed tomographic pulmonary angiography (CTPA) result. CUS, compression ultrasonography; DVT, deep vein thrombosis; V/Q, ventilation/perfusion; VTE, venous thromboembolism. 215 International Society on Thrombosis and Haemostasis

5 118 L. Moores et al. (4/39; 1%; 95% CI.7 2) had a proximal DVT and received anticoagulant therapy. Of 13 patients who proceeded to V/Q lung scanning, two had PE (one had also DVT by CUS) and were anticoagulated. In the 43 patients who had negative test results, no anticoagulant treatment was given, and the patients were followed for 3 months (Fig. 2). VTE during the 3-month follow-up The study had complete primary outcome information for all patients at the end of the 3-month follow-up. Of the 129 patients with a high probability of PE who had negative CTPA results, and did not undergo anticoagulant therapy, six returned during the 3-month follow-up with clinical symptoms that may have been caused by VTE; none of the 43 patients with negative additional test results returned with symptoms of VTE. Repeated CTPA demonstrated non-fatal PE in two patients; thus, the false-negative rate was 1.9% (7/371; 95% CI.5 3.3) and the negative predictive value was 98% (Fig. 2). Summary of outcomes The overall results were as follows: of the 134 patients with a high clinical probability of PE and an adequate CTPA result, the sensitivity of CTPA for the diagnosis of PE was 98% (364 of 371 patients; 95% CI 96 99) (Table 3). The negative predictive value was 95% (127 of 134 patients; 95% CI 91 99), and the likelihood ratio for a negative test result was.2 (95% CI.1.4). None of the patients with an alternative diagnosis had VTE during follow-up. The rate of VTE in the group of patients with negative additional test results was %, as compared with 3.3% (2/6; 3.3%; 95% CI 7.9) in the group of patients without an alternative diagnosis who did not undergo additional testing for PE. Discussion PIOPED II established the diagnostic performance of multidetector CTPA against an algorithm-based reference criterion in the evaluation of patients with suspected PE [11]. As in their first study, the investigators incorporated clinical pretest probability assessment and the determination of CTPA performance against a reference criterion. The overall sensitivity was adequate, at 83%. However, the authors noted that the negative predictive value was high in patients with a low or moderate pretest probability, but a disappointing 6% in patients deemed to have a high pretest probability. This improved to 82% with the addition of computed tomography (CT) venography (CTV), prompting the authors to recommend combined testing in these patients [16]. The addition of CTV, however, is controversial. It adds a significant amount of radiation; and, although studies have confirmed that it improves the sensitivity of CT imaging, it only modestly improves the negative predictive value. When used in combination with a clinical decision rule and a D-dimer test result, CTPA showed a high negative predictive value for the evaluation of patients with suspected PE [17,18]. With current CT scanning techniques, we found a much higher negative predictive value of CTPA alone (95%), and a very low rate of subsequent VTE in patients with negative imaging findings (1.6%; 95% CI, 3.7). This is consistent with prior prospective studies and metaanalyses, which have shown the rate of recurrence after a negative CTPA result to be low [17,19] and comparable to that seen after negative conventional angiography [13,2], even in high-risk populations such as patients with malignancy, previous VTE, heart failure, and chronic obstructive pulmonary disease [21]. Although some of these studies did not stratify the patients according to pretest probability, the Christopher Investigators demonstrated a recurrence rate of only 1.3% in > 1 patients with a likely diagnosis of PE according to the dichotomous Wells rule [22]. This disparity in the accuracy of CTPA versus clinical outcomes has been noted for over a decade, and has been attributed to the fact that CTPA, even with multidetector technology, probably misses small, isolated, subsegmental emboli [23]. The low rate of recurrence supports the use of CTPA as a stand-alone imaging technique in most patients. However, our study highlights the difficulty in applying this reasoning when the results of CT scanning are discordant with clinical judgement. Patients with a high pretest probability of PE, without an alternative Table 3 Venous thromboembolic events Diagnostic strategy n Total VTEs, n (%) [95% CI] Fatal PE, n (%) [95% CI] PE excluded by CTPA (5.2) [1.5 9.] () [. 2.8] CTPA showing alternative 26 () [. 13] () [. 13] diagnosis PE excluded by CTPA 48 5 (1) [1.8 19] () [. 7.4] (underwent additional testing*) PE excluded by CTPA (did 86 2 (2.3) [ 5.5] () [ 4.3] not undergo additional testing) PE excluded by CTPA and 43 () [. 8.2] () [. 8.2] additional testing (both studies gave negative results) PE excluded by CTPA (no alternative diagnosis and did not undergo additional testing) 6 2 (3.3) [ 7.9] () [. 6.] CI, confidence interval; CTPA, computed tomographic pulmonary angiography; PE, pulmonary embolism; VTE, venous thromboembolism. *Ventilation/perfusion scan and/or lower limb ultrasonography testing. 215 International Society on Thrombosis and Haemostasis

6 Multidetector CTPA and high probability of PE 119 diagnosis, and who underwent no further diagnostic imaging had a recurrence rate of 3.3%, which is almost twice that seen in all-comers, and five times the rate seen in patients with a low pretest probability of PE. In this group of patients, it might be reasonable to obtain a CUS scan to evaluate the presence of DVT. In our study, ultrasonography testing identified all but one falsenegative CTPA result, and this approach would avoid the radiation and contrast dye associated with V/Q scanning, CTV, or conventional angiography. A prospective management trial on the use of CUS in this setting is warranted. Our study is limited by its non-interventional methodology. The study protocol did not mandate a specific approach to testing, and we do not know what patient outcomes would have been if additional testing had not led to anticoagulation therapy. In addition, the study was performed at a single academic medical center, and all of the patients were ambulatory patients presenting to the ED. The results may not be generalizable to an inpatient population. In conclusion, a normal multidetector CTPA result alone may not safely exclude PE in patients with a high clinical pretest probability. In patients with no clear alternative diagnosis after CTPA, particularly those with significant underlying cardiopulmonary disease, further testing should be strongly considered. Addendum L. Moores, J. Kline, V. Tapson, R. Yusen, and D. Jimenez were responsible for the study concept and design. A. K. Portillo, S. Resano, A. Vicente, P. Arrieta, J. Corres, and D. Jimenez were responsible for the acquisition of data. L. Moores, J. Kline, V. Tapson, R. Yusen, and D. Jimenez drafted the manuscript. L. Moores, J. Kline, A. K. Portillo, S. Resano, A. Vicente, P. Arrieta, J. Corres, V. Tapson, R. Yusen, and D. Jimenez critically revised the manuscript for important intellectual content. L. Moores and D. Jimenez supervised the study. The corresponding author, D. Jimenez, had full access to all of the data in the study, and had final responsibility for the decision to submit for publication. Acknowledgements The study was funded by Instituto de Salud Carlos III (FIS 211 [PI11/246 to D. Jimenez]). Disclosure of Conflict of Interests The authors state that they have no conflict of interest. References 1 Uresandi F, Monreal M, Garcıa-Bragado F, Domenech P, Lecumberri R, Escribano P, Zamorano JL, Jimenez S, Ruiz- Artacho P, Lozano F, Romera A, Jimenez D. National consensus on the diagnosis, risk stratification and treatment of patients with pulmonary embolism. Arch Bronconeumol 213; 49: Konstantinides S, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman M, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, et al.; Authors/Task Force Members. 214 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). Eur Heart J 214; 35: Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis and chronic thromboembolic pulmonary hypertension. Circulation 211; 123: Schoepf UJ, Goldhaber SZ, Costello P. Spiral computed tomography for acute pulmonary embolism. Circulation 24; 19: 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 2; 132: Mullins MD, Becker DM, Hagspiel KD, Philbrick JT. The role of spiral volumetric computed tomography in the diagnosis of pulmonary embolism. Arch Intern Med 2; 16: van Strijen MJ, de Monye W, Schiereck J, Kieft GJ, Prins MH, Huisman MV, Pattynama PM; Advances in New Technologies Evaluating the Localisation of Pulmonary Embolism Study Group. Single-detector helical computed tomography as the primary diagnostic test in suspected pulmonary embolism: a multicenter clinical management study of 51 patients. Ann Intern Med 23; 138: Musset D, Parent F, Meyer G, Ma^ıtre S, Girard P, Leroyer C, Revel MP, Carette MF, Laurent M, Charbonnier B, Laurent F, Mal H, Nonent M, Lancar R, Grenier P, Simonneau G; Evaluation du Scanner Spirale dans l Embolie Pulmonaire study group. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multi-center outcome study. Lancet 22; 36: Perrier A, Roy P-M, Sanchez O, Le Gal G, Meyer G, Gourdier AL, Furber A, Revel MP, Howarth N, Davido A, Bounameaux H. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 25; 352: van Belle A, B uller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW, Kramer MH, Kruip MJ, Kwakkel-van Erp JM, Leebeek FW, Nijkeuter M, Prins MH, Sohne M, Tick LW. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 26; 295: Stein PD, Fowler SE, Goodman LR, Gottschalk A, Hales CA, Hulla RD, Leeper KV, Popovich J, Quinn DA, Sos TA, Sostman HD, Tapson VF, Wakefield TW, Weg JG, Woodard PK; for the PIOPED II Investigators. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 26; 354: Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, Turpie AG, Bormanis J, Weitz J, Chamberlain M, Bowie D, Barnes D, Hirsh J. Derivation of a simple clinical model to categorize patients probability of pulmonary embo- 215 International Society on Thrombosis and Haemostasis

7 12 L. Moores et al. lism: increasing the model s utility with the SimpliRED D-dimer. Thromb Haemost 2; 83: PIOPED Investigators. Value of ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of the pulmonary embolism diagnosis (PIOPED). JAMA 199; 263: 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: Fisher L, van Belle G. Biostatistics: A Methodology for the Health Sciences. New York: Wiley, 1993: Stein PD, Woodard PK, Weg JG, Wakefield TW, Tapson VF, Sostman HD, Sos TA, Quinn DA, Leeper KV Jr, Hull RD, Hales CA, Gottschalk A, Goodman LR, Fowler SE, Buckley JD; PIOPED II Investigators. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. Radiology 27; 242: Moores LK, Holley AB. Computed tomography pulmonary angiography and venography: diagnostic and prognostic properties. Semin Resp Crit Care Med 28; 29: Mos IC, Klok FA, Kroft LJ, De Roos A, Dekkers OM, Huisman MV. Safety of ruling out acute pulmonary embolism by normal computed tomography pulmonary angiography in patients with an indication for computed tomography: systematic review and meta-analysis. J Thromb Haemost 29; 7: Moores LK, King CS, Holley AB. Current approach to the diagnosis of acute nonmassive pulmonary embolism. Chest 211; 14: Henry JW, Relyea B, Stein PD. Continuing risk of thromboemboli among patients with normal pulmonary angiograms. Chest 1995; 17: Sohne M, Kruip MJ, Nijkeuter M, Tick L, Kwakkel H, Halkes SJ, Huisman MV, Buller HR; Christopher Study Group. Accuracy of clinical decision rule, D-dimer and spiral computed tomography in patients with malignancy, previous venous thromboembolism, COPD or heart failure and in older patients with suspected pulmonary embolism. J Thromb Haemost 26; 4: Writing Group for the Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 26; 295: Perrier A, Bounameaux H. Accuracy or outcome in suspected pulmonary embolism. N Engl J Med 26; 354: International Society on Thrombosis and Haemostasis