ORIGINAL INVESTIGATION. The Bedside Investigation of Pulmonary Embolism Diagnosis Study

Transcription

1 ORIGINAL INVESTIGATION The Bedside Investigation of Pulmonary Embolism Diagnosis Study A Double-blind Randomized Controlled Trial Comparing Combinations of 3 Bedside Tests vs Ventilation-Perfusion Scan for the Initial Investigation of Suspected Pulmonary Embolism Marc A. Rodger, MD, MSc; Christopher N. Bredeson, MD, MSc; Gwynne Jones, MD; Pasteur Rasuli, MD; François Raymond, MD; Anne Marie Clement, RN; Alan Karovitch, MD; Helene Brunette, RRT; Dimitri Makropoulos, MD; Mark Reardon, MD; Ian Stiell, MD, MSc; Rama Nair, PhD; Philip S. Wells, MD, MSc Background: We sought to determine whether using combinations of 3 bedside tests (7-variable clinical model, non enzyme-linked immunosorbent assay D-dimer test, and alveolar dead-space fraction) to exclude pulmonary embolism (PE) before diagnostic imaging was as safe as a standard strategy of starting with ventilationperfusion (V/Q) scan. Methods: In this double-blind, randomized, controlled equivalency trial, patients were randomized to initial bedside tests or to initial without bedside tests. Patients assigned to the bedside test group had a sham performed if at least 2 of 3 bedside test results were negative; otherwise, they underwent an actual. Further diagnostic management was determined by a blinded physician after. The primary outcome measure was recurrent venous thromboembolic events during 3 months among patients who were not taking anticoagulant agents after the initial investigations were completed. Results: Four hundred fifty-eight consecutive adults with suspected PE were eligible for the study; 398 of 399 consenting and randomized patients completed the study. The follow-up venous thromboembolic event rate was 2.4% in thebedsidetestgroupvs3.0% inthev/qscangroup(p=.76). Pulmonary embolism was excluded in 34% (67/199) of the bedside test group patients with at least 2 negative results on 3 bedside tests vs 18% (35/199) excluded using only the 7-variable clinical model and the D-dimer test. Conclusion: Excluding PE with at least 2 negative results on 3 bedside tests safely eliminates the need for diagnostic imaging in 34% of patients with suspected PE. Arch Intern Med. 2006;166: Author Affiliations: University of Ottawa, Ottawa Health Research Institute, and Departments of Medicine (Drs Rodger, Jones, Karovitch, and Wells and Ms Clement), Radiology (Drs Rasuli and Raymond), Emergency Medicine (Drs Makropoulos, Reardon, and Stiell), Respiratory Therapy (Ms Brunette), and Epidemiology and Community Medicine (Dr Nair), Ottawa Hospital, Ottawa, Ontario; and Department of Medicine, Medical College of Wisconsin, Milwaukee (Dr Bredeson). PULMONARY EMBOLISM (PE) IS A common potentially lethal yet treatable condition. 1-3 Pulmonary embolism is considered in the differential diagnosis of many clinical presentations, yet fewer than 35% of patients suspected of having PE actually have PE. 4,5 Diagnostic imaging for suspected PE is generally available during limited hours and only in larger centers, complicating the diagnostic approach for many patients with suspected PE. Ventilation-perfusion (V/Q) scan is often recommended for the investigation of suspected PE, but most s for suspected PE are nondiagnostic. Options after a nondiagnostic include pulmonary angiography, serial noninvasive leg studies for deep vein thrombosis, and helical computed tomography. Each of these options has limitations, including cost, inaccessibility, inconvenience, and potential complications. Recent investigations have focused on using bedside tools to exclude PE without diagnostic imaging, as well as on refining the diagnostic management algorithm to minimize the need for subsequent imaging after It has been previously demonstrated that, by using a simple 7-variable clinical model, patients See also pages 147, 169, and 176 with suspected PE can be categorized into pretest subgroups (low, intermediate, or high and unlikely or likely PE) (Figure 1). 5-7 A low pretest (based on the 7-variable clinical model) and a negative non enzyme-linked immunosorbent assay D- dimer test result safely exclude PE without the need for diagnostic imaging. 5 Alveolar dead-space fraction (AVDSf) represents ventilation of those alveoli that are not involved in gas exchange (ie, alveoli that are not perfused or are poorly perfused, as occurs in PE). 8 It has recently been demonstrated that a low AVDSf com- 181

2 A 7-Variable Clinical Model Predictor Variable Points Clinical Signs or Symptoms of DVT 3.0 Alternate Diagnosis Less Likely Than PE 3.0 Heart Rate >100 Beats/min 1.5 Previous DVT or PE 1.5 Major Surgery or Immobilization Within 4 wk 1.5 Active Malignant Neoplasm 1.0 Hemoptysis 1.0 Consecutive patients with suspected PE who were referred to our nuclear medicine department at Ottawa Hospital (General Campus [October 1, 1998, to February 1, 2002] and Civic Campus [February 15, 2000, to July 31, 2001]) for were eligible for the study. Patients were ineligible if they were younger than 18 years, were unable to give informed consent, were expected to survive less than 3 months, were receiving ventilatory assistance, were previously enrolled in the BIOPED study, were known to have chronic PE or had PE diagnosed in the last 3 months, were taking full-dose anticoagulant agents, or had vena caval interruption for confirmed venous thromboembolism (VTE). INTERVENTION B C D-Dimer Test Alveolar Dead-Space Fraction Phase 1 PCO 2 Phase 2 Phase 2 PETCO 2 Phase 3 Tracheo- Bronchoalveolar Unit Phase 1 PaCO 2 Phase 3 CO 2 -Volume Capnogram bined with a negative D-dimer test result in ambulatory patients with suspected PE has a high negativepredictive value. 8,9 We evaluated combinations of the 7-variable clinical model by Wells et al, 10 non enzyme-linked immunosorbent assay D-dimer test, and AVDSf in a single bedside investigation of pulmonary embolism diagnosis (BIOPED method) (with at least 2 negative 3 bedside tests excluding PE). Compared with using 2 of the predictors alone, we sought to determine whether the BIOPED method would be safer, was less resource intensive, and could exclude a larger proportion of patients with suspected PE. METHODS STUDY DESIGN The study was a double-blind, randomized, controlled equivalency trial comparing the BIOPED method with as the initial investigation in patients with suspected PE. The study was conducted from October 1, 1998, to February 1, 2002, at Ottawa Hospital, Ottawa, Ontario, a large academic tertiary care center serving a local population of more than 1 million, and was approved by the institutional ethics review board. PATIENTS Alveolar Dead-Space Fraction PaCO 2 PETCO 2 PaCO 2 Dead-Space Equation Figure 1. Bedside investigation of pulmonary embolism (PE) diagnosis predictors. A, Seven-variable clinical model ( 4.0 points, negative; and 4.0 points, positive). B, D-dimer assay (negative or positive). C, Alveolar dead-space fraction ( 0.15, negative; and 0.15, positive). If at least 2 predictors are negative, PE is excluded; if at least 2 predictors are positive, PE is possible and further investigation is required. DVT indicates deep vein thrombosis; solid circle, blood clot; and PETCO 2, end-tidal PCO 2 level. After written informed consent was obtained for each patient, the next consecutively numbered sealed opaque envelope with a randomly assigned allocation (BIOPED group or group) was opened. Patients were managed as shown in Figure 2. All study patients, regardless of randomization allocation, had 3 BIOPED tests performed, the results of which were kept blinded from the investigators. All study patients were evaluated by their referring physicians using a standardized patient assessment form that included 7 variables in the clinical model by Wells et al. 10 All patients had volumetric capnograms (continuous carbon dioxide vs volume tracings) measured at bedside by respiratory therapists, with the patient breathing through a mouthpiece attached to an airway adapter with a mainstream carbon dioxide volume sensor (CosmoPlus; Respironics Novametrix, Wallingford, Conn). Calibration was verified before each use with gases of known carbon dioxide concentration. Once the patient was breathing at a stable respiratory rate (±2 breaths per minute during 2 minutes) and had a stable end-tidal PCO 2 (±1 mm Hg during 2 minutes), a blood sample was obtained for arterial blood gas analysis. The AVDSf was subsequently calculated as follows: AVDSf=(PaCO 2 endtidal PCO 2 )/PaCO 2. 8 The AVDSf measurements were reported to unblinded study personnel as being 0.15 or lower or being higher than 0.15 but were not disclosed to the patients or to their physicians. If AVDSf measurements could not be obtained (as was the case in 133 of 399 patients), they were assumed to be positive (primary reasons why the AVDSf could not be obtained were an inability to achieve a stable respiratory rate or a stable end-tidal PCO 2 [n=64] and an inability to obtain an arterial blood gas level [n=25]). All study patients had D-dimer analysis using the SimpliRED whole-blood agglutination D-dimer test (AGEN Biomedical, Ltd, Brisbane, Australia) or the Accuclot latex agglutination D-dimer test (Sigma Diagnostics, St Louis, Mo) if the SimpliRED test was unavailable (n=51). These assays have been demonstrated to have similar accuracy. 11 Among 12 patients in whom results were missing, the D-dimer test results were assumed to be positive. Based on the results of the 7-variable clinical model, D- dimer test, and AVDSf, unblinded study personnel assigned all patients a BIOPED diagnosis. A BIOPED-negative diagnosis was assigned if at least 2 of 3 bedside test results were negative (7-variable clinical model score 4.0 points, negative D-dimer assay, and AVDSf 0.15). A BIOPED-positive diagnosis was assigned if at least 2 of 3 bedside test results were positive (7-variable clinical model score 4.0 points, positive D-dimer assay, and AVDSf 0.15). Patients randomized to the BIOPED group of the study who had BIOPED-negative results (in whom PE was considered excluded) received a sham in the nuclear medicine department, which was subsequently reported as showing no evidence. Patients randomized to the BIOPED group who had BIOPED-positive results (in whom PE was considered possible) underwent an actual. Patients randomized to the group (BIOPED-negative or BIOPED-positive result) underwent an actual. Results of the s were reported according to Prospective Investigation of Pulmonary Embolism Diagnosis study 4 criteria, except for normal or near-normal results, which were 182

3 Patients With Suspected PE 399 BIOPED Tests (7-Variable Clinical Model, D-Dimer Test, and Alveolar Dead-Space Fraction) Randomization 199 BIOPED Group 199 V/Q Scan Group (1 Withdrew Consent) 67 BIOPED Negative 132 BIOPED Positive BIOPED Test Results Ignored Sham V/Q Scan Actual V/Q Scan Actual V/Q Scan No PE 24 No PE 72 Low Probability PE 20 Intermediate Probability PE 16 High Probability PE 110 Low Probability PE 32 Intermediate Probability PE 13 High Probability PE 44 No PE 4 VTE 0 VTE Further Testing Ordered by Treating Physician Further Testing Ordered by Treating Physician 0 VTE 1 Treatment Failure 5 VTE 2 Treatment Failures Figure 2. Study algorithm. Bedside investigation of pulmonary embolism diagnosis (BIOPED) negative represents at least 2 negative 3 bedside tests; BIOPED positive represents at least 2 positive 3 bedside tests. Treatment failure represents patients taking anticoagulant agents after initial investigation for suspected pulmonary embolism (PE) who had venous thromboembolism (VTE) during follow-up. V/Q indicates ventilation-perfusion. reported as showing no evidence. After the nuclear medicine department reports were released (indicating no evidence or low, intermediate, or high ), the blinded treating physician determined whether further testing was required for suspected PE. Study personnel documented any further testing that was completed and whether patients were taking anticoagulant agents at the time of discharge. At discharge, patients were given written instructions to contact the blinded study physicians if they experienced any symptoms of recurrent VTE. All patients reporting leg symptoms were evaluated for deep vein thrombosis by compression ultrasonography or by venography. All patients with suspected PE recurrence were investigated by. Pulmonary embolism was considered excluded if the was normal. However, all patients with nonnormal s were further tested by pulmonary angiography or by spiral computed tomography. Patients were seen 3 months after discharge to document any recurrent events or bleeding episodes that were previously unreported and to complete an assessment of patient and study physician blinding. OUTCOME MEASURES The primary outcome measure was recurrent VTE events during 3 months in patients not taking anticoagulant agents or vena caval interruption after initial investigations for suspected PE. The following criteria were used to diagnose a VTE event (PE or deep vein thrombosis) on follow-up: (1) compression ultrasonography revealing new noncompressibility above the trifurcation of the popliteal vein, (2) venography demonstrating a new constant intraluminal filling defect above the trifurcation of the popliteal vein, (3) pulmonary angiography demonstrating a constant intraluminal filling defect or a cutoff of a vessel greater than 2.5 mm in diameter, (4) spiral computed tomography demonstrating an intraluminal filling defect in a segmental or greatersized pulmonary artery, and (5) PE discovered at autopsy. Secondary outcome measures were the following: (1) allcause mortality, (2) major bleeding episodes during the 3 months, and (3) number of diagnostic tests used in the investigation for PE. Major bleeding complications were defined as any overt hemorrhage resulting in a decrease in hemoglobin level greater than 20 g/l or requiring transfusion of at least 2 U of packed red blood cells. All suspected outcome events were adjudicated by 2 blinded physicians (M.A.R. and P.S.W.). STATISTICAL ANALYSIS All analyses were based on intent to test by 2 of us (M.A.R. and R.N.). A priori, we believed that the minimum clinically important difference (MCID) in the primary outcome measure (3- month recurrent VTE rate) was 3%, accepting a 10% chance of falsely rejecting the null hypothesis (ie, 1-tailed =.10) and a 10% chance of falsely not rejecting the hypothesis (ie, 90% power); therefore, we would require a sample size of 570. Because of funding limitations, the trial was terminated early after having recruited 399 patients. The null hypothesis was tested by examining the 95% confidence interval surrounding the difference in event rates between the 2 study groups among patients who were not taking anticoagulant agents. Given an MCID of 3% if the 95% confidence interval around the difference in event rates excluded a 3% difference, we would conclude equivalence. Diagnostic accuracy of the bedside tests was determined by calculating sensitivity, specificity, negativepredictive value, positive-predictive value, and likelihood ratios for each bedside test individually and in combinations of 2 and 3. For the diagnostic accuracy analyses, 2 2 tables were con- 183

4 366 Excluded Did Not Meet Inclusion Criteria 59 Refused to Participate 0 Patients Withdrew Consent 67 BIOPED Negative 824 Consecutive Patients Assessed for Trial Eligibility 458 Eligible Patients 399 Patients Consented and Randomized 199 Patients Allocated to BIOPED Group 199 Patients Included in Study 1 Patient Withdrew Consent 132 BIOPED Positive 200 Patients Allocated to V/Q Scan Group 199 Patients Included in Study Table 1. Baseline Characteristics of the Study Population* Characteristic BIOPED Group (n = 199) V/Q Scan Group (n = 200) Demographics Age, mean ± SD, y 53.5 ± ± 18.8 Male-female ratio 68:131 66:134 Patient source Emergency department 137 (68.8) 122 (61.0) Inpatient 58 (29.1) 71 (35.5) Other 4 (2.0) 7 (3.5) Medical history Malignant neoplasm, active, 56 (28.1) 39 (19.5) palliative, or in treatment Surgery in the last month 29 (14.6) 22 (11.0) Previous deep vein thrombosis 22 (11.1) 24 (12.0) or pulmonary embolism Immobilization, 3 d bedridden 45 (22.6) 52 (26.0) in the last month Symptoms Dyspnea 142 (71.4) 140 (70.0) Chest pain 151 (75.9) 144 (72.0) Leg pain or swelling 45 (22.6) 61 (30.5) Hemoptysis 11 (5.5) 15 (7.5) Signs Tachypnea 20 breaths/min 48 (24.1) 58 (29.0) Heart rate 100 beats/min 76 (38.2) 89 (44.5) Leg swelling, edema, or tenderness along deep veins 56 (28.1) 73 (36.5) 4 Follow-up VTE 0 Follow-up VTE 1 Treatment Failure 5 Follow-up VTE 2 Treatment Failures Abbreviations: BIOPED, bedside investigation of pulmonary embolism diagnosis; V/Q, ventilation-perfusion. *Data are given as number (percentage) unless otherwise indicated. Figure 3. Study participant flow chart. BIOPED indicates bedside investigation of pulmonary embolism diagnosis; V/Q, ventilation-perfusion; and VTE, venous thromboembolism. structed using all study patients (regardless of randomization group). This was made possible by performing all 3 bedside tests in all study patients regardless of randomization allocation (Figure 2). Patients were considered PE negative if they were not taking anticoagulant agents after initial testing for PE and had no confirmed VTE at the 3-month follow-up. Patients were considered PE positive if they were not taking anticoagulant agents after initial testing for PE or had a confirmed VTE event at the 3-month follow-up. t Test was used to compare the mean number of tests performed after in each study group. RESULTS Eight hundred twenty-four patients were screened, 458 of whom were eligible for the study (Figure 3). The most common reasons for ineligibility were an inability to provide informed consent (30%), current anticoagulation therapy for proven deep vein thrombosis (25%), and life expectancy less than 3 months (15%). Three hundred ninety-nine patients consented to participate, 1 patient withdrew consent (who preferred not to wait for investigation of suspected PE), and no patients were lost to follow-up. Baseline characteristics were comparable between the 2 study groups except that patients randomized to the BIOPED group were more likely to have a malignant neoplasm but were less likely to be tachypneic (Table 1). In the primary outcome analysis, 4 (2.4%) of 165 patients not taking anticoagulant agents in the BIOPED group had a VTE event during the 3-month follow-up period vs 5 (3.0%) of 169 patients not taking anticoagulant agents in the group who had a VTE event during the 3-month follow-up period (P=.76). The 95% confidence interval around the 0.6% difference in favor of the BIOPED group was 4.1% to 2.9% and excluded our a priori assigned MCID of 3% (Table 2). Of 199 patients randomized to the BIOPED group, 67 had at least 2 negative 3 bedside tests (which excluded PE in 34% of patients). Only 18% (35/199) would have been excluded using just the 7-variable clinical model and the D-dimer test. Fifty-seven VTE events were confirmed during the initial workups of suspected PE (ie, the index visits) (Table 3). Of 65 patients taking anticoagulant agents at the time of their index visits, 57 had confirmed PE and 6 had probable PE; the latter 6 had s indicating an intermediate, with 5 of them showing normal subsequent ultrasonography. The remaining 2 patients were taking anticoagulant agents for atrial fibrillation after their index visits. Adding AVDSf to the 7-variable clinical model and the D-dimer test in the BIOPED method more than doubled the proportion of patients excluded from 16% to 32%, with comparable negative-predictive values (95.4% and 94.7%) (Table 4). No significant difference was noted in the results of the BIOPED method using the Simpli- RED D-dimer test (sensitivity, 89.8%; and specificity, 184

5 Table 2. Patients Not Taking Anticoagulant Agents After Workup for Suspected Pulmonary Embolism (PE) and Experiencing Venous Thromboembolism (VTE) During Follow-up Patient No. Group Randomization BIOPED PE Diagnosis 7-Variable Clinical Model Score D-Dimer Assay Alveolar Dead-Space Fraction Initial Nuclear Medicine Department Results 1 BIOPED Negative 4.0 Negative 0.40 No evidence, sham 2 BIOPED Negative 4.0 Positive 0.15 No evidence, sham 3 BIOPED Negative 1.5 Negative 0.11 No evidence, sham 4 BIOPED Negative 4.5 Negative 0.06 No evidence, sham 5 Positive 7.5 Positive Not available Low 6 Positive 3.0 Positive 0.21 Low 7 Positive 1.0 Positive 0.16 Low 8 Positive 3.0 Positive 0.17 Low 9 Positive 7.0 Positive 0.18 Intermediate Further Diagnostic Imaging Follow-up VTE Confirmation of VTE None PE on day 2 High on None None DVT on day 80 DVT on day 30 CUS CUS None PE on day 1 Pulmonary angiography initial CUS of symptomatic leg only initial CUS and pulmonary angiography spiral CT initial CUS serial CUS DVT and PE on day 28 DVT and PE on day 40 DVT and PE on day 38 PE on day 3 PE on day 16 CUS, spiral CT High on CUS, CUS, spiral CT Pulmonary angiography Abbreviations: BIOPED, bedside investigation of pulmonary embolism diagnosis; CT, computed tomography; CUS, compression ultrasonography; DVT, deep vein thrombosis; PE, pulmonary embolism; V/Q, ventilation-perfusion. CT Comments 7-Variable clinical model incorrectly applied by house staff Patient with metastatic carcinoma DVT after femoral vein puncture for cardiac catheterization Presented with next-day syncope... Initial pulmonary angiogram interpreted as chronic PE Patient with recurrent lymphoma New hemoptysis Hemoptysis, increased chest pain Table 3. Diagnostic Tests After s During Workup for Suspected Pulmonary Embolism (PE)* Initial CUS Serial CUS Spiral Computed Tomography Pulmonary Angiography Venography BIOPED group No evidence (n = 91) 22 (0) 3 (0) 1 (0) 0 0 Probability Low (n = 72) 44 (4) 6 (0) 10 (1) 7 (2) 0 Intermediate (n = 20) 18 (0) 6 (1) 8 (2) 4 (2) 0 High (n = 16) 8 (3) 0 1 (1) 1 (1) 0 group No evidence (n = 44) 16 (2) 3 (0) 2 (0) 0 1 (0) Probability Low (n = 110) 66 (3) 15 (0) 13 (0) 5 (2) 0 Intermediate (n = 32) 27 (4) 4 (0) 13 (3) 5 (5) 0 High (n = 13) 8 (4) 0 1 (0) 1 (0) 0 Abbreviations: BIOPED, bedside investigation of pulmonary embolism diagnosis; CUS, compression ultrasonography; V/Q, ventilation-perfusion. *Data are given as number of tests (number of positive results). Sums to 199 patients because 1 patient withdrew consent. 185

6 Table 4. Accuracy Analysis of the Combinations of Bedside Tests* Combination Sensitivity, % Specificity, % Negative-Predictive Value, % Likelihood Ratio True-Negative Proportion, % BIOPED method 90.1 ( ) 38.4 ( ) 94.7 ( ) 0.26 ( ) 31.5 ( ) 7-Variable clinical model and D-dimer test 95.6 ( ) 18.7 ( ) 95.4 ( ) 0.23 ( ) 15.5 ( ) 7-Variable clinical model and AVDSf 91.2 ( ) 19.9 ( ) 91.7 ( ) 0.44 ( ) 16.5 ( ) D-dimer test and AVDSf 92.6 ( ) 29.0 ( ) 95.1 ( ) 0.25 ( ) 24.1 ( ) Abbreviations: AVDSf, alveolar dead-space fraction; BIOPED, bedside investigation of pulmonary embolism diagnosis. *Data are given as percentage (95% confidence interval). 40.1%) vs the Accuclot D-dimer test (sensitivity, 88.9%; and specificity, 23.8%). Six patients experienced bleeding episodes during the 3-month follow-up period; 3 were adjudicated as major bleeding episodes (2 in the BIOPED group and 1 in the group) and 3 as minor bleeding episodes (2 in the BIOPED group and 1 in the group). There was no statistically significant difference in total bleeding episodes, major bleeding episodes, minor bleeding episodes, or all-cause mortality between the 2 study groups (P=.45). The mean number of diagnostic imaging tests performed to investigate suspected PE was 1.36 per patient in the BIOPED group vs 1.90 per patient in the V/Q scan group (P.001) (Table 3). COMMENT This study establishes that using a combination of 3 bedside tests to exclude PE is as safe as using a as the initial investigation for patients with suspected PE. Using 2 of 3 bedside predictors resulted in a rate of subsequent VTE during 3 months that was comparable to that associated with a standard approach of initial investigation with a (without the use of bedside tests). The addition of AVDSf to the 7-variable clinical model and the D-dimer test doubled the number of patients in whom PE could be safely excluded compared with the use of only the 7-variable clinical model and the D- dimer test. This doubling was achieved despite the fact that AVDSf measurements were indeterminate in one third of patients tested. Efforts to increase the proportion of patients with conclusive AVDSf results, such as using less stringent criteria for stability of breathing at the time of AVDSf measurement, will need to be evaluated. Hyperventilation at the time of arterial blood gas measurement can lower the PaCO 2 level and falsely normalize AVDSf results in patients with PE. Furthermore, we were obligated for patient safety to assume that a bedside test result was positive if it was unavailable. This may have biased the results in favor of finding a higher sensitivity and a lower specificity for AVDSf. Six of 8 patients who had VTEs on follow-up had high AVDSf measurements at baseline (Table 2). This raises the possibility that AVDSf not only is useful in the diagnostic management but also is a predictor for risk of development of subsequent symptomatic PE. On average, the use of initial bedside tests resulted in 0.6 fewer tests being conducted per patient compared with the standard approach. Given the bedside nature of these tests, this approach can be adopted in smaller facilities without access to diagnostic imaging rather than immediately transferring patients with suspected PE to larger centers for diagnostic imaging. To our knowledge, our study is the first randomized trial comparing 2 diagnostic strategies for suspected PE. Randomized trials of competing diagnostic strategies eliminate selection bias that may be seen in cohort studies examining new diagnostic tests. If a new diagnostic strategy is compared with the gold standard in a lowrisk population, high negative-predictive values can be demonstrated by virtue of the low prevalence of disease in the population studied (eg, ambulatory outpatients in PE diagnostic studies). Examining the same diagnostic strategy against the standard diagnostic strategy in a randomized trial permits a direct comparison of 2 competing strategies without selection bias. Our study used clinical outcome as a primary outcome measure, which is the ultimate test of a diagnostic intervention. We demonstrated no significant difference in follow-up VTE event rates among patients initially tested using our bedside strategy vs patients tested with standard. The 3-month VTE event rate in the BIOPED group was 2.4%, which was 0.6% lower than that in the group, with a 95% confidence interval that excluded our MCID of 3%. Some may argue that a 3% MCID is too high. However, if we assume that 15% of recurrences are fatal, this 3% difference in recurrence rates translates into a mortality difference of 0.45% at 3 months, 12 which is comparable to the 0.4% mortality risk that was associated with the use of pulmonary angiography to diagnose PE among 1400 subjects. 13 Furthermore, the MCID used in our study was also used in a recent large trial of the treatment of patients with VTE with low-molecular-weight heparin sodium. 12 The accuracy analysis demonstrated a negativepredictive value ( 95%) that was lower than expected with the combinations of the 3 bedside tests. Had we designed a prospective cohort study with initial and follow-up VTE as the clinical outcome measure, we may have been reluctant to conclude that the combinations of bedside tests were safe enough to exclude PE. This highlights the importance of conducting randomized controlled trials of competing diagnostic strategies to eliminate the risk of false conclusions caused by selection bias (eg, among patient populations with varying risks of VTE recurrence). The lower than expected negative-predictive value was likely a consequence of the high risk of recur- 186

7 rence in our study population (2.7% during 3 months among patients not taking anticoagulant agents). For example, our study population had higher proportions of hospitalized patients, patients with malignant neoplasms, and patients with PE compared with those in another recent investigation diagnostic management. 14 CONCLUSIONS A diagnostic management strategy using at least 2 negative 3 bedside tests (7-variable clinical model, D-dimer test, and AVDSf) to exclude PE before is as safe as using initial among patients with suspected PE. The addition of AVDSf to the other 2 bedside tests doubles the proportion of patients who can be safely excluded at the bedside and eliminates the need for diagnostic imaging in 34% of patients with suspected PE. Accepted for Publication: June 20, Correspondence: Marc A. Rodger, MD, MSc, Ottawa Hospital, General Campus, 1812-E Box 201, 501 Smyth Rd, Ottawa, Ontario, Canada K1H 8L6. Financial Disclosure: None. Funding/Support: This study was funded by grant 4508 from the Heart and Stroke Foundation of Canada, Ottawa. Dr Rodger is the recipient of a new investigator award from the Heart and Stroke Foundation of Ontario, Ottawa. Dr Wells is the recipient of a research chair from Canada Research Chairs, Ottawa. Dr Stiell is the recipient of a Distinguished Investigator award from the Canadian Institutes of Health Research, Ottawa. Role of the Sponsor: The Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. Acknowledgment: We are grateful to the many busy clinicians who completed data collection forms; to the staff of the Department for their cooperation; to Denise Blanchette, RRT, and the many respiratory therapists who participated and provided valuable input in the AVDSf analysis; to Jane Browing and Ted Tabor from Respironics Novametrix for valuable input and support with AVDSf measurement; to Bill Kerr, BA, and Greg Ralston, BA, for editorial support; to Julie Beck, BSc, for data collection, data entry, and data analysis; and to Michèle Willson for assistance in preparing the manuscript. REFERENCES 1. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Arch Intern Med. 1991;151: Silverstein MD, Heit JA, Mohr DN, Petterson TM, O Fallon WM, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158: Nordstrom M, Lindblad B. Autopsy-verified venous thromboembolism within a defined urban population: the city of Malmo, Sweden. APMIS. 1998;106: PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990;263: Wells PS, Anderson DR, Rodger MA, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med. 2001;135: Wells PS, Anderson DR, Rodger MA, et al. Derivation of a simple clinical model to categorize patients of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83: Chagnon I, Bounameaux H, Aujesky D, et al. Comparison of two clinical prediction rules and implicit assessment among patients with suspected pulmonary embolism. Am J Med. 2002;113: Rodger MA, Jones G, Rasuli P, et al. Steady-state end-tidal alveolar dead space fraction and D-dimer: bedside tests to exclude pulmonary embolism. Chest. 2001; 120: Kline JA, Israel EG, Michelson EA, O Neil BJ, Plewa MC, Portelli DC. Diagnostic accuracy of a bedside D-dimer assay and alveolar dead-space measurement for rapid exclusion of pulmonary embolism: a multicenter study. JAMA. 2001; 285: Wells PS, Ginsberg JS, Anderson DR, et al. Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med. 1998; 129: Kovacs MJ, MacKinnon KM, Anderson DR, et al. A comparison of three rapid D-dimer methods for the diagnosis of venous thromboembolism. Br J Haematol. 2001;115: Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337: Stein PD, Athanasoulis C, Alavi A, et al. Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation. 1992;85: Kruip MJ, Leclercq MG, van der Heul C, Prins MH, Buller HR. Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies: a systematic review. Ann Intern Med. 2003;138: