Author + information
- Received February 5, 2019
- Revision received May 19, 2019
- Accepted June 3, 2019
- Published online August 5, 2019.
- Patrick Badertscher, MDa,b,c,∗@BadertscherPat,
- Jeanne du Fay de Lavallaz, MDa,b,∗@JDFDLz,
- Angelika Hammerer-Lercher, MDd,
- Thomas Nestelberger, MDa,b,
- Tobias Zimmermann, MDa,b,
- Marc Geiger, MDa,b,
- Orell Imahorn, MDa,b,
- Òscar Miró, MDb,e,
- Emilio Salgado, MDb,e,
- Michael Christ, MDf,
- Louise Cullen, MD, PhDb,g,
- Martin Than, MDb,h,
- F. Javier Martin-Sanchez, MDb,i,
- Salvatore Di Somma, MD, PhDb,j,
- W. Frank Peacock, MDb,k,
- Dagmar I. Keller, MDl,
- Juan Pablo Costabel, MDm,
- Joan Walter, MDa,b,
- Jasper Boeddinghaus, MDa,b,
- Raphael Twerenbold, MDa,b,
- Adriana Méndez, MDd,
- Boris Gospodinov, MDd,
- Christian Puelacher, MDa,b,n,
- Desiree Wussler, MDa,b,
- Luca Koechlin, MDa,b,o,
- Damian Kawecki, MDb,p,
- Nicolas Geigy, MDq,
- Ivo Strebel, PhDca,b,
- Jens Lohrmann, MDa,
- Michael Kühne, MDa,
- Tobias Reichlin, MDa,r,
- Christian Mueller, MDa,b,∗ (, )@CRIBasel,
- for the BASEL IX Investigators
- aCardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland
- bGREAT network, Rome, Italy
- cDepartment of Cardiology, University of Illinois at Chicago, Chicago, Illinois
- dDepartment of Laboratory Medicine, Kantonsspital Aarau, Switzerland
- eHospital Clinic, Barcelona, Catalonia, Spain
- fGeneral Hospital, Paracelsus Medical University, Nürnberg, Germany
- gRoyal Brisbane & Women's Hospital, Herston, Queensland, Australia
- hChristchurch Hospital, Christchurch, New Zealand
- iServicio de Urgencias, Hospital Clínico San Carlos, Madrid, Spain
- jEmergency Medicine, Department of Medical-Surgery Sciences and Translational Medicine, University Sapienza Rome, Sant’Andrea Hospital, Rome, Italy
- kDepartment of Emergency Medicine, Baylor College of Medicine, Houston, Texas
- lUniversity Hospital Zürich, Zürich, Switzerland
- mInstituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina
- nDepartment of Internal Medicine, University Hospital Basel, University of Basel, Basel, Switzerland
- oDepartment of Cardiac Surgery, University Hospital Basel, University of Basel, Basel, Switzerland
- p2nd Department of Cardiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
- qEmergency Department, Kantonsspital Liestal, Liestal, Switzerland
- rDepartment of Cardiology, Inselspital Bern, Bern, Switzerland
- ↵∗Address for correspondence:
Prof. Christian Müller, CRIB and Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
Background The prevalence of pulmonary embolism (PE) in patients presenting with syncope to the emergency department (ED) is largely unknown. This information, however, is necessary to balance the potential medical benefit or harm of systematic PE screening in patients presenting with syncope to the ED.
Objectives This study sought to determine the prevalence of PE in patients with syncope.
Methods Unselected patients presenting with syncope to the ED were prospectively enrolled in a diagnostic multicenter study. Pre-test clinical probability for PE was assessed using the 2-level Wells score and the results of D-dimer testing using age-adapted cutoffs. Presence of PE was evaluated by imaging modalities, when ordered as part of the clinical assessment by the treating ED physician or by long-term follow-up data.
Results Long-term follow-up was complete in 1,380 patients (99%) at 360 days and 1,156 patients (83%) at 720 days. Among 1,397 patients presenting with syncope to the ED, PE was detected at presentation in 19 patients (1.4%; 95% confidence interval [CI]: 0.87% to 2.11%). The incidence of new PEs or cardiovascular death during 2-year follow-up was 0.9% (95% CI: 0.5% to 1.5%). In the subgroup of patients hospitalized (47%), PE was detected at presentation in 15 patients (2.3%; 95% CI: 1.4% to 3.7%). The incidence of new PEs or cardiovascular death during 2-year follow-up was 0.9% (95% CI: 0.4% to 2.0%).
Conclusions PE seems to be a rather uncommon cause of syncope among patients presenting to the ED. Therefore, systematic PE-screening in all patients with syncope does not seem warranted. (BAsel Syncope EvaLuation Study [BASEL IX]; NCT01548352)
Syncope is a common cause for patient presentation to the emergency department (ED) (1,2). Establishing the etiology often is challenging, albeit critical for the initiation of effective therapy (1,2). Among several other cardiovascular disorders, pulmonary embolism (PE) is a potential and important cause of syncope, particularly because highly effective treatment such as oral anticoagulation is available. The prevalence of PE in patients presenting with syncope is largely unknown (3–6). Previous pilot studies had important methodological limitations and provided highly conflicting estimates (3–6). Knowledge of the prevalence of PE in hemodynamically stable patients presenting with syncope is, however, necessary to decide on the potential medical benefit or harm of systematic PE screening in all patients with syncope (3–5,7,8).
In addition to the conflicting data regarding the prevalence of PE, uncertainty remains regarding the clinical significance of often incidentally detected small perfusion defects on computed tomographic pulmonary angiography (CTPA) possibly indicating PE (9–13). Exemplifying this, in a recent study, 42% of patients with low probability for PE who underwent CTPA had false-positive results (12). Additional evidence of overdiagnosis of PE emerged from a large epidemiological study in the United States (13). Previous case reports described the Bezold-Jarisch type reflex or dysrhythmias as potential mechanisms leading to syncope in hemodynamically stable patients without acute right ventricular failure (14,15). However, these seem rather rare cases, and generally, a causal link between peripheral PE and syncope in hemodynamically stable patients remains questionable. These concerns challenge a recent Italian study suggesting that 1 of 6 patients presenting with syncope has underlying PE (6).
We therefore performed a large international diagnostic study evaluating the prevalence of PE using central adjudication based on quantification of the pre-test probability and D-dimers in all patients, CTPA and ventilation perfusion (V/Q) scan when performed during clinical care, and long-term follow-up regarding venous thromboembolism or cardiovascular death (possibly indicating PE) in all other patients.
Study design, setting, and selection of participants
The BASEL IX study (BAsel Syncope EvaLuation Study) is an ongoing prospective international diagnostic multicenter study enrolling unselected patients in 13 hospitals in 8 countries (Switzerland, Spain, Germany, Italy, Poland, New Zealand, Australia, and the United States of America) in 3 regions (Europe, Oceania, and North America). The study is designed to contribute to improving the management of patients presenting with syncope to the ED. Patients able and willing to provide written informed consent, and more than 40 years of age, presenting with syncope to the ED within 12 h after the syncopal event were recruited. Syncope was defined identically for all participating centers according to current European Society of Cardiology guidelines (7,16).
For this analysis, we excluded patients receiving ongoing anticoagulation therapy irrespective of the syncopal event and/or missing D-dimer measurements. The study was carried out according to the principles of the Declaration of Helsinki pre-registered (NCT01548352) and was approved by the local ethics committees. The authors designed the study, gathered and analyzed the data according to the STROBE guidelines (17) for observational studies (see the Online Appendix for details), vouched for the data and analysis, wrote the paper, and made the decision to submit the manuscript for publication.
Routine clinical assessment
All patients underwent a clinical assessment that included standardized and detailed assessment of pre-defined details of medical history, including previous syncope events and circumstances of current syncope, vital signs, physical examination, routine laboratory tests, radiological investigations, and a 12-lead electrocardiogram (ECG). Additional investigation results were collected if performed as part of clinical routine (e.g., 24-h ECG, implantable loop device, tilt table testing, echocardiography) including imaging for PE with CTPA or V/Q scan during the initial work-up or during recurrent hospitalization or outpatient treatment. Participating centers used standardized operating procedures for the diagnostic workup of patients presenting with syncope to the ED according to current guidelines (7,16). These standardized operating procedures did not mandate testing for PE in all patients with syncope to the ED, but testing when additional symptoms such as dyspnea increased the likelihood for PE. The attending physician ordered CTPA or V/Q scans based on his/her clinical judgment. All clinical decisions were independent of the present study.
Immediately after informed consent was obtained, venous blood was collected in plastic EDTA (ethylenediaminetetraacetic acid) tubes, centrifuged, and then stored at −80°C. Measurement of D-dimers was performed in a blinded fashion in a dedicated core laboratory using the Innovance D-dimer assay (Siemens Healthcare, Tarrytown, New York). This assay has a lower limit of detection of 0.17 mg/l and an upper reference value of 35.2 mg/l (18). As recommended, age-adapted cutoffs were used (19–21). In patients 50 years of age or younger, a D-dimer result <0.5 mg/l was considered negative. For patients older than 50 years of age, we used the formula: age in years divided by 100 (7).
The clinical pre-test probability of PE was defined according to the 2-level Wells score (22,23), which classifies PE as being “likely” or “unlikely.” The Wells score was calculated according to the original definition (22,23) with the use of our extensive study dataset for each patient individually. A total Wells score ≤4 was considered as a low clinical pre-test probability (“unlikely”) for PE. A total Wells score >4 was considered as a high clinical pre-test probability (“likely”) for PE. All included variables in the 2-level Wells score (22,23) are depicted in detail in the Online Appendix.
Assessment of PE
The presence or absence of PE was centrally adjudicated as suggested in current clinical practice guidelines (7) on the basis of sequential testing including quantification of pre-test probability using the 2-level Wells score (22,23) and D-dimers using age-adjusted cutoffs in all patients, CTPA and V/Q scan, when performed during clinical care, and long-term follow-up regarding venous thromboembolism and cardiovascular death (possibly indicating PE) in all other patients. This concept is based on the well-documented high recurrence rate of PE in patients not receiving anticoagulation (8). Patients were determined to not have an index PE if the initial clinical work-up (CTPA and V/Q scan when clinically indicated), the initial study-specific work-up (Wells score and D-dimers in all patients), and 2-year follow-up did not show evidence of venous thromboembolism or cardiovascular death (possibly indicating PE). The imaging criteria for PE were an intraluminal filling defect on CTPA or a perfusion defect of at least 75% of a segment with corresponding normal ventilation (9–13). When PE was diagnosed, a central location was adjudicated using CTPA when the location of the embolus was visualized in the main trunk of the pulmonary artery and/or in the right or left main pulmonary arteries, and using V/Q scan when the perfusion defect was larger than 25% of the total lung area (24). Each scan was read by a certified radiologist.
Patients were contacted 12 and 24 months after discharge by telephone or in written form to determine the prevalence of PE during follow-up. In addition, dedicated research doctors and nurses from all 13 recruiting sites gathered an extensive study dataset including patient’s hospital notes on rehospitalizations or outpatient treatments during follow-up, the family physician’s records, and national death registries. We documented the diagnosis of PE during follow-up based on a positive result of CTPA or V/Q scan. The same imaging criteria for the detection of PE as described earlier in the text were applied during follow-up. Cardiovascular death was adjudicated in all patients with death within 30 days of acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to PE, death within 7 days following a cardiac procedure, and in all patients without autopsy.
The primary study outcome was the prevalence of PE at presentation and the incidence of new PEs and cardiovascular death during 2-year follow-up. Secondary outcomes included the diagnostic yield of CTPA and V/Q for PE in patients selected for these imaging techniques according to current guidelines (7,8).
Continuous variables are presented as mean ± SD when normally distributed, and median with 25th and 75th percentiles when non-normally distributed. Categorical variables are expressed as numbers and percentages. The Mann-Whitney U test was applied for comparison of continuous variables, and categorical variables were compared by Pearson chi-square test and Fisher exact test, as appropriate. The prevalence of PE and the associated 95% confidence interval (CI) were calculated for the entire group of patients and for relevant subgroups according to the normal approximation of the binomial distribution. Pre-defined subgroup analyses included patients hospitalized and patients hospitalized for their first syncope, because a previous study exclusively reported on the prevalence of PE in the latter subgroup (6). Targeted overall sample size was 1,840 patients to ensure a similar number of hospitalized patients as in the Italian study (6). Assumptions included a hospitalization rate of 35%, and 85% of eligible patients (21). All hypothesis testing was 2-tailed, and p values <0.05 were considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (SPSS, Chicago, Illinois) and R version 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria).
Characteristics of study subjects
From May 2010 until February 2017, 1,895 consecutive patients were enrolled in the BASEL IX study, of which 1,397 patients were eligible for this analysis (Online Figure 1). Median age was 69 years, and 42% were women (Table 1). A complete follow-up at 12 months was available in 1,380 patients (99%) and at 24 months in 1,156 patients (83%). Median duration of follow-up was 751 days (interquartile range: 722 to 873 days).
Diagnosis: Prevalence of PE at presentation among patients presenting with syncope to the ED
Among 1,397 patients presenting with syncope to the ED, PE at presentation was ruled out by the combination of low clinical pre-test probability for PE (Wells score ≤4) and a negative D-dimer test in 612 patients (44%). Among the remaining patients, PE at presentation was ruled out by CTPA or V/Q scan in 88 patients (6.3%) and ruled in, in 19 patients (1.4%).
Prognosis: Occurrence of PE and cardiovascular death during 2 years of clinical follow-up
Among the 678 remaining patients (49%) without CTPA or V/Q scan performed during the initial work-up, evidence of venous thromboembolism became apparent during 2 years of clinical follow-up in 8 patients (0.6%). Four patients (0.3%) had cardiovascular death during the 2 years of clinical follow-up. No evidence of venous thromboembolism or cardiovascular death became apparent despite the absence of anticoagulation in 666 patients (48%). Among the 612 patients in whom PE was ruled out by the combination of low clinical pre-test probability and a negative D-dimer test, in no patient (0%) did evidence of venous thromboembolism or cardiovascular death become apparent during 2 years of clinical follow-up.
The prevalence of PE at presentation to the ED was 1.4% (95% CI: 0.87% to 2.11%) and the incidence of new PEs and cardiovascular death during 2-year follow-up was 0.9% (95% CI: 0.5% to 1.5%) (Figure 1). A detailed overview of these patients is provided in Tables 2, 3, and 4.
Subgroup of patients hospitalized
A total of 656 patients (47%) were hospitalized. The hospitalization rate among the 13 centers in 3 regions was highly variable: 28% to 87%. Presenting symptoms and final diagnosis of these patients are presented in Online Tables 1 and 2. Overall, the prevalence of PE in patients hospitalized for syncope was 2.3% (95% CI: 1.4% to 3.7%) and the incidence of new PEs and cardiovascular death during 2-year follow-up was 0.9% (95% CI: 0.4% to 2.0%).
Subgroup of hospitalized patients with first episode of syncope
A total of 254 hospitalized patients (18%) had their first episode of syncope. Overall, the prevalence of PE in patients hospitalized with first episode of syncope was 4.3% (95% CI: 2.4% to 7.6%), and the incidence of new PEs and cardiovascular death during 2-year follow-up was 0.8% (95% CI: 0.2% to 3.0%).
Diagnostic yield of imaging for PE
The attending physician ordered CTPA or V/Q scan based on his/her clinical judgment in 125 patients presenting with syncope to the ED, in 88 patients hospitalized and in 38 patients hospitalized for a first episode of syncope. The diagnostic yield of imaging for PE in syncope patients was 14% in those investigated with CTPA or V/Q scans (95% CI: 9% to 22%), 16% (95% CI: 9% to 25%) in hospitalized patients and 29% (95% CI: 15% to 46%) in those hospitalized for a first episode of syncope.
Central versus peripheral location of PE
Among the 19 patients diagnosed with PE at presentation, PE was identified in a central location in 11 patients (58%). Among the 8 patients diagnosed with PE during follow-up, PE was identified in a central location in 1 patient (13%).
In this large, international, multicenter study prospectively enrolling patients in 3 regions, we evaluated the prevalence of PE among patients presenting with syncope to the ED using the recommended combination and integration of clinical, laboratory, and imaging data within a systematic workup for PE (7).
We report 4 major findings (Central Illustration). First, among unselected ED patients presenting with syncope, the prevalence was 1.4%. Second, among patients hospitalized for syncope and patients hospitalized for a first syncope, the prevalence slightly increased to 2.3% and 4.3%, respectively. Therefore, the prevalence of PE observed in this study was substantially lower than recently suggested in an Italian pilot study of 560 patients hospitalized for a first syncope (17.3%) that largely relied on imaging data with the inherent and well-documented risk of overestimation due to false-positive results (6,12,13). This discrepancy in estimated prevalence has important clinical consequences. Although the high prevalence of PE reported in the Italian pilot study (6) suggested that systematic screening for PE might be warranted in all patients presenting with syncope, our findings extend and corroborate other recent pilot studies and suggest that PE work-up should be tailored to patients in whom additional signs and symptoms such as dyspnea (40% of patients in this study), signs on physical examination such as clinical signs of deep vein thrombosis (17% of patients in this study), or signs in the 12-lead ECG at presentation such as right bundle branch block (36% of patients in this study) suggesting the presence of PE as the underlying cause (5,25–29). A retrospective analysis based on several international administrative databases found a prevalence of PE of <1% of all patients with syncope (25). Furthermore, a retrospective, cross-sectional study from Canada reported a prevalence of venous thromboembolism of 1.4% in hospitalized patients for syncope (26). Similarly, a retrospective, secondary analysis of prospectively gathered data from a single-center study in the United States found a PE prevalence of all patients presenting to the ED with syncope of 1.4% (5). Notably, in this study, the vast majority of patients with PE (>80%) were diagnosed using the tailored approach already during the initial work-up in the ED. Third, the yield of tailored diagnostic imaging for PE as applied in this pragmatic study in patients presenting with syncope to the ED was low (16%), and again much lower as compared with that reported for the systematic use of imaging for PE in the Italian study (41%) (6). Fourth, the hospitalization rate among the 13 centers in 3 regions was highly variable and ranged from 28% to 87%. This raises concern that due to uncontrolled selection bias, findings from patients hospitalized for syncope cannot be reliably extrapolated to either patients hospitalized with syncope in other institutions, nor to the overall ED population of patients with syncope (6).
These findings not only extend and corroborate previous work on the prevalence of PE in patients with syncope (3–6,15,25,26,30), but also put the pros and cons of functional versus anatomic testing into perspective. Incidental findings on anatomic testing can be seen as an opportunity for possibly life-saving therapy such as anticoagulation for a previously undiagnosed disease such as venous thromboembolism. Incidental findings on anatomic testing, however, also often lead to patient anxiety, further diagnostic procedures that are at times risky and costly, and the dilemma of initiation of anticoagulation in patients in whom the risk–benefit ratio of anticoagulation has not been appropriately defined in large randomized controlled trials (8,31–35). The combined functional and anatomic diagnostic work-up applied in this large international study seems to at least partly overcome these limitations and likely provides the most accurate estimate for the true prevalence of PE among patients presenting with syncope (8).
It is important to highlight that our findings apply to patients stable enough to provide written informed consent, because this was mandatory for inclusion in this study. We cannot comment on the prevalence of PE in the less common patients with syncope who are in unstable hemodynamic or respiratory conditions at the time of ED presentation. The diagnostic work-up in these unstable patients differs substantially from that in stable patients and includes rapid echocardiography and liberal use of CTPA in patients with echocardiographic evidence of right ventricular dilatation (1,2). Of note, written informed consent was also required in the Italian pilot study (6).
This study has important methodological strengths that differentiate it from previous studies on the prevalence of PE in syncope patients: prospective design, global representation of patients, and long-term follow-up. Although not all patients underwent a systematic workup for PE with imaging modalities, we were able to determine whether PE was diagnosed in the subsequent time period in 99% and 83% of patients at 360 and 720 days, respectively, after their ED visit. We would expect clinically relevant PE accounting for syncope to manifest itself during the 720-day follow-up period. Given this low number of PEs during long-term follow-up—only 12 patients were diagnosed with a PE during follow up, the first occurring 55 days after the index event—it is fair to assume that the diagnosis of PE was infrequently missed despite the fact that the majority of patients did not undergo a systematic imaging workup. In addition, it is well known that injury increases D-dimer levels independent of thromboembolism (36,37). Because syncope is often associated with falls, it is likely that in patients with fractures and extensive bruising, D-dimer levels will be elevated due to the clotting process. This might explain the low prevalence of thromboembolism in patients with elevated D-dimer levels at presentation.
Differences among baseline characteristics and methodological details may have contributed to the discrepant findings of this study and the Italian study (7). First, the median age was significantly higher in the Italian study (80 years) as compared with this one (69 years). Second, the Italian study allowed up to 48 h after hospital admission to enrollment, whereas patients were enrolled within 12 h after ED presentation in this study. Accordingly, some of the peripheral PEs documented in the Italian study may have been the consequence of hospitalization rather than its cause.
First, we recruited patients presenting to the ED. Therefore, it is unknown whether our findings can be extrapolated to patients presenting to primary care. Second, we cannot comment on patients who present later than 12 h after symptom onset because these patients were excluded from our study. Third, this study used long-term follow-up regarding venous thromboembolism and cardiovascular death possibly related to PE during long-term follow-up (median 751 days) in patients not receiving anticoagulation as 1 component in the estimation of the prevalence of PE underlying syncope. This may have led to an overestimation of the true prevalence, because most of the clinically apparent PEs occurred several months after the index presentation and may have been completely unrelated to it. This methodological component, however, also may have led to an underestimation of the true prevalence of PE, because even during long-term follow-up, a small proportion of PEs may not lead to clinically apparent recurrence despite the absence of anticoagulation (8). Fourth, some of the patients on long-term anticoagulants and therefore excluded from the primary analysis may not have taken their medications before presentation. However, when assessing the 234 patients on long-term anticoagulant treatment excluded from the primary analysis in a sensitivity analysis, only 1 patient (0.4%; 95% CI: 0.1% to 2.4%) was diagnosed with a PE at presentation, and in no patient (0%) did evidence of venous thromboembolism or cardiovascular death become apparent during 2-year follow-up.
Our findings do not support a high rate of PE among ED patients presenting with syncope and thus do not suggest the need for a systematic screening for PE in all patients presenting with syncope to the ED.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: PE is an uncommon cause of syncope, and routine testing for PE is generally not productive in the evaluation of patients with syncope in the emergency department.
TRANSLATIONAL OUTLOOK: Additional research should be directed to characterizing the occasional clinical situations in which syncope is a more frequent manifestation of PE.
The authors thank the patients who participated in the study, the staff of the participating emergency departments, the research coordinators, and the laboratory technicians, particularly Michael Freese, Claudia Stelzig, Kathrin Meissner, Esther Garrido, MD, Irina Klimmeck, RN, Janine Voegele, Fausta Chiaverio, RN, María Suárez Cadenas, and Miguel Angel García Brinón for their most valuable efforts. In addition, the authors wish to thank Melanie Wieland, RN, Isabel Campodarve, MD, Joachim Gea, MD, Helena Mañé Cruz, Sofìa Calderon, and Miguel Angel García Briñón. Additional BASEL IX Investigators and contributors to this paper can be found in the Online Appendix.
↵∗ Drs. Badertscher and du Fay de Lavallaz contributed equally to this work.
This work was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel (Switzerland), the University of Basel (Switzerland), Abbott, BRAHMS, Singulex, the University Hospital Basel (Switzerland), and the Emergency Medicine Foundation (Australia). Dr. Badertscher has received research funding from the “University of Basel,” the “Stiftung für Herzschrittmacher und Elektrophysiologie,” and the “Freiwillige Akademische Gesellschaft Basel.” Dr. Nestelberger has received speaker/consulting honoraria from Beckman-Coulter. Dr. Cullen has received grants and personal fees from Abbott Diagnostics and Siemens (outside of the submitted work); and has received personal fees from Beckman Coulter. Dr. Than has received grants and personal fees from Abbott, Alere, and Roche (outside of the submitted work); and has received grants from Beckman. Dr. Martin-Sanchez has received speaker, advisory, or consulting fees from Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Pfizer, The Medicines Company, Otsuka, Thermo Fisher, Cardiorentis, and Sanofi; and has received research grants from the Spanish Ministry of Health and FEDER, Mapfre, Novartis, Bayer, Merck Sharp & Dohme, Abbott, and Orion-Pharma. Dr. Peacock has received research grants from Abbott, Braincheck, Immunarray, Janssen, Roche, and ZS Pharma; has served as a consultant for Abbott, AstraZeneca, Bayer, Beckman, Boehrhinger Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Ortho Clinical Diagnostics, Relypsa, Roche, and Siemens; has provided expert testimony for Johnson and Johnson; and has ownership interests in Comprehensive Research Associates LLC, and Emergencies in Medicine LLC, Ischemia DX, LLC. Dr. Boeddinghaus has received support from the University Hospital Basel (Division of Internal Medicine), the Swiss Academy of Medical Sciences and Julia und Gottfried Bangerter-Rhyner-Stiftung; and has received speaker/consulting honoraria from Siemens. Dr. Twerenbold has received grants from the Swiss National Science Foundation (Grant No P300PB_167803), the University Hospital Basel, the University of Basel and the Cardiovascular Research Foundation Basel; and has received consulting/speaker honoraria from Roche Diagnostics, Abbott Diagnostics, Siemens, Singulex, and Brahms, outside of the submitted work. Dr. Puelacher has received a research grant from Roche Diagnostics (outside of the submitted study). Prof. Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the European Union, the KTI, the Cardiovascular Research Foundation Basel, Abbott, AstraZeneca, Biomerieux, Beckman Coulter, BRAHMS, Critical Diagnostics, Indorsia, Radiometer, Roche, Siemens, and Singulex; and has received speaker/consulting honoraria or travel support from Abbott, Amgen, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, BRAHMS, Cardiorentis, Daiichi-Sankyo, Indorsia, Novartis, Roche, Sanofi, Siemens, and Singulex. Dr. Kühne has received personal fees from Bayer, Daiichi-Sankyo, Pfizer-Bristol-Myers Squibb, and Boehringer Ingelheim, outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Abbreviations and Acronyms
- confidence interval
- computed tomographic pulmonary angiography
- emergency department
- pulmonary embolism
- ventilation perfusion
- Received February 5, 2019.
- Revision received May 19, 2019.
- Accepted June 3, 2019.
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