JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 74, NO.

6, 2019

ª 2019 PUBLISHED BY ELSEVIER ON BEHALF OF THE

AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

Prevalence of Pulmonary Embolism in

Patients With Syncope
Patrick Badertscher, MD,a,b,c,* Jeanne du Fay de Lavallaz, MD,a,b,* Angelika Hammerer-Lercher, MD,d
Thomas Nestelberger, MD,a,b Tobias Zimmermann, MD,a,b Marc Geiger, MD,a,b Orell Imahorn, MD,a,b
Òscar Miró, MD,b,e Emilio Salgado, MD,b,e Michael Christ, MD,f Louise Cullen, MD, PHD,b,g Martin Than, MD,b,h
F. Javier Martin-Sanchez, MD,b,i Salvatore Di Somma, MD, PHD,b,j W. Frank Peacock, MD,b,k Dagmar I. Keller, MD,l
Juan Pablo Costabel, MD,m Joan Walter, MD,a,b Jasper Boeddinghaus, MD,a,b Raphael Twerenbold, MD,a,b
Adriana Méndez, MD,d Boris Gospodinov, MD,d Christian Puelacher, MD,a,b,n Desiree Wussler, MD,a,b
Luca Koechlin, MD,a,b,o Damian Kawecki, MD,b,p Nicolas Geigy, MD,q Ivo Strebel, PHDC,a,b Jens Lohrmann, MD,a
Michael Kühne, MD,a Tobias Reichlin, MD,a,r Christian Mueller, MD,a,b for the BASEL IX Investigators

ABSTRACT

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 multi-
center 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) (J Am Coll Cardiol 2019;74:744–54) © 2019 Published by Elsevier on behalf of the
American College of Cardiology Foundation.

From the 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;
Listen to this manuscript’s
f
General Hospital, Paracelsus Medical University, Nürnberg, Germany; gRoyal Brisbane & Women’s Hospital, Herston, Queens-
audio summary by
land, Australia; hChristchurch Hospital, Christchurch, New Zealand; iServicio de Urgencias, Hospital Clínico San Carlos, Madrid,
Editor-in-Chief
Spain; jEmergency Medicine, Department of Medical-Surgery Sciences and Translational Medicine, University Sapienza Rome,
Dr. Valentin Fuster on
Sant’Andrea Hospital, Rome, Italy; kDepartment of Emergency Medicine, Baylor College of Medicine, Houston, Texas; lUniversity
JACC.org.
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; and
the rDepartment of Cardiology, Inselspital Bern, Bern, Switzerland. *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

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.06.020

JACC VOL. 74, NO. 6, 2019 Badertscher et al. 745
AUGUST 13, 2019:744–54 Pulmonary Embolism and Syncope

S yncope is a common cause for patient presen- Previous case reports described the Bezold- ABBREVIATIONS

tation to the emergency department (ED) Jarisch type reflex or dysrhythmias as po- AND ACRONYMS

(1,2). Establishing the etiology often is chal- tential mechanisms leading to syncope in
CI = confidence interval
lenging, albeit critical for the initiation of effective hemodynamically stable patients without
CTPA = computed tomographic
therapy (1,2). Among several other cardiovascular dis- acute right ventricular failure (14,15). How-
pulmonary angiography
orders, pulmonary embolism (PE) is a potential and ever, these seem rather rare cases, and
ECG = electrocardiogram
important cause of syncope, particularly because generally, a causal link between peripheral
ED = emergency department
highly effective treatment such as oral anticoagula- PE and syncope in hemodynamically stable
PE = pulmonary embolism
tion is available. The prevalence of PE in patients pre- patients remains questionable. These con-
V/Q = ventilation perfusion
senting with syncope is largely unknown (3–6). cerns challenge a recent Italian study sug-
Previous pilot studies had important methodological gesting that 1 of 6 patients presenting with syncope
limitations and provided highly conflicting estimates has underlying PE (6).
(3–6). Knowledge of the prevalence of PE in hemody- We therefore performed a large international
namically stable patients presenting with syncope is, diagnostic study evaluating the prevalence of PE us-
however, necessary to decide on the potential medi- ing central adjudication based on quantification of
cal benefit or harm of systematic PE screening in all the pre-test probability and D-dimers in all patients,
patients with syncope (3–5,7,8). CTPA and ventilation perfusion (V/Q) scan when
performed during clinical care, and long-term follow-
SEE PAGE 755
up regarding venous thromboembolism or cardio-
In addition to the conflicting data regarding the vascular death (possibly indicating PE) in all other
prevalence of PE, uncertainty remains regarding the patients.
clinical significance of often incidentally detected
small perfusion defects on computed tomographic METHODS
pulmonary angiography (CTPA) possibly indicating
PE (9–13). Exemplifying this, in a recent study, 42% of STUDY DESIGN, SETTING, AND SELECTION OF
patients with low probability for PE who underwent PARTICIPANTS. The BASEL IX study (BAsel Syncope
CTPA had false-positive results (12). Additional evi- EvaLuation Study) is an ongoing prospective inter-
dence of overdiagnosis of PE emerged from a large national diagnostic multicenter study enrolling
epidemiological study in the United States (13). unselected patients in 13 hospitals in 8 countries

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 Elek-
trophysiologie,” 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, Instru-
ment 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.

Manuscript received February 5, 2019; revised manuscript received May 19, 2019, accepted June 3, 2019.
746 Badertscher et al. JACC VOL. 74, NO. 6, 2019

Pulmonary Embolism and Syncope AUGUST 13, 2019:744–54

T A B L E 1 Baseline Characteristics of the Patients

PE at No PE at PE During No PE During
All Patients Presentation Presentation Follow-Up Follow-Up
(N ¼ 1,397) (n ¼ 19) (n ¼ 1,378) (n ¼ 8) (n ¼ 1,370) p Value* p Value†

Age, yrs 69 (56–80) 72 (62–82) 69 (56–80) 82 (78–84) 69 (56–80) 0.34 0.02

Female 582 (41.7) 8 (42.1) 574 (41.7) 6 (75.0) 568 (41.5) 1.00 0.12
Hospitalized 656 (47.0) 15 (78.9) 641 (46.5) 3 (37.5) 638 (46.6) 0.01 0.88
Vital parameters
Heart rate, beats/min 73 (64–84) 90 (82–92) 73 (64–84) 60 (58–60) 73 (64–84) <0.01 <0.01
Systolic BP, mm Hg 131 (116–147) 138 (125–144) 130 (116–147) 118 (111–130) 130 (116–147) 0.29 0.22
Diastolic BP, mm Hg 74 (63–83) 82 (71–88) 73 (63–82) 70 (56–75) 73 (63–82) 0.04 0.17
Breathing rate, breaths/min 16 (14–18) 19 (16–21) 16 (14–18) 16 (14–18) 16 (14–18) 0.04 0.98
Risk factors
Hypertension 805 (57.8) 10 (55.6) 795 (57.8) 3 (37.5) 792 (57.9) 1.00 0.42
Hypercholesterolemia 190 (13.7) 2 (10.5) 188 (13.7) 1 (12.5) 187 (13.7) 1.00 1.00
Diabetes 504 (37.4) 7 (38.9) 497 (37.4) 1 (14.3) 496 (37.5) 1.00 0.38
Current smoking 273 (19.8) 1 (5.3) 272 (20.0) 1 (12.5) 271 (20.1) 0.15 1.00
History of smoking 420 (30.5) 5 (26.3) 415 (30.6) 2 (25.0) 413 (30.6) 0.81 1.00
History
Coronary artery disease 249 (18.2) 3 (17.6) 246 (18.2) 2 (25.0) 244 (18.2) 1.00 0.64
Previous MI 155 (11.1) 2 (10.5) 153 (11.1) 2 (25.0) 151 (11.0) 1.00 0.22
Arrhythmia‡ 192 (14.0) 4 (22.2) 188 (13.9) 2 (25.0) 186 (13.8) 0.30 0.31
Valvular heart disease 110 (8.1) 1 (5.3) 109 (8.1) 1 (14.3) 108 (8.1) 1.00 0.45
Previous stroke 87 (6.3) 0 (0.0) 87 (6.4) 1 (12.5) 86 (6.4) 0.63 0.41
Epilepsy 49 (3.5) 1 (5.3) 48 (3.5) 0 (0.0) 48 (3.5) 0.50 1.00
First syncope 545 (40.0) 12 (63.2) 533 (39.7) 3 (37.5) 530 (39.7) 0.07 1.00
Wells score items
Clinical signs of DVT 8 (0.6) 5 (27.8) 3 (0.2) 0 (0.0) 3 (0.2) <0.01 1.00
Alternative diagnosis 126 (9.0) 19 (100.0) 107 (7.8) 0 (0.0) 107 (7.8) <0.01 0.87
Heart rate >100 beats/min 108 (7.7) 3 (15.8) 105 (7.6) 0 (0.0) 105 (7.7) 0.18 1.00
Immobilization 34 (2.5) 3 (16.7) 31 (2.3) 1 (12.5) 30 (2.2) 0.01 0.17
Previous VTE 79 (5.7) 3 (15.8) 76 (5.5) 2 (25.0) 74 (5.4) 0.09 0.07
Hemoptysis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) NA NA
Active cancer 69 (5.0) 1 (5.3) 68 (5.0) 2 (25.0) 66 (4.9) 1.00 0.06
Syncope situation
Orthostatic 165 (12.0) 1 (5.3) 164 (12.1) 0 (0.0) 164 (12.1) 0.72 0.61
While standing 650 (47.1) 15 (78.9) 635 (46.7) 3 (37.5) 632 (46.7) 0.01 0.87
Exertion 108 (7.9) 4 (21.1) 104 (7.7) 0 (0.0) 104 (7.7) 0.06 1.00
While sitting 519 (37.6) 3 (15.8) 516 (37.9) 5 (62.5) 511 (37.7) 0.06 0.16
While lying 44 (3.2) 0 (0.0) 44 (3.2) 0 (0.0) 44 (3.2) 1.00 1.00
Presence of injury 190 (14.1) 8 (42.1) 182 (13.7) 1 (12.5) 181 (13.7) <0.01 1.00
Clinical features
Chest pain 120 (8.6) 3 (15.8) 117 (8.5) 0 (0.0) 117 (8.5) 0.22 1.00
Dyspnea 281 (21.0) 11 (57.9) 270 (20.4) 1 (12.5) 269 (20.5) <0.01 0.91
RR >20 breaths/min 195 (20.3) 6 (50.0) 189 (20.0) 1 (16.7) 188 (20.0) 0.03 1.00
ECG changes
RBBB or incomplete RBBB 196 (14.0) 7 (36.8) 189 (13.7) 3 (37.5) 186 (13.6) 0.01 0.15
Ns ST-segment deviation 302 (22.2) 5 (26.3) 297 (22.2) 0 (0.0) 297 (22.3) 0.60 0.21
Continued on the next page

(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 ac-
cording to current European Society of Cardiology
guidelines (7,16).
JACC VOL. 74, NO. 6, 2019 Badertscher et al. 747
AUGUST 13, 2019:744–54 Pulmonary Embolism and Syncope

T A B L E 1 Continued

PE at No PE at PE During No PE During
All Patients Presentation Presentation Follow-Up Follow-Up
(N ¼ 1,397) (n ¼ 19) (n ¼ 1,378) (n ¼ 8) (n ¼ 1,370) p Value* p Value†

Long-term medication
ASA 444 (31.8) 5 (26.3) 439 (31.9) 5 (62.5) 434 (31.7) 0.81 0.12
b-blockers 363 (26.0) 5 (26.3) 358 (26.0) 3 (37.5) 355 (25.9) 1.00 0.44
Antiarrhythmic agents 23 (1.6) 0 (0.0) 23 (1.7) 0 (0.0) 23 (1.7) 1.00 1.00
ACE inhibitors/ARBs 588 (42.1) 9 (47.4) 579 (42.0) 4 (50.0) 575 (42.0) 0.81 0.92
Calcium antagonists 228 (16.3) 3 (15.8) 225 (16.3) 0 (0.0) 225 (16.4) 1.00 0.37
Diuretic agents 366 (26.2) 3 (15.8) 363 (26.3) 4 (50.0) 359 (26.2) 0.43 0.22
Nitroglycerin 65 (4.7) 1 (5.3) 64 (4.6) 1 (12.5) 63 (4.6) 0.60 0.32

Values are median (interquartile range) or n (%). *Direct comparison between patients with PE at presentation and no PE at presentation. †Direct comparison between patients
with PE during follow-up and no PE during follow-up. ‡Arrhythmia ¼ history of supraventricular or ventricular tachycardia.
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; ASA ¼ acetylsalicylic acid; BP ¼ blood pressure; DVT ¼ deep vein thrombosis;
ECG ¼ electrocardiogram; MI ¼ myocardial infarction; Ns ¼ nonspecific; PE ¼ pulmonary embolism; RBBB ¼ right bundle branch block; RR ¼ respiratory rate; VTE ¼ venous
thromboembolism.

For this analysis, we excluded patients receiving
ongoing anticoagulation therapy
the syncopal event and/or missing D-dimer mea-
surements. 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
publication.
ROUTINE CLINICAL ASSESSMENT. All patients un-
derwent a clinical assessment that included stan-
dardized and detailed assessment of pre-defined
details of medical history, including previous syn-
cope 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 clin-
ical routine (e.g., 24-h ECG, implantable loop de-
vice, 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 diag-
nostic 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 de-
irrespective of cisions were independent of the present study.
BIOCHEMICAL MEASUREMENTS. 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, Tar-
rytown, New York). This assay has a lower limit of
detection of 0.17 mg/l and an upper reference value of
manuscript for
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).
WELLS SCORE. 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 “un-
likely.” 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
748 Badertscher et al.
Pulmonary Embolism and Syncope
patients, CTPA and V/Q scan, when performed dur-
ing 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 anti-
coagulation (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 ev-
idence of venous thromboembolism or cardiovascu-
lar 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 certi-
fied radiologist.
FOLLOW-UP. 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 diag-
nosis 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. Cardiovas-
cular 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.
OUTCOME. 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 diag-
nostic yield of CTPA and V/Q for PE in patients
selected for these imaging techniques according to
current guidelines (7,8).
STATISTICAL ANALYSIS. Continuous variables are
presented as mean  SD when normally distributed,
JACC VOL. 74, NO. 6, 2019
AUGUST 13, 2019:744–54
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 contin-
uous 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 calcu-
lated for the entire group of patients and for relevant
subgroups according to the normal approximation of
the binomial distribution. Pre-defined subgroup ana-
lyses 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). As-
sumptions 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 statisti-
cally significant. Statistical analyses were performed
using IBM SPSS Statistics for Windows, version 22.0
(SPSS, Chicago, Illinois) and R version 3.3.1 (R Foun-
dation for Statistical Computing, Vienna, Austria).
RESULTS
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 syn-
cope 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 CARDIO-
VASCULAR 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
JACC VOL. 74, NO. 6, 2019 Badertscher et al. 749
AUGUST 13, 2019:744–54 Pulmonary Embolism and Syncope

F I G U R E 1 Systematic Work-Up for PE Among Patients Presenting With Syncope to the ED

Patients presenting with syncope to the ED

n = 1397 (100%)

Wells score and D-dimer testing

Low pre-test probability and High pre-test probability or

negative D-dimer assay positive D-dimer assay or both
n = 612 (44%) n = 785 (56%)

n = 88 (6.3%) CTPA or V/Q scan No Imaging

n = 107 (7.7%) n = 678 (49%)

Prevalence of PE at PE ruled out at presentation PE found at presentation Observe

presentation n = 701 (50%) n = 19 (1.4%) n = 678 (49%)

New PE or CV death New PE or CV death New PE or CV death

2-year clinical
during FU during FU during FU
follow-up
n = 0 (0%) n = 0 (0%) n = 12 (0.9%)

All patients were assessed for the presence of pulmonary embolism (PE) with the use of a validated approach that incorporates clinical pre-test probability for PE using
the Wells score and the results of D-dimer testing using age-adapted cutoffs. In patients who had a low (“unlikely”) clinical pre-test probability (Wells score #4) and a
negative D-dimer assay, PE at presentation was ruled out. Among the remaining patients, imaging (computed tomographic pulmonary angiography [CTPA] or venti-
lation perfusion [V/Q] scan) ruled out PE at presentation in 88 patients (6.3%) and documented PE in 19 patients (1.4%). Among the remaining patients, 2-year clinical
follow-up data did not provide evidence of PE in 666 patients (48%), and did provide evidence of PE (PE documented by imaging or cardiovascular (CV) death) in
12 patients (0.9%). ED ¼ emergency department; FU ¼ follow-up.

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 thrombo-
embolism 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 prob-
ability and a negative D-dimer test, in no patient (0%)
did evidence of venous thromboembolism or cardio-
vascular death become apparent during 2 years of
clinical follow-up.
MAIN FINDING. 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 to 4.
SUBGROUP OF PATIENTS HOSPITALIZED. A total of
656 patients (47%) were hospitalized. The hospitali-
zation 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 car-
diovascular 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 hospi-
talized patients (18%) had their first episode of syn-
cope. Overall, the prevalence of PE in patients
750 Badertscher et al. JACC VOL. 74, NO. 6, 2019

Pulmonary Embolism and Syncope AUGUST 13, 2019:744–54

T A B L E 2 Patients With PE Found at Presentation (n ¼ 19)

ECG
Age, Blood Pressure, Heart Rate, Chest ECG ST-Segment Wells D-Dimer, mg/l Localization Imaging First Episode Day PE
yrs Sex mm Hg beats/min Pain Dyspnea RBBB Deviation Score (Study Sample) of PE Technique Hospitalized of Syncope Found

68 M 84/53 92 n n n n 1.5 23.57 p CTPA y n 5

51 F 152/65 73 n y n y 6 0.48 p V/Q y y 1
56 M 130/85 104 n y n y 6 13.44 c CTPA n n 1
44 F 118/79 91 y y y n 0 8.6 c CTPA y n 1
72 M 142/86 87 n n y n 1.5 14.58 c CTPA y y 1
64 M 140/109 110 n n n y 1.5 18.88 c CTPA y y 1
84 F 138/70 91 n n n n 0 6.86 p CTPA y n 3
91 M 168/107 93 n n y n 1.5 13.31 p CTPA n y 1
86 F 179/104 85 n y n n 0 7.57 c CTPA y y 1
62 M 118/78 90 n n n y 0 1.19 p CTPA n n 1
60 F 138/79 84 n y y n 4.5 3.96 c CTPA n n 1
82 F 134/72 82 n y y n 3 10.88 c V/Q y y 1
81 M 140/94 80 n y y n 0 61 c CTPA y y 1
79 F 145/82 123 n y n y 0 10.07 c CTPA y y 1
63 M 150/85 82 n y n n 0 4.07 p CTPA y y 1
78 M 120/57 94 n y n n 0 50.8 c CTPA y y 1
72 M 139/88 110 n n y n 1 19.76 p CTPA y y 2
89 F 115/50 90 n y n n 1.5 58.2 p CTPA y n 1
67 M 137/89 82 n n n n 3 12.13 c CTPA y y 1

c ¼ central; CTPA ¼ computed tomographic pulmonary angiography; n ¼ no; p ¼ peripheral; y ¼ yes; V/Q ¼ ventilation/perfusion scan; other abbreviations as in Table 1.

hospitalized with first episode of syncope was 4.3% 15% to 46%) in those hospitalized for a first episode
(95% CI: 2.4% to 7.6%), and the incidence of new PEs of syncope.
and cardiovascular death during 2-year follow-up was CENTRAL VERSUS PERIPHERAL LOCATION OF PE.
0.8% (95% CI: 0.2% to 3.0%). Among the 19 patients diagnosed with PE at presen-
DIAGNOSTIC YIELD OF IMAGING FOR PE. The tation, PE was identified in a central location in
attending physician ordered CTPA or V/Q scan based 11 patients (58%). Among the 8 patients diagnosed
on his/her clinical judgment in 125 patients present- with PE during follow-up, PE was identified in a
ing with syncope to the ED, in 88 patients hospital- central location in 1 patient (13%).
ized and in 38 patients hospitalized for a first episode
of syncope. The diagnostic yield of imaging for PE in DISCUSSION
syncope patients was 14% in those investigated with
CTPA or V/Q scans (95% CI: 9% to 22%), 16% (95% CI: In this large, international, multicenter study pro-
9% to 25%) in hospitalized patients and 29% (95% CI: spectively enrolling patients in 3 regions, we

T A B L E 3 Patients With PE Found During Follow-Up (n ¼ 8)

ECG
Age, Blood Pressure, Heart Rate, Chest ECG ST-Segment Wells D-Dimer, mg/l Localization Imaging First Episode Day PE
yrs Sex mm Hg beats/min Pain Dyspnea RBBB Deviation Score (Study Sample) of PE Technique Hospitalized of Syncope Found

80 F 126/58 55 n n n n 0 1.54 p CTPA n y 1,274

87 F 105/43 65 n n n n 1.5 1.51 p CTPA n n 276
70 M 120/81 59 n n n n 2.5 2.34 p CTPA n n 122
83 F 113/51 58 n y y n 0 2.12 p CTPA y n 624
86 F 100/69 57 n n n n 1.5 2.46 p CTPA y n 691
64 M 115/72 60 n n y n 1 0.89 p CTPA n y 55
84 F 144/75 60 n n y n 0 2.15 p CTPA n n 152
81 F 174/75 60 n n n n 0 1.77 c CTPA y y 147

Abbreviations as in Tables 1 and 2.

JACC VOL. 74, NO. 6, 2019 Badertscher et al. 751
AUGUST 13, 2019:744–54 Pulmonary Embolism and Syncope

T A B L E 4 Patients With Cardiovascular Death During Follow-Up (n ¼ 4)

ECG
Age, Blood Pressure, Heart Rate, Chest ECG ST-Segment Wells D-Dimer, mg/l First Episode Day
yrs Sex mm Hg beats/min Pain Dyspnea RBBB Deviation Score (Study Sample) Hospitalized of Syncope of Death

46 M 133/74 84 n n y n 0 1.19 n n 1,076

43 M 102/56 66 n n n n 0 2.86 y y 333
73 M 134/58 59 n n n n 0 32.97 y n 548
68 F 103/48 89 n n n n 0 1.57 y n 489

Abbreviations as in Tables 1 and 2.

evaluated the prevalence of PE among patients pre-
senting with syncope to the ED using the recom-
mended 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 hos-
pitalized 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
(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 pa-
tients 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). Further-
more, a retrospective, cross-sectional study from
Canada reported a prevalence of venous thrombo-
embolism of 1.4% in hospitalized patients for syn-
cope (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 cen-
ters 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 extrap-
olated to either patients hospitalized with syncope
results in other institutions, nor to the overall ED popula-
tion 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 previ-
ously undiagnosed disease such as venous throm-
boembolism. 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 anti-
coagulation 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 interna-
tional study seems to at least partly overcome these
limitations and likely provides the most accurate
estimate for the true prevalence of PE among pa-
tients presenting with syncope (8).
It is important to highlight that our findings apply
to patients stable enough to provide written informed
752 Badertscher et al. JACC VOL. 74, NO. 6, 2019

Pulmonary Embolism and Syncope AUGUST 13, 2019:744–54

C E NT R AL IL L U STR AT IO N What Is the Prevalence of Pulmonary Embolism in Syncope?

Badertscher, P. et al. J Am Coll Cardiol. 2019;74(6):744–54.

We prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. Pre-test clinical
probability for pulmonary embolism (PE) was assessed using the 2-level Wells score and the results of D-dimer testing using age-adapted cutoffs. Presence of PE at
presentation was evaluated by imaging modalities, when ordered as part of the clinical assessment by the treating ED physician and incidence of PE by long-term
follow-up data (median duration of follow-up was 751 days [interquartile range: 722 to 873 days]).

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 echocardi-
ography and liberal use of CTPA in patients with
echocardiographic evidence of right ventricular dila-
tation (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 ac-
counting 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
JACC VOL. 74, NO. 6, 2019
AUGUST 13, 2019:744–54
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 presen-
tation in this study. Accordingly, some of the pe-
ripheral PEs documented in the Italian study may
have been the consequence of hospitalization rather
than its cause.
STUDY LIMITATIONS. 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 syn-
cope. 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 unre-
lated 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
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ACKNOWLEDGMENTS The authors thank the pa-
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KEY WORDS diagnostic testing, pulmonary
embolism, syncope
A PPE NDI X For an expanded Methods
section, additional BASEL IX Investigators and
contributors, as well as a supplemental figure
and tables, please see the online version of this
paper.