Prevalence of Pulmonary Embolism (PE) Among Patients Referred to Emergency Departments for Dyspnea on Exertion
Conditions: Pulmonary Embolism
Sponsor: Arianna Anticoagulazione Foundation

 
 
Fondazione Arianna Anticoagulazione 
Via Paolo Fabbri 1/3 • 40138 Bologna • Tel 051 341471 • Fax 051 343604 • Email  segreteria@fondazionearianna.org 
 
 
 
OBSERVATIONAL STUDY PROTOCOL PEDIS 
 
Title of the study: 
Prevalence of pulmonary embolism (PE) among patients referred to 
Emergency Departments for dyspnea on exertion 
Code of the study:            PEDIS 
Version of Protocol:  
Final Version 1.2  
Date:   
 
 
16.10.2019 
Promoter: 
 
 
Fondazione Arianna Anticoagulazione 
Via Paolo Fabbri 1/3  
40138 Bologna (BO) 
Italy 
Tel +39051341471 
Fax +39051343604 
e-mail segreteria@fondazionearianna.org 
Coordinator Site: 
Unità Operativa Complessa Medicina Generale “M. Valentini” Azienda 
Ospedaliera di Cosenza.  
Principal Investigator:  
Dott.  Carlo Bova 
Unità Operativa Complessa Medicina Generale “M. Valentini” Azienda 
Ospedaliera di Cosenza.  
Tel. e Fax 0984681401 
e-mail: c.bova@aocs.it 
 
 
 
 
 
 
 
 
 
 

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INDEX 
 
 
Background Information and Rationale ................................................................................................ 4 
General Aims and Study Objectives ..................................................................................................... 4 
Objectives ....................................................................................................................................... 4 
Investigational Plan .............................................................................................................................. 4 
Study design ................................................................................................................................... 4 
Setting ............................................................................................................................................. 5 
Timeline .......................................................................................................................................... 5 
Study population ............................................................................................................................ 5 
Inclusion Criteria ........................................................................................................................... 5 
Exclusion Criteria .......................................................................................................................... 5 
Study Procedures ................................................................................................................................. 5 
Enrolment Procedures ................................................................................................................... 5 
Definition of the conclusion of the study ....................................................................................... 6 
Outcome of the study ........................................................................................................................... 6 
Primary endpoint ........................................................................................................................... 6 
Secondary endpoints ...................................................................................................................... 6 
Statistical consideration........................................................................................................................ 6 
Bias ................................................................................................................................................. 6 
Sample size ..................................................................................................................................... 6 
Statistical analysis plan .................................................................................................................. 6 
Study administration ............................................................................................................................ 7 
Data collection and management ................................................................................................... 7 
Ethics .............................................................................................................................................. 7 
Informed Consent Form ................................................................................................................ 7 
Procedures implemented to guarantee data confidentiality ......................................................... 7 
Administrative Issues ........................................................................................................................... 8 
Support of the study ....................................................................................................................... 8 
Publication ...................................................................................................................................... 8 
Data handling and record keeping ................................................................................................ 8 
Final report and publication .......................................................................................................... 8 
References ........................................................................................................................................... 9 
 
 
 
 

 
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List of abbreviation and acronyms 
 
CI 
Confiedence interval 
CT scan 
computed tomography scan 
EC 
Ethics Commitee 
e-CRF 
Electronic Case Report Form 
IRB 
Istitutional Review Board 
PE 
Pulmonary Embolism 
PIOPED 
Prospective Investigation of Pulmonary Embolism Diagnosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Background Information and Rationale  
Pulmonary embolism (PE) is an insidious disease, frequently not recognized or mistaken for other 
pathologies, and is accompanied by a high mortality rate if not properly identified and treated (1). The 
onset modalities that often lead to erroneous diagnostic conclusions include angina-type chest pain, 
right or congestive heart failure, the exacerbation of chronic obstructive pulmonary disease, 
pneumonic pulmonary thickening, pleuritic pleural effusion and syncope (2). Recently it has been 
shown that the application of an adequate diagnostic algorithm can allow the recognition of PE in over 
17% of patients hospitalized for a syncopal episode (3). In the PIOPED II study, 16% of patients with 
documented PE had come to the observation for exertional dyspnea, that is, a shortness of breath for 
physical activities that usually do not determine it (4). The most common cause is congestive heart 
failure. Other conditions that can cause it are chronic obstructive pulmonary disease, lung disease (e.g. 
pneumonia), aortic stenosis, severe anemia, hyperthyroidism, lung cancer, liver and kidney disease and 
psychopathological disorders. Although PE has been identified among the conditions that can cause 
exertional dyspnea (4), it is rarely suspected and its prevalence in subjects who reach the Emergency 
Departments for this condition is unknown. 
 
The international guidelines for the diagnostic approach to patients with suspected EP recommend the 
use of a clinical probability score in combination with the result of a laboratory test, the D-Dimer (2). 
The most commonly used stratification model is the one described by Wells and associates, which 
scores a number of partly anamnestic and partly clinical parameters, and allows to identify as having a 
high pre-test clinical probability those subjects who score at least 4 (5). Based on the results of several 
clinical studies, patients with both a low clinical probability and negative D-Dimer can be regarded as 
not having PE (2). Accordingly, these patients do not require further diagnostic tests. In order to 
reduce the risk of false positivity D-Dimer tests (test of high sensitivity to thromboembolism, but of 
poor specificity), an algorithm that takes into account the patient's age has been successfully tested in 
subsequent studies of wide international impact. More specifically, it has been shown that with the 
adoption of sensitive D-dimer tests (cutoff 500 ng/ml) it is safe to withhold pulmonary CT 
angiography from patients older than 50 years whose laboratory test does not exceed a value that is 
achieved my multiplying their age by 10 (6). 
 
General Aims and Study Objectives 
This observational, cross-sectional, multicenter Italian study aims at investigating the prevalence of PE 
in a consecutive series of patients who refer to the Emergency Departments (either spontaneously or 
sent by their attending physicians) for the recent (less than one months) development of exertional 
dyspnea.  
 
Objectives 
To assess the prevalence of PE (and its 95% CI) in the overall population as well as in relevant 
subgroups (patients who will be imaged, patients without potential explanations for dyspnea). 
 
Investigational Plan   
Study design 
The PEDIS study is an observational study, national multicenter and no Profit. 

 
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Setting 
Emergency departments 
 
Timeline 
Data planned for the study beginning (first patient enrollment): 1 July 2018 
Data planned for the last patient enrollment: 1 September 2019 or the achievement of the target of 600 
patients. 
 
Study population 
All consecutive patients who refer to the Emergency Departments of the participating centers will be 
eligible for the study provided they are older than 18 and younger than 75 years, and have developed 
one or more episodes of exertional dyspnea since less than one month.   
 
Inclusion Criteria 
Subjects meeting the following criteria 
• 
Age older than 18 and younger than 75  
• 
Recent (less than one month) development of exertional dyspnea  
Exclusion Criteria 
Subjects meeting the following criteria: 
• 
Anticoagulation required for other indications 
• 
Contraindication to CT angiography (allergy to the contrast dye, severe renal failure 
[creatinine clearance < 30 ml/min]) 
• 
Involvement in simultaneous clinical trials  
• 
Unable to provide their written informed consent 
 
Study Procedures 
Enrolment Procedures 
All eligible patients will be interviewed and examined by trained study physicians. The presence of 
already known potential explanations for the dyspnea (see before) will be assessed. In addition, 
symptoms of the lower extremities will be elicited, as well as the presence of risk factors for venous 
thromboembolism (VTE), including recent surgery, trauma or infectious disease, ongoing hormonal 
treatment, prolonged immobilization, active cancer and history of VTE. The severity of dyspnea will 
be classified according to the modified scale of the Medical Research Council. 
The presence or absence of pulmonary embolism will be assessed with the use of a validated algorithm 
based on pre-test clinical probability and D-dimer result. The D-dimer level will be assessed with the 
quantitative assay routinely used in each participating center, and the cut-off will be adjusted to 
patients age in a standardized fashion. The pre-test clinical probability will be assessed by the 
simplified Wells score that classifies it as being “likely” or “unlikely”. In patients in whom the pre-test 
clinical probability is low (“unlikely”) and the D-dimer result is negative, no further testing will 

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be done, and PE will be considered excluded. In patients with high clinical probability, positive D-
dimer result, or both, computed tomography (CT) pulmonary angiography will be performed.  
Criterion for the presence of PE will be an intraluminal filling defect on CT angiography. In patients 
with PE, the thrombotic burden will be assessed by a central adjudication committee through the 
identification of the most proximal location of the embolus on CT angiography. 
 
Definition of the conclusion of the study 
Stoplines: 
• after enrolling 300 patients, if the lower limit of the 95% CI of the prevalence of PE is > 20%; 
otherwise: 
• after enrolling 600 patients 
Outcome of the study 
Primary endpoint 
• 
Prevalence of PE in the overall population 
Secondary endpoints: 
Prevalence of PE in the following subgroups: 
• 
patients with high pre-test clinical probability and/or positive D-dimer 
• 
patients without potential explanations for the dyspnea 
• 
each of the 5 severity groups of the modified scale of the Medical Research Council 
Statistical consideration 
Bias 
To avoid patient's selection bias, the investigators are asked to consecutively include the observed 
patients or, if it is not possible, to declare the criterion adopted for enrolment (e.g. one day a week, one 
week a month, etc.). 
 
Sample size 
Based on pilot data, we assume a prevalence of PE in patients with dyspnea on exertion between 10 
and 15%. In order to obtain a two-sided 95% confidence interval (CI) of 2.5% for the prevalence of 
PE, we estimate that a sample size of 550 patients is required. All centers will be asked to contribute 
patients until the achievement of the overall sample size. 
 
Statistical analysis plan 
The prevalence of PE and the associated 95% CI will be calculated for the entire group of patients and 
for relevant subgroups. For comparison of baseline characteristics between patients with and without 
PE, the chi-square test will be used for categorical parameters, while the Student’s t-test will be used 
for continuous parameters. Odds ratios and their 95% CIs will be calculated using logistic regression. 
The 95% CIs and P values will be calculated according to the normal approximation of the binomial 
distribution. No adjustments will be made for multiple testing. 
An interim analysis will be perfoermed after the inclusion of 300 patients. If the lower limit of the 95% 
CI around the prevalence of PE is > 20%, the study will be interrupted.  
 

 
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Study administration 
Data collection and management 
Patient’s personal data will be collected (in anonymous form), date of birth, gender, weight, height, 
liver and hepatic enzymes, past clinical history, thrombotic/haemorrhagic risk factors, lifestyle habits, 
type of treatment 
The monitor of the study will check data quality and completeness by remote monitoring.  
Data will be anonymously entered by the investigator in the eCRF, by assigning a patient identification 
code. 
The adopted database is REDCap stored in the server owned by Fondazione Arianna 
Anticoagulazione, which is responsible for maintaining, and backing up the database..  
Each access to the eCRF will be managed by personal user name and a password. 
The security system requires that the password be changed at the first access; it requires a length of at 
least 8 characters and provides for a periodic 3-month expiry. 
It is obviously possible to disable the login, if it is deemed necessary by the system administrator. 
Investigators can have full access only to their patient’s data. 
Every night the data backup is automatically performed. 
 
Ethics 
The study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and in compliance with the protocol and ICH-GCP.  
This is an observational study and all drug prescriptions and clinical investigations are independent 
from the study. 
The protocol and any amendments and the informed consent form (or information/non-opposition 
letter, as allowed by local regulations) will have to obtain Institutional Review Board or Ethics 
committee (IRB/EC) approval prior to initiation of the study.  
 
Informed Consent Form 
Participation in this study is entirely voluntary. Informed consent will be obtained in accordance with 
the Declaration of Helsinki, ICH GCP and local regulations. A properly executed, written, informed 
consent will be obtained from each subject prior to entering the subject into the trial.  Information 
should be given in both oral and written form and subjects (or their legal representatives) must be 
given ample opportunity to inquire about details of the study.  If appropriate and required by the local 
IRB/IEC, assent from the subject will also be obtained.  If a subject is unable to sign the informed 
consent form (ICF) a legal representative may sign for the subject. A copy of the signed consent form 
will be given to the subject or legal representative of the subject and the original will be maintained 
with the subject’s records. Once a patient has been enrolled in the study, he/she may withdraw his/her 
consent to participate in the study at any time without prejudice. Patients will not be entered in the 
database if the informed consent has not been obtained.  
 
Procedures implemented to guarantee data confidentiality 
The investigators collected patient’s personal data in anonymous form by assigning a patient 
identification code.  

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The adopted database is RedCap. Data anonymously entered in the eCRF will be recorded and stored 
in the server owned by Fondazione Arianna Anticoagulazione. Each access to the eCRF will be 
managed by personal user name and a password. 
The security system requires that the password be changed at the first access; it requires a length of at 
least 8 characters and provides for a periodic 3-month expiry. 
It is obviously possible to disable the login, if it is deemed necessary by the system administrator. 
Investigators can have full access only to their patient’s data. Every night the data backup is 
automatically performed. 
 
Administrative Issues  
Support of the study 
Participation in the PEDIS study is entirely voluntary and no form of remuneration or refund is given 
to the investigators. 
The PEDIS study is supported by own funds of the Promoter, for the preparation, working and 
maintenance of all the necessary activities, i.e. informatic and monitoring activities, statistical analysis 
of results, production of reports and publication of scientific papers. 
 
Publication 
Role of Promoter and Investigators  
The Promoter and the investigators may suggest specific analysis, regarding all or some data of the 
central database. The authorship of the article must provide who proposed the analysis, who performed 
the data analysis, who took part in writing the article. 
 
Data handling and record keeping  
All data and results and all intellectual property rights to the data and results derived from the study 
will be the property of the Promoter Fondazione Arianna Anticoagulazione according to D.M. 17 
Dicembre 2004. This study is a No Profit Study (D.M. 17 Dicembre 2004, Art. 1, comma 2, lettera c). 
 
Final report and publication  
Within 12 months from the completion of the trial and in accordance with ICH-GCP, the promoter 
provides the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with 
any reports required. All data and results and all intellectual property rights to the data and results 
derived from the study will be the property of Fondazione Arianna Anticoagulazione, who may utilize 
the data in various ways, such as for submission to government regulatory authorities or disclosure to 
other investigators.  All publication or communication (oral or written) will respect the international 
requirements: “Uniforms requirements for Manuscripts Submitted to Biomedical Journals”.   
 
 
 

 
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References 
1. Bell WR, Simon TL. Current status of pulmonary thromboembolic disease: Pathophysiology, 
diagnosis, prevention, and treatment. Am Heart J 1982; 103: 239-62. 
2. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and 
management of acute pulmonary embolism. Eur Heart J 2014; 35: 3033-69. 
3. Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pulmonary embolism 
among patients hospitalized for syncope. N Engl J Med 2017; 375: 1524-31. 
4. Stein PD, Beemath A, Matta F, et al. Clinical characteristics of patients with acute pulmonary 
embolism: data from PIOPED II. Am J Med 2007; 120: 871-9. 
5. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize 
patients probability of pulmonary embolism: increasing the models utility with the SimpliRED 
d-dimer. Thromb Haemost 2000; 83: 416-20. 
6. Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-dimer cutoff levels to rule out 
pulmonary embolism: the ADJUST-PE study. JAMA 2014; 311: 1117-24. 
7. Launois C, Barbe C, Bertin E, et al. The modified Medical Research Council scale for the 
assessment of dyspnea in daily living in obesity: a pilot study. BMC Pulmonary Medicine 
2012; 12: 61.