Efficacy and Safety of an Active Strategy for the Diagnosis and Treatment of Acute Pulmonary Embolism (PE) in Patients With Unexplained Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): a Randomized Clinical Trial
Phase: NA
Conditions: Pulmonary Embolism, Chronic Obstructive Pulmonary Disease
Sponsor: Ministry of Health, Spain

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PROTOCOL 
 
Significance of puLmonary embolIsm in COPD Exacerbations 
 
Short title: SLICE 
 
ClinicalTrials.gov Number: NCT02238639 
 
Supported by: 
Fundación para la Investigación Biomédica del Hospital Universitario 
Ramón y Cajal 
 
Version Number: 5.0 
 
03 SEP 2018 
 
 
 
 
 
  
 
 

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SUMMARY OF CHANGES 
 
Document 
Date of issue 
Summary of change 
Revised protocol 05 
03 September 2018 
Incorporates amendment 05 
Amendment 05 
03 September 2018 
This amendment was written to: 
Include the new sample size 
calculationa 
Revised protocol 04 
10 February 2016 
Incorporates amendment 04 
Amendment 04 
10 February 2016 
This amendment was written to: 
Modify the end point 
“readmission”b  
Clarify the definition of initial 
suspicion of PEc 
Revised protocol 03 
10 February 2016 
Incorporates amendment 03 
Amendment 03 
10 February 2016 
This amendment was written to: 
Modify the end point 
“readmission”b  
Clarify the definition of initial 
suspicion of PEc 
Revised protocol 02 
07 November 2015 
Incorporates amendment 02 
Amendment 02 
07 November 2015 
This amendment was written to: 
Include breastfeeding as an 
exclusion criterion 
Revised protocol 01 
16 May 2015 
Incorporates amendment 01 
Amendment 01 
16 May 2015 
This amendment was written to: 
Include clinically relevant non 
major bleeding as a safety eventd 
Original protocol 
01 September 2014 
Not applicable 
 
 
aNew sample size calculation: 
After the last interim analysis, the DSMB increased the expected evaluability 
rate from 75% to 95%. Therefore, the final sample size decreased to 746 
patients (373 per arm). 
 

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bPrimary efficacy outcome: 
“Readmission for any cause” was changed by “readmission for COPD 
exacerbation”. 
 
cDefinition of initial suspicion of PE 
Defined as the indication of a D-dimer testing or a multidetector computed 
tomography (CT) angiogram by the attending physician in the Emergency 
Department. 
 
dDefinition of clinically relevant non major bleeding 
Any sign or symptom of hemorrhage (e.g., more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) 
that does not fit the criteria for the ISTH definition of major bleeding but does 
meet at least one of the following criteria: 1) requiring medical intervention by a 
healthcare professional; 2) leading to hospitalization or increased level of care; 
or 3) prompting a face to face (i.e., not just a telephone or electronic 
communication) evaluation. 
 
 
 
 

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STEERING COMMITTEE 
 
Co-Chairmen (Principal Investigators): 
Alvar Agustí. Hospital Clinic, Barcelona (Spain) 
AAGUSTI@clinic.cat 
David Jiménez. Hospital Ramón y Cajal, Madrid (Spain) 
djimenez.hrc@gmail.com 
Manuel Monreal. Hospital German Trias i Pujol, Badalona (Spain) 
mmonreal.germanstrias@gencat.cat 
Remedios Otero. Hospital Virgen del Rocío, Sevilla (Spain) 
rotero@separ.es 
 
Steering Committee: 
Laurent Bertoletti. Université de Saint-Etienne (France) 
laurent.bertoletti@gmail.com 
Francis Couturaud. University Hospital of Brest (France) 
francis.couturaud@chu-brest.fr 
Menno Huisman. Leiden University Medical Center, Leiden (Netherlands) 
M.V.Huisman@lumc.nl 
José Luis Lobo Beristaín. Hospital Universitario Araba, Vitoria (Spain) 
JOSELUIS.LOBOBERISTAIN@osakidetza.eus 
Roger D. Yusen. Barnes Jewish Hospital, St. Louis (USA) 
yusenr@wustl.edu 
 
Writing Committee: 
David Jiménez. Hospital Ramón y Cajal, Madrid (Spain) 
Behnood Bikdeli. Brigham and Women’s Hospital, Harvard Medical School, 
Boston (USA) 
behnood.bikdeli@yale.edu 
Manuel Monreal. Hospital German Trias i Pujol, Badalona (Spain) 
Roger Yusen. Barnes Jewish Hospital, St. Louis (USA) 

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Critical Events Adjudication Committee: 
Deisy Barrios. Hospital Ramón y Cajal, Madrid (Spain) 
ddbb_2601@hotmail.com 
Raquel Morillo. Hospital Ramón y Cajal, Madrid (Spain) 
ake_1986@hotmail.com 
 
Data Safety Monitoring Board: 
Víctor Abraira. Hospital Ramón y Cajal, Madrid (Spain) 
victor.abraira@hrc.es 
Vicente Gómez del Olmo. Hospital Ramón y Cajal, Madrid (Spain) 
vgomezdelolmo@hotmail.com 
 
Central Reading: 
Javier Alarcón. Hospital Ramón y Cajal, Madrid (Spain) 
Josejavier.alarcon@salud.madrid.org 
Agustina Vicente. Hospital Ramón y Cajal, Madrid (Spain) 
 
Trial Statistician: 
Alfonso Muriel. Hospital Ramón y Cajal, Madrid (Spain) 
alfonso.muriel@uah.es 
 
Data Monitoring: 
S&H Medical Science Service 
 
 
 

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TRIAL OBJECTIVES 
 
 
 
The objectives of the trial are: 
 
To assess the clinical effect of an active strategy for the diagnosis and treatment of pulmonary 
embolism (PE), compared to usual care, in patients with unexplained exacerbations of chronic 
obstructive pulmonary disease (COPD) who require hospital admission. 
 
To assess the prevalence of PE in patients with unexplained exacerbations of COPD who 
require hospital admission. 
 
 
To identify those clinical variables associated with a diagnosis of PE in patients with 
unexplained exacerbations of COPD who require hospital admission. 
 
 
To determine the positive predictive value of D-dimer testing for the diagnosis of PE in patients 
with unexplained exacerbations of COPD who require hospital admission.

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STUDY PLAN 
 
 
Screening: 
Visit 1 
Day -1 
Enrollment: 
Visit 2 
Day 0 
Follow-up: 
Visit 3 
Day 7 + 2 
Follow-up: 
Visit 4 
Day 30 + 5 
Follow-up: 
Visit 5 
Day 90 + 7 
Medical history 
X 
 
 
 
 
Demographic 
variables 
X 
 
 
 
 
Physical 
examination 
X 
 
X 
X 
X 
COPD 
diagnosis 
X 
 
 
 
 
Inclusion 
and 
exclusion 
criteria 
X 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
Hematology 
tests 
X 
 
 
 
 
Biochemistry 
tests 
X 
 
 
 
 
Coagulation 
tests 
X 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
D-dimer 
 
Intervention 
group 
 
 
 
Multidetector 
CT 
pulmonary 
angiogram 
 
Intervention 
group 
 
 
 
ASSESSMENT 
OF: 
 
 
 
 
 
Recurrent VTE 
 
 
X 
X 
X 
Death 
 
 
X 
X 
X 
Bleedinga 
 
 
X 
X 
X 
Adverse 
eventsa 
 
 
X 
X 
X 
Length 
of 
hospital stay 
 
 
X 
Xb 
 
Readmission 
 
 
X 
X 
X 
 
Abbreviations: COPD, chronic obstructive pulmonary disease; CT, computed 
tomography; VTE, venous thromboembolism. 

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aSee definitions in the protocol. 
bIf hospital admission longer than 7 + 2 days. 

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ABBREVIATED PROTOCOL 
 
Title: 
Efficacy and safety of an active strategy for the 
diagnosis and treatment of acute pulmonary embolism 
(PE) in patients with unexplained exacerbations of 
chronic obstructive pulmonary disease (COPD): a 
randomized clinical trial. 
 
 
Investigators: 
 
Multicentre. 
 
 
Participating sites: 
Approximately 18 study centers. 
 
 
Clinical phase: 
 
III 
 
 
Objectives: 
The primary objective is to assess the benefit of an 
active strategy for the diagnosis and treatment of PE, 
compared to usual care, in patients with unexplained 
exacerbations of COPD who require hospital 
admission. 
 
 
The secondary objective is to assess the safety of an 
active strategy for the diagnosis and treatment of PE 
compared to usual care in patients with unexplained 
exacerbations of COPD who require hospital 
admission. 
 

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Methodology: 
Prospective, international, multicenter, randomized 
(1:1), open-label with blind end-point evaluation 
(PROBE), parallel-group trial. 
 
 
No. de subjects: 
 
Approximately 746 patients. 
       Each strategy: 
Approximately 373 patients. 
 
 
Diagnosis and main 
criteria for exclusion: 
Patients admitted to the hospital because of COPD 
exacerbation. COPD exacerbation is defined as any 
worsening of respiratory symptoms sufficiently severe 
to 
warrant 
an 
admission 
to 
the 
Emergency 
Department in a patient with known COPD. Patients 
with an initial clinical suspicion of PE or deep vein 
thrombosis (DVT), a diagnosis of pneumothorax, 
pneumonia, or lower respiratory tract infection will be 
excluded from the trial. 
 
 
Strategies:  
 
Intervention group: 
All included patients will undergo D-dimer testing. A 
negative plasma D-dimer value (defined as a D-dimer 
level below the manufacturers assay threshold) will 
rule out pulmonary embolism, and no further 
examination will be performed. For patients with a 
positive D-dimer value, a thoracic multidetector helical 
computed tomography scan will be performed. 
 

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Control group: 
All included patients will undergo standard clinical 
management of their exacerbations, as deemed 
appropriate by the attending physician. 
 
 
Criteria for efficacy: 
Primary end point 
• Clinical composite endpoint of all-cause mortality or 
venous thromboembolism recurrence or need for 
COPD readmission within 90 days. 
 
Secondary end points 
• All-cause mortality within 90 days. 
• Venous thromboembolic recurrence within 90 days. 
• Need for COPD readmission within 90 days. 
• Length of hospital stay. 
 
Criteria for safety: 
Primary end point 
• Major bleeding within 90 days. 
 
Secondary end points 
• Clinically relevant non-major bleeding within 90 
days. 
• Serious adverse events within 90 days. 
 
 
Statistical analysis: 
Intent-to-treat (ITT) analysis on superiority of an active 
strategy for the diagnosis and treatment of PE in 
patients with unexplained exacerbations of COPD 
requiring hospital admission. 
 

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Primary criteria 
The primary ITT analysis on the primary end points 
will be carried out by a two-sided chi-square test on 
proportions. In addition, the 95% confidence interval 
on the relative risks will be presented. 
 
Secondary efficacy criteria 
The secondary ITT analysis on the secondary efficacy 
end points will be carried out by a two-sided chi-
square test on proportions. In addition, the 95% 
confidence interval on the relative risks will be 
presented. The survival status during 90 days follow-
up will be analyzed by showing Kaplan-Meier curves, 
and management differences will be compared by 
means of log-rank test. 
 
Secondary safety analysis 
Safety end points will be tabulated by management 
group. All (dichotomized) end points will be analyzed 
by chi-square test on proportions, and the 95% 
confidence interval on the relative risks will be 
presented. In addition, continuous safety monitoring 
will be done by the Data and Safety Monitoring Board. 
 
Interim analysis 
Interim analysis will be made by the Data Center after 
recruitment of 50% of the total number of patients. 
Theses analyses will be made in order to allow sample 
size reassessment or early stop of the trial for efficacy 
or futility. 

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TABLE OF CONTENTS  
 
 
 
 
 
Page 
 
ABBREVIATIONS  
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
1. BACKGROUND  
 
 
 
 
 
 
16 
 
 
1.1 Study justification  
 
 
 
 
 
16 
1.2 Hypothesis  
 
 
 
 
 
 
17 
1.3 Objectives  
 
 
 
 
 
 
17 
 
2. METHODOLOGY 
 
 
 
 
 
 
20 
      2.1   Design 
 
 
 
 
 
 
 
20 
      2.2   Setting 
 
 
 
 
 
 
 
20 
      2.3   Study subjects 
 
 
 
 
 
 
21 
2.4   Randomization 
 
 
 
 
 
 
22 
      2.5   Study procedures 
 
 
 
 
 
22 
      2.6   Criteria for termination of the trial 
 
 
 
23 
      2.7   Definition of study end points  
 
 
 
23 
      2.8   Surveillance and follow-up 
 
 
 
 
28 
      2.9   Cost-effectiveness analysis 
 
 
 
 
28 
      2.10 Statistical plan 
 
 
 
 
 
 
29 
 
3. STUDY PROCEDURES 
 
 
 
 
 
33 
      3.1 Informed consent  
 
 
 
 
 
33 
      3.2 Screening and eligibility assessment 
 
 
 
33 
      3.3 Enrollment and in-hospital period 
 
 
 
34 
      3.4 Subsequent assessments 
 
 
 
 
35 
      3.5 End of trial assessment  
 
 
 
 
35 
 
4. STUDY ORGANIZATION 
 
 
 
 
 
37 
      4.1 Steering Committee 
 
 
 
 
 
37 
      4.2 Investigators 
 
 
 
 
 
 
37 

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      4.3 Adjudication 
 
 
 
 
 
 
37 
      4.4 Data Safety Monitoring Board 
 
 
 
 
37 
      4.5 Data management  
 
 
 
 
 
38 
      4.6 Central readings 
 
 
 
 
 
 
38 
 
5. CALENDAR 
 
 
 
 
 
 
 
39 
 
6. LEGAL ISSUES  
 
 
 
 
 
 
40 
 
7. REFERENCES  
 
 
 
 
 
 
44 
 
TABLES 
 
 
 
 
 
 
 
 
47 
 
APPENDIX  
 
 
 
 
 
 
 
49 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
CCUS 
Complete Compression UltraSound 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CT 
Computed Tomographic 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
FEV1 
Forced Expiratory Volume in one second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
PE 
Pulmonary Embolism 
PP 
Per Protocol 
PROBE 
Prospective Randomized Open, Blinded Endpoint 
QALY 
Quality-Adjusted Life Year 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SEPAR 
Sociedad Española de Neumología y Cirugía Torácica 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SLICE 
Significance of puLmonary embolIsm in COPD Exacerbations 
V/Q 
Ventilation/Perfusion 
VTE 
Venous Thromboembolism 
 
 
 

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1. BACKGROUND 
 
1.1 Study justification 
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity 
and mortality worldwide and represents a huge economic burden for the 
healthcare system (1-3). COPD patients may suffer from exacerbations, defined 
as acute worsening of respiratory symptoms that results in additional therapy (4, 
5). COPD exacerbations are independent predictors of mortality in COPD and 
also drive disease progression, with approximately 25% of the lung function 
decline attributed to exacerbations (6). 
 
The most common triggers of exacerbations are infections and air pollution, but 
noninfectious factors were thought to cause approximately 20% of acute 
exacerbations of COPD in a hospital study (7). In addition, other frequent 
clinical conditions may mimic the symptoms of COPD exacerbations, including 
congestive heart failure, pneumonia, pneumothorax, pleural effusion and 
pulmonary embolism (PE) (8). 
 
The exact prevalence of PE in unexplained exacerbations of COPD is unclear 
based on the current data. Over the past decade, several studies have reported 
the prevalence of venous thromboembolism (VTE) in COPD, primarily from 
hospitalized patients (9-12). However, due to the heterogeneities in race, 
sample size, study design, research setting, and enrollment criteria, there were 
remarkable differences in reported data among these studies. Tillie-Leblond et 
al evaluated PE in a series of 197 consecutive patients with COPD and 
exacerbation of unknown origin, and found that the frequency of PE was 25% 
(13). However, that study was performed in a highly selected subgroup of 
patients. Rutschmann et al. showed that the prevalence of PE and deep vein 
thrombosis (DVT) in patients who were admitted to Emergency Department and 
with acute exacerbations of moderate-to-severe COPD was only 3.3% and 
2.2%, respectively (14). In fact, a recent meta-analysis found a lower 

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prevalence of PE of 16% in exacerbations of compared with previous studies 
(15). 
 
In patients with clinical suspicion of PE, there are some data suggesting that 
some PE diagnoses are less severe, and these patients might not benefit from 
anticoagulation therapy (16). For instance, in the PIOPED study (17), the 
prevalence of PE was 10% in patients with a nondiagnostic ventilation/perfusion 
(V/Q) scan and a low clinical probability of PE. Nevertheless, such patients 
have a low-3-month thromboembolic risk provided they have no proximal DVT. 
This highlights the important point that not all PEs are clinically important, 
especially if the main site for potential recurrence is free of clots. Particularly for 
patients with COPD exacerbations, some PE might be clinically unimportant, 
and the risk of submitting a patient with a clinically insignificant PE to 
anticoagulant treatment might outweigh the benefit (18). 
 
Data from randomized controlled trials regarding the clinical effectiveness of an 
active search for PE in patients who have unexplained exacerbations of COPD 
are lacking. The objective of the Significance of Pulmonary Embolism in COPD 
Exacerbations (SLICE) is to compare health outcomes in patients with 
unexplained exacerbations of COPD who required hospital admission and who 
were randomly assigned to an active search for PE with the use of D-dimer and 
computerized tomography (CT) pulmonary angiogram, or to usual care. 
 
1.2 Hypothesis 
For patients with unexplained exacerbations of COPD who required hospital 
admission, an active search for PE with the use of D-dimer and, if positive, 
contrast-enhanced, PE-protocol, multidetector CT will improve health outcomes, 
compared to usual care. 
 
1.3 Objectives 
The primary objective of the SLICE trial is: 

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• To demonstrate the clinical benefits of an active strategy for the 
diagnosis and treatment of PE compared to usual care in patients with 
unexplained exacerbations of COPD who require hospital admission. 
 
Secondary objectives of the SLICE trial are: 
• To assess the prevalence of PE in patients with unexplained 
exacerbations of COPD who require hospital admission. 
• To identify those clinical variables associated with a diagnosis of PE in 
patients with unexplained exacerbations of COPD who require hospital 
admission. 
• To determine the positive predictive value of D-dimer testing for the 
diagnosis of PE in patients with unexplained exacerbations of COPD who 
require hospital admission. 
 
Primary end point 
Primary efficacy end point 
• Clinical composite endpoint of death from any cause, non-fatal 
(recurrent) symptomatic VTE, or readmission for COPD exacerbation 
within 90 days after enrollment. 
 
Primary safety end point 
• Major bleeding within 90 days after enrollment. 
 
Secondary end points 
Secondary efficacy end points 
• Death from any cause within 90 days after enrollment. 
• Nonfatal (recurrent) symptomatic VTE within 90 days after enrollment. 
• Need of readmission for COPD exacerbation within 90 days after 
enrollment. 
• Length of hospital stay. 

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Secondary safety end points 
• Clinically relevant non-major bleeding within 90 days after enrollment. 
• Serious adverse events within 90 days after enrollment. 
 
 
 

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2. METHODOLOGY 
 
2.1 Design 
SLICE is an investigator-initiated, phase III, prospective, multicenter, 
randomized (1:1), open-label with blind end-point evaluation (PROBE), parallel-
group trial comparing the efficacy and safety of an active search for PE 
(intervention group) with usual care (control group) in patients with unexplained 
exacerbations of COPD who require hospital admission (ClinicalTrials.gov 
identifier NCT02238639). 
 
 
 
2.2 Setting 
Emergency, Respiratory and Internal Medicine Departments in 18 Spanish 
University Hospitals. 
 

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2.3 Study subjects 
Inclusion criteria (Table 1) 
Patients are required to fulfill the following inclusion criteria: 
1. Confirmation of COPD according to SEPAR-ALT criteria: post-
bronchodilator forced expiratory volume in one second (FEV1)/forced vital 
capacity (FVC) < 0.7. 
2. Hospital admission because COPD exacerbation without initial clinical 
suspicion of PE in the Emergency Department (according by the 
Emergency Department physician evaluation). 
 
Exclusion criteria (Table 2) 
A patient will be excluded from the study if ANY of the following apply: 
1. Contraindication to multidetector CT pulmonary angiography (allergy to 
intravenous contrast medium, or renal failure defined as a creatinine 
clearance less than 30 mL/min, according to the Cockroft-Gault formula 
[appendix 1]). 
2. Refusal to give informed consent. 
3. Pregnancy, or breast feeding. 
4. Life expectancy less than 3 months. 
5. Anticoagulant therapy at the time of hospital admission. 
6. Diagnosis of pneumothorax, or pneumonia (fever [temperature >38ºC two 
times at least 12 hours apart], and purulent sputum, and new infiltrate in 
chest X-ray) at the time of hospital admission. 
7. Diagnosis of lower respiratory tract infection (fever [temperature >38ºC two 
times at least 12 hours apart], or increased sputum volume and increased 
sputum purulence) at the time of hospital admission. 
8. Indication of invasive mechanical ventilation at the time of hospital 
admission. 
9. Participation in any other investigational drug or device study in the 
past four weeks. 
10. Geographic inaccessibility that precludes follow-up. 

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2.4. Randomization 
In a patient with unexplained exacerbations of COPD requiring hospital 
admission, randomization should occur in the first 24 hours after admission. The 
trial will use a computer-generated randomization scheme. Randomization will 
be stratified by center and, within the centers, performed in blocks of 4 and 6 to 
ensure balanced distribution of the management groups. Randomization will be 
performed centrally via the Internet (www.estudioslice.org), and management 
allocation will be concealed from all investigators. 
 
2.5 Study procedures 
All patients will receive standard clinical management (usual care) for their 
COPD exacerbation according to the clinician's preference and local standards. 
 
Intervention group 
Patients in the intervention group will have blood samples collected from an 
antecubital vein, and will undergo D-dimer testing within 12 hours after 
randomization. Cut-off levels for defining elevated D-dimer will be defined by the 
Department of Clinical Chemistry at each participating site. For patients with a 
negative D-dimer, a diagnosis of PE will be ruled out. For patients with a 
positive D-dimer, a contrast-enhanced, PE-protocol, multidetector CT will be 
performed. CT pulmonary angiography results will be categorized as positive for 
PE if an intraluminal filling defect is seen in (sub)segmental or more proximal 
branches, and will be considered negative if no filling defect is observed. Scans 
will be considered technically inadequate only if main or lobar pulmonary 
vessels are not visualized. Though not mandatory, the protocol suggests the 
use of complete lower limb compression ultrasonography (CCUS) to detect 
concomitant DVT for patients with isolated subsegmental PE. 
 
If the diagnosis of PE is confirmed, patients will receive anticoagulant treatment 
according to guideline recommendations: parenteral anticoagulation (i.e., 

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unfractionated heparin, low-molecular-weight heparin, or fondaparinux) 
overlapped and followed by vitamin K antagonists; or parenteral anticoagulation 
followed by dabigatran or edoxaban; or monotherapy with apixaban or 
rivaroxaban (19). 
 
Control group 
Patients in the control group will receive standard clinical management (usual 
care) for their COPD exacerbation according to the clinician's preference and 
local standards. 
 
After hospital discharge, all patients (in the intervention and control arms) will be 
treated according to the national and international recommendations for the 
management of stable COPD (1, 2). 
 
2.6 Criteria for termination of the trial 
Premature termination of the trial may happen under the following conditions: 
• Occurrence of unknown or increase of known adverse events that 
render the risk/benefit ratio unacceptable. 
• Interim analysis indicates reason. 
• An unacceptable high number of SAEs. 
• Ethical justification. 
• Recruitment rate is too low such that it is unrealistic to consider 
completion of the trial within an acceptable period of time. 
• Decision of the authorities. 
 
2.7 Definition of study end points 
Efficacy 
The primary efficacy end point is the composite of death from any cause, non-
fatal (recurrent) symptomatic VTE, or readmission for COPD exacerbation 
within 90 days after enrollment. 
 

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Confirmation of (recurrent) symptomatic PE requires symptoms of PE and a 
new or an extension of a previous intraluminal-filling defect in (sub)segmental or 
more proximal branches on PE-protocol chest CT pulmonary angiography. 
Confirmation of (recurrent) symptomatic DVT requires symptoms of DVT and 
the following criteria: 1) In the absence of previous DVT investigations at 
baseline, a non-compressible venous segment on ultrasonography; 2) if there 
were previous DVT investigations at baseline, abnormal lower limb CCUS 
where compression had been normal; or, if previously non-compressible, a 
substantial increase (>4 mm) in diameter of the thrombus during full 
compression. 
 
Secondary efficacy end points include: 
• Death from any cause within 90 days after enrollment. 
• Nonfatal (recurrent) symptomatic VTE within 90 days after enrollment. 
• Readmission for exacerbation of COPD within 90 days after enrollment. 
• Length of hospital stay. 
 
Safety 
The primary safety end point is major bleeding within 90 days after enrollment. 
 
Major bleeding is defined according to the guidelines of the International 
Society of Thrombosis and Haemostasis (20), as acute clinically overt bleeding 
associated with one or more among the following: a decrease in hemoglobin of 
2 g/dL or more, a transfusion of two or more units of packed red blood cells, 
bleeding that occurs in at least one of the following critical sites (intracranial, 
intraspinal, intraocular, pericardial, intraarticular, intramuscular with 
compartment syndrome or retroperitoneal), bleeding that is fatal (defined as a 
bleeding event that the central independent committee adjudicate as the 
primary cause of death or contributing directly to death) and bleeding that 
necessitates surgical intervention. 
 

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Secondary safety end points include: 
• Clinically relevant non-major bleeding within 90 days after enrollment. 
• Serious adverse events (SAE) within 90 days after enrollment. 
 
A bleeding event is classified as a clinically relevant non-major bleeding 
event if it is overt (i.e., is symptomatic or visualized by examination) not meeting 
the criteria for major bleeding, requires medical attention or is associated with 
discomfort for the subject such as pain, or impairment of activities of daily life. 
 
Adverse event (AE): any untoward medical occurrence in a patient or clinical 
investigation participants, which does not necessarily have to have a causal 
relationship with the study intervention. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom or 
disease temporally associated with the use of the study medication/procedure, 
whether or not considered related to the study medication. 
 
Adverse reaction (AR): all untoward and unintended responses to a medicinal 
product related to any dose. The phrase "responses to a medicinal product" 
means that a causal relationship between a study medication and an AE is at 
least a reasonable possibility, i.e., the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
sponsor as having a reasonable suspected causal relationship to the study 
medication/procedure qualify as adverse reactions. 
 
Serious adverse event: an event that fulfils one or more of the 
following criteria: 
• Fatal. 
• Immediately life-threatening. 
• Results in persistent or significant disability/incapacity. 
• Requires or prolongs in-patient hospitalization. 

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• Is a congenital anomaly/birth defect. 
• Any other reason representing a significant hazard comparable 
to the criteria mentioned above. 
 
Serious adverse reaction (SAR): an adverse event (expected or unexpected) 
that is both serious and, in the opinion of the reporting investigator, believed 
with reasonable probability to be due to one of the study treatments, based on 
the information provided. 
 
Suspected unexpected serious adverse reaction (SUSAR): a serious adverse 
reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g. Investigator’s Brochure for an unapproved 
investigational product or summary of product characteristics for an approved 
product). 
 
A central independent adjudication committee whose members are unaware of 
management allocation will adjudicate all suspected study outcomes during the 
study period. 
 
Causality and expectedness 
The relationship of each adverse event to the trial intervention must be 
determined by a medically qualified individual according to the following 
definitions: 
Related: The adverse event follows a reasonable temporal sequence from trial 
intervention. It cannot reasonably be attributed to any other cause. 
Not Related: The adverse event is probably produced by the participant’s 
clinical state or by other modes of therapy administered to the participant. 
 
Procedures for recording AEs 

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All AEs occurring during the study observed by the investigator or reported by 
the participant, whether or not attributed to study intervention, will be recorded 
on the e-CRF. 
 
The following information will be recorded: description, date of onset and end 
date, severity, assessment of relatedness to study intervention, other suspect 
drug or device and action taken. Follow-up information should be provided as 
necessary. 
 
AEs considered related to the study intervention as judged by a medically 
qualified investigator or the sponsor will be followed until resolution or the event 
is considered stable.  All related AEs that result in a participant’s withdrawal 
from the study or are present at the end of the study, should be followed up until 
a satisfactory resolution occurs. 
 
The relationship of AEs to the study intervention will be assessed by a medically 
qualified investigator. Any pregnancy occurring during the clinical study and the 
outcome of the pregnancy should be recorded and followed up for congenital 
abnormality or birth defect. 
 
Reporting procedures for SAEs 
All SAEs must be reported to the Steering Committee or designated 
organization within one working day of discovery or notification of the event. 
The Steering Committee or designated organization will perform an initial check 
of the report, request any additional information. All SAE information must be 
recorded on an SAE forms and faxed to the Steering Committee or designated 
organization. Additional information received for a case (follow-up or corrections 
to the original case) need to be detailed on a new SAE form and faxed to the 
Steering Committee or designated organization. 
 

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It may be appropriate that some SAEs do not require immediate reporting, but 
this must be justified. Justification might be determined, for example, by 
admission to hospital, or prolongation of hospitalization, where this is to be 
expected in the underlying disease or condition. 
Type and duration of follow-up of subjects after SAEs 
SAEs will be followed until resolved or considered stable. All SAE case report 
forms will be included in the e-CRF and will trigger an alert at the Data and 
Safety Monitoring Board. 
 
2.8 Surveillance and follow-up 
The study requires the following scheduled visits (see Section 3. Study 
procedures for details): enrollment, 1 week, 1 month, and 3 months after 
randomization. Additional visits are performed if new symptoms and/or signs of 
VTE or bleeding occur during the study period or anytime it is deemed 
necessary by the investigator. Clinical examination, laboratory and diagnostic 
imaging are performed if the patient develops symptoms or signs suggestive of 
(recurrent) VTE. 
 
2.9 Cost-effectiveness analysis 
The study will calculate the incremental cost-effectiveness ratio (ICER) 
according to the following formula: 
 
Cost active strategy – Cost usual care 
Effectiveness active strategy – Effectiveness usual care 
 
where Cost active strategy and Cost usual care represent costs associated with the 
active strategy and usual care, respectively; while Effectiveness active strategy and 
Effectiveness usual care represent the clinical consequences as quality-adjusted 
life year (QALY) in both arms. 
 

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2.10 Statistical plan 
Statistical design 
SLICE is an investigator-initiated, phase III, prospective, international, 
multicenter, randomized (1:1), open-label with blind end-point evaluation, 
parallel-group trial comparing the efficacy and safety of an active search for PE 
(intervention group) with usual care (control group) in patients with unexplained 
exacerbations of COPD who require hospital admission 
 
Null and alternative hypotheses 
The primary aim of the trial is to demonstrate superiority in the intent-to-treat 
analysis of an active search for PE over usual care with regard to primary end 
point as the composite of death from any cause, non-fatal (recurrent) 
symptomatic VTE, or readmission for COPD exacerbation within 90 days after 
enrollment (90daycomposite). 
 
The null and alternative hypotheses are as follows: 
H0: 90daycompositeintervention = 90daycompositecontrol 
H1: 90daycompositeintervention ≠ 90daycompositecontrol 
 
Analyses 
The intention-to-treat (ITT) analysis dataset will be the source of data for all 
analyses. This will include all randomized participants regardless of actual 
receipt or compliance with the intervention. Safety analyses will also be 
performed in the safety analysis set, which will consist of all participant who 
receive D-dimer testing. In addition, a per-protocol (PP) analysis of all patients 
randomized and managed without major protocol violations/deviations will be 
carried out; this dataset will support sensitivity analyses to complement the 
primary ITT analyses. 
 
Protocol deviations (minor) refer to incidents involving non-compliance 
with the protocol that are unlikely to have a significant impact on the 

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participant’s rights, safety or welfare, or on data integrity. Examples of 
deviations include forgetting to complete a procedure at a specified visit or a 
patient receiving an inadequate management strategy. 
 
Protocol violations (major) refer to more serious incidents involving non-
compliance with the protocol that may result in significant effect on the 
participant’s rights, safety, or welfare or data integrity. Protocol violations 
could result in the participant being excluded from the eligibility analysis 
and/or result in the participant being discontinued from the trial. Examples of 
violations include non-compliance with inclusion/exclusion criteria or 
inadequate risk classification. 
 
Efficacy analyses 
The primary ITT analyses will be carried out by the chi square test on 
proportions, or the Fisher exact test. In addition, the corresponding 95% on 
the relative risks will be presented. 
 
Safety analyses 
The secondary ITT analyses will be carried out by the chi square test on 
proportions, or the Fisher exact test. In addition, the corresponding 95% on 
the relative risks will be presented. 
 
Patient accountability 
Disposition of patients, patient status and patients excluded from ITT will be 
summarized by group (intervention and control). Descriptive statistics for 
primary reason for patient’s withdrawal will be also presented by group 
(intervention and control) as well as a list of these patients sorted by group 
(intervention and control). 
 
Drop-outs 

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Reasons for drop-outs in each group (intervention and control) will be displayed. 
A detailed list of drop-out patients will also be provided. 
 
Baseline characteristics 
Baseline characteristics will be tabulated and comparability / differences 
between the treatment groups will be examined by means of descriptive 
statistics. 
 
Subgroup analysis 
The following subgroup analyses will be carried out: age (<75 versus >75), sex 
(women versus men), COPD severity (FEV1 >80%, 50% <FEV1 <80%, 30% 
<FEV1 <50%, and FEV1 <30%), hospital size (<300 beds versus >300 beds) 
and season (autumn, winter, spring, summer). 
 
Interim analysis 
We will conduct an interim analysis after recruitment of 50% of the study 
population. To preserve an overall type I error rate of 0.05 for the entire trial, the 
O’Brien-Fleming type boundary (alpha of 0.005) will be used for early trial 
stoppage. Futility will be assessed with conditional power, an approach that 
quantifies the probability of rejecting the null hypothesis of no effect. Stopping 
rule for futility will be based on a conditional power less than 20%. 
 
Handling of missing data 
Missing data won’t be replaced, and analysis will be made on all evaluable 
patients. If necessary, sensitivity analyses will be made on the primary and 
secondary end points using worst case and/or multiple imputations (see 3.5.3). 
Missing or incomplete data for survival analyses will be managed by censored 
data analyses. 
 
Sample size 

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Previous studies have shown short-term rates of death, thromboembolic events, 
or readmission of approximately 40% at day 90 among patients who required 
hospital admission because of an exacerbation of COPD (21, 22). An estimated 
355 participants will be needed in each trial group to detect a clinically important 
10% absolute reduction in the primary outcome (i.e., from 40% to 30%) with 
80% power at 5% significance level. The 10% reduction was based on 
consultation with primary and secondary care colleagues (general practitioners 
and pulmonologists) who considered a 10% reduction to be small but clinically 
important. Since an interim analysis showed that 3% of patients were lost to 
follow-up, the Steering Committee anticipated a 5% loss to follow-up. This 
inflated each study group to 373 patients, giving 746 patients in total. 

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3. STUDY PROCEDURES 
 
The study is divided in three distinct periods: screening (visit 1), enrollment and 
in-hospital period (visits 2 and 3), and follow-up period (visits 4 and 5). 
 
3.1 Informed consent 
The participant must personally sign and date the latest approved version of the 
informed consent form before any study specific procedures are performed. 
 
Written and verbal versions of the Participant Information Sheet and Informed 
Consent will be presented to the participants detailing no less than: the exact 
nature of the study; the implications and constraints of the protocol; the known 
side effects and any risks involved in taking part. It will be clearly stated that the 
participant is free to withdraw from the study at any time for any reason without 
prejudice to future care, and with no obligation to give the reason for withdrawal. 
 
The participant will be allowed as much time as wished to consider the 
information and the opportunity to question the Investigator, their general 
practitioner (GP) or other independent parties to decide whether they will 
participate in the study. Written informed consent will then be obtained by 
means of participant dated signature and dated signature of the person who 
presented and obtained the informed consent. The person who obtained the 
consent must be suitably qualified and experienced, and have been authorized 
to do so by Principal Investigator. A copy of the signed Informed Consent will be 
given to the participants. The original signed form will be retained at the study 
site. 
 
3.2 Screening and eligibility assessment 
Start of period: When a given patient is admitted to the hospital because 
unexplained COPD exacerbation. 
 

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End of period: Twenty-four hours after decision to admit to hospital. 
 
Setting: Emergency Department. 
 
e-CRF entries: 
• Demographics: date of birth, gender 
• Medical history 
• Concomitant medication 
• Physical examination: height, weight, heart rate, systolic blood pressure, 
temperature, respiratory rate, arterial oxyhemoglobin saturation 
• Inclusion and exclusion criteria 
• Laboratory tests: hemogram, biochemistry, and hemostasis 
• Chest X-ray 
• Informed consent 
 
3.3 Enrollment and in-hospital period 
Start of period: When a given patient is randomized. 
 
End of period: When a given patient is discharged. 
 
Setting: Hospital. 
 
e-CRF entries: 
• Randomization group: intervention or control group 
• D-dimer test results (Intervention group) 
• CT pulmonary angiogram result (Intervention group) 
• Symptomatic new or recurrent VTE 
• Death 
• Primary cause of death 
• Major bleeding 

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• Clinically relevant non-major bleeding 
• Serious adverse events 
• Treatment for COPD exacerbation 
• Hospital discharge 
 
At day 7, it will be recorded if the patient was discharged or not. Hospital 
discharge is defined as end of hospitalization or if the patient is transferred for 
long-term rehabilitation. 
 
3.4 Subsequent assessments 
Visits: Day 30 + 5 and Day 90 + 7. 
 
Setting: Outpatient basis. 
 
e-CRF entries: 
• Recording of concomitant medications 
• Symptomatic new or recurrent VTE 
• Death 
• Primary cause of death 
• Major bleeding 
• Clinically relevant non-major bleeding 
• Serious adverse events 
• Rehospitalization 
• Primary cause of rehospitalization 
 
3.5 End of trial assessment 
The end of trial is the date of the last visit of the last participant. 
 
Visits: Day 30 + 5 and Day 90 + 7. 
 

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Setting: Outpatient basis. 
 
e-CRF entries: 
• Recording of concomitant medications 
• Symptomatic new or recurrent VTE 
• Death 
• Primary cause of death 
• Major bleeding 
• Clinically relevant non-major bleeding 
• Serious adverse events 
• Rehospitalization 
• Primary cause of rehospitalization 
 
 

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4. STUDY ORGANIZATION 
 
4.1 Steering Committee 
The Steering Committee will meet periodically to assess the progress, provide 
scientific input on the protocol and possible amendments as well as on the 
“state of the art” and any ongoing development during the study which could 
have consequences for the performance of the study, and address policy issues 
and operational aspects of the protocol and recommendations of the Data 
safety Monitoring Board (DSMB). 
 
4.2 Investigators 
Participating investigators will be responsible for enrollment of patients who 
meet the inclusion and none of the exclusion criteria, obtaining informed 
consent, and management of patients randomized to the intervention. 
Participating investigators will not be allowed to manage patients randomized to 
usual care. 
 
4.3 Adjudication 
A committee of two clinical experts from Ramon y Cajal Hospital (Spain) who 
will be unaware of the study-group assignments will confirm all outcomes and 
classify the cause of all deaths as due to PE, due to COPD, due to bleeding, or 
due to another cause. 
 
4.4 Data Safety Monitoring Board 
The DSMB will consist of independent clinicians and statisticians. At regular 
intervals the DSMB will review safety and outcome data provided by SH 
Medical and report to the Chairman of the Steering Committee. The DSMB will 
also conduct analyses of data at the request of the Steering Committee. 
 
In order to assure patient safety, the DSMB will be provided in a timely fashion 
with data on safety end points in periodic cumulative reports. 

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4.5 Data management 
Study data will be entered into the electronic case report forms (e-CRFs), 
embedded in the SLICE database by the authorized principal investigators or 
sub-/co-investigators (www.estudioslice.org). The data-management of the 
study database maintenance will be performed by the CRO (SH Medical) 
according to its own Standard Operating Procedures. Data evaluated by the 
DSMB will be extracted periodically from the trial database. After data base 
lock, the database will be transferred to the Chairman. 
 
4.6 Central readings 
Image interpretations for all radiological tests except venous ultrasonography 
will be based on agreement of two certified readers in the SLICE trial who were 
from Ramón y Cajal Hospital. Readers will be unaware of all clinical information 
and of the study arm.

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5. CALENDAR 
It is estimated that the trial duration will be 4 years. After legal approvals, it is 
expected that enrollment will begin the last trimester of 2014. 

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6. LEGAL ISSUES 
The trial will be carried out: 
 
• In compliance with the protocol. 
 
• In compliance with Conventions of the Council of Europe on Human 
Rights and Biomedicine, UNESCO Declaration. 
• In accordance with the Declaration of Helsinki, version as of Oct. 
1996, the International Conference on Harmonization (ICH) 
Harmonized Tripartite Guideline for Good Clinical Practice (GCP) 
and in accordance with applicable Spanish regulatory requirements. 
 
-Informed consent: Ethical and legal requirements in accordance with 
international declarations (e.g., Declaration of Helsinki, Conventions of the 
Council of Europe on Human Rights and Biomedicine, UNESCO 
Declaration) will be fulfilled in this study. The person who informs the 
subject should be a physician. An informed consent document that includes 
both information about the trial and the consent form will be prepared and 
given to the subject. This document will comply with all local requirements 
and the requirements set out in GCP. The document must be in a language 
understandable to the subject and must specify who informed the subject. 
After reading the informed consent document, the subject is asked to give 
consent in writing. 
  
The subject's consent must be confirmed at the time of consent by the 
personally dated signature of the subject or the subject's legally authorized 
representative (means an individual or judicial or other body authorized 
under applicable law to consent on behalf of a prospective subject to the 
subject's participation in the procedures involved in research). A copy of 
the signed consent document must be given to the subject or the subject's 
legally authorized representative. The original signed consent document 
will be retained by the investigator (a copy may be requested by the 
sponsor). 

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The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors appointed by the Sponsor, or by appropriate 
IEC/IRB members or by inspectors from regulatory authorities. Should a 
protocol amendment be made, the subject consent form and subject information 
form may need to be revised to reflect the changes to the protocol. It is the 
responsibility of the investigator to ensure that an amended consent form is 
reviewed and received approval/favorable opinion from the ICE or IRB, and 
that it is signed by all subjects subsequently entered in the trial and those 
currently in the trial, if affected by the amendment. 
 
-Confidentiality: Individual subjects medical information obtained as a result 
of this study is considered confidential (according to Spanish regulations, 
LOPD 15/1999) and disclosure to third parties is prohibited with the 
exceptions noted below. Subject confidentiality will be further ensured by 
utilizing subject identification code numbers to correspond to treatment data 
in the computer files. Such medical information may be given to the patient's 
personal physician or to other appropriate medical personnel responsible for 
the subject's welfare. Data generated as a result of this trial are to be 
available for inspection on request by the participating physicians, the 
Sponsor’s representatives, by the IEC/IRB and the regulatory health 
authorities. 
 
-Insurance cover: The Sponsor will take out no-fault insurance cover for 
all subjects included in the trial. The conditions of this insurance cover 
are available to the investigators on request. The investigator can make 
this information available to subjects on request. 
 
-Adverse events: Following the subject’s written consent to participate in the 
study, which must be obtained before any screening procedures, all SAEs 
must be collected, including those thought to be associated with clinical study 

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procedures. All SAEs must be reported to the Sponsor (Hospital Ramón y 
Cajal) within 24 hours of awareness. 
 
-Publication policy: The Sponsor is dedicated to supporting the process of 
free exchange of relevant scientific information. Any publication of the 
results of this trial must be consistent with the publication policy of the 
Sponsor (Hospital Ramón y Cajal) and Executive Committee. Some 
general rules are laid down below. 
 
This study represents a joint effort between the Sponsor and the 
investigators. A publication policy will be presented by the Writing 
Committee and approved by the Steering Committee: 
 
• 
All investigators and members of these committees agree to 
abide by the policy. 
 
• 
Agreement on authorship of the main paper -Conditions for secondary 
manuscripts. 
 
• 
It is foreseen that the Study Chairman, Co-chairman and the Writing 
Committee will prepare a manuscript plan to ensure timely and high-
quality presentation and publication of the study results and provide 
this to the Sponsor for due consideration. Local publication of part(s) 
of the results is not allowed before the publication of the main study. 
 
• 
The Study Chairman and Co-chairman will submit any manuscript to 
members of the Steering Committee for comment and release prior to 
the actual submission to a learned society or scientific journal. 
 
• 
After this, Investigators may submit secondary papers, but these 
should be provided according to the publication policy for review 
and approval. 
 

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One week should be allowed for review by the Sponsor of abstracts planned 
to be submitted to a learned society, and 3 weeks should be allowed for 
review of papers planned to be submitted to a scientific journal. 
 
 
 

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7. REFERENCES 
 
1. Peces-Barba G, Barberá JA, Agusti A, Casanova C, Casas A, Izquierdo JL, 
et al. Guía de práctica clínica de diagnóstico y tratamiento de la 
Enfermedad Pulmonar Obstructiva Crónica. Normativa SEPAR-ALAT. Arch 
Bronconeumol 2008; 44: 271-281. 
2. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, 
management and prevention of chronic obstructive pulmonary disease. 
NHLBI/WHO/GOLD. Am J Respir Crit Care Med 2007; 176: 532-555. 
3. Sobradillo Peña V, Miravitlles M, Gabriel R, et al. Geographic variations in 
prevalence and underdiagnosis of COPD. Chest 2000; 118: 981-989. 
4. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the 
diagnosis, management, and prevention of chronic obstructive lung disease 
(GOLD) workshop summary. Am J Respir Crit Care Med 2001; 163: 1256-
1276. 
5. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, 
management, and prevention of chronic obstructive pulmonary disease: 
GOLD executive summary. Am J Respir Crit Care Med 2013; 187: 347-365. 
6. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause 
and prevention. Lancet 2007; 370(9589): 786-796. 
7. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation 
in chronic obstructive pulmonary disease severe exacerbations. Am J 
Respir Crit Care Med 2006; 173: 1114-1121. 
8. Beghé B, Verduri A, Roca M, et al. Exacerbation of respiratory symptoms in 
COPD patients may not exacerbations of COPD. Eur Respir J 2013; 41: 
993-995. 
9. Winter JH, Buckler PW, Bautista AP, et al. Frequency of venous thrombosis 
in patients with an exacerbation of chronic obstructive lung disease. Thorax 
1983; 38: 605-608. 

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10. Schonhofer B, Kohler D. Prevalence of deep-vein thrombosis of the leg in 
patients with acute exacerbation of chronic obstructive pulmonary disease. 
Respiration 1998; 65: 173-177. 
11. Erelel M, Cuhadaroglu C, Ece T, et al. The frequency of deep venous 
thrombosis and pulmonary embolus in acute exacerbation of chronic 
obstructive pulmonary disease. Respir Med 2002; 96: 515-518. 
12. Mispelaere D, Glerant JC, Audebert M, et al. Pulmonary embolism and 
sibilant types of chronic obstructive pulmonary disease decompensations. 
Rev Mal Respir 2002; 19: 415-423. 
13. Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in 
patients with unexplained exacerbations of chronic obstructive pulmonary 
disease: prevalence and risk factors. Ann Intern Med 2006; 144: 390-396. 
14. Rutschmann OT, Cornuz J, Poletti PA, et al. Should pulmonary embolism 
be suspected in exacerbation of chronic obstructive pulmonary disease? 
Thorax 2007; 62: 121-125. 
15. Rizkallah J, Man P, Sin D. Prevalence of pulmonary embolism in acute 
exacerbations of COPD. Chest 2009; 135: 786-793. 
16. Anderson D, Kahn SR, Rodger MA, et al. Computed tomographic 
pulmonary angiography vs ventilation-perfusion lung scanning in patients 
with suspected pulmonary embolism. JAMA 2007; 298: 2743-2753. 
17. The Prospective Investigation on Pulmonary Embolism Diagnosis 
Investigators. Value of the ventilation-perfusion scan in acute pulmonary 
embolism. JAMA 1990; 263: 2753-2759. 
18. Nijkeuter M, Sohne M, Tick LW, et al. The natural course of 
hemodynamically stable pulmonary embolism: clinical outcome and risk 
factors from a large prospective cohort study. Chest 2007; 13: 517-523. 
19. Konstantinides SV, Torbicki A, Agnelli G, et al; Authors/Task Force 
Members. 2014 ESC Guidelines on the diagnosis and management of 
acute pulmonary embolism: The Task Force for the Diagnosis and 
Management of Acute Pulmonary Embolism of the European Society of 

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Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). 
Eur Heart J 2014; 35: 3033-3073. 
20. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on 
Control of Anticoagulation. Definition of clinically relevant non-major 
bleeding in studies of anticoagulants in atrial fibrillation and venous 
thromboembolic disease in non-surgical patients: communication from the 
SSC of the ISTH. J Thromb Haemost 2015; 13: 2119-2126. 
21. Pozo-Rodríguez F, Lopez Campos JL, Alvarez Martinez CJ, et al. Clinical 
audit of COPD patients requiring hospital admissions in Spain: AUDIPOC 
Study. Plos One 2012; 7: e42156. 
22. Fidahussein SS, Croghan IT, Cha SS, Klocke DL. Posthospital follow-up 
visits and 30-day readmission rates in chronic obstructive pulmonary 
disease. Risk Management and Healthcare Policy 2014; 7: 105-112. 
 
 
 

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Table 1. Inclusion criteria 
 
Inclusion criteria 
Previous diagnosis of COPD: post-bronchodilator forced expiratory volume in 
one second (FEV1) / forced vital capacity (FVC) < 0.7 
Hospital admission because COPD exacerbation without initial clinical 
suspicion of PE in the Emergency Department (according to the Emergency 
Department physician evaluation) 
 
Definition of initial suspicion of PE 
Defined as the indication of a D-dimer testing or a multidetector computed 
tomography (CT) angiogram by the attending physician in the Emergency 
Department. 

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Table 2. Exclusion criteria 
 
Exclusion criteria 
Unable to provide informed consent 
Contraindication to a contrast-enhanced, PE-protocol, multidetector 
computerized tomography (CT) pulmonary angiogram: allergy to intravenous 
contrast medium, or renal failure defined as a creatinine clearance < 30 
mL/min, based on the Cockroft-Gault equation 
Anticoagulant therapy at the time of hospital admission 
Pregnancy, or breast feeding 
Life expectancy of less than 3 months 
Diagnosis of pneumothorax, or pneumonia (fever [temperature > 38ºC], and 
purulent sputum, and new infiltrate in chest X-ray) 
Diagnosis of lower respiratory tract infection (fever [temperature > 38ºC], 
increased sputum volume and/or increased sputum purulence). 
Indication of invasive mechanical ventilation at the time of hospital admission 
Inability to comply with study assessments 
 
 
 

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Appendix 1. Cockroft-Gault formula 
 
CrCl (male) = ([140-age] × weight in kg)/(serum creatinine × 72) 
CrCl (female) = CrCl (male) × 0.85