Investigation of Outpatient PUlmonary REhabilitation in Patients Suffering From Post-PE Syndrome: a Randomized Waitlist-controlled Trial - the PURE-PE Study
Phase: NA
Conditions: Pulmonary Embolism
Sponsor: Medical University of Vienna

Investigation of outpatient PUlmonary REhabilitation in patients 
suffering from post-PE syndrome: a randomized waitlist-
controlled trial – the PURE-PE study 
NCT: NCT04615130 
Principal investigators:  
Assoc.-Prof. Priv.-Doz. Dr. Cihan Ay1 
Dr. Ralf Harun Zwick2 
 
Coordinating investigator: 
Dr. Stephan Nopp1 
 
 
 
1Department of Medicine I, Clinical Division of Haematology & Haemostaseology, 
Medical University, Vienna, Austria 
2Outpatient Pulmonary Rehabilitation, Therme Wien Med, Vienna, Austria 
 
 
 

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Study Synopsis 
Title 
Investigation of outpatient PUlmonary REhabilitation in patients 
suffering from post-PE syndrome: a randomized waitlist-controlled 
trial 
Short title 
PURE-PE study  
NCT Number 
NCT04615130 
Primary objective 
The primary objective of the study is to assess the effects of 
outpatient pulmonary rehabilitation (PR) in patients suffering from 
post-PE syndrome on exercise capacity measured by difference in 
6-minute walk test (6MWT). 
Secondary objectives To assess the effect of outpatient PR on: 
1. Maximal exercise capacity  
2. Inspiratory muscle strength  
3. Dyspnea 
4. Functional limitations 
5. Quality of life 
Study design 
This study is a multicenter, parallel, randomized waitlist-controlled 
trial that primarily focuses on the short-term benefit of outpatient 
PR on patients after acute PE.  
Patients will be randomized into an intervention and a control 
cohort. The intervention cohort will receive 6 weeks of outpatient 
PR, while patients in the other treatment arm will serve as control. 
After completion of the randomized study, the second arm will 
undergo PR as well. After one year, a follow-up with regards to 
long-term benefit will be performed.  
Study population 
1) Inclusion criteria 
a. Post-PE syndrome diagnosed 
b. Possibility of starting rehabilitation between 12 and 36 
weeks after initial event of PE 
2) Exclusion criteria 
a. Chronic pulmonary diseases 
b. Active cancer  
c. Pregnancy 
d. Myocardial infarction or cardiac surgery one year prior to 
inclusion 
e. Congenital heart disease, congestive heart failure 
f. History of stroke 

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g. Any previous inpatient or outpatient PR 
Primary endpoint 
Difference in 6MWT (m) at baseline and after 6 weeks 
Secondary endpoints Difference in exercise parameters 
1. Difference in peak oxygen consumption (VO2/kg/min) measured 
with spiroergometry 
2. Difference in maximal workload (Wmax) in cycle ergometer 
tests 
3. Difference in one-repetition maximum for lower extremities 
4. Difference in one-repetition maximum for upper extremities 
5. Difference in maximal inspiratory muscle pressure (Pimax) 
6. Difference in inspiratory muscle endurance (Tlim) 
Difference in dyspnea parameters 
7. Difference in dyspnea at rest and exertion measured with the 
Modified Medical Research Council Dyspnea Scale (mMRC) 
and BORG scale 
Quality of life, functional limitations and others 
8. Change in quality of life will be measured with the EQ-5D-5L 
9. Change in functional limitations assessed with the PROMIS 
Physical function short form and the post-VTE functional status 
scale 
10. Change in anxiety and depression measured with HADS 
Study start and 
duration  
We anticipate starting enrolment in June 2021. Based on our case 
number estimation we aim to include a total number of 48 patients 
over a period of 2 years. Follow-up will be performed one year after 
PR which will result in a total duration of 3 years. 
 
 

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BACKGROUND 
Pulmonary embolism (PE) is an acute complication of venous thromboembolism 
(VTE), which is potentially life-threatening. The incidence of PE has increased over 
time, while its case fatality rate has declined [1, 2]. A significant proportion of 
survivors of acute PE are at risk of disabling long-term sequela, commonly referred to 
as the post-PE syndrome [3, 4]. The post-PE syndrome, with its most severe 
manifestation - chronic thromboembolic pulmonary hypertension (CTEPH) - is 
characterized by persistent dyspnea, chronic (cardiopulmonary) functional limitations 
and decreased quality of life. The incidence of the post-PE syndrome has been 
reported to reach up to 50%, and up to 4% of PE patients may manifest with CTEPH 
[5-7]. 
While many studies in PE survivors have focused on investigation of risk of 
recurrence, presence of residual thrombosis and right ventricular strain [8], only few 
studies examined persistent dyspnea and functional outcomes. Of note, reduced 
physical performance, assessed with the 6-min walk test (6MWT), has been reported 
in approximately half of all patients with PE, which again is associated with 
decreased health-related quality of life [9-11]. Similarly, patient-reported outcome 
measures have indicated acute decline in physical function after PE, which highlights 
the need for measures to improve functional deficits in patients with PE [12]. 
After acute myocardial infarction participation in a cardiopulmonary rehabilitation 
program is recommended to increase functional capacity and quality of life, and 
decrease cardiovascular mortality [13]. However, in patients with PE, evidence for 
rehabilitation is scarce and participation in rehabilitation programs after PE is not 
routine. One retrospective analysis and one prospective study proved feasibility and 
safety of inpatient pulmonary rehabilitation (PR) in PE survivors [14, 15], but no study 

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have evaluated the effect of outpatient PR in patients with PE so far. Only recently, a 
guideline for exercise training and rehabilitation was released for patients with 
chronic pulmonary hypertension, including CTEPH [16]. Whether a broader 
population of patients with PE and persisting symptoms and functional limitations 
would benefit from rehabilitation is unknown. 
Study rationale 
Patients with PE may suffer from long-term consequences, including decreased 
functional capacity with chronic exercise limitations. Current guidelines suggest 
diagnostic workup to identify such patients with post-PE symptoms. However, if 
CTEPH could be excluded, no standardized treatment is available. Cardiopulmonary 
rehabilitation has been shown to be effective in a variety of cardiopulmonary 
diseases. But data on the benefits of PR in patients with PE are scarce, and no data 
about the effects of outpatient PR in PE patients are available so far.  
 
STUDY DESIGN 
This study is a multicentric, academically sponsored, parallel, randomized waitlist-
controlled trial that primarily focuses on the short-term benefit of outpatient PR on 
patients after acute PE. It is important to point out, that only the recruiting part of the 
study will be multicentric. The main study including intervention and study 
assessments will take place in one center only (Therme Wien Med). 
All patients planning undergoing outpatient PR at the Therme Wien Med due to post-
PE symptoms after acute PE are eligible and will be asked for inclusion. After 
inclusion, patients will be randomized into two treatment arms and will be equally 
allocated. One arm will receive 6 weeks of outpatient PR, while patients in the other 

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treatment arm will serve as control. After completion of the study, the second arm will 
undergo PR as well. PR will be performed according to the Austrian guidelines of 
outpatient PR. [17] 
A follow-up will be performed one year after completion of PR and quality of life, 
functional limitations, dyspnea and long-term benefits will be assessed. 
 
PARTICIPANTS 
Eligibility criteria: 
All patients above 18 years who get referred to the outpatient PR center are 
screened for inclusion and exclusion criteria. If patients fulfill all inclusion criteria and 
meet none of the exclusion criteria, patients are asked to consent into study 
inclusion. After written informed consent, patients will be randomized to the treatment 
or control arm. 
 
Inclusion criteria: 
1. Post-PE syndrome (except patients previously diagnosed with CTEPH) diagnosed 
by any of the following: 
 Post-PE functional impairment criteria: 
o New or progressive dyspnea, exercise intolerance and/or diminished 
functional status following a diagnosis of acute symptomatic or 
incidental pulmonary embolism treated with effective therapeutic 
anticoagulation for at least 3 months 

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 Anticoagulation is considered effective if a direct oral 
anticoagulant (DOAC) or Vitamin K-Antagonist was used 
according to guidelines [18] 
o No apparent non-PE related alternative explanation on 
echocardiography, pulmonary function testing and CPET, or other 
diagnostic testing 
 Post-PE Cardiac Impairment criteria 
o Confirmed acute symptomatic or incidental pulmonary embolism treated 
with effective therapeutic anticoagulation for at least 3 months 
o Intermediate/high echocardiographic probability of pulmonary 
hypertension according to ESC criteria, defined as (newly developed if 
prior echocardiographic data are available) estimated peak 
regurgitation velocity >2.8 m/s, or  ≤2.8 m/s associated with at least one 
of the following: 
 RVEDD >30 mm, or RVEDD/LVEDD >0.9 
 Hypokinesia of the RV free wall 
 Exertional dyspnoea corresponding to NYHA class II, III or IV 
 Chronic Thromboembolic Disease criteria 
o Exertional dyspnoea of the NYHA class II, III or IV 
o Persistent thromboembolic material in pulmonary artery tree despite 3 
months of adequate anticoagulant therapy 
o Normal mPAP at rest 
2. Possibility of starting rehabilitation between 12 and 36 weeks after initial event of 
PE.  

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Due to difficulties faced during the COVID-19 pandemic (i.e., very long waiting 
periods to get approval for undergoing rehabilitation, very long waiting lists at the 
rehabilitation unit to start rehabilitation), the decision was made to extend the 
inclusion period to up to 36 weeks after the acute PE event. 
Exclusion criteria 
 CTEPH diagnosis * 
o Criteria 
 At least one mismatched segmental perfusion defect 
demonstrated by ventilation/perfusion scanning after 3 months of 
adequate therapeutic anticoagulation 
 Resting mean pulmonary arterial pressure (mPAP) ≥25 mmHg 
measured by invasive right heart catheterization 
 Pulmonary capillary wedge pressure ≤15 mmHg 
 Chronic pulmonary diseases: COPD, interstitial lung diseases, asthma (only 
patients with severe asthma defined as a FEV1 ≤ 80% will be excluded), a 
statement on COVID-19 was amended due to the pandemic # 
 Active cancer 
o Cancer is considered active, if any of the following applies: 
 has not received potentially curative cancer treatment; or 
 there is evidence that cancer treatment has not been curative 
(e.g. metastatic, progressive or recurrent disease); or 
 cancer treatment is ongoing. [19] 
 Pregnancy 
 Myocardial infarction or cardiac surgery one year prior to inclusion 
 Congenital heart disease, congestive heart failure 
 History of stroke 

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 Any previous inpatient or outpatient PR 
* CTEPH patients will be excluded, because rehabilitation has been proven effective 
in those patients. [20] 
# Patients with a history of moderate, severe, or critical COVID-19 as defined by the 
World Health Organization (WHO) [21] will be excluded from the study. 
Additional criteria that are absolute contraindications for pulmonary 
rehabilitation 
 Acute and decompensated disease states with severe functional restrictions of 
various organ systems (e.g. heart, kidney and liver insufficiency, unstable angina 
pectoris, hemodynamically unstable arrhythmias, acute spinal cord injury, 
untreated hormonal disorders, acute psychological disorders) 
 open tuberculosis 
 active infectious diseases and acute inflammatory processes 
 Stressful and time-consuming therapy that significantly impair the ability to 
rehabilitate (e.g. chemotherapy or radiation therapy after malignancy) 
 Participants who are not sufficiently resilient due to physical or mental impairment 
and / or cannot be mobilized and therefore cannot actively use the rehabilitation 
facility 
 lack of motivation for therapy 
 massive incontinence 
 drugs and alcohol addiction 
 

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Settings and locations where the data is collected 
Inclusion and randomization will be performed at the Outpatient Pulmonary 
Rehabilitation, Therme Wien Med. PR itself, all tests and performance measurements 
will also be carried out at the Therme Wien Med. Similarly, all data will be collected 
there. 
STUDY PROCEDURE 
Pre-Visit 
Patients who get referred to outpatient PR will routinely visit the rehabilitation center 
to arrange a starting date. Here the patients will be screened for eligibility. If all 
inclusion and none of the exclusion criteria are met, the patient will be asked to 
participate in the study. After inclusion the patient will be randomized into the 
intervention or the control arm. Participants in the intervention group will undergo PR 
routinely. Patients in the control arm will arrange a starting date for their rehabilitation 
as well and a date for the 2-day baseline visit 6 weeks prior to their starting date of 
the rehabilitation will be set. 
 
Baseline visit 
Note, baseline visit refers to the starting date of the rehabilitation in the intervention 
group and to the baseline visit in the control group 6 weeks prior to their starting date 
of the PR. 
At baseline visit, referral site will be noted and a structured interview about the 
patient’s medical history will be performed. Information on the PE event including 
severity/anatomical extent, diagnostic method (CTPA, ventilation-perfusion lung 

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scanning, pulmonary angiography), unprovoked/provoked (recent surgery or trauma, 
immobilization, estrogen therapy, active cancer), admitted to intensive care unit, 
concurrent symptomatic DVT, known thrombophilic condition, previous venous 
thromboembolism, right ventricular strain in initial CT or echocardiography. Dyspnoe 
(mMRC, BORG), functional limitations (WHO functional class) will be recorded.  
Furthermore, age, weight, BMI, comorbidities (presented separately and combined 
using the Charlson Comorbidity Index), socioeconomic status will be assessed. A 
recent echocardiogram, which is obligatory for undergoing PR will be added to the 
chart.  
 
Baseline assessments  
At baseline, assessments of cardiopulmonary exercise test (peak VO2), 6MWT, 
inspiratory muscle strength (Pimax, Tlim), maximal workload (Wmax), upper and 
lower extremity strength will be performed. Similarly, measurements of quality of life 
and functional limitations will be assessed. All measurements are further prescribed 
below. 
Those assessment will be conducted within the first 2 days of starting rehabilitation in 
the intervention group and in the control group, assessments will be performed on 2 
consecutive days 6 weeks prior to rehabilitation. On the first day of assessment 
spiroergometry to assess peak VO2 and Wmax will be performed. On the second day 
6MWT, inspiratory muscle pressure assessment, and maximal upper and lower 
extremity strength will be measured. Between measurements patients will have at 
least half an hour to regenerate. Furthermore, it is ensured that there is at least 1 
hour between 6MWT and assessment of lower extremity strength. 

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End of study 
After 6 weeks - at the end of the study - all assessment, which were performed at 
baseline, will be repeated. Adverse events and complications including bleeding 
events, myocardial infarction, and unexpected hospital admissions will be recorded. 
Further, comments will be made in case any patient experienced a disease or an 
event that might potentially influence an outcome. To measure compliance, the 
number of completed sessions will be recorded. 
 
Follow-up study 
After completion of the primary randomized study, follow-up will be performed in a 
different study setting. Since we conduct a waitlist-controlled trial, the control group 
will undergo rehabilitation as well. Therefore, the whole study population will be 
followed up in a prospective cohort setting. One year after the completion of the 
outpatient PR, patients will be contacted via mail and phone and a follow-up will be 
performed with regards to quality of life, functional limitations, hospital admissions, 
smoking habits, recurrent events, comorbidities and medication.  
 
 

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Study flow charts 
Flow chart 1 
 
 
 
Flow chart 2 
Inclusion 
Randomization 
Rehabilitation 
Group 
Control group 
Rehabilitation 
Analysis 
6 weeks 
6 weeks 
1-year follow-up 
Primary outcome:  
peak oxygen uptake 
(VO2) 

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INTERVENTION 
Patients randomized to the treatment group will all undergo a multi-professional and 
individualized PR according to the Austrian guidelines for outpatient PR [17]. Three 
times a week for 3 to 4 hours, participants will complete endurance, strength and 
inspiratory muscle training over 6 weeks. Exercises were individually prescribed 
following a medical evaluation and an exercise tolerance test by the medical 
consultant of the program. 
 
Outpatient pulmonary rehabilitation program 
Patients will undergo a comprehensive interdisciplinary and individualized 
rehabilitation program according to the Austrian guidelines for outpatient PR that has 
been described before in detail [17]. On three half days per week over a period of 6 
weeks patients complete 60 rehabilitation sessions of 50 minutes each. Forty-six of 
the 60 sessions are training sessions only, which accounts for a net workout time of 
approximately 38 hours. The exercise sessions consisting of endurance, strength and 
Intervention 
group 
Control 
group 
Rehabilitation 
Follow-Up 
Rehabilitation 
Wait 
Follow-Up 
T0 
T1 
T2 
T3 

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inspiratory muscle training will performed under supervision of medical staff, 
physiotherapists and sport scientists. Endurance training implements cycle ergometer 
exercises targeting a heart rate calculated by the Karvonen formula [22], strength 
training include 4-6 muscle groups including upper and lower extremity. All patients 
will receive inspiratory respiratory muscle training using a special training device 
(Eumedics -RESPIFIT S). Physiotherapy sessions focus on improvement of 
pulmonary problems, mobility and coordination. Additionally, the program consists of 
individualized patient education, which includes 4 disease- and medical treatment-
specific sessions, 2 sessions focusing on nutritional counseling, and 4 psychologic 
sessions. If indicated further psycho-social counseling and smoking cessation 
sessions will be offered to all participants. Medical evaluation and assessments at 
admission and discharge of PR accounts for another 4 sessions.  
 
MEASUREMENTS 
All variables and measurements  
Demographic data 
Variable 
Units/categories 
Scale 
Time points T 
Age 
Years 
Metric 
T0 
Gender 
Female, male 
Nominal 
T0 
Weight 
kg 
Metric 
T0, T1, T2, T3 
Height 
cm 
Metric 
T0 
Smoking 
Current, Former, Never 
Nominal 
T0, T3 
Education level 
Hauptschule 
Polytechnische Oberschule 
Oberstufengymnasium/Matura 
FH/Universität 
Nominal 
T0 
Marital status 
Married 
Single 
Nominal 
T0 

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Partnership 
Widowed 
Seperated 
Job 
Seeking employment 
In Training 
Employed 
In pension 
Self employed 
Nominal 
T0 
 
PE characteristics 
Variable 
Units/categories 
Scale 
Time points T 
Site of PE 
Unilateral, Bilateral 
Nominal 
T0 
Location of PE 
Central 
Lobar 
Segmental 
Subsegmental 
Nominal 
T0 
DVT present at index 
event 
Yes, No 
Nominal 
T0 
Triggering events 
No event 
Oestrogen use 
Recent surgery 
Long travel 
Immobility 
Nominal 
T0 
 
Exercise parameters 
Units/categories 
Scale 
Time points T 
6MWT 
meter 
Metric 
T0, T1, T2 
Cardiopulmonary 
exercise testing 
 
 
 
Maximal workload 
Watt 
Metric 
T0, T1, T2 
VO2 max 
ml O2/min 
ml O2/min/kg 
Metric 
T0, T1, T2 
CO2 max 
ml O2/min 
ml O2/min/kg 
Metric 
T0, T1, T2 
Ventilation equivalent 
O2 
/ 
Metric 
T0, T1, T2 

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Ventilation equivalent 
CO2 
/ 
Metric 
T0, T1, T2 
Minute ventilation 
volume 
ml 
Metric 
T0, T1, T2 
Tidal volume 
ml/kg/min 
Metric 
T0, T1, T2 
Heart rate at rest 
rate/min 
Metric 
T0, T1, T2 
Heart rate at maximal 
exertion 
rate/min 
Metric 
T0, T1, T2 
Blood pressure at rest 
and maximal exertion 
mmHg 
Metric 
T0, T1, T2 
Constant-work-rate test 
at 70% 
min 
Metric 
T0, T1, T2 
BORG scale at rest and 
maximal exertion 
1-10 
Ordinal 
T0, T1, T2 
Other assessments 
 
 
 
1-MSTST 
counts 
Metric 
T0, T1, T2 
Maximal inspiratory 
muscle pressure 
mbar 
Metric 
T0, T1, T2 
Inspiratory muscle 
endurance 
min 
Metric 
T0, T1, T2 
Lower extremity 
strength 
kg 
Metric 
T0, T1, T2 
Upper extremity 
strength 
kg 
Metric 
T0, T1, T2 
 
Questionnaires and other outcomes  
Questionnaire, Scales 
Scale 
Time points T 
5-level EQ-5D version (EQ-5D-5L) 
Ordinal 
T0, T1, T2, T3 
PEmb-QOL 
Ordinal 
T0, T1, T2, T3 
PROMIS Short Form v2.0 – Physical 
Function 10a 
Ordinal 
T0, T1, T2, T3 
Post-VTE functional status scale 
Ordinal 
T0, T1, T2, T3 
Modified Medical Research Council (mMRC) scale 
Ordinal 
T0, T1, T2, T3 
Hospital Anxiety and Depression Scale (HADS) 
Ordinal 
T0, T1, T2, T3 
Fagerström-Questionnaire 
Ordinal 
T0, T1, T2, T3 
Other outcomes 
Units/categories 
 
 
Adherence 
Number of completed session 
Metric 
T1, T2 
 

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The 6-minute walk test 
The 6MWT is a simple frequently used method in cardiopulmonary studies, and a 
difference of 30.5 m between measurements is considered a minimal clinical 
important difference [23, 24]. Assessment of 6MWT will be performed on a 30 meter 
walking course according to the standardized protocol of the American Thoracic 
Society [25]. 
 
Cardiopulmonary exercise testing 
Peak exercise capacity is defined as “the maximum ability of the cardiovascular 
system to deliver oxygen to exercising skeletal muscle and of the exercising muscle 
to extract oxygen from the blood”. Consequently, exercise tolerance is determined by 
three factors: pulmonary gas exchange; cardiovascular performance, including the 
peripheral vascular tree; and skeletal muscle metabolism [26]. 
At maximal exercise, the Fick equation is expressed as follows: 
Vo2max  =  (SVmax × HRmax) × (Cao2max − Cvo2max) 
where SV is the stroke volume, HR is the heart rate, CaO2 is the arterial oxygen 
content, and CvO2 is the mixed venous oxygen content. 
Cardiopulmonary exercise will be performed with incremental testing according to 
protocol on a cycle ergometer. [26] Starting with 20W the patient will be challenged 
by increasing the workload by 10W each minute until he/her reached his/her maximal 
workload. The following measurements will be taken: Peak oxygen content (PVo2), 
ventilatory anaerobic threshold (VAT), maximum heart rate (HRmax), heart rate 
reserve (HRR), blood pressure (BP), ventilatory reserve (VR), respiratory rate (RR), 
minute ventilation/carbon dioxide output ratio (VE/Vco2) at VAT. 

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Reasons for termination, symptoms and complications will be noted and subjective 
assessment of effort will be assessed with the BORG scale.  
 
Maximal workload 
A continuous and maximal escalating protocol will be used, comprised of an initial 
resting period for six minutes with the patient sitting on the cycle ergometer, followed 
by a four-minute warm-up of pedaling without any workload, and later, by the 
escalating phase with a maximum duration between eight and twelve minutes. 
 
Inspiratory muscle strength 
Maximal inspiratory muscle strength (Pimax) in mbar and inspiratory muscle 
endurance (Tlim) in minutes will be measured with the training device Eumedics -
RESPIFIT S.  
 
Upper and lower extremity strength 
The maximal one-repetition maximum for upper and lower extremities will be 
measured and performed with a training machine. Maximal measurable weight with 
the machine will be 160 kg. 
 
Quality of life, functional limitations and anxiety 
Quality of life will be measured with the EQ-5D-5L [27] and the PEmb-QoL [28]. 
Functional limitations will be assessed with the PROMIS Physical Function short form 
[29] and the post-VTE functional status scale. [30]  

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Anxiety and Depression will be assessed using Hospital Anxiety and Depression 
Scale (HADS) [31].[32] 
Additionally, Fagerström-Test will be used to assess cigarette dependence of the 
participants and to assess effectiveness of smoking cessation session during 
rehabilitation. [33] 
 
ASSESSMENT OF SAFETY 
The study does not intervene in the management of medical issues. As all physical 
assessments are routinely performed at the PR center as well management of 
medical issues which arise during the study will be handled as done during routine. 
However, everything will be recorded and presented to the safety board members. 
The following events will be recorded and reported as a serious adverse event: 
 Death 
 Life-threatening (subject at immediate risk of death) 
 Requires in-patient hospitalization* 
 Persistent or significant disability or incapacity 
 Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the subject 
and may require a surgical intervention to prevent one of the outcomes listed 
in this definition. 
*Any pre-scheduled procedures which requires hospitalization will not be reported as 
an SAE.  

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Data and safety monitoring board (DSMB) 
The board members will meet after 24 participants have undergone rehabilitation. 
Should safety issues arise that the DSMB feel compromises the trial and/or 
participant safety, then the committee will be convened to consider amending or 
stopping the trial. 
 
The safety board members include: 
Ass.-Prof. Dr. Karin Janata-Schwatczek – Department of Emergency Medicine, 
Medical University of Vienna, Vienna, Austria 
Assoc. Prof. Priv. Doz. Dr. Jolanta Siller-Matula, PhD – Department of Medicine II, 
Clinical Division of Cardiology, Medical University Vienna, Vienna, Austria 
PD Dr. Johannes Thaler, PhD – Department of Medicine I, Clinical 
Division of Haematology & Haemostaseology, Medical University Vienna, Vienna, 
Austria 
 
OUTCOMES 
Primary outcome: 
The primary outcome is difference in 6MWT from baseline to 6 weeks. 
For the intervention group, 6MWT will be assessed at admission (until 3rd training 
session) and discharge (last three training sessions). For the control group, 6MWT 

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will be assessed 6 weeks prior to their starting point of their PR and at the beginning 
of their outpatient PR. 
 
Secondary Outcomes: 
Difference in exercise parameters: 
1. Change in peak oxygen uptake (VO2/kg)  
2. Difference in maximal workload (Wmax) on cycle ergometer test 
3. Difference in one-repetition maximum for lower extremities 
4. Difference in one-repetition maximum for upper extremities 
5. Difference in maximal inspiratory muscle pressure (Pimax) 
6. Difference in inspiratory muscle endurance (Tlim) 
Dyspnea parameters 
7. Difference in dyspnea at rest and exertion measured with the Modified Medical 
Research Council Dyspnea Scale (MMRC) and BORG scale 
Quality of life, functional limitations and others 
8. Change in quality of life will be measured with the EQ-5D-5L 
9. Change in functional limitations will be assessed with the PROMIS Physical 
Function short form and the post-VTE functional status scale 
10. Change in anxiety and depression measured with HADS 
 

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Randomization 
Allocation sequence generation 
Randomization will be performed using permuted block randomization with block 
sizes of 2 and 4 and a 1:1 ratio. The site, which refers the patient to PR, will be 
considered as a factor for stratification. Here 3 sites will be considered as a factor 
(AKH, Krankenhaus Hietzing, and all others). At the beginning of the study, 
generation of the random allocation sequence will be performed by Dr. Stephan 
Nopp using the web-based Randomizer software (Version 2.0.3 © Institute for 
Medical Informatics, Statistics and Documentation, Medical University of Graz), which 
ensures that the sequence is hidden to all users. 
 
Allocation concealment 
Enrolling and assigning the patients to the different treatment arms will be done by 
Dr. Ralf Harun Zwick, the head of the outpatient PR unit using the Randomizer 
software. By entering the participant’s name into the randomization software, the 
program will automatically assign the participant to the different treatment groups. A 
unique study participant number and study group allocation will be given after 
entering the patients’ basic information and eligibility criteria. Furthermore, the 
allocation concealment is ensured by the Randomizer software and the permuted 
block randomization.  
 
Implementation 
Generation of the random allocation sequence will be performed by Dr. Stephan 
Nopp using the Randomizer Software. Enrolling and assigning the patients to the 

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different treatment arms will be done by Dr. Ralf Harun Zwick, the head of the 
outpatient PR unit. 
 
Blinding 
Patients will be kept uniformed about the different nature of the treatment arms and 
their allocation. The participants will be informed that they participate in a study with 
different time points on starting rehabilitation, but they will not know about the nature 
of the study arms and to which arm they got allocated to. On the site of the outpatient 
PR only Dr. Ralf Harun Zwick knows about the allocation of the patients. 
Assessments (e.g. spiroergometry, 6MWT) will be performed by the outpatient 
rehabilitation staff who will be blinded to the treatment arm of the participants. They 
will not be instructed about the nature of the ongoing study and especially not to 
which treatment arm the patients belong to. This is possible because the exercise 
measurements are part of the routine program which is completed by all patients 
undergoing PR at this center. 
 
STATISTICAL CONSIDERATIONS 
Sample Size 
Sample size estimation was based on certain assumptions, including that a week 6 
mean change from baseline 6MWD of at least 30.5 meters between treatment and 
control group would be considered a clinically meaningful change. This estimation 
was taken from a systematic review on minimal clinically important difference (MCID) 
of patients with cardiopulmonary disease. [24] Assumptions on standard deviations 
are based on a previously published article on rehabilitation by our group. [34] 

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A sample size of 20 in each group will have 80% power to detect a difference in 
means of 30.5m assuming that the Group 1 standard deviation, σ₁, is 40 and the 
Group 2 standard deviation, σ₂, is 20 (ratio of Group 2 to Group 1 standard deviation 
is 0.5) using a two group Satterthwaite t-test with a 0.05 two-sided significance level. 
To correct for a potential design effect, estimated sample size number will be 
multiplied by 1.2. This accounts for a total sample size of 48 patients for both 
treatment arms. 
In addition, sample size estimation was performed for the main secondary endpoint 
change of VO2/peak oxygen consumption.  
Data from the ELOPE-study reporting on PE patients showed a mean (SD) VO2 peak 
of 1,971.2 (663.3) mL/min or 23.3 (9.2) mL/kg/min at 1 year. Patients with functional 
limitations (VO2 peak < 80%), reached a VO2 peak of 18.9 (4.2) mL/kg/min. [9] Few 
data on clinically important difference in VO2 peak is available to date and no data on 
VO2 and MCID in PE patients exists. Therefore, MCID estimation are based on 
known results in different diseases. In severe COPD a change in 40 mL/min (0.5 
mL/kg/min for an 80kg patient) is considered a meaningful change. Further, data on 
pulmonary arterial hypertension (PAH) patients show an increase in 1-1.5 mL/kg/min 
after rehabilitation. [35] Based on these data we estimate that a change in 2 
mL/kg/min, which would approximately account for a 10% increase from the baseline 
VO2 value, would definitely be considered a meaningful change. [36] Standard 
deviation for sample size calculation was estimated based on previous studies. [9, 
35, 36] 
Therefore, with a sample size of 24 in each group we should be able to detect a 
difference of 2 mL/kg/min peak VO2 assuming the intervention group standard 
deviation, σ₁, is 3 mL/kg/min and the control group standard deviation, σ₂, is 1.5 

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mL/kg/min (ratio of Group 2 to Group 1 standard deviation is 0.333) using a two 
group Satterthwaite t-test with a 0.05 two-sided significance level.  
Final analysis will be conducted using Analysis of Covariance (ANCOVA) model 
using baseline as a covariate. 
For all other secondary exercise parameter outcomes, no minimal important 
difference is known. However, the sample size of 48 patients will be big enough to 
detect at least a 10% increase of the baseline variable assuming that the control 
group will not or only slightly improve in performance on each assessment.  
Sample size calculations were performed using nQuery 8 (Version 8.5.1.0, Statistical 
Solutions Ltd.) 
 
Analysis 
In order to correct for the regression to the mean effect, statistical analysis for the 
primary outcome comparing peak VO2 between the two treatment arms will be 
performed using Analysis of Covariance (ANCOVA) model using baseline value as a 
covariate. 
Both, intention-to-treat and per-protocol analysis, will be reported. Intention-to-treat 
analysis will be performed according to randomization. Per-protocol analysis will be 
performed with all participants completing at least 80% of the outpatient PR sessions 
in the intervention group. Sensitivity analysis will be performed adjusted for age and 
sex. 

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Similarly, all other exercise parameters, scores on functional limitation and quality of 
life scores will be assessed by comparing the mean difference in group A and group 
B using an ANCOVA with baseline value as a covariate. 
Patient demographics, clinical characteristics, and follow-up data will be summarized 
as mean and standard deviation, median and 25th-75th percentile (i.e. interquartile 
range [IQR]), or frequencies and proportions, as appropriate.  
Quality of life questionnaires will be analyzed in a blinded fashion.  
 
DATA HANDLING AND RECORD KEEPING 
Electronic Case Reports Forms Data (eCRF) collection will be performed using a 
web-based system. Only trained research personnel will have authorization with an 
access password to enter and modify eCRFs. The web-based system functions with 
a secure server and backups will be done regularly. An audit trail will be implemented 
that will track who enters the data and when. All data queries, responses to queries 
and changes to the data will be captured in the eCRF. 
 
 

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