A two-centre RCT is being performed at the outpatient departments of Østfold Hospital Trust (ØHT) and Akershus University Hospital (AHUS) in Norway. Patients with PPS are 1:1 randomized (using sealed envelopes) into 2 arms; an intervention arm and a control arm. In addition, a group of patients with no PPS following PE will be examined at baseline to compare patients with and without persistent dyspnea after PE in terms of exercise capacity, daily physical activity, dyspnea and HRQoL.
The primary study objective is to explore the short-term changes in exercise capacity from baseline to 12 weeks after inclusion between groups as measured by the incremental shuttle walk test (ISWT). The secondary objectives are to explore the long term effect of the rehabilitation program on exercise capacity 36 weeks after inclusion between groups (ISWT) as well as changes in exercise endurance (ESWT), subjective symptoms of dyspnea, daily physical activity levels and HRQoL from baseline to 12 and 36 weeks after inclusion.
Figure 1: Study design
Patients diagnosed and treated for PE 6 months to 6 years previously at ØHT or AHUS are identified from ØHT’s Thrombosis registry (TROLL registry – NSD 28435/3/LMR) (ØHT only) or via ICD-10 discharge codes (AHUS). Patients are invited to participate by postal mail.
Inclusion criteria include: age 18-75 years, objectively diagnosed symptomatic PE (greater than isolated sub-segmental PE) by CTPA 6 months to 6 years prior to inclusion to the study, persistent dyspnea defined as modified Medical Research Council (mMRC) breathlessness scale grade > 1 that had appeared or worsened after the diagnosis of PE, and the ability to provide written informed consent.
Exclusion criteria include: pulmonary diseases (such as COPD GOLD >2 or restrictive pulmonary diseases, lung cancer or pleural disease), heart failure, CTEPH, significant valvular heart disease, patients with a condition that would interfere with the ability to comply with the study protocol or to give informed consent (e.g. history of drug abuse, excessive alcohol beverage consumption, cognitive dysfunction, or severe psychiatric disease), active malignancy or recurrent, metastatic or inoperable disease, life expectancy less than 3 months, and pregnancy.
The investigators performing the walking tests at follow-up are blinded to the patients’ group allocation.
Patients in the intervention group are allocated to a basic pulmonary rehabilitation program consisting of a supervised, outpatient exercise program for 1 hour twice weekly for 8 weeks. Experienced physiotherapists construct an individually adapted exercise program based on existing pulmonary rehabilitation programs (combining relaxation, interval training at moderate intensity measured with the Borg scale, and resistance training), and an educational session provided by a doctor and a physiotherapist. The educational session includes topics, such as normal anatomy and physiology of the respiratory and circulatory system, information on PE and PPS, breathing strategies, and benefits of exercise/physical activity. Training attendance is documented and patients will be given a simple home-based exercise program, consisting of resistance exercises that can be performed without equipment, to be performed once to twice weekly during the intervention period.
Patients randomised to the control group will receive usual care without specific instructions to exercise (no active intervention).
Primary outcome measure
The primary endpoint of the study is improvement in physical capacity as measured by the ISWT. This walking test has been developed to assess exercise capacity and is valid, reliable, and responsive in a number of study populations, including patients with cardiac and respiratory diseases (15). The patient walks between two shuttles along a 9 meter track in a tempo guided by audible sounds which increase in speed every minute for a maximum of 12 minutes. The test ends when the patient cannot manage to keep the correct speed or has to stop because of symptoms (such as dyspnea or fatigue). Standardised instructions will be provided before the test commences. In order to exclude a learning effect, the ISWT is performed twice at baseline with at least 15 minutes between tests. Peripheral oxygen saturation is registered and patients will report their subjective experience of dyspnea during exertion using the Borg scale before and immediately after the test (16). The Borg scale is commonly used for assessing perceived exertion during field walk tests. The minimal clinical important difference (MCID) for the ISWT is 70 meters in patients with cardiac disease and 48 meters in patients with COPD (17, 18).
Secondary outcome measures
Endurance Shuttle Walk Test
The endurance shuttle walk test (ESWT) is a derivative of the ISWT. The patient walks between two shuttles along a 9 meter track at a predefined speed, usually at 85% of the maximum speed derived from the ISWT. The test ends when the patient cannot continue because of symptoms (such as dyspnea or fatigue) or for a maximum of 20 minutes (test completion). The outcome of the ESWT is usually reported as time (minutes and seconds), although in some studies the distance completed (meters) has been used. Studies suggest that the ESWT is more sensitive to change after rehabilitation when compared to the 6MWT and ISWT (19, 20). However, compared to our primary endpoint (ISWT), there is less evidence on using the ESWT and there are no reference values for the PPS population. The MCID for the ESWT has been demonstrated to be 174 – 279 seconds in COPD after pulmonary rehabilitation (21).
Modified MRC dyspnea scale
The mMRC scale is a widely used tool for evaluating the limitation of activities due to dyspnea. This short questionnaire consists of five statements describing the patient`s respiratory disability, ranging from 0 (“not troubled by breathlessness except on strenuous exercise”) to 4 (“too breathless to leave the house or breathless when dressing or undressing”). The MCID for the mMRC is 0.5 points (22).
The Shortness of Breath Questionnaire
The Shortness of Breath Questionnaire (SOBQ) is a patient-reported outcome measure which assesses subjective symptoms of dyspnea associated with activities of daily living (ADL). The SOBQ includes 24 items and each is scored on a scale from 0 (“not at all”) to 5 (“maximal/unable to do because of breathlessness”). Total scores range from 0 to 120 with a higher score indicating a higher degree of dyspnea.
Sensewear activity monitor
Daily physical activity is measured using a Sensewear activity monitor. The participants will wear the monitor for 1 week before and 1 week after the intervention period to investigate whether the intervention results in a change in daily physical activity or not by measuring number of steps taken per day and time spent in different activity intensities. Sensewear is a multisensor activity monitor combining a triaxial accelerometer and is shown to be a reliable and valid tool for measuring physical activity in people with respiratory disease (23, 24).
The EQ-5D-5L has been developed by the Euroqol Group as a patient-reported outcome measure to assess generic health status and HRQoL in 5 different dimensions; mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 possible answers ranging from 1 to 5 with a higher score indicating worse possible state, and these scores can be aggregated to a utility score on a 0–1 scale using a tariff of preferences derived from a general population (25). In addition, the patient subjectively scores their general HRQoL on a visual analogue scale from 0 (“worst imaginable state of health”) to 100 (“best imaginable state of health”).
Pulmonary Embolism Quality of Life Questionnaire
The Pulmonary Embolism Quality of Life Questionnaire (PEmb-QoL) is a disease-specific patient-reported outcome measure to assess HRQoL following PE (26). The PEmb-QoL has 40 items over 6 domains, which assess symptom frequency, the time of day when complaints are at their worst, as well as the effect of pulmonary-speciﬁc symptoms on ADL and work-related problems. Scores for each domain range from 0 to 100 with the average score of all six domains being used to calculate the total score. A lower score indicates better HRQoL. The MCID for the PEmb-QoL is 15 points (27).
The Hospital Anxiety and Depression Scale
The Hospital Anxiety and Depression Scale (HADS) is a patient-reported outcome measure assessing symptoms of depression and anxiety. The HADS provides a total score with a 0 – 42 range with a higher score indicating that the patient is more symptomatic. Scores of ≥19 points indicate symptoms corresponding to cases of anxiety and depression, whilst scores between 15 and 18 points suggest possible symptoms of anxiety and depression. It is also possible to calculate a score for anxiety or depression only (range 0 – 21 points). Scores of ≥11 points indicate symptoms that can be compatible with anxiety/depression, and 8 – 10 points suggest possible symptoms of anxiety/depression. The MCID for the HADS has been suggested to be a reduction in 1.3 to 1.8 points in COPD patients undergoing pulmonary rehabilitation (28).
All outcome measures are completed at baseline, 12 and 36 weeks after inclusion (Figure 1). In addition, a complete baseline evaluation is performed on all participants including a full history and medical examination, routine blood tests and biobanking (10 ml EDTA plasma, 10 ml citrated plasma, 10 ml serum and 10 ml in paxgene), ventilation and perfusion scintigraphy, pulmonary function test (including spirometry, whole body plethysmography, carbon monoxide diffusing capacity of the lung) and transthoracic echocardiography. In addition, cardiac magnetic resonance imaging is performed on 50 participants without PPS, and 50 participants with PPS before and after rehabilitation. Finally, patients will be asked to complete questions on self-reported physical activity and exercise habits.
Data are stored in the secure research server at ØHT to which only the project investigators have access.
Data management and analysis
The results will be analyzed according to the intention-to-treat principle. Baseline characteristics will be described by mean and standard deviation, median and interquartile range or number and proportions as appropriate. The effect of the intervention on the primary outcome (ISWT) will be assessed by comparing the change in exercise capacity after 12 weeks. The primary analysis based on the baseline data and data after 12 weeks will be conducted as a linear regression. The subsequent analysis, which will include data after 36 weeks, will have three measurements per individual to assess the short term and long term effect of the intervention, and will therefore be analyzed using a linear mixed model. This variant of multiple linear regression allows for addressing such correlations as well as adjusting for possible confounders such as age, body mass index, sex, and treatment centre. HRQoL, general activity and the mMRC breathlessness scale will be compared between the 2 groups at 12 weeks using appropriate statistical tests depending on the normality of data. In addition, the model will also account for missing values.
Sample size calculation
There is currently no data on the physical capacity of PPS patients as measured by ISWT. Therefore, in concurrence with the Danish study that was ongoing when we designed our protocol (29) we have based our sample size calculations on the mean improvement in ISWT previously reported in patients with cardiac and respiratory disease. Rolving et al assumed that the achieved difference will be around 70 meters, i.e. comparable to cardiac patients. Based on 6MWT results from a previous study in patients with PPS (6), patients walked between 413 to 480 meters on 6MWT, which is closer to the cardiac population. Therefore, we assume a baseline ISWT for PE patients to be 390 meters.
Based on calculations, our clinical experience, and on previous findings, an improvement of 60 meters or more on the ISWT will be considered as being of clinical relevance. Given these assumptions, a required sample size to test for that effect size with a type 1 error of 5% and a type 2 error of 20%, 86 patients are needed in each study arm. By adding 10% attrition, the required sample size will be a total of 190 patients.