Exercise‐based rehabilitation programmes for pulmonary hypertension
Norman R Morris
Fiona D Kermeen
Arwel W Jones
Joanna YT Lee
Anne E Holland
Corresponding author.
Collection date 2023.
Abstract
Background
Individuals with pulmonary hypertension (PH) have reduced exercise capacity and quality of life. Despite initial concerns that exercise training may worsen symptoms in this group, several studies have reported improvements in functional capacity and well‐being following exercise‐based rehabilitation.
Objectives
To evaluate the benefits and harms of exercise‐based rehabilitation for people with PH compared with usual care or no exercise‐based rehabilitation.
Search methods
We used standard, extensive Cochrane search methods. The latest search date was 28 June 2022.
Selection criteria
We included randomised controlled trials (RCTs) in people with PH comparing supervised exercise‐based rehabilitation programmes with usual care or no exercise‐based rehabilitation.
Data collection and analysis
We used standard Cochrane methods. Our primary outcomes were 1. exercise capacity, 2. serious adverse events during the intervention period and 3. health‐related quality of life (HRQoL). Our secondary outcomes were 4. cardiopulmonary haemodynamics, 5. Functional Class, 6. clinical worsening during follow‐up, 7. mortality and 8. changes in B‐type natriuretic peptide. We used GRADE to assess certainty of evidence.
Main results
We included eight new studies in the current review, which now includes 14 RCTs. We extracted data from 11 studies. The studies had low‐ to moderate‐certainty evidence with evidence downgraded due to inconsistencies in the data and performance bias. The total number of participants in meta‐analyses comparing exercise‐based rehabilitation to control groups was 462. The mean age of the participants in the 14 RCTs ranged from 35 to 68 years. Most participants were women and classified as Group I pulmonary arterial hypertension (PAH). Study durations ranged from 3 to 25 weeks. Exercise‐based programmes included both inpatient‐ and outpatient‐based rehabilitation that incorporated both upper and lower limb exercise.
The mean six‐minute walk distance following exercise‐based rehabilitation was 48.52 metres higher than control (95% confidence interval (CI) 33.42 to 63.62; I² = 72%; 11 studies, 418 participants; low‐certainty evidence), the mean peak oxygen uptake was 2.07 mL/kg/min higher than control (95% CI 1.57 to 2.57; I² = 67%; 7 studies, 314 participants; low‐certainty evidence) and the mean peak power was 9.69 W higher than control (95% CI 5.52 to 13.85; I² = 71%; 5 studies, 226 participants; low‐certainty evidence). Three studies reported five serious adverse events; however, exercise‐based rehabilitation was not associated with an increased risk of serious adverse event (risk difference 0, 95% CI −0.03 to 0.03; I² = 0%; 11 studies, 439 participants; moderate‐certainty evidence). The mean change in HRQoL for the 36‐item Short Form (SF‐36) Physical Component Score was 3.98 points higher (95% CI 1.89 to 6.07; I² = 38%; 5 studies, 187 participants; moderate‐certainty evidence) and for the SF‐36 Mental Component Score was 3.60 points higher (95% CI 1.21 to 5.98 points; I² = 0%; 5 RCTs, 186 participants; moderate‐certainty evidence). There were similar effects in the subgroup analyses for participants with Group 1 PH versus studies of groups with mixed PH. Two studies reported mean reduction in mean pulmonary arterial pressure following exercise‐based rehabilitation (mean reduction: 9.29 mmHg, 95% CI −12.96 to −5.61; I² = 0%; 2 studies, 133 participants; low‐certainty evidence).
Authors' conclusions
In people with PH, supervised exercise‐based rehabilitation may result in a large increase in exercise capacity. Changes in exercise capacity remain heterogeneous and cannot be explained by subgroup analysis. It is likely that exercise‐based rehabilitation increases HRQoL and is probably not associated with an increased risk of a serious adverse events. Exercise training may result in a large reduction in mean pulmonary arterial pressure. Overall, we assessed the certainty of the evidence to be low for exercise capacity and mean pulmonary arterial pressure, and moderate for HRQoL and adverse events. Future RCTs are needed to inform the application of exercise‐based rehabilitation across the spectrum of people with PH, including those with chronic thromboembolic PH, PH with left‐sided heart disease and those with more severe disease.
Keywords: Adult; Aged; Female; Humans; Male; Middle Aged; Bias; Exercise; Exercise Therapy; Exercise Therapy/adverse effects; Hypertension, Pulmonary; Quality of Life
Plain language summary
Exercise‐based rehabilitation in pulmonary hypertension
Key messages
In people with pulmonary hypertension who are medically stable, exercise‐based rehabilitation is most likely to be safe and improve quality of life. The evidence suggests that exercise‐based rehabilitation may result in a large increase in exercise capacity and a reduction in mean pulmonary arterial pressure.
What is pulmonary hypertension?
Pulmonary hypertension is a condition in which the blood pressure in the arteries that carry blood from the heart to the lungs is elevated well above normal. Often with a gradual onset, it affects people of all ages, reduces their quality of life and results in premature death. Exercise‐based rehabilitation is recommended for other chronic lung and heart disease populations; however up until recently, exercise was not recommended for pulmonary hypertension.
What did we want to find out?
We wanted to review the evidence from well‐designed clinical trials that compared exercise‐based rehabilitation with usual care.
What did we do?
We searched medical databases for clinical trials comparing exercise training versus usual care in people with PH to see if exercise improved short‐ and long‐term outcomes such as exercise capacity, health‐related quality of life, serious side effects and changes in the pressure in the pulmonary circulation. The updated review included 14 studies with 574 people, and we included data from 11 studies in analyses (462 participants).
What did we find?
The studies reported that exercise‐based rehabilitation may result in large increases in exercise capacity as evaluated by how far people could walk in six minutes and maximal oxygen consumption using a specialised exercise test; however, there was marked variability in this response. Health‐related quality of life was also most likely to be improved and exercise‐based rehabilitation may also result in a large reduction in the pressure in the pulmonary circulation. Serious side effects were rare and exercise‐based rehabilitation was unlikely to increase the risk of them.
What are the limitations of the evidence?
The evidence from these trials was of low to moderate quality. The main limitations in the studies was a lack of allocation concealment (participants knew whether they were in the exercise group or not, which could cause bias) and studies did not report the results of all the outcome data. In addition, some outcomes, for example exercise capacity, had a variable response, which we could not explain by examining different subgroups of people.
How up to date is this evidence?
The evidence is current to 28 June 2022.
Summary of findings
Summary of findings 1. Exercise compared to control for pulmonary hypertension.
| Exercise compared to control for pulmonary hypertension | ||||||
| Patient or population: people with pulmonary hypertension Settings: inpatient or outpatient rehabilitation, or both Intervention: exercise training Comparison: control: people who had usual care and did not undertake exercise training programme | ||||||
| Outcomes | Illustrative comparative effects* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Certainty of the evidence (GRADE) | What happens | |
| Control | Exercise | |||||
| Exercise capacity: 6MWD Distance, metres Follow‐up median 12 weeks | The mean change in 6MWD ranged from −29 m to 16.9 m | The mean change in 6MWD in the intervention groups was48.52 m higher (33.42 to 63.62 higher) | — | 418 (11 studies) | ⊕⊕⊝⊝ Lowa,b | Exercise training may result in a large increase in 6MWD. PAH subgroup (3 studies, 71 participants): mean 6MWD for intervention group was63.97 m higher (95% CI 8.74 to 119.21 higher; P = 0.02, I² = 75%). Mixed PH subgroup (8 studies, 347 participants): mean 6MWD for intervention group was44.16 m higher (95% CI 28.97 to 59.36 higher; P < 0.001, I² = 72%). Examining heterogeneity, inpatient vs outpatient exercise training: included inpatient exercise training (5 studies, 280 participants): mean 6MWD for intervention group was50.54 m higher (95% CI 39.00 to 62.07 higher; P < 0.001, I² = 81%). Outpatient exercise training (6 studies, 138 participants): mean 6MWD for intervention group was36.69 m higher (95% CI 27.85 to 45.52 higher; P < 0.001, I² = 53%). Minimal important difference was 30 m. |
| Exercise capacity: VO2peak Oxygen uptake, mL/kg/min Follow‐up median 13.5 weeks | The mean change in VO2peak ranged from −0.5 mL/kg/min to 0.4 mL/kg/min | The mean VO2peak in the intervention groups was2.07 mL/kg/min higher (1.57 to 2.57 higher) | — | 314 (7 studies) | ⊕⊕⊝⊝ Lowb,c | Exercise training may increase peak oxygen uptake. PAH subgroup (2 studies, 36 participants): mean VO2peak in the intervention groups was1.28 mL/kg/min higher (95% CI 0.19 lower to 2.75 higher; P = 0.09, I² = 0%). Mixed PH subgroup (5 studies, 278 participants): mean VO2peak in the intervention groups was2.17 mL/kg/min higher (95% CI 1.64 to 2.70 higher, P < 0.001, I² = 72%). Examining heterogeneity, inpatient vs outpatient exercise training: included inpatient exercise training (3 studies, 217 participants): mean VO2peak for intervention group was2.00mL/kg/min higher (95% CI 1.36 to 2.64 higher, P < 0.001, I² = 83%). Outpatient exercise training (4 studies, 97 participants): mean VO2peak for intervention group was2.18 mL/kg/min higher (95% CI 1.38 to 2.98 higher, P < 0.001, I² = 21%). |
| Exercise capacity: peak power watts Follow‐up median 13.5 weeks | The mean change in Wpeak ranged from −4 W to 10 W | The mean exercise capacity: peak power in the intervention groups was9.69 W higher (5.52 to 13.85 higher) | — | 226 (5 studies) | ⊕⊕⊝⊝ Lowb,d | Exercise training may increase peak power. PAH subgroup (2 studies, 36 participants): mean peak power in the intervention groups was14.24 W higher (95% CI 5.78 to 22.70 higher; P < 0.001, I² = 0%). Mixed PH subgroup (3 studies, 190 participants): mean Wpeak in the intervention groups was8.22 W higher (95% CI 3.43 to 13.01 higher; P < 0.001, I² = 84%). Examining heterogeneity, inpatient vs outpatient exercise training: included inpatient exercise training (3 studies, 190 participants): mean peak power in the intervention groups was8.22 W higher (95% CI 3.43 to 13.01 higher; P = 0.008, I² = 84%). Outpatient exercise training only (2 studies, 36 participants): mean peak power in the intervention groups was14.24 W higher (95% CI 5.78 to 22.70 higher; P < 0.001, I² = 0%). |
| Serious adverse events Follow‐up median 12 weeks | 1 total for control group | — | RD 0 (–0.03 to 0.03) | 439 (11 studies) | ⊕⊕⊕⊝ Moderatee | Exercise training is probably not associated with an increased risk of a serious adverse event. PAH subgroup (3 studies, 109 participants): RD –0.01 (95% CI –0.07 to 0.06). 1 death reported in the control group (Rakhmawati 2020). Mixed PH subgroup (8 studies, 330 participants): RD 0.01 (95% CI –0.03 to 0.04). |
| HRQoL SF‐36: PCS units Follow‐up median 11 weeks. Note higher scores = better health status | The mean change in the PCS ranged from ‐1 to 3.9 points | The mean HRQoL SF‐36: PCS in the intervention groups was3.98 points higher (1.89 to 6.07 higher) | — | 187 (5 studies) | ⊕⊕⊕⊝ Moderated | Exercise training likely improves the physical components of HRQoL. PAH subgroup (2 studies, 33 participants): mean HRQoL SF‐36: PCS in the intervention groups was4.63 higher (95% CI 0.80 to 8.47 higher). Mixed PH subgroup (3 studies, 33 participants): mean HRQoL SF‐36: PCS in the intervention groups was3.71 higher (95% CI 1.20 to 6.19 higher). |
| HRQoL SF‐36: MCS units Follow‐up median 11 weeks. Note higher scores = better health status | The mean change in the MCS ranged from −3.1 to 2.3 points. | The mean HRQoL SF‐36: MCS in the intervention groups was3.60 points higher (1.21 to 5.98 higher) | — | 186 (5 studies) | ⊕⊕⊕⊝ Moderated | Exercise training likely improves the mental components of HRQoL. PAH subgroup (2 studies, 33 participants): mean HRQoL SF‐36: MCS in the intervention groups was4.17 points higher (95% CI 0.01 to 8.34 higher). Mixed PH subgroup (3 studies, 153 participants): mean HRQoL SF‐36: MCS in the intervention groups was3.31 points higher (95% CI 0.40 to 6.22 higher). |
| Cardiopulmonary haemodynamics (mPAP) mmHg Follow‐up median 12 weeks | The mean change in the mPAP ranged from 5 to 5.8 mmHg. | The mPAP in the exercise group was9.29 mmHg lower (12.96 to 5.61 mmHg lower) | — | 133 (2 studies) | ⊕⊕⊝⊝ Lowf | Exercise training may result in a large decrease in mPAP. |
| *The basis for the response on control is the median control group response across studies. 6MWD: 6‐minute walk distance;CI: confidence interval;HRQoL: health‐related quality of life;MCS: Mental Component Summary;MD: mean difference;mPAP: mean pulmonary arterial pressure;PAH: pulmonary arterial hypertension;PCS: Physical Component Summary;PH: pulmonary hypertension;RD: risk difference;SF‐36: 36‐item Short Form;VO2peak: peak oxygen capacity;W: watts. | ||||||
| GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate. | ||||||
a No studies reported allocation concealment or blinding of participants or personal to intervention (performance bias). Five of 11 studies reported incomplete outcome data. Downgraded one level. b Inconsistency: I² > 60%. Downgraded one level. c No studies reported allocation concealment or blinding of participants or personal to intervention (performance bias). Three of seven studies reported incomplete outcome data. Downgraded one level. d No studies reported allocation concealment or blinding of participants or personal to intervention (performance bias). Three of five studies reported incomplete outcome data. Downgraded one level. e No studies reported allocation concealment or blinding of participants or personal to intervention (performance bias). Downgraded one level. f Both studies had high risk of performance bias (participants and personnel not blinded), high risk of attrition bias and high risk of reporting bias. Downgraded two levels.
Background
Description of the condition
Pulmonary hypertension (PH) is a progressive vasculopathy characterised by extensive remodelling of the pulmonary vasculature resulting in a narrowing of the arterial lumen (Casserly 2009). There is a marked increase in pulmonary vascular resistance resulting in right ventricular remodelling and eventual failure, which, in most cases, results in patient death (Tuder 2013). Confirmatory diagnosis of PH is made via right heart catheterisation in which the patient has a resting mean pulmonary arterial pressure (mPAP) greater than 25 mmHg (Galie 2015). In 2019, the World Symposium on Pulmonary Hypertension recommended lowering the diagnostic mPAP for PH to 20 mmHg (Simonneau 2019); however, this has yet to obtain universal acceptance. PH may arise in association with a broad range of disease states (over 40) of both known and unknown cause. International guidelines classified PH into the following five clinical groups (Simonneau 2019).
Group 1: pulmonary arterial hypertension (PAH)
Group 2: PH due to left heart disease
Group 3: PH due to lung diseases or hypoxia, or both
Group 4: chronic thromboembolic PH (CTEPH)
Group 5: PH with unclear multifactorial mechanisms
The incidence of PH varies markedly between the five clinical groups (Strange 2012). In one observational cohort study of over 10,000 participants from Armadale and the surrounding region in Western Australia,Strange 2012 reported the minimum indicative prevalence for all groups of PH was 326/100,000, with left heart disease associated with Group 2 being most prevalent. A more‐recent population‐based study of 50,529 people with PH from Ontario, Canada, collected between 1993 and 2012, also reported that Group 2 was the most prevalent and that yearly prevalence rates increased across the duration of the study (Wijeratne 2018). Looking at the global impact of PH, Hoeper and colleagues note that the prevalence of PH is 1% of the global population, with prevalence rising to around 10% in people aged older than 65 years (Hoeper 2016).
Regardless of aetiology, PH is characterised by limited exercise capacity and a progressive increase in breathlessness. Historically treatment options for PH were limited and patient prognosis poor. One early National Institutes of Health (NIH) Registry (published in the early 1980s), which included idiopathic, congenital and drug‐induced PAH, reported a one‐year survival rate of only 68% and three‐year survival rate of only 48% (Rich 1987). The development of PH‐specific drug therapies, targeted at the pulmonary vasculature, has significantly improved prognosis. More‐recent registry data (2000 to 2014) reported improved survival rates of over 90% at one year and 73% to 77% at three years (Radegran 2016).
Advances in PH‐specific therapies have improved survival and slowed disease progression. As a result, other treatment options aimed at improving outcomes such as exercise capacity and quality of life have been explored. In people with other chronic heart and lung diseases, there is strong evidence that exercise training improves functional capacity, quality of life and even long‐term survival (Spruit 2013). However, until very recently, exercise rehabilitation has been actively discouraged in people with PH for fear it would worsen symptoms and negatively impact on cardiac function (Galie 2013). One more‐recent statement by the European Respiratory Society on exercise training in PH has noted improvements in exercise capacity, muscular function, quality of life and potentially right ventricular function (Grunig 2019a); however, gaps in the knowledge exist including an understanding of the optimal training dose, characteristics of supervision, mechanisms of adaptation and the impact of exercise training on long‐term survival (Galie 2013).
Description of the intervention
Exercise‐based rehabilitation programmes including aerobic and strength training elements are designed to improve both aerobic capacity and muscle strength. Aerobic training involves the activation of a large skeletal muscle mass through an extended period of cycling or walking exercise that is between 20 and 40 minutes in duration. Strength training programmes involve upper and lower body muscle groups with the participant completing a number of sets of exercises at a fixed percentage of a one‐repetition maximum (RM) (Spruit 2013). Several different approaches to exercise training have been employed. Supervised programmes may be offered in an outpatient, inpatient or remote setting, involving two to three sessions per week typically over at least a four‐week period. Training approaches vary in intensity, including moderate‐intensity continuous training to high‐intensity interval training.
How the intervention might work
In healthy young and older patients, exercise training results in improved oxygen transport and uptake at peak exercise through both central and peripheral adaptations. Central adaptations include an increase in maximal cardiac output, through an increase in stroke volume (Ogawa 1992). Central adaptations are the result of volume overload‐mediated cardiac remodelling that leads to improved cardiac function at rest and during exercise (Ogawa 1992;Pluim 2000). In the periphery, greater skeletal muscle oxidative capacity occurs with an increase in enzymes associated with cellular respiration, in particular those involved in the citric acid cycle (the Krebs cycle) and oxidative phosphorylation (Coggan 1992;Gollnick 1973). In addition, there is an increase in the capillary density per myofibril (Coggan 1992;Gollnick 1973). As a result of these central and peripheral adaptations, there is an increased delivery of oxygen to the exercising myofibril, and an increased capacity to metabolise oxygen for the production of adenosine triphosphate. Transition between myofibril types typically occurs with an increase in the fast twitch oxidative and a decrease in fast twitch glycolytic fibres following exercise training (Coggan 1992;Ennion 1995;Gollnick 1973). Moreover, there is an increase in the cross‐sectional area of slow twitch (Type I) and Type IIa fibres in trained individuals (Coggan 1992;Gollnick 1973).
In PH, the factors that contribute to exercise limitation are complex (Babu 2016b;Fowler 2012;Panagiotou 2015). The changes in the pulmonary vasculature associated with PH results in a significant increase in pulmonary arterial pressure and right ventricular afterload during exercise (Provencher 2008;Riley 2000). Right ventricular contractility is decreased and there is a reduced capacity for stroke volume and, therefore, for cardiac output to increase during exercise (Fowler 2012). Moreover, people with PH have a reduced heart rate response to exercise (chronotropic incompetence), which further decreases the ability for cardiac output to increase during exercise (Provencher 2006). As a result, people with PH have a blunted increase in cardiac output during exercise that significantly reduces peak oxygen transport. In the periphery, people with PH appear to have marked skeletal muscle dysfunction consistent with a reduced oxidative capacity (Mainguy 2010a). Compared to healthy people, people with PH had a lower percentage of Type I fibres and increased concentrations of enzymes associated with glycolytic (anaerobic) metabolism (Mainguy 2010a). These central and peripheral changes would result in a substantial reduction in the ability to transport and utilise oxygen during exercise, resulting in a significant decrease in exercise capacity.
In people with chronic lung disease, lower limb exercise training and strength training have both been demonstrated to increase exercise capacity and quality of life (Spruit 2013). The primary site of adaptation appears to be the skeletal muscle, with little change in cardiac function following exercise training in people with chronic heart and lung disease (Vogiatzis 2013). For example, in people with chronic obstructive pulmonary disease there is evidence that exercise training results in improved skeletal muscle structure and function with little change in cardiac function (Vogiatzis 2013;Whittom 1998). Whilst preliminary evidence in a few people suggests that there is some improvement in skeletal muscle function following exercise training in PH (de Man 2009;Mainguy 2010b), it remains unclear if these changes result in improved exercise capacity or if they relate to improved long‐term outcomes. Currently, there is limited evidence for any central changes following exercise training in PH.
Why it is important to do this review
A previous Cochrane Review was undertaken in 2017 (Morris 2017). Whilst this review reported that exercise‐based rehabilitation resulted in an improvement in exercise capacity and was not associated with any adverse events, it only included six studies and that the quality of the evidence was low. Additional studies examining the efficacy of exercise‐based rehabilitation have now been published and some international societies have begun providing specific guidelines regarding exercise‐based rehabilitation in PH. The Thoracic Society of Australia and New Zealand recommended exercise training for PH in their 2017 guidelines for pulmonary rehabilitation (Alison 2017a); however, it was noted that this was a weak recommendation based on low‐certainty evidence. More recently, the European Respiratory Society published a statement on exercise training in PH reporting improvements in exercise capacity, muscular function, quality of life and potentially right ventricular function (Grunig 2019a). However, it was noted that further studies were needed to consolidate these findings and the impact of exercise training on disease risk profiles and to establish optimal training methodology. Indeed, the most recent European Cardiac and Respiratory Societies Guidelines for the diagnosis and treatment of PH recommend supervised exercise training for people with PAH under medical therapy (Class of recommendation: 1; level of evidence A) (Humbert 2022). With the broadening of international acceptance of exercise training in PH, albeit based on a limited body of evidence, the purpose of this review was to consolidate the current evidence on exercise‐based rehabilitation in PH and examine both efficacy and safety of the intervention.
Objectives
To evaluate the benefits and harms of exercise‐based rehabilitation for people with PH compared with usual care or no exercise‐based rehabilitation.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs). We included studies reported in full or abstract form as well as any relevant, unpublished data.
Types of participants
We included adults with a diagnosis of PH. We included all five clinical groups of PH (Simonneau 2019), independent of whether the participants were stable on therapy (i.e. change of therapy over the past three months).
Types of interventions
We included trials comparing exercise‐based rehabilitation with usual care or no exercise‐based rehabilitation. Exercise‐based rehabilitation of any frequency and duration was eligible for inclusion, including inpatient, outpatient or home‐based settings. We included exercise programmes of any length; however, we only included trials in which exercise training was supervised. We excluded exercise programmes that only provided exercise advice. We included exercise‐based programmes prescribing aerobic or strength training, or both.
We planned to analyse exercise‐rehabilitation that only included a strength‐training programme separately; however, we found no such trials.
The control group included individuals randomised to a programme of education or usual care that had no specific exercise prescription component.
Types of outcome measures
Primary outcomes
All outcome measures were reported immediately prior to the intervention being commenced (before measurement) and immediately after the completion of the exercise‐based intervention or control period.
Exercise capacity
Measures of exercise capacity included, but were not confined to, outcomes such as the six‐minute walk distance (6MWD), peak exercise capacity (VO2peak), peak power (Wpeak) and measures derived during the assessment of exercise capacity such as breathing efficiency (VE/VCO2 slope) and anaerobic threshold
Serious adverse events during the intervention period. We used this measure to assess the short‐term safety of exercise training in PH. We defined adverse events as:
mortality during the exercise/control intervention period;
disease progression, defined according to the investigators' definition;
symptoms precluding training, such as illness, lightheadedness, syncope or presyncope; and
discontinuation of the study
Health‐related quality of life (HRQoL) measured by any validated generic or disease‐specific quality‐of‐life measure
Secondary outcomes
Cardiopulmonary haemodynamics
These included measures made using echocardiographic, right heart catheter or magnetic resonance imaging techniques
Outcome measures included, but were not confined to, indices such as mPAP, mean pulmonary vascular resistance, right ventricular systolic pressure, tricuspid annular plane systolic excursion, ventricular ejection fraction, ventricular end diastolic volume and ventricular end systolic volume
Functional Class measured using the New York Heart Association (NYHA) Classification (NYHA 1994) or World Health Organization (WHO) Functional Classification (Rubin 2004)
Clinical worsening during the follow‐up period
Impact of exercise training on clinical worsening assessed using the investigators definition
Typically, clinical worsening was defined using a combination of outcomes including survival, hospitalisation due to PH, transplantation, requirement for additional pharmacological therapy, a reduction in Functional Class and or a reduction in 6MWD (Frost 2013)
For the purpose of this study, we treated mortality during the follow‐up period as a separate secondary outcome measure
Mortality during the follow‐up period
We recorded all deaths reported following the exercise intervention
We treated these deaths separately to those that occurred during the exercise training period, which were recorded by the primary outcome measure, serious adverse events
B‐type natriuretic peptide
A commonly used marker of right ventricular dysfunction in PH that is correlated with survival (Casserly 2009)
We examined changes in B‐type natriuretic peptide following exercise‐based rehabilitation
Reporting one of more of the outcomes listed here was not an inclusion criterion for the review.
Search methods for identification of studies
Electronic searches
We identified trials from searches of the following databases:
The Cochrane Airways Register of Trials;
Cochrane Central Register of Controlled Trials (CENTRAL; 2021, issue 8) (via the Cochrane Register of Studies (CRSO);
MEDLINE (Ovid);
Embase (Ovid);
Physiotherapy Evidence Database (PEDro).
The database search strategies are listed inAppendix 1. The previously published review included searches up to August 2016 and the search period for this most recent update was from the previous end date to 28 June 2022 with no restriction on language or type of publication. We handsearched conference abstracts and grey literature from the CENTRAL database.
Searching other resources
We checked reference lists of all primary studies and review articles for additional references. We searched for errata or retractions from included studies published in full text on PubMed. We conducted a search of ClinicalTrials.gov (clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) search portal (apps.who.int/trialsearch/) (seeAppendix 1 for search strategies).
Data collection and analysis
Selection of studies
Two review authors (AH and NM for the previous review and JL and AJ in this updated search) independently screened titles and abstracts for inclusion and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved the full‐text study reports/publications, and two review authors (NM and AH) independently screened the full‐text, identified studies for inclusion, and identified and recorded reasons for exclusion of the ineligible studies. We resolved any disagreements through discussion. We identified and excluded duplicates and collated multiple reports of the same study so that each study rather than each report was the unit of interest in the review. We used Covidence to manage the selection process (Covidence). We recorded the selection process in sufficient detail to complete a PRISMA flow diagram (Figure 1) andCharacteristics of excluded studies table.
1.
PRISMA flow diagram.
Data extraction and management
We used a data collection form for study characteristics and outcome data that was piloted on one study in the review. Two review authors (AJ and JL) extracted study characteristics from included studies.
We extracted the following study characteristics.
Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals and date of study.
Participants: number enroled, mean age, age range, gender, severity of condition, diagnostic criteria, baseline echocardiography and right heart catheter data, baseline lung function, inclusion criteria and exclusion criteria.
Interventions: intervention, training dose (intensity, frequency and duration of exercise training), comparison, concomitant medications and excluded medications.
Outcomes: primary and secondary outcomes specified and collected, and time points reported.
Notes: funding for trial, and notable conflicts of interest of trial authors.
We noted in theCharacteristics of included studies table if outcome data were not reported in a usable way. We resolved disagreements by consensus. One review author (NM) transferred data into Cochrane's statistical software, Review Manager 5 (Review Manager 2020). A second review author (AJ) spot‐checked study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Two review authors (NM and AH for the previous review and JL and AJ in this updated search) independently assessed risk of bias for each study using the criteria outlined in theCochrane Handbook for Systematic Reviews of Interventions and the RoB 1 tool (Higgins 2011). We resolved any disagreements by discussion.
We assessed the risk of bias according to the following domains.
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective outcome reporting
Other bias
We graded each potential source of bias as high, low or unclear and provided a quote from the study report together with a justification for our judgement in the risk of bias table. We summarised the risk of bias judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different from for a HRQoL scale).
When considering treatment effects, we considered the risk of bias for the studies that contributed to that outcome.
Assessment of bias in conducting the systematic review
We conducted the review according to the published protocol (Morris 2014), and reported any deviations from it in theDifferences between protocol and review section of the systematic review.
Measures of treatment effect
We analysed dichotomous data as odds ratios (ORs), with 95% confidence intervals (CIs). For continuous data, we used mean differences (MDs) when studies used the same scales or standardised mean differences (SMDs) when studies used different scales, with 95% CIs. Where it was reported, we used the change from baseline. Where the change from baseline was not reported, we used the adjusted results or final score. We did not combine data expressed as change from baseline with that reported as other metrics. We entered data presented as a scale with a consistent direction of effect.
We undertook meta‐analyses only where this was meaningful, that is, if the treatments, participants and the underlying clinical questions were similar enough for pooling to make sense.
We narratively described skewed data reported as medians and interquartile ranges.
Where a single trial reported multiple trial arms, we planned to include only the relevant arms; however, the search identified no trials of this nature.
Unit of analysis issues
Where studies randomly allocated the participants to either the exercise‐based rehabilitation or control, we considered the participant as the unit of analysis. We excluded cross‐over trials due to the potential carry‐over effects of exercise training.
Dealing with missing data
We contacted trial investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study was identified as abstract only). Where this was not possible, and the missing data were thought to introduce serious bias, we explored the impact of including such studies in the overall assessment of results using a sensitivity analysis.
Assessment of heterogeneity
We used the I² statistic to measure heterogeneity amongst the trials in each analysis (Higgins 2003). We classified heterogeneity as low when the I2 statistic was less than 30%, moderate when the I2 statistic was 30% to 50%, substantial when the I2 statistic was 50% to 75% and considerable when the I2 statistic was greater than 75%. If we identified substantial heterogeneity, we explored possible causes by prespecified subgroup analysis (Deeks 2011).
Assessment of reporting biases
If we were able to pool more than 10 trials, we created and examined a funnel plot to explore possible small‐study and publication biases.
Data synthesis
We performed a pooled quantitative synthesis where the trials were clinically homogeneous. We pooled data using a random‐effects model to incorporate between‐study heterogeneity into the meta‐analysis. We used data from an intention‐to‐treat (ITT) analysis where available. Where the trials were clinically heterogeneous, we performed a narrative synthesis. We used RevMan HAL, developed by the Cochrane Schizophrenia Group to construct a first draft of the results section (szg.cochrane.org/revman-hal).
Subgroup analysis and investigation of heterogeneity
We planned to carry out the following subgroup analyses.
Type of PH:
we analysed data separately for people with PAH only (Group 1).
Severity of PH:
we planned to compare the outcomes of less severe disease classification (NYHA Class I/II) with those with more severe disease classification (NYHA Class III/IV); however, there were insufficient data available.
We used the following outcomes in subgroup analyses:
exercise capacity;
serious adverse events;
HRQoL.
We used the formal test for subgroup interactions.
Sensitivity analysis
We performed sensitivity analyses to examine the effects of methodological quality on the pooled estimate by removing studies that were at high or unclear risk of bias for the domains of blinding and incomplete outcome data.
Summary of findings and assessment of the certainty of the evidence
We created a summary of findings table using the following outcomes: exercise capacity, serious adverse events, HRQoL, cardiopulmonary haemodynamics, Functional Class, clinical worsening during follow‐up and mortality during the follow‐up period. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of a body of evidence as it related to the studies that contributed data to the meta‐analyses for the prespecified outcomes. We used methods and recommendations described in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro GDT software (GRADEpro GDT). We justified all decisions to downgrade or upgrade the certainty of the evidence in the footnotes section ofTable 1, and we made comments to aid readers' understanding of the review where necessary.
Results
Description of studies
SeeCharacteristics of included studies;Characteristics of excluded studies;Characteristics of studies awaiting classification andCharacteristics of ongoing studies tables for complete details.
Results of the search
The study flow diagram is shown inFigure 1. This updated review includes 14 studies. The original review identified 2451 records which, following removal of duplicates and exclusion, resulted in the inclusion of six studies (Morris 2017). The most recent search covered August 2016 to February 2022 and identified 1868 new records. We identified one additional record through handsearching. After removing duplicates and exclusion of irrelevant titles or abstracts, we assessed 49 studies (73 records) for eligibility. Of these, 26 studies (39 records) were excluded from review (seeCharacteristics of excluded studies table for reasons). We identified eight new studies (Atef 2021;Butane 2021;Ertan 2022;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Rakhmawati 2020;Wojciuk 2021), 11 studies are awaiting classification (NCT00477724;NCT00491309;NCT02558582;NCT02579954;NCT03045666;NCT03288025;NCT03955016;NCT04188756;NCT04224012;NCT04909008;NCT05242380), and there are two ongoing studies (McGregor 2020;Morris 2018). Two studies (four records) that were included in the previous review were moved to previous included or excluded studies) (Morris 2017).
Included studies
We included 14 studies (Atef 2021;Butane 2021;Chan 2013;Ehlken 2016;Ertan 2022;Ganderton 2013;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Ley 2013;Mereles 2006;Rakhmawati 2020;Wilkinson 2007;Wojciuk 2021; seeCharacteristics of included studies table).
A summary of the included studies is provided inTable 2. All included studies were parallel‐group RCTs. The total number of included participants across all studies was 571 (intervention and control groups). Study sample sizes ranged from 10 (Ganderton 2013) to 129 (Grünig 2020) participants. Only one was a multicentred trial (Grünig 2020), with all others being single‐centred trials. Most participants had PAH (Group 1 PH) or CTEPH. The mean age of participants ranged from 35 to 68 years, and the group mPAP on right heart catheterisation ranged from 40 mmHg to 62 mmHg. All included participants were classified as being stable on medical therapy. Most study participants completed at least part of their rehabilitation programme in an inpatient setting (61% of the included participants:Ehlken 2016;Grünig 2020;Ley 2013;Mereles 2006). In addition to supervised exercise training, nine studies also included an unsupervised home‐based component (Atef 2021;Butane 2021;Ehlken 2016;Ertan 2022;Ganderton 2013;Mereles 2006;Rakhmawati 2020;Wilkinson 2007;Wojciuk 2021). Inpatient exercise training was typically performed daily whereas outpatient and home‐based exercise training was undertaken three to five times per week. Exercise training typically consisted of aerobic exercise of the lower limbs using either cycling or walking on a treadmill, or overground. Exercise intensity was regulated with heart rate or using rating of perceived exertion. Whilst there were no studies that only implemented a strength training protocol, most studies included both upper and lower limb strength training within the exercise protocol. All studies reported measuring exercise capacity with 12 studies using the 6MWD and eight studies using a cardiopulmonary exercise test (CPET).Wilkinson 2007 reported using the incremental shuttle walk to measure changes in exercise capacity. Most studies reported changes in HRQoL, with the 36‐item Short‐Form (SF‐36) the most commonly measurement tool.
1. Summary of study characteristics.
| Study | Study design (grouping) | Number of participants | Participant age (years), gender | Pulmonary arterial pressure (mmHg) | Duration of programme | Delivery mode: inpatient/ outpatient/ home | Exercise modality | Training dose (frequency/duration) | Training intensity | Outcome measures | Funding sources |
| Atef 2021 | RCT (parallel) | Exercise: 15 (1 withdrawal) Control: 15 | Age: Exercise: 48 (SD 7) Control: 47 (SD 8) Gender: unclear | mPAP: unclear PASP: Exercise: 58 (SD 15) Control: 58 (SD 15) | 12 weeks | Outpatient |
| Training frequency: 3 times/week Training duration: 15–30 min | 1 min at lower workload (e.g. 20 W) and 1 min at higher workload (e.g. 35 W). 60–70% of heart rate reserve; 60–70% of VO2 max |
| Cairo University |
| Butane 2021 | RCT (parallel) | Exercise: 10 (1 withdrawal) Control: 9 (2 withdrawals) | Age: Exercise: 61.6 (SD 18.5) Control: 68.3 (SD 16.6) Gender: (male/female) Exercise: 1/8 Control: 0/7 | mPAP: Exercise: 44.1 (SD 15.7) Control: 49.1 (SD 14.4) | 12 weeks | Home. Training supervised at the centre in weeks 1, 4 and 12; home‐based training with weekly telephone consultation for the remainder |
| Training frequency:
Training duration:
|
|
| Unclear |
| Chan 2013 | RCT (parallel) | Exercise: 10 Control: 13 | Age: Exercise: 53 (SD 13) Control: 55.5 (SD 8.5) Gender: (male/female) Exercise: 0/10 Control: 0/13 | mPAP: Exercise: 40.3 (SD 13.8) Control: 43.8 (SD 14.2) | 10 weeks | Outpatient |
| Training frequency: 2–3 times/week Training duration: 30–45 min | 70–80% of heart rate reserve |
| US National Institutes of Health |
| Ehlken 2016 | RCT (parallel) | Exercise: 46 Control: 41 | Age: Exercise: 55 (SD 15) Control: 57 (SD 15) Gender: (male/female) Exercise: 20/26 Control: 20/21 | mPAP: Exercise: 41 (SD 11.7) Control: 37.6 (SD 11.8) | 15 weeks | Inpatient (3 weeks) Outpatient (unsupervised; performed at home; 12 weeks) |
| Training frequency: Inpatient:
Outpatient (performed at home):
Training duration:
| 60–80% of heart rate reserve Heart rate maintained at < 120 bpm; oxygen saturation maintained at > 85% |
| Centre for Pulmonary Hypertension, Thorax clinic at the University of Heidelberg, Germany |
| Ertan 2022 | RCT (parallel) | Exercise: 15 (3 withdrawals) Control: 12 | Age: Exercise: 49.6 (SD 9.9) Control: 44.3 (SD 9.4) Gender: (male/female) Exercise: 2/10 Control: 3/9 | mPAP: Exercise: 47.2 (SD 18.8) Control: 40.5 (SD 18.0) | 8 weeks | Outpatient twice/week Home (unsupervised) once/week |
| Training frequency: ≥ 3 times/week (2 days at hospital and ≥ 1 at home) Training duration: initially 30 min; then increased by 5 min once every 2 weeks to a max of 45 min after 8 weeks depending on exercise tolerance | Clinical symptom scores were used to determine exercise intensity Heart rate maintained at 120 bpm; perceived exertion level at 3–4 on modified Borg scale |
| Istanbul University – Cerrahpasa Scientific Research Projects Unit |
| Ganderton 2013 | RCT (parallel) | Exercise: 5 Control: 5 | Age: Exercise: 51 (range 40–53) Control: 53 (range 42–57) Gender: (male/female) Exercise: 0/5 Control: 1/4 | mPAP Exercise: 23 (range 19–29) Control: 49 (range 20–65) | 12 weeks | Outpatient, supervised sessions. Commenced 1 home‐based unsupervised session/week in last 4 weeks of supervised programme; then asked to continue with home programme (unsupervised) for an additional 12 weeks |
| Training frequency: 3 times/week Training duration: 60 min | 60–70% of heart rate max (based on age predicted max, 220 – age); SpO2 maintained at ≥ 92%; < 4 on Borg scale Exercise intensity progressed based on the individual's response to training |
| Advanced Lung Disease Unit at Royal Perth Hospital and the Lung Institute of Western Australia |
| González‐Saiz 2017 | RCT (parallel) | Exercise: 20 (1 withdrawal) Control: 20 (4 withdrawals) | Age: Exercise: 46 (SD 11) Control: 45 (SD 12) Gender: (male/female) Exercise: 12/8 Control: 12/8 | mPAP Exercise: 47 (SD 15) Control: 47 (SD 14) | 8 weeks | Outpatient |
| Training frequency:
Training duration:
|
|
| Cátedra Real Madrid‐Universidad |
| Grünig 2020 | RCT (parallel) | Exercise: 68 (10 did not complete primary end point) Control: 61 (3 did not complete primary end point) | Age: Exercise: 52 (SD 12) Control: 55 (SD 13) Gender: (male/female) Exercise: 40/18 Control: 45/13 | mPAP Exercise: 46.5 (SD 15.5) (n = 55) Control: 46.7 (SD 14.9) (n = 51) | 10–30 days (inpatient) 11–12 weeks (home, unsupervised) | Inpatient/home |
| Training frequency: Inpatient: 5–7 days/week Home: 3–7 days/week Training duration:
| 40–60% peak workload |
| Fondo Europeo de Desarrollo Regional (FEDER), EU |
| Kagioglou 2021 | RCT (parallel) | Exercise: 16 (4 withdrawals) Control: 16 (6 withdrawals) | Age: Exercise: 54.7 (SD 15.6) Control: 53.1 (SD 12.1) Gender: (male/female) Exercise: 6/6 Control: 3/7 | mPAP Exercise: 42.3 (SD 15.5) Control: 53.1 (SD 12.1) | 6 months | Outpatient |
| Training frequency: 3 times/week Training duration: 45–60 min |
|
| Unclear |
| Ley 2013 | RCT (parallel) | Exercise: 10 Control: 10 | Age: Exercise: 47 (SD 8) Control: 54 (SD 14) Gender: (male/female) Exercise: 2/8 Control: 4/6 | mPAP Exercise: 48 (SD 19) Control: 50 (SD 15) | 3 weeks | Inpatient |
| Training frequency:
Training duration:
|
|
| German National Research Agency |
| Mereles 2006 | RCT (parallel) | Exercise: 15 Control: 15 | Age: Exercise: 47 (SD 12) Control: 53 (SD 14) Gender: (male/female) Exercise: 5/10 Control: 5/10 | mPAP Exercise: 49.5 (SD 17.6) Control: 49.6 (SD 12.3) | 3 weeks (inpatient) 12 weeks (outpatient) | Inpatient/home (unsupervised) |
| Training frequency: Inpatient:
Outpatient:
Training duration:
|
|
| German Pulmonary Hypertension Group, Pulmonale Hypertonie e.V., Rheinstetten, Germany |
| Rakhmawati 2020 | RCT (parallel) | Exercise: 20 (1 withdrawal) Control: 19 (3 withdrawals) | Age: Exercise: 37.5 (SD 8.8) Control: 35.5 (SD 10.4) Gender: (male/female) Exercise: 1/19 Control: 2/16 | mPAP Exercise: 61.4 (SD 14.2) Control: 56.8 (SD 11.6) | 2 weeks (inpatient) 10 weeks (outpatient) | Outpatient (supervised every 2 weeks), home (3 times/week, unsupervised) |
| Training frequency: 3 times/week Training duration: 30 min (inpatient); continuous or 2 × 15 min or 3 × 10 min (outpatient) | 60–70% of the max heart rate by age |
| Universitas Gadjah Mada, Jogjakarta, Indonesia |
| Wilkinson 2007 | RCT (parallel) | Exercise: 18 Control: 18 | Age: unclear Gender: unclear | mPAP: unclear | 3 months | Outpatient/home |
| Single 1‐to‐1 class with a physiotherapist followed by home training using exercise prescription. Follow‐up telephone support was provided throughout the intervention period | Exercise tailored to participant's needs |
| Royal Hallamshire Hospital, Sheffield, UK |
| Wojciuk 2021 | RCT (parallel) | Exercise: 23 (2 refused intervention, 4 lost to follow‐up, 1 excluded from analysis) Control: 23 (23 lost to follow‐up due to COVID‐19) | Age: Exercise: 48.9 (SD 18.3) Control: 53.7 (SD 12.8) Gender: (male/female) Exercise: 9/7 Control: 10/13 | mPAP Exercise: 47.2 (SD 14.9) Control: 49.1 (SD 14.4) | 24 weeks | Home |
| Training frequency: 5 days/week, once/day Training duration: March training: > 30 min interrupted every 2 minutes by 1 of 5 respiratory exercises | 4–5 on modified Borg scale; 60–70% of heart rate reserve |
| Medical University of Bialystok, Bialystok, Poland |
6MWD: six‐minute walk distance; bpm: beats per minute; EQ‐5D‐3L: European Quality of Life 5 Dimensions 3 Level Version; HADS: Hospital Anxiety Depression Scale; HRQoL: health‐related quality of life; max: maximum; min: minute; mPAP: mean pulmonary arterial pressure; n: number; NT‐proBNP: N‐terminal pro‐brain natriuretic peptide; NYHA: New York Heart Association; PASP: pulmonary arterial systolic pressure; PEmax: maximal expiratory pressure; PImax: maximal inspiratory pressure; PVR: pulmonary vascular resistance; QoL: quality of life; RCT: randomised controlled trial; rep: repetition; SD: standard deviation; SpO2: oxygen saturation; VE: pulmonary ventilation; VCO2: carbon dioxide production; VO2peak: peak oxygen capacity; Wpeak: peak workload; WHO: World Health Organization.
Excluded studies
The current review excluded 41 studies (Albarrati 2021;Aslan 2020;Babu 2013;Babu 2014;Babu 2019;Barbosa 2011;Becker‐Grunig 2013;Bernheim 2007;Bhasipol 2018;Chia 2017;Dowman 2017;Ehlken 2014;Farias da Fontoura 2018;Fox 2011;Fukui 2016;Gerhardt 2017;Grunig 2011;Grunig 2012;Iliuta 2019;jRCT1030210240;Kabitz 2014;Kahraman 2020;Karapolat 2019;Kolesnikova 2011a;Kolesnikova 2011b;Mackenzie 2017;Marvisi 2013;Missana 2020;Morris 2020;Nagel 2012;NCT03186092;NCT03476629;NCT04254289;NCT04559516;NCT04683822;Ontiyuelo 2019;Robalo Cordeiro 2011;Rokach 2019;Skibarkienė 2019;Tran 2020;Yilmaz 2020; seeCharacteristics of excluded studies table). Common reasons for excluding studies were not being RCTs, no specific exercise training such as aerobic or strength training, or an ineligible study population.
Studies awaiting classification
Eleven studies are awaiting classification (NCT00477724;NCT00491309;NCT02558582;NCT02579954;NCT03045666;NCT03288025;NCT03955016;NCT04188756;NCT04224012;NCT04909008;NCT05242380; seeCharacteristics of studies awaiting classification table).
Ongoing studies
Two studies are ongoing (McGregor 2020;Morris 2018; seeCharacteristics of ongoing studies table).
Risk of bias in included studies
Details on our judgements on the potential risks of bias are summarised inFigure 2 andFigure 3, with full details in theCharacteristics of included studies table.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Ten studies provided details on how the randomisation sequence was generated, and we judged them at low risk (Butane 2021;Ertan 2022;Ganderton 2013;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Ley 2013;Mereles 2006;Rakhmawati 2020;Wojciuk 2021). For the remaining studies we were unable to ascertain details of random sequence generation (unclear risk of bias).
None of the studies provided details on how allocation was concealed, and were at unclear risk of bias in this domain.
Blinding
Given the nature of the intervention (exercise training) it was not possible to blind participants or personnel to the intervention. Therefore, all studies were at high risk of bias for blinding of participants and personnel. Ten studies reported blinding of outcome assessors and were at low risk of detection bias (Butane 2021;Chan 2013;Ganderton 2013;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Ley 2013;Mereles 2006;Rakhmawati 2020;Wilkinson 2007). The remaining studies were at unclear risk of detection bias.
Incomplete outcome data
Six studies were at low risk of attrition bias with each of these studies reporting no or very small numbers of dropouts (Atef 2021;Chan 2013;Ganderton 2013;González‐Saiz 2017;Ley 2013;Mereles 2006). The two largest studies (195 participants in total) were at high risk of attrition bias with each reporting a greater number of dropouts in the intervention group (Ehlken 2016: 17% dropout in the intervention group versus 0% in the control;Grünig 2020: 15% dropout in the intervention group versus 5% in the control). The six remaining studies were also at high risk of attrition bias due to a high number of withdrawals, or unbalanced withdrawal rates between groups, or both (Butane 2021;Ertan 2022;Kagioglou 2021;Rakhmawati 2020;Wilkinson 2007;Wojciuk 2021).
Selective reporting
Five studies were at low risk of reporting bias (Atef 2021;Ganderton 2013;González‐Saiz 2017;Ley 2013;Mereles 2006). Six studies did not provide complete results when compared to those provided on the trial registry and were at high risk of bias (Chan 2013;Ehlken 2016;Ertan 2022;Grünig 2020;Wilkinson 2007;Wojciuk 2021). Of the outcome measures not reported onlyWojciuk 2021 did not report outcomes that would have affected this review, namely changes in Functional Class and brain natriuretic peptide (BNP). However, we did not extract any data from this study as it did not report any control data. The remaining studies provided insufficient details to ascertain reporting bias and were at unclear risk (Butane 2021;Kagioglou 2021;Rakhmawati 2020).
Other potential sources of bias
Six studies were at low risk with regard to other sources of bias (Chan 2013;Ganderton 2013;González‐Saiz 2017;Kagioglou 2021;Ley 2013;Wojciuk 2021). We were unable to rule out possible selection bias in five studies (unclear risk) (Atef 2021;Butane 2021;Ertan 2022;Grünig 2020;Rakhmawati 2020). NeitherMereles 2006 norWilkinson 2007 provided a CONSORT diagram and hence there were no details of how many participants they screened to achieve the enrolment target (high risk) (Schulz 2010).Ehlken 2016, whilst providing a CONSORT diagram, provided no details on how many participants were screened and how they applied the inclusion/exclusion criteria to achieve the target enrolment of 95 participants (high risk).
Effects of interventions
See:Table 1
The 14 RCTs included in this review compared exercise‐based rehabilitation to no intervention, education alone or usual care (Atef 2021;Butane 2021;Chan 2013;Ehlken 2016;Ertan 2022;Ganderton 2013;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Ley 2013;Mereles 2006;Rakhmawati 2020;Wilkinson 2007;Wojciuk 2021). We used data extracted from published journal articles or, in one instance, a published PhD thesis (Ganderton 2013). Three studies did not contribute to the data synthesis (Atef 2021;Wilkinson 2007;Wojciuk 2021). We were unable to extract primary or secondary outcome data fromWilkinson 2007 (published only as an abstract) despite attempts to contact the study authors. Similarly, we were unable to extract data for synthesis fromAtef 2021. Whilst the authors reported changes in exercise capacity (VO2peak), the magnitude of change could not be ascertained. Attempts to contact the author and clarify the magnitude of change were unsuccessful. Finally,Wojciuk 2021 did not present control group data for comparison as all control participant data were lost to follow‐up due to the impact of coronavirus‐19 (COVID‐19) on measurement of trial outcomes.
Hence, comparisons between exercise‐based rehabilitation and control used data from 11 studies. SeeTable 1 for the main comparisons between the intervention and control groups. In total, there were 21 outcomes evaluated including primary outcomes of exercise capacity, serious adverse events and HRQoL.
Primary outcomes
Exercise capacity: six‐minute walk distance
Eleven studies reported changes in 6MWD (Butane 2021;Chan 2013;Ehlken 2016;Ertan 2022;Ganderton 2013;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Ley 2013;Mereles 2006;Rakhmawati 2020). There was a change in 6MWD in 211 participants who completed the exercise‐based rehabilitation intervention and 207 participants who acted as a control. Exercise training may result in a large increase in 6MWD compared to control, with the lower end of the CI exceeding the minimal important difference of 30 metres (MD 48.52 metres, 95% CI 33.42 to 63.62; I² = 72%; 11 studies, 418 participants; low‐certainty evidence;Analysis 1.1) (Holland 2014;Mathai 2012).
1.1. Analysis.
Comparison 1: Exercise versus control, Outcome 1: Exercise capacity: 6‐minute walk distance (6MWD)
We also examined the responses by different subgroups of PH using the classification outlined byHoeper 2013. Eight studies included a mixed group of participants with PH, including both those with PAH (i.e. those from Group I,Hoeper 2013) and CTEPH (i.e. Group 4,Hoeper 2013) (Butane 2021;Ehlken 2016;Ertan 2022;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Ley 2013;Mereles 2006). We were unable to extract data separately for the subgroups in these studies. We performed a subgroup analysis for three studies that only included participants with PAH (Group 1) comparing with those of mixed PH (Chan 2013;Ganderton 2013;Rakhmawati 2020). For the PAH group, the mean increase in 6MWD favoured exercise‐based rehabilitation and exceeded the minimal important difference (MD 63.97 metres, 95% CI 8.74 to 119.21; I² = 75%; 3 studies, 71 participants; low‐certainty evidence;Analysis 1.1), and was not different from the mixed PH group (MD 44.16 metres, 95% CI 28.97 to 59.36; I² = 72%; 8 studies, 347 participants; low‐certainty evidence;Analysis 1.1; test for subgroup differences: Chi² = 0.46, degrees of freedom (df) = 1 (P = 0.50), I² = 0%).
Given the substantial heterogeneity in the change in 6MWD with exercise‐based rehabilitation across studies (I² = 72%), we explored a possible source using a post hoc analysis evaluating the setting for exercise‐based rehabilitation comparing inpatient‐based (four studies;Ehlken 2016;Grünig 2020;Ley 2013;Mereles 2006) versus outpatient‐based (seven studies;Butane 2021;Chan 2013;Ertan 2022;Ganderton 2013;González‐Saiz 2017;Kagioglou 2021;Rakhmawati 2020) programmes. We hypothesised that differences in exercise‐based rehabilitation setting may account for some heterogeneity, as inpatient programmes allowed for closer supervision, a greater intensity of exercise prescription and hence a greater improvement in exercise capacity. Studies that included inpatient‐based exercise rehabilitation (61% of the sample) reported improvements in 6MWD favouring exercise‐based rehabilitation; however, the increase in 6MWD remained heterogeneous across studies (MD 59.39 metres, 95% CI 29.95 to 88.82; I² = 77%; 4 studies, 245 participants; low‐certainty evidence;Analysis 1.2). Outpatient‐based programmes also favoured exercise‐based rehabilitation, with a heterogeneous response (MD 43.21 metres, 95% CI 23.84 to 62.57; I² = 72%; 7 studies, 173 participants; low‐certainty evidence;Analysis 1.2). There was no difference in inpatient and outpatient programmes for change in 6MWD (Analysis 1.2; test for subgroup differences: Chi² = 0.81, df = 1 (P = 0.37), I² = 0%).
1.2. Analysis.
Comparison 1: Exercise versus control, Outcome 2: Exercise capacity: 6MWD inpatient vs outpatient studies
As we had more than 10 trials for the 6MWT outcome measure we generated a funnel plot of all the 6MWT data (Figure 4). On inspection, there appears to be asymmetry in the funnel plot, with a lack of smaller studies with minimal or no effect on 6MWD. This would suggest there may be publication bias with fewer smaller, negative or small effect studies being reported.
4.
Figure 4. Funnel plot comparison: exercise intervention versus usual care for change in six‐minute walk distance following exercise‐based rehabilitation.
Exercise capacity: cardiopulmonary exercise test
Seven studies reported changes in peak exercise capacity measured using CPET (Chan 2013;Ehlken 2016;Ganderton 2013;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Mereles 2006). Exercise training may increase VO2peak and peak power compared to control (VO2peak: MD 2.07 mL/kg/min, 95% CI 1.57 to 2.57; I² = 62%; 7 studies, 314 participants; low‐certainty evidence;Analysis 1.3; peak power: MD 9.69 W, 95% CI 5.52 to 13.85; I² = 71%; 5 studies, 226 participants; low‐certainty evidence;Analysis 1.5). There is no reported minimal important difference for CPET‐derived measures of exercise capacity in PH. Three studies reported changes in the anaerobic threshold, one of which was reported as time to anaerobic threshold (Chan 2013), whilst the other two reported this in millilitres per minute (Ganderton 2013;Mereles 2006). The increase in the anaerobic threshold favoured the exercise rehabilitation group (SMD 1.05, 95% CI 0.53 to 1.58; I² = 0%; 3 studies, 66 participants; low‐certainty evidence;Analysis 1.7).
1.3. Analysis.
Comparison 1: Exercise versus control, Outcome 3: Exercise capacity: peak exercise capacity (VO2peak)
1.5. Analysis.
Comparison 1: Exercise versus control, Outcome 5: Exercise capacity: peak power
1.7. Analysis.
Comparison 1: Exercise versus control, Outcome 7: Exercise capacity: anaerobic threshold
Subgroup analysis for participants with PAH found no evidence of a difference between groups in VO2peak (MD 1.27 mL/kg/min, 95% CI −0.21 to 2.76; I² = 0%; 2 studies, 36 participants; low‐certainty evidence;Analysis 1.3). For the mixed PH group there was a change in VO2peak favouring the exercise rehabilitation group but there was substantial heterogeneity (MD 2.17 mL/kg/min, 95% CI 1.64 to 2.70; I² = 72%; 5 studies, 278 participants; low‐certainty evidence;Analysis 1.3). However, there was no evidence of a difference between the PAH and PH groups (test for subgroup differences: Chi² = 1.24, df = 1 (P = 0.27), I² = 19.5%;Analysis 1.3). There was an increase in Wpeak for the both the PAH and the mixed PH subgroup favouring exercise‐based rehabilitation (PAH: MD 14.24 W, 95% CI 5.78 to 22.70; I² = 0%; 2 studies, 36 participants; low‐certainty evidence; mixed PH: MD 8.22 W, 95% CI 3.43 to 13.01; I² = 84%; 3 studies, 190 participants; low‐certainty evidence;Analysis 1.5); however, the response for the mixed PH group was heterogeneous. There was no evidence of a difference between the PAH and PH groups (test for subgroup differences: Chi² = 1.47, df = 1 (P = 0.23), I² = 32.0%;Analysis 1.5).
We examined the heterogeneity related to the setting for exercise‐based rehabilitation by examining the rehabilitation setting. Studies that included an inpatient‐based exercise rehabilitation programmes reported an increase in VO2peak favouring exercise‐based rehabilitation, but the response remained heterogeneous (MD 2.00 mL/kg/min, 95% CI 1.36 to 2.64; I² = 83%; 3 studies, 217 participants; low‐certainty evidence;Analysis 1.4) (Ehlken 2016;Grünig 2020;Mereles 2006). Studies of outpatient‐based programmes reported a similar increase in VO2peak favouring exercise‐based rehabilitation (MD 2.18 mL/kg/min, 95% CI 1.38 to 2.98; I² = 21%; 4 studies, 97 participants; moderate‐certainty evidence;Analysis 1.4) (Chan 2013;Ganderton 2013;González‐Saiz 2017;Kagioglou 2021). There was no evidence of a difference in the change in VO2peak between settings (test for subgroup differences: Chi² = 0.12, df = 1 (P = 0.73), I² = 0%;Analysis 1.4). The changes in Wpeak for participants that included an inpatient programme or were solely based in an outpatient/home programme are shown inAnalysis 1.6. For both settings, the increase favoured exercise‐based rehabilitation and there was no difference in the change in Wpeak between settings (test for subgroup differences: Chi² = 1.47, df = 1 (P = 0.23), I² = 32%). The response remained heterogeneous for the inpatient group (I² = 84%), whereas the result was consistent for the outpatient group (I² = 0%).
1.4. Analysis.
Comparison 1: Exercise versus control, Outcome 4: Exercise capacity: VO2peak, inpatient vs outpatient studies
1.6. Analysis.
Comparison 1: Exercise versus control, Outcome 6: Exercise capacity: peak power, inpatient vs outpatient studies
Overall the certainty of evidence for changes in exercise capacity was low due to lack of allocation concealment, incomplete outcome data reporting and inconsistency. For details, seeTable 1.
Serious adverse events
Eleven studies provided details on serious adverse events (seePrimary outcomes). Meta‐analysis demonstrated that there was no increased risk of serious adverse events with exercise‐based rehabilitation compared to usual care (RD 0, 95% CI −0.03 to 0.03; I² = 0%; 11 studies, 439 participants; moderate‐certainty evidence;Analysis 1.8). In total, there were five serious adverse events reported across the 11 studies. One study reported a participant death in the control group and no adverse events in the exercise group (Rakhmawati 2020). Two other studies reported serious adverse events (Ganderton 2013;Grünig 2020). In their multicentred trial,Grünig 2020 reported three adverse events in the exercise group (decompensated diabetes, generalised oedema and stroke). One study reported a single participant having to stop exercise training for a single session due to extreme lightheadedness (Ganderton 2013). No other studies reported any serious adverse events (i.e. mortality, disease progression, symptoms that precluded training or discontinuation of the study). Subgroup analysis of serious adverse events for the PAH versus mixed PH groups found no evidence of a difference between groups (test for subgroup differences: Chi² = 0.13, df = 1 (P = 0.72), I² = 0%;Analysis 1.8).
1.8. Analysis.
Comparison 1: Exercise versus control, Outcome 8: Serious adverse events
Overall the certainty of evidence for serious adverse events was moderate due to lack of allocation concealment. For details, seeTable 1.
Health‐related quality of life
Studies reported quality of life using either the SF‐36 questionnaire (Chan 2013;Ehlken 2016;Ganderton 2013;González‐Saiz 2017;Grünig 2020;Kagioglou 2021;Mereles 2006), or the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), a PH‐specific questionnaire (Chan 2013;Ganderton 2013). One study reported changes in the quality of life using the EQ‐5D‐3L (Rakhmawati 2020).
We reported the changes in the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the SF‐36 inAnalysis 1.9 andAnalysis 1.10, as these provide an indication of the global improvement in both physical and emotional dimensions of quality of life measured using this tool. Five studies reported changes in PCS and MCS (Chan 2013;Ganderton 2013;González‐Saiz 2017;Grünig 2020;Kagioglou 2021). Analysis showed that improvements in HRQoL favoured exercise‐based interventions for PCS and MCS (PCS: MD 3.98, 95% CI 1.89 to 6.07; I² = 38%; 5 studies, 187 participants; moderate‐certainty evidence; MCS: MD 3.60, 95% CI 1.21 to 5.98; I² = 0%; 5 studies, 186 participants; moderate‐certainty evidence). Subgroup analysis for the participants with PAH demonstrated a similar improvement favouring exercise‐based rehabilitation in both the PCS and MCS (PCS: MD 4.63, 95% CI 0.80 to 8.47; I² = 0%; 2 RCTs, 33 participants; moderate‐certainty evidence; MCS: MD 4.17, 95% CI 0.01 to 8.34; I² = 0%; 2 studies, 33 participants; moderate‐certainty evidence) (Chan 2013;Ganderton 2013). There was no evidence of a difference between the PAH and mixed PH subgroups for the change in PCS and MCS (PCS: test for subgroup differences: Chi² = 0.16, df = 1 (P = 0.69), I² = 0%; MCS: test for subgroup differences: Chi² = 10.11, df = 1 (P = 0.74), I² = 0%).
1.9. Analysis.
Comparison 1: Exercise versus control, Outcome 9: Health‐related quality of life (HRQoL) 36‐item Short Form (SF‐36): Physical Component Summary
1.10. Analysis.
Comparison 1: Exercise versus control, Outcome 10: HRQoL SF‐36: Mental Component Summary
Two studies examined changes in HRQoL using the CAMPHOR and reported greater improvement in the exercise‐based rehabilitation group than usual care in each of the subscores for activities, symptoms and overall quality of life (activities: MD −1.33, 95% CI −3.56 to 0.90; I² = 67%; 2 studies, 33 participants; moderate‐certainty evidence;Analysis 1.19; symptoms: MD −3.08, 95% CI −7.78 to 1.62; I² = 88%; 2 studies, 36 participants; low‐certainty evidence;Analysis 1.20; overall quality of life: MD −5.42, 95% CI −8.03 to −2.81; I² = 29%; 2 studies, 36 participants; moderate‐certainty evidence;Analysis 1.21) (Chan 2013;Ganderton 2013).
1.19. Analysis.
Comparison 1: Exercise versus control, Outcome 19: HRQoL: CAMPHOR Activities
1.20. Analysis.
Comparison 1: Exercise versus control, Outcome 20: HRQoL: CAMPHOR Symptoms
1.21. Analysis.
Comparison 1: Exercise versus control, Outcome 21: HRQoL: CAMPHOR Quality of Life
Five studies reported changes in quality of life using all (or some) of the eight domains of the SF‐36 (Chan 2013;Ehlken 2016;Ganderton 2013;Grünig 2020;Mereles 2006). Improvements favoured exercise‐based rehabilitation for SF‐36 domains of Role Physical, Mental Health, Vitality and Social Function (Role Physical: MD 20.46, 95% CI 13.77 to 27.15; I² = 0%; 5 studies, 220 participants; moderate‐certainty evidence;Analysis 1.12; Mental Health: MD 6.95, 95% CI 2.12 to 11.79; I² = 42%; 4 studies, 191 participants; moderate‐certainty evidence;Analysis 1.15; Vitality: MD 9.67, 95% CI 2.61 to 16.73; I² = 59%; 5 studies, 219 participants; moderate‐certainty evidence;Analysis 1.17; Social Function: MD 12.20, 95% CI 7.32 to 17.08; I² = 27%; 5 studies, 222 participants; moderate‐certainty evidence;Analysis 1.18). There was probably little to no difference between exercise‐based rehabilitation and usual care in the SF‐36 domains of Physical Function, Bodily Pain, General Health and Role Emotional (Physical Function: MD 5.29, 95% CI −1.15 to 11.73; I² = 33%; 5 studies, 216 participants; moderate‐certainty evidence;Analysis 1.11; Bodily Pain: MD 4.17, 95% CI −2.01 to 10.36; I² = 0%; 4 studies, 192 participants; moderate‐certainty evidence;Analysis 1.13; General Health: MD 2.14, 95% CI −4.45 to 8.74; I² = 45%; 4 studies, 188 participants; moderate‐certainty evidence:Analysis 1.14; Role Emotional: MD 3.16, 95% CI −4.98 to 11.30; I² = 0%; 4 studies, 191 participants; moderate‐certainty evidence;Analysis 1.16).
1.12. Analysis.
Comparison 1: Exercise versus control, Outcome 12: HRQoL SF‐36: Role Physical
1.15. Analysis.
Comparison 1: Exercise versus control, Outcome 15: HRQoL SF‐36: Mental Health
1.17. Analysis.
Comparison 1: Exercise versus control, Outcome 17: HRQoL SF‐36: Vitality
1.18. Analysis.
Comparison 1: Exercise versus control, Outcome 18: HRQoL SF‐36: Social Function
1.11. Analysis.
Comparison 1: Exercise versus control, Outcome 11: HRQoL SF‐36: Physical Function
1.13. Analysis.
Comparison 1: Exercise versus control, Outcome 13: HRQoL SF‐36: Bodily Pain
1.14. Analysis.
Comparison 1: Exercise versus control, Outcome 14: HRQoL SF‐36: General Health
1.16. Analysis.
Comparison 1: Exercise versus control, Outcome 16: HRQoL SF‐36: Role Emotional
Overall the certainty of evidence for serious adverse events was moderate due to lack of allocation concealment and incomplete outcome data reporting. For details, seeTable 1.
Secondary outcomes
Cardiopulmonary haemodynamics
Two studies reported changes in cardiopulmonary haemodynamics measured using right heart catheterisation following exercise‐based rehabilitation (Ehlken 2016;Grünig 2020). Using subsets of the study participants (Ehlken 2016: 31 exercise and 28 control;Grünig 2020: 38 exercise and 36 control), there were reductions in mPAP favouring exercise training (MD −9.29, 95% CI −12.96 to −5.61; I² = 0%; 2 RCTs, 133 participants; moderate‐certainty evidence;Analysis 1.22).
1.22. Analysis.
Comparison 1: Exercise versus control, Outcome 22: Cardiopulmonary haemodynamics
Functional class
Two studies reported changes in Functional Class for exercise and control groups (Ganderton 2013;Mereles 2006). There was an improvement in Functional Class favouring exercise rehabilitation (MD −0.46, 95% CI −0.64 to −0.28; I² = 57%; 2 studies, 40 participants; moderate‐certainty evidence;Analysis 1.23).
1.23. Analysis.
Comparison 1: Exercise versus control, Outcome 23: Functional Class
Clinical worsening during follow‐up period
There were no available data for analysis.
Mortality during the follow‐up period
There were no available data for analysis.
B‐type natriuretic peptide
Four studies reported changes in B‐type natriuretic peptide for exercise and control groups (Ehlken 2016;González‐Saiz 2017;Grünig 2020;Rakhmawati 2020). There was no evidence of a difference between exercise‐based rehabilitation and usual care (MD −68.69, 95% CI −154.89 to 17.51; I² = 0%; 4 studies, 220 participants; moderate‐certainty evidence;Analysis 1.24).
1.24. Analysis.
Comparison 1: Exercise versus control, Outcome 24: B‐type natriuretic peptide
Sensitivity analysis
For our sensitivity analysis, we removed studies that did not specify blinding of outcome measurements or had incomplete outcome data (attrition bias). As a result, we removed two studies from the analysis of exercise outcomes (Ehlken 2016;Wilkinson 2007). Sensitivity analysis did not change the pattern of findings for exercise capacity, with the exercise group showing improvements in 6MWD, VO2peak and Wpeak compared to control (6MWD: MD 59.56 metres, 95% CI 37.64 to 81.49; I² = 75%; 8 studies, 199 participants; low‐certainty evidence;Analysis 1.25; VO2peak: MD 2.27 mL/kg/m², 95% CI 1.53 to 3.00; I² = 4%; 8 studies, 135 participants; moderate‐certainty evidence;Analysis 1.26; Wpeak: MD 15.27 W, 95% CI 8.57 to 21.97; I² = 0%; 3 studies, 66 participants; moderate‐certainty evidence;Analysis 1.27). There were similar findings for HRQoL measured using the PCS and MCS (PCS: MD 4.61, 95% CI 1.17 to 8.05; I² = 51%; 4 studies, 88 participants; moderate‐certainty evidence;Analysis 1.28; MCS: MD 4.33, 95% CI 1.41 to 7.24; I² = 8%; 4 studies, 87 participants; moderate‐certainty evidence;Analysis 1.29).
1.25. Analysis.
Comparison 1: Exercise versus control, Outcome 25: Exercise capacity: 6MWD, sensitivity analysis
1.26. Analysis.
Comparison 1: Exercise versus control, Outcome 26: Exercise capacity: VO2peak, sensitivity analysis
1.27. Analysis.
Comparison 1: Exercise versus control, Outcome 27: Exercise capacity: peak power, sensitivity analysis
1.28. Analysis.
Comparison 1: Exercise versus control, Outcome 28: HRQoL SF‐36: Physical Component Score sensitivity analysis
1.29. Analysis.
Comparison 1: Exercise versus control, Outcome 29: HRQoL SF‐36: Mental Component Score sensitivity analysis
Subgroup analysis
Severity of pulmonary hypertension
There were insufficient data to perform subgroup analysis according to disease severity
Discussion
Summary of main results
The current analysis suggests that exercise‐based rehabilitation improves exercise capacity measured using 6MWD and CPET (VO2peak, Wpeak and anaerobic threshold). In addition, there were clinically important improvements in quality of life, measured using both PH‐specific and generic tools. Exercise‐based rehabilitation was not associated with an increased risk of serious adverse events.
Building from the earlier review (Morris 2017), which included six RCTs, the current review sourced an additional eight RCTs comparing exercise‐based rehabilitation with no exercise or usual care. In total, 11 RCTs contributed to meta‐analysis in the current review. Previously, we were unable to report on the impact of exercise‐based rehabilitation on central haemodynamics due to insufficient data (Morris 2017). However, the addition to the current review of the second‐largest study to date, which also measured central haemodynamics, has provided additional evidence to suggest that rather than having a negative impact on mPAP, exercise‐based rehabilitation resulted in a large and clinically important fall in mPAP when compared to control (−9.29 mmHg, 95% CI −12.96 to −5.61). Changes in B‐type natriuretic peptide were similar between groups, and we were unable to comment on changes in Functional Class due to insufficient data. Based on these studies, our analysis suggests that exercise‐based rehabilitation is safe, does not increase mPAP, and results in clinically meaningful changes in exercise capacity and quality of life.
Overall completeness and applicability of evidence
The aim of this review was to update the previous review examining the efficacy of exercise‐based rehabilitation in people with PHMorris 2017. The previous review identified six studies, five of which were included in the analysis (170 participants in total). This updated review identified eight additional RCTs, of which 11 were included in the data synthesis, with a total of 462 participants. Similar to our previous review (Morris 2017), most participants in the studies had a diagnosis of PAH, so our results should be applied primarily in that group. There were a few participants with CTEPH; however, their results could not be extracted separately, so it is difficult to be confident regarding the effects of exercise rehabilitation in this group. Of the studies completed to date, none have included groups of participants who had PH associated with connective tissue disease, PH due to left heart disease or PH due to lung disease, so our results cannot be applied to these groups. One study examined the effect of exercise‐based rehabilitation on participants with uncorrected atrial septal defect‐associated PH (Rakhmawati 2020). Few participants in Functional Class IV were included, so the impact of exercise rehabilitation in those with the most severe disease remains unclear. Importantly, all studies only included participants who were stable on medical therapy (including no recent syncope), so it is in this group that the results of this review on exercise‐based rehabilitation can be applied.
Whilst there were significant improvements in exercise capacity measured using 6MWD and CPET, there was substantial variation across studies. We were unable to determine whether this was due to the differences in study populations (PAH versus other), the severity of the disease (where there was insufficient evidence to assess) or the rehabilitation setting. Five of 11 studies that reported changes in exercise capacity used an inpatient rehabilitation programme of at least three weeks in duration, with exercise training taking place seven days per week (Ehlken 2016;Grünig 2020;Ley 2013;Mereles 2006;Rakhmawati 2020). There was no evidence of a difference between inpatient‐based and outpatient‐based exercise programmes that reported changes in exercise capacity (P = 0.06).
The exercise rehabilitation protocols tested included lower limb endurance training (walking or cycling), usually with resistance exercises for the upper and lower limbs. These protocols are similar to those recommended for standard pulmonary (Spruit 2013) and cardiac (Piepoli 2014) rehabilitation programmes. Additional components in some studies included stretching, breathing techniques such as pursed lip breathing, body perception, yoga and respiratory muscle training (Butane 2021;Ehlken 2016;González‐Saiz 2017;Grünig 2020;Ley 2013;Mereles 2006). No study examined the impact of strength training alone with most exercise protocols blending both aerobic (endurance) and strength training. Further data are required to identify the contribution of aerobic and strength training alone and of the additional components to rehabilitation outcomes. The similarity of the core rehabilitation components to those delivered in pulmonary and cardiac rehabilitation programmes (lower limb endurance training, upper and lower limb resistance training) suggests that people with PH could receive their rehabilitation within these existing services, which could improve uptake into practise. However, some studies in this review used specialised exercise prescription and monitoring practises that may not occur routinely in existing cardiopulmonary rehabilitation programmes (e.g. low‐intensity interval training, continuous monitoring of oxyhaemoglobin saturation and heart rate, restriction of exercise heart rate to less than 120 beats per minute) (Ehlken 2016;Ley 2013;Mereles 2006).
Whilst there were a total of five serious adverse events reported across 11 studies (415 participants), analysis found that exercise‐based rehabilitation was not associated with an increased risk of serious adverse events. However, it should be noted that studies did not apply a universal definition for adverse events. Whilst some provided a clear definition for the type of adverse events being detected (González‐Saiz 2017;Grünig 2020), others provided no details (Atef 2021;Kagioglou 2021), and merely noted that adverse events would be reported. It is worth noting that exercise is not entirely without risk in people with PH (Morris 2015), and international guidelines currently suggest that exercise rehabilitation should be undertaken "… by centres experienced in both PH patient care and rehabilitation of compromised patients" (Galie 2015).
We found two studies that are currently ongoing. One study is examining the role of exercise‐based rehabilitation in an outpatient setting (Morris 2018), whilst the other implemented a supervised home‐based programme (McGregor 2020). The results of these studies are pending.
Quality of the evidence
We were able to extract data from 11 of 14 studies all of which were published articles enabling us to report on a range of outcome measures. However, several sources of bias remained. No studies provided details on how allocation was concealed; however, 10 of 14 studies reported details on how they generated randomisation sequence. Like most exercise‐based rehabilitation interventions it was impossible to blind participants to the group allocation. Offsetting this somewhat was the fact that 10 studies noted that outcome assessors were blinded to group allocation, which is important for rehabilitation studies where many of the important outcomes (exercise capacity, HRQoL) could be affected by knowledge of group assignment.
Using GRADE, the outcomes provided low‐ to moderate‐certainty evidence. Review outcomes rated with moderate certainty included HRQoL and adverse events. Low‐certainty evidence included our primary outcome of exercise capacity (6MWD, VO2peak and Wpeak). The risk of bias was increased due to attrition bias, particularly in two of the largest studies completed to date (Ehlken 2016;Grünig 2020). Moreover, the changes in exercise capacity were heterogeneous and, whilst we explored this uncertainty by comparing the site of exercise‐based rehabilitation (inpatient versus outpatient), other factors must still be contributing to this heterogeneity.
Potential biases in the review process
Two review authors independently extracted all data using Covidence and resolved discrepancies through discussion (Covidence). Two review authors also independently assessed risk of bias. We included studies that were published only in abstract form to ensure that we included all available trials. However, despite attempts to contact the study authors, three studies did not contribute data that could be included in meta‐analysis (Atef 2021;Wilkinson 2007;Wojciuk 2021). This may have influenced assessment of trial quality and some estimates of effect.
We included a post‐hoc subgroup analysis (inpatient versus outpatient rehabilitation setting) that was not included in our original protocol (Morris 2014). This was because the marked heterogeneity in exercise outcomes prompted us to further explore the differences between studies, but substantial heterogeneity remained. Moreover, we acknowledge that it is difficult to draw firm conclusions from this analysis due the post‐hoc nature of the approach. Another factor that could have contributed to the heterogeneity of results could have been related to the advances in pharmacological therapy for PH over time, which may have in turn impacted on the responses to exercise‐based rehabilitation. Unfortunately, we were unable to examine the effects of these advances in therapy, as specific pharmacological management was infrequently reported.
Agreements and disagreements with other studies or reviews
Several systematic reviews on exercise training in PH have been published to date (Albanaqi 2021;Babu 2016a;Buys 2015;Pandey 2015;Yan 2021;Yuan 2015). One early systematic review,Buys 2015 examined only controlled trials up to December 2013, not all of which were randomised. They extracted five studies, three of which we included in our analyses (Chan 2013;Ley 2013;Mereles 2006); however, we excluded the other two studies as participants were non‐randomly allocated to exercise or control groups (Fox 2011;Martinez‐Quintana 2010). The results of this early systematic review of RCTs generated similar results as the current review with a large increase in 6MWD and VO2peak (6MWD: MD for exercise group 72.5 m, 95% CI 46.0 to 99.1; 5 studies; VO2peak: MD for exercise group 2.2 mL/kg/min, 95% CI 46.0 to 99.1; 3 studies). Other early systematic reviews included both RCTs and observational studies, and hence analysed a larger number of studies (Babu 2016a;Pandey 2015;Yuan 2015).Babu 2016a reported that exercise training resulted in large changes in exercise capacity, HRQoL and very few adverse events in 15 included studies, four of which were RCTs.Yuan 2015 undertook a meta‐analysis and reported large increases in exercise capacity (6MWD and peak exercise capacity), HRQoL (measured using the SF‐36) and few adverse events in the 12 studies they classified as being either randomised (two studies), observational‐control (four studies) or observational (six studies). The authors undertook a subgroup analysis of RCTs and whilst, producing similar results to our study for exercise capacity (MD for exercise group 62 m, 95% CI 45.6 to 78.8), these authors included data fromWeinstein 2013, which we considered to be a duplicate report of one of the studies included in our review (Chan 2013).
More‐recent systematic reviews of exercise‐based rehabilitation also reported substantial improvements in exercise capacity.Albanaqi 2021 (nine studies, data extracted up to June 2020) andYan 2021 (eight studies, data extracted up to January 2021) both reported similar increases in 6MWD as our review for the exercise group (Albanaqi 2021: MD 47.7 m, 95% CI 32.4 to 61.0; 10 studies;Yan 2021: MD 47.8 m, 95% CI 33.9 to 61.7; 8 studies).Albanaqi 2021 also reported similar changes in VO2peak to our review (MD 2.79 mL/kg/min, 95% CI 2.00 to 3.59). Notably these reviews included RCTs that examined solely inspiratory muscle training, which we did not consider for our review (Aslan 2020;Tran 2020). Moreover, neither of these reviews included the more recently published RCTs of exercise‐based rehabilitation that we included (Atef 2021;Butane 2021;Grünig 2020;Kagioglou 2021;Wojciuk 2021). Studies that included both inpatient and supervised home‐based exercise were included in the previous (Ehlken 2016;Ley 2013;Mereles 2006) and current review (Grünig 2020;Rakhmawati 2020). It is worth noting thatWojciuk 2021, which consisted of supervised home‐based exercise training, was included in the current review given the high level of home supervision and the structure of the exercise‐based rehabilitation programme.
Authors' conclusions
Implications for practice.
The results of this updated review suggest that supervised exercise‐based rehabilitation in people with pulmonary hypertension (PH) who are stable on medical therapy may lead to large improvements in exercise capacity, which for the 6MWD exceeded the minimal important difference. The conclusions are based on low‐certainty evidence with marked heterogeneity in the results that was not explained by subgroup analyses. There is moderate‐certainty evidence that exercise‐based rehabilitation is safe, with few adverse events reported. Moderate‐certainty evidence suggests that exercise‐based rehabilitation likely results in an increase in health‐related quality of life. The low‐certainty evidence for the change in pulmonary haemodynamics suggest that exercise‐based rehabilitation may result in large decreases in mean pulmonary arterial pressure. The results of this review apply primarily to people with moderate severity PH (New York Heart Association (NYHA)/World Health Organization (WHO) Functional Class II and III); the impact of rehabilitation in more severe PH (Class IV) is unknown. The duration of benefits for exercise‐based rehabilitation in PH remain unknown.
Implications for research.
Given the inconsistency of results of studies to date, particularly for changes in exercise capacity, future randomised controlled trials are needed to inform the application of exercise‐based rehabilitation across the spectrum of people with PH, including diagnostic subgroups such as chronic thromboembolic PH (WHO Group 4), PH with left‐sided heart disease (WHO Group 2) and those with more severe disease. It is essential that future trials provide clarity around participant selection in a CONSORT diagram, so that it is clear to which population the results can be applied. Additional studies are required to determine the optimal exercise training strategy for people with PH, including modality and intensity of training, length of programme, degree of supervision and the optimal setting for delivery of exercise training (e.g. inpatient versus outpatient). Longer‐term studies are required to assess the durability of benefits, and to determine the effect of exercise rehabilitation on critical outcomes such as time to clinical worsening and survival.
What's new
| Date | Event | Description |
|---|---|---|
| 21 March 2023 | New citation required and conclusions have changed | Eight new studies added to the review. Data on quality of life outcomes strengthened |
| 21 March 2023 | New search has been performed | Updated |
History
Protocol first published: Issue 10, 2014 Review first published: Issue 1, 2017
Acknowledgements
TheBackground andMethods sections of this review are based on a standard template used by Cochrane Airways.
The authors and Cochrane Airways' Editorial Team are grateful to the following peer and consumer reviewers for their time and comments: Matthew N Bartels, MD, MPH, Albert Einstein College of Medicine/Montefiore Health System, Bronx, NY (USA) and Abraham Samuel Babu, PhD, Department of Physiotherapy, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, India; Department of Cardiology, Austin Health, University of Melbourne (Australia).
This project was supported by the National Institute for Health and Care Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Airways Group. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service, or the Department of Health and Social Care.
Appendices
Appendix 1. Database search strategies
Cochrane Airways Register of Trials
#1 PULM:MISC1 #2 MeSH DESCRIPTOR Hypertension, Pulmonary Explode All #3 MeSH DESCRIPTOR Pulmonary Heart Disease #4 "pulmonary vascular disease":TI,AB #5 #1 or #2 or #3 or #4 #6 MeSH DESCRIPTOR exercise Explode All #7 MeSH DESCRIPTOR Exercise Therapy Explode All #8 MeSH DESCRIPTOR Exercise Tolerance #9 MeSH DESCRIPTOR Physical Fitness #10 MeSH DESCRIPTOR Physical Exertion #11 MeSH DESCRIPTOR Ergometry #12 MeSH DESCRIPTOR Bicycling #13 MeSH DESCRIPTOR Weight Lifting #14 MeSH DESCRIPTOR Muscle Strength #15 exercis*:TI,AB #16 conditioning or ergometry or treadmill or endurance or "upper limb" or "lower limb":TI,AB #17 walk* or swim* or cycle* or cycling or bicycl* or jog*:TI,AB #18 ((strength* or resistance* or weight*) NEAR3 train*):TI,AB #19 aerobic*:TI,AB #20 rehabilitat*:TI,AB #21 #6 OR #7 OR #8 or #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 #22 #5 and #21
CENTRAL (CRSO)
#1MESH DESCRIPTOR Hypertension, Pulmonary EXPLODE ALL TREES #2MESH DESCRIPTOR Pulmonary Heart Disease #3(pulmonary* NEAR3 hypertens*):TI,AB,KY #4("pulmonary vascular disease*"):TI,AB,KY #5#1 OR #2 OR #3 OR #4 #6MESH DESCRIPTOR Exercise EXPLODE ALL TREES #7MESH DESCRIPTOR EXERCISE THERAPY EXPLODE ALL TREES #8MESH DESCRIPTOR Exercise Tolerance #9MESH DESCRIPTOR Physical Fitness #10MESH DESCRIPTOR Physical Exertion #11MESH DESCRIPTOR Ergometry EXPLODE ALL TREES #12MESH DESCRIPTOR Bicycling #13MESH DESCRIPTOR Weight Lifting #14MESH DESCRIPTOR Muscle Strength EXPLODE ALL TREES #15exercis*:TI,AB,KY #16(conditioning or ergometry or treadmill or endurance or "upper limb" or "lower limb"):TI,AB,KY #17(walk* or swim* or cycle* or cycling or bicycl* or jog*):TI,AB,KY #18((strength* or resistance* or weight*) NEAR3 train*):TI,AB,KY #19aerobic*:TI,AB,KY #20rehabilitat*:TI,AB,KY #21#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 #22#5 AND #21
MEDLINE (Ovid)
1. exp Hypertension, Pulmonary/
2. Pulmonary Heart Disease/
3. (pulmonary adj3 hypertens$).ti,ab.
4. pulmonary vascular disease.ti,ab.
5. or/1‐4
6. exp Exercise/
7. exp Exercise Therapy/
8. Exercise Tolerance/
9. Physical Fitness/
10. Physical Exertion/
11. exp Ergometry/
12. Bicycling/
13. Weight Lifting/
14. Muscle Strength/
15. exercis$.ti,ab.
16. (conditioning or ergometry or treadmill or endurance or "upper limb" or "lower limb").ti,ab.
17. (walk$ or swim$ or cycle$ or cycling or bicycl$ or jog$).ti,ab.
18. ((strength$ or resistance$ or weight$) adj3 train$).ti,ab.
19. aerobic$.ti,ab.
20. rehabilitat$.ti,ab.
21. or/6‐20
22. 5 and 21
23. (controlled clinical trial or randomised controlled trial).pt.
24. (randomised or randomised).ab,ti.
25. placebo.ab,ti.
26. randomly.ab,ti.
27. trial.ab,ti.
28. groups.ab,ti.
29. or/23‐28
30. Animals/
31. Humans/
32. 30 not (30 and 31)
33. 29 not 32
34. 22 and 33
Embase (Ovid)
1. exp pulmonary hypertension/ 2. (pulmonary adj3 hypertens$).ti,ab. 3. pulmonary vascular disease.ti,ab. 4. or/1‐3 5. exp exercise/ 6. exp kinesiotherapy/ 7. exp ergometry/ 8. exp bicycle/ 9. exp weight lifting/ 10. muscle strength/ 11. exercis$.ti,ab. 12. (conditioning or ergometry or treadmill or endurance or "upper limb" or "lower limb").ti,ab. 13. (walk$ or swim$ or cycle$ or cycling or bicycl$ or jog$).ti,ab. 14. ((strength$ or resistance$ or weight$) adj3 train$).ti,ab. 15. aerobic$.ti,ab. 16. rehabilitat$.ti,ab. 17. or/5‐16 18. 4 and 17 19. Randomized Controlled Trial/ 20. randomisation/ 21. controlled clinical trial/ 22. Double Blind Procedure/ 23. Single Blind Procedure/ 24. Crossover Procedure/ 25. (clinica$ adj3 trial$).tw. 26. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (mask$ or blind$ or method$)).tw. 27. exp Placebo/ 28. placebo$.ti,ab. 29. random$.ti,ab. 30. ((control$ or prospectiv$) adj3 (trial$ or method$ or stud$)).tw. 31. (crossover$ or cross‐over$).ti,ab. 32. or/19‐31 33. exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ 34. human/ or normal human/ or human cell/ 35. 33 and 34 36. 33 not 35 37. 32 not 36 38. 18 and 37
PEDro
| Field | Search term |
| Abstract & Title | pulmonary hypertension |
| Method | clinical trial |
ClinicalTrials.gov
| search field | search term |
| Study type | Interventional |
| Condition | Pulmonary hypertension |
| intervention | Exercise |
Data and analyses
Comparison 1. Exercise versus control.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Exercise capacity: 6‐minute walk distance (6MWD) | 11 | 418 | Mean Difference (IV, Random, 95% CI) | 48.52 [33.42, 63.62] |
| 1.1.1 Pulmonary arterial hypertension subgroup | 3 | 71 | Mean Difference (IV, Random, 95% CI) | 63.97 [8.74, 119.21] |
| 1.1.2 Mixed pulmonary hypertension subgroup | 8 | 347 | Mean Difference (IV, Random, 95% CI) | 44.16 [28.97, 59.36] |
| 1.2 Exercise capacity: 6MWD inpatient vs outpatient studies | 11 | 418 | Mean Difference (IV, Random, 95% CI) | 48.29 [33.32, 63.27] |
| 1.2.1 Inpatient exercise training | 4 | 245 | Mean Difference (IV, Random, 95% CI) | 59.39 [29.95, 88.82] |
| 1.2.2 Outpatient exercise training | 7 | 173 | Mean Difference (IV, Random, 95% CI) | 43.21 [23.84, 62.57] |
| 1.3 Exercise capacity: peak exercise capacity (VO2peak) | 7 | 314 | Mean Difference (IV, Fixed, 95% CI) | 2.07 [1.57, 2.57] |
| 1.3.1 Mixed pulmonary hypertension subgroup | 5 | 278 | Mean Difference (IV, Fixed, 95% CI) | 2.17 [1.64, 2.70] |
| 1.3.2 Pulmonary arterial hypertension subgroup | 2 | 36 | Mean Difference (IV, Fixed, 95% CI) | 1.27 [‐0.21, 2.76] |
| 1.4 Exercise capacity: VO2peak, inpatient vs outpatient studies | 7 | 314 | Mean Difference (IV, Fixed, 95% CI) | 2.07 [1.57, 2.57] |
| 1.4.1 Inpatient exercise training | 3 | 217 | Mean Difference (IV, Fixed, 95% CI) | 2.00 [1.36, 2.64] |
| 1.4.2 Outpatient exercise training | 4 | 97 | Mean Difference (IV, Fixed, 95% CI) | 2.18 [1.38, 2.98] |
| 1.5 Exercise capacity: peak power | 5 | 226 | Mean Difference (IV, Fixed, 95% CI) | 9.69 [5.52, 13.85] |
| 1.5.1 Mixed pulmonary hypertension subgroup | 3 | 190 | Mean Difference (IV, Fixed, 95% CI) | 8.22 [3.43, 13.01] |
| 1.5.2 Pulmonary arterial hypertension subgroup | 2 | 36 | Mean Difference (IV, Fixed, 95% CI) | 14.24 [5.78, 22.70] |
| 1.6 Exercise capacity: peak power, inpatient vs outpatient studies | 5 | 226 | Mean Difference (IV, Fixed, 95% CI) | 9.69 [5.52, 13.85] |
| 1.6.1 Inpatient exercise training | 3 | 190 | Mean Difference (IV, Fixed, 95% CI) | 8.22 [3.43, 13.01] |
| 1.6.2 Outpatient exercise training | 2 | 36 | Mean Difference (IV, Fixed, 95% CI) | 14.24 [5.78, 22.70] |
| 1.7 Exercise capacity: anaerobic threshold | 3 | 66 | Std. Mean Difference (IV, Random, 95% CI) | 1.05 [0.53, 1.58] |
| 1.8 Serious adverse events | 11 | 439 | Risk Difference (M‐H, Random, 95% CI) | 0.00 [‐0.03, 0.03] |
| 1.8.1 Mixed pulmonary hypertension subgroup | 8 | 330 | Risk Difference (M‐H, Random, 95% CI) | 0.01 [‐0.03, 0.04] |
| 1.8.2 Pulmonary arterial hypertension subgroup | 3 | 109 | Risk Difference (M‐H, Random, 95% CI) | ‐0.01 [‐0.07, 0.06] |
| 1.9 Health‐related quality of life (HRQoL) 36‐item Short Form (SF‐36): Physical Component Summary | 5 | 187 | Mean Difference (IV, Fixed, 95% CI) | 3.98 [1.89, 6.07] |
| 1.9.1 Mixed pulmonary hypertension subgroup | 3 | 154 | Mean Difference (IV, Fixed, 95% CI) | 3.71 [1.22, 6.19] |
| 1.9.2 Pulmonary arterial hypertension subgroup | 2 | 33 | Mean Difference (IV, Fixed, 95% CI) | 4.63 [0.80, 8.47] |
| 1.10 HRQoL SF‐36: Mental Component Summary | 5 | 186 | Mean Difference (IV, Fixed, 95% CI) | 3.60 [1.21, 5.98] |
| 1.10.1 Mixed pulmonary hypertension subgroup | 3 | 153 | Mean Difference (IV, Fixed, 95% CI) | 3.31 [0.40, 6.22] |
| 1.10.2 Pulmonary arterial hypertension subgroup | 2 | 33 | Mean Difference (IV, Fixed, 95% CI) | 4.17 [0.01, 8.34] |
| 1.11 HRQoL SF‐36: Physical Function | 5 | 216 | Mean Difference (IV, Random, 95% CI) | 5.29 [‐1.15, 11.73] |
| 1.12 HRQoL SF‐36: Role Physical | 5 | 220 | Mean Difference (IV, Random, 95% CI) | 20.46 [13.77, 27.15] |
| 1.13 HRQoL SF‐36: Bodily Pain | 4 | 192 | Mean Difference (IV, Random, 95% CI) | 4.17 [‐2.01, 10.36] |
| 1.14 HRQoL SF‐36: General Health | 4 | 188 | Mean Difference (IV, Random, 95% CI) | 2.14 [‐4.45, 8.74] |
| 1.15 HRQoL SF‐36: Mental Health | 4 | 191 | Mean Difference (IV, Random, 95% CI) | 6.95 [2.12, 11.79] |
| 1.16 HRQoL SF‐36: Role Emotional | 4 | 191 | Mean Difference (IV, Random, 95% CI) | 3.16 [‐4.98, 11.30] |
| 1.17 HRQoL SF‐36: Vitality | 5 | 219 | Mean Difference (IV, Random, 95% CI) | 9.67 [2.61, 16.73] |
| 1.18 HRQoL SF‐36: Social Function | 5 | 222 | Mean Difference (IV, Random, 95% CI) | 12.20 [7.32, 17.08] |
| 1.19 HRQoL: CAMPHOR Activities | 2 | 33 | Mean Difference (IV, Random, 95% CI) | ‐1.33 [‐3.56, 0.90] |
| 1.20 HRQoL: CAMPHOR Symptoms | 2 | 36 | Mean Difference (IV, Random, 95% CI) | ‐3.08 [‐7.78, 1.62] |
| 1.21 HRQoL: CAMPHOR Quality of Life | 2 | 36 | Mean Difference (IV, Random, 95% CI) | ‐5.42 [‐8.03, ‐2.81] |
| 1.22 Cardiopulmonary haemodynamics | 2 | 133 | Mean Difference (IV, Random, 95% CI) | ‐9.29 [‐12.96, ‐5.61] |
| 1.23 Functional Class | 2 | 40 | Mean Difference (IV, Random, 95% CI) | ‐0.46 [‐0.64, ‐0.28] |
| 1.24 B‐type natriuretic peptide | 4 | 220 | Mean Difference (IV, Random, 95% CI) | ‐68.69 [‐154.89, 17.51] |
| 1.25 Exercise capacity: 6MWD, sensitivity analysis | 8 | 199 | Mean Difference (IV, Random, 95% CI) | 59.56 [37.64, 81.49] |
| 1.26 Exercise capacity: VO2peak, sensitivity analysis | 5 | 127 | Mean Difference (IV, Random, 95% CI) | 2.27 [1.53, 3.00] |
| 1.27 Exercise capacity: peak power, sensitivity analysis | 3 | 66 | Mean Difference (IV, Random, 95% CI) | 15.27 [8.57, 21.97] |
| 1.28 HRQoL SF‐36: Physical Component Score sensitivity analysis | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.28.1 All participants | 4 | 88 | Mean Difference (IV, Random, 95% CI) | 4.61 [1.17, 8.05] |
| 1.29 HRQoL SF‐36: Mental Component Score sensitivity analysis | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.29.1 All participants | 4 | 87 | Mean Difference (IV, Random, 95% CI) | 4.33 [1.41, 7.24] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Atef 2021.
| Study characteristics | ||
| Methods | Study design: RCT | |
| Participants | Baseline characteristics Exercise training
Control
| |
| Interventions | Exercise training
Control
| |
| Outcomes | Measured before and after 12‐week intervention Exercise capacity (VO2peak) Other (PASP) | |
| Identification | ||
| Notes | Funding: unclear | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "and the sealed envelope approach was used for randomisation, to two groups with an allocation ratio of 1:1." Comment: did not report details on randomisation aspects (i.e. how sequence was generated). |
| Allocation concealment (selection bias) | Unclear risk | Quote: "and the sealed envelope approach was used for randomisation, to two groups with an allocation ratio of 1:1." Comment: insufficient information on concealment (e.g. who managed the process, opaque envelopes?). |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: not possible to blind participants to intervention. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: no information. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: only 1 withdrawal. |
| Selective reporting (reporting bias) | Low risk | Comment: reported to clinical trials registration. |
| Other bias | Unclear risk | Comment: data found not to be normally distributed but unclear which outcome data. |
Butane 2021.
| Study characteristics | ||
| Methods | Study design: RCT | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: NYHA Functional Class II–III, aged 18–80 years, clinically stable and receiving optimised medical therapy for ≥ 3 months before entering study | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | 6MWD Sleep quality: Pittsburgh Sleep Quality Index HADS Inspiratory Pressure Test | |
| Identification | ||
| Notes | Funding: unclear | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization process was done by block randomisation method." |
| Allocation concealment (selection bias) | Unclear risk | Comment: no information reported. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: no information. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "An independent researcher ensured a blinded assessment." |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: unbalanced withdrawals (intervention 1 (10%), control 2 (23%)); no ITT. |
| Selective reporting (reporting bias) | Unclear risk | Comment: no trial registration reported. |
| Other bias | Unclear risk | Quote: "This is a prospective, randomised and controlled interventional study and we present the preliminary results, as the second follow‐up assessment is still ongoing. As mentioned above these are the preliminary results of a bigger ongoing study." Comment: unclear if this interim analysis was prespecified. |
Chan 2013.
| Study characteristics | ||
| Methods | Study design: RCT Study grouping: parallel | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: WHO group 1 PH; recruited from local outpatient clinics; enroled between September 2009 and October 2011; aged 21–82 years; had PH diagnosed by resting mPAP ≥ 25 mmHg measured using right‐sided heart catheterisation; receiving stable PH therapies for ≥ 3 months; sedentary; had no pulmonary rehabilitation for 6 months prior to enrolment Exclusion criteria: WHO and NYHA Functional Class I and could walk 400 m during 6MWT; WHO and NYHA Functional Class IV and could not walk 50 m during a 6MWT; FEV1/FVC ratio ≤ 65%; history of ischaemic heart disease; ejection fraction < 40%; documented pulmonary capillary wedge pressure ≥ 18 mmHg; significant hepatic, renal or mitochondrial dysfunctions; severe psychiatric disease; use of medications that may limit exercise capacity or ability to adapt to exercise training; antiretroviral therapies; illicit drugs; tobacco use; pregnancy Pretreatment: control group had worse lung function | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | 6MWD VO2peak Anaerobic threshold HRQoL (SF‐36): Physical Functioning HRQoL (SF‐36): Role Physical HRQoL (SF‐36): Bodily Pain HRQoL (SF‐36): General Health HRQoL (SF‐36): Vitality HRQoL (SF‐36): Social Function HRQoL (SF‐36): Role Emotional HRQoL (SF‐36): Mental Health HRQoL (SF‐36): Physical Component Summary HRQoL (SF‐36): Mental Component Summary HRQoL (CAMPHOR): Symptoms HRQoL (CAMPHOR): Activities HRQoL (CAMPHOR): QoL NYHA Class | |
| Identification | ||
| Notes | Funding: US National Institutes of Health (Intramural Funds 1 Z01CL060068‐05 CC) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Patients who enrolled in the protocol were sequentially assigned subject numbers that randomly corresponded to a group receiving concurrent patient education plus aerobic exercise training (EXE) or to a group that received only the patient education portion of the regimen (EDU)." |
| Allocation concealment (selection bias) | Unclear risk | Comment: not specified. Quote: " Following the baseline evaluations, patients were informed of the group to which they were randomly assigned," |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "Study personnel were blind to the randomisation of patients during all baseline evaluations." |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Investigators administering the CPET, 6MWT, and questionnaires were blind to randomisation at baseline." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "criterion (Fig. 1). All 29 of these patients performed base‐ line testing. Based on their test responses, two of these patients were required to obtain additional medical clearance prior to beginning the intervention. One patient declined further participation while the other patient was cleared for participation and subsequently assigned a new subject number upon re‐entry into the protocol. This patient was originally assigned a subject number corresponding to EXE, but at re‐entry the randomisation procedure resulted re‐assignment to EDU. As such, 28 patients in total participated in either the EXE or EDU groups (Fig. 1). Of the 14 patients allocated to the EXE group, two patients withdrew due to changes in medication and one withdrew due to low attendance at the exercise sessions. One patient in the EDU group was withdrawn from the study due to medication changes." |
| Selective reporting (reporting bias) | High risk | Comment: trial protocol at ClinicalTrials.gov stated that they were also going to collect International Physical Activity Questionnaires, stages of exercise change, exercise self‐efficacy, profile of mood states and near‐infrared spectroscopy |
| Other bias | Low risk | No other bias identified. |
Ehlken 2016.
| Study characteristics | ||
| Methods | Study design: RCT Study grouping: parallel | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: people with PAH and inoperable or persistent CTEPH and chronic right heart failure who were stable on disease‐targeted medication for ≥ 2 months prior to inclusion. Medication remained unchanged during study. Exclusion criteria: not specified Pretreatment: none reported | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | 6MWD VO2peak Wpeak (peak power) Morbidity measured as adverse events Disease progression Precluded from training HRQoL (SF‐36): Physical Functioning HRQoL (SF‐36): Role Physical HRQoL (SF‐36): Bodily Pain HRQoL (SF‐36): General Health HRQoL (SF‐36): Vitality HRQoL (SF‐36): Social Function HRQoL (SF‐36): Role Emotional HRQoL (SF‐36): Mental Health Discontinued training Haemodynamics: mPAP (mmHg), PVR (dynes/s/cm5), cardiac output (L/min) B‐type natriuretic peptide | |
| Identification | Author's name: Nicola Ehlken Institution: University Hospital Heidelberg Email: nicola.ehlken@med.uni‐heidelberg.de Address: Amalienstrasse 5, Heidelberg D‐69126, Germany | |
| Notes | Funding: Centre for Pulmonary Hypertension, Thorax Clinic at the University of Heidelberg, Germany paid open access publication charges for the article. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: methods of randomisation not specified. |
| Allocation concealment (selection bias) | Unclear risk | Comment: allocation concealment not specified. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: not possible to blind participants to intervention. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote: "Assessment of 6MWD, SF‐36 and other efficacy parameter were performed by investigators who were blinded to the clinical data." Comment: unclear whether assessors were blinded to group allocation, especially for primary outcome. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: differential attrition: 17% lost to follow‐up in exercise group, 0% lost to follow‐up in control group. |
| Selective reporting (reporting bias) | High risk | Comment: not all outcomes specified in trial protocol were reported. |
| Other bias | High risk | CONSORT diagram did not report how many people were assessed to arrive at the 95 participants enroled. |
Ertan 2022.
| Study characteristics | ||
| Methods | Study design: RCT | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: aged 18–80 years; diagnosed with PH according to European Society of Cardiology/European Respiratory Society guideline; followed by Department of Chest Diseases ≥ 6 months; not participating in the rehabilitation programme in last year Exclusion criteria: WHO Functional Class IV; PH due to left heart diseases; PH due to lung diseases or hypoxia, or both; treatment and medication change in last 3 months; co‐operation problems; successful pulmonary endarterectomy operation; smoking; uncontrolled cardiovascular diseases; orthopaedic or neurological disorders (or both) that could limit exercise tests; recent history of syncope | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | Exercise capacity (endurance shuttle walk test, incremental shuttle walk test, 6MWD) HRQoL (EmPHasis‐10) | |
| Identification | ||
| Notes | Funding: unclear | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomly assigned to groups 1:1 using a computerized (GraphPad Software, San Diego, California) random number generator." |
| Allocation concealment (selection bias) | Unclear risk | Comment: insufficient information on allocation concealment. Quote: "Randomization was performed by a researcher (GKA) who did not take part in the assessments." |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: no information reported; not possible to blind intervention. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: unclear if staff completing assessments were blinded. Quote: "This was a randomised controlled, prospective, and single‐blind research" and "Randomization was performed by a researcher (GKA) who did not take part in the assessments" |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: 20% dropout in intervention; 0% in control; no ITT analyses. |
| Selective reporting (reporting bias) | High risk | Comment: trial registry record only included 'Endurance Exercise Capacity (endurance shuttle walk test)' |
| Other bias | Unclear risk | Comment: unclear how allocation was unbalanced: sample size calculation, (quote) "12 patients were stated to be required for each group with a 90% power (two‐tailed, a = 0.05, effect size: 1.34)"; Randomisation:" Patients were randomly assigned to the walking or control groups 1:1 using a computerized (GraphPad Software, San Diego, California) random number generator;" Figure 1: 27 patients were randomised: 12 to control vs 15 to intervention |
Ganderton 2013.
| Study characteristics | ||
| Methods | Study design: RCT Study grouping: parallel | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: confirmed diagnosis of idiopathic PAH, familial PAH or PAH associated with connective tissue disorders, based on elevated pulmonary arterial pressures (> 25 mmHg at rest or > 30 mmHg during exercise) measured by RHC; medically stable and had been receiving PAH‐specific medication for 3 months prior to enrolment; WHO Functional Class II or III; willing to complete the 12‐week supervised and 12‐week home exercise training programmes. Exclusion criteria: resting hypoxaemia requiring supplemental oxygen therapy; significant musculoskeletal disease, claudication pain, neurological or cognitive impairment, psychiatric/psychological or mood disorders that may have affected their ability to undertake exercise testing or training; history of moderate or severe chronic lung disease; cardiac disease associated with cardiac failure, poorly controlled angina, unstable cardiac rhythm; participated in a supervised exercise training programme within last 12 months Pretreatment: none | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | 6MWD VO2peak Wpeak Anaerobic threshold HRQoL (SF‐36): Physical Functioning HRQoL (SF‐36): Role Physical HRQoL (SF‐36): Bodily Pain HRQoL (SF‐36): General Health HRQoL (SF‐36): Vitality HRQoL (SF‐36): Social Function HRQoL (SF‐36): Role Emotional HRQoL (SF‐36): Mental Health HRQoL (CAMPHOR): Symptoms HRQoL (CAMPHOR): Activities HRQoL (CAMPHOR): QoL Morbidity Disease progression Symptoms precluding training Discontinued training NYHA class HRQoL (SF‐36): Physical Component Summary HRQoL (SF‐36): Mental Component Summary Assessed at baseline, 12 weeks postintervention and 24 weeks (follow‐up) | |
| Identification | Country: Australia Setting: outpatient, hospital Comments: – Author's name: Louise Ganderton Institution: Curtin University Email: louise.ganderton@health.wa.gov.au Address: School of Physiotherapy, Faculty of Health Sciences, The University of Sydney | |
| Notes | Funding: Advanced Lung Disease Unit at Royal Perth Hospital and the Lung Institute of Western Australia Protocol paper published: Ganderton 2011 Thesis available: catalogue.curtin.edu.au/discovery/fulldisplay?docid=alma9939026542901951&context=L&vid=61CUR_INST:CUR_ALMA | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote from thesis: "Permuted block randomisation with block sizes of four was used to generate a randomisation chart. Fourteen blocks were created in total using a web‐based research randomiser." |
| Allocation concealment (selection bias) | Unclear risk | Comment: not specified. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: not possible to blind participants to intervention. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote from thesis: "The primary investigator (LG) carried out all assessments at baseline, 12 weeks and 24 weeks and was blinded to the participants group allocation … The physiotherapists responsible for conducting the exercise training sessions were not involved in any of the formal assessments." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: data available on all recruited participants for ITT. However planned to enrol 34 and only recruited 10. |
| Selective reporting (reporting bias) | Low risk | Comment: all outcomes reported. |
| Other bias | Low risk | Comment: no other bias identified. |
González‐Saiz 2017.
| Study characteristics | ||
| Methods | Study design: RCT | |
| Participants | Baseline characteristics Exercise training
Control
| |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | Measured before and after the 8‐week training programme Exercise capacity using 6MWD (m) and VO2peak (mL/kg/min) Adverse events QoL using SF‐36 proBNP 5 sit‐to‐stand | |
| Identification | ||
| Notes | Funding: grant from Cátedra Real Madrid‐Universidad; LGS was supported by a research training scholarship from GSK to conduct the study. AL and MM: Fondo de Investigaciones Sanitarias and Fondos Feder. CF‐L: postdoctoral Sara Borrell contract. FS‐G: Conselleria de Educación, Investigación, Cultura y Deporte de la Generalitat Valenciana. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Following an informative session, those willing to participate signed an informed con‐sent form prior to baseline end point assessment, after which they were assigned to a standard care (control) or intervention group (exercise) with a block on sex using a computer‐generated list of random numbers." |
| Allocation concealment (selection bias) | Unclear risk | Quote: "The researchers responsible for assessing participants' eligibility and study outcomes were blinded to group allocation." Comment: insufficient information on concealment of sequence/allocation. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: not possible to blind participants to intervention. Quote: "The researchers responsible for assessing participants' eligibility and study outcomes (but not the study participants or the researchers supervising the exercise sessions) were blinded to group allocation." |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The researchers responsible for assessing participants' eligibility and study outcomes (but not the study participants or the researchers supervising the exercise sessions) were blinded to group allocation." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: minimal withdrawals. Analyses adhered to the ITT principle, |
| Selective reporting (reporting bias) | Low risk | Comment: reported according to trial registry. |
| Other bias | Low risk | Comment: inspiratory equipment provided but no clear conflict with study. |
Grünig 2020.
| Study characteristics | ||
| Methods | Study design: RCT Study grouping: parallel | |
| Participants | Baseline characteristics Exercise training
Control
| |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | Primary end point (change from baseline to 15 weeks after rehabilitation)
Secondary end points (change from baseline to 15 weeks after rehabilitation)
| |
| Identification | ||
| Notes | Funding: grants from Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (PI17/1515), Fondo Europeo deDesarrollo Regional (FEDER), EU. 'Una manera de hacer Europa'. HD was a postdoctoral research fellow of the FWO‐Flanders. Actelion Germany supported PH experts to visit Heidelberg to observe the training programme. Exercise training study in Glasgow (UK) was funded jointly by Actelion, MSD and PHA‐UK. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "patients were randomly assigned to either a 'training group' or a 'control group' using a permuted block randomisation procedure with sealed envelopes, stratified by centre." |
| Allocation concealment (selection bias) | Unclear risk | Comment: no information reported. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: not possible to blind intervention. Quote: "It is intrinsically not possible to blind a training study." |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Efficacy parameters were assessed at baseline and after 15 weeks by investigators who were blinded to the clinical data. However, investigators involved in data analysis were blinded as far as possible including clinical data and QoL assessments. Due to organizational reasons, not all centres were, however, able to perform blinded assessments of 6MWD, though the walking distance of previous assessments was not known to the investigators." |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: greater dropout rate in exercise group (15% in exercise vs 5% in control). Unmatched reasons for dropout. No ITT analysis. |
| Selective reporting (reporting bias) | High risk | Comment: trial registry record listed 55 different outcomes, 8 of which were noted as 'optional.' The registry included 'assessment of survival,' 8 outcomes related to 'lung function,' 'change in WHO Functional Class' that were all not reported or referred to in paper. In addition, not all echocardiographic parameters from trial registry were reported in paper. |
| Other bias | Unclear risk | Comment: imbalance in randomisation (68 to exercise; 61 to control). |
Kagioglou 2021.
| Study characteristics | ||
| Methods | Study design: RCT | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: people with stable precapillary PH classified as group 1 (PAH) or group 4 (CTEPH) inoperable disease, diagnosed according to current guidelines; WHO Functional Class ≤ III; stable medical and pharmaceutical therapy for ≥ 3 months before randomisation; abstain from any form of structured exercise training for ≥ 3 months before screening Exclusion criteria: history of unstable angina, uncontrolled arterial hypertension, reduced oxygen saturation at rest with ambulatory oxygen therapy requirements, musculoskeletal or neurological impairments; psychological or cognitive disorders that may affect participation to exercise | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | 6MWD VO2peak Anaerobic threshold VCO2 VE VE/VCO2 slope Resting blood pressure Resting HR Body surface area HRQoL (SF‐36): Physical Component Summary HRQoL (SF‐36): Mental Component Summary State Trait Inventory Becks Depression Inventory Timed Up‐and‐Go Grip strength Lower limb strength Sit‐to‐stand test (lower limb strength) | |
| Identification | ||
| Notes | Funding: unclear | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The study was a randomised controlled trial. The sample size was calculated with G∗Power 3.1.9 [8], and after the baseline evaluation, an online statistical computing web programming (https://www.randomizer.org) was used for the randomisation process. A random assignment of the 32 participants in blocks of 2 was done." |
| Allocation concealment (selection bias) | Unclear risk | Comment: not reported. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "All patients were informed about the purpose and the procedures of the study and gave written informed consent before randomisation." |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The researchers who conducted the assessments of participants were blinded to patient group allocation." |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: intervention: 25% dropout; control: 38% dropout; no ITT analysis. |
| Selective reporting (reporting bias) | Unclear risk | Comment: no trial registration reported. |
| Other bias | Low risk | Comment: no other bias identified. |
Ley 2013.
| Study characteristics | ||
| Methods | Study design: RCT Study grouping: parallel | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: aged ≥ 18 years, confirmed PAH and CTEPH who underwent complete clinical work‐up including RHC; stable under optimised medical therapy (e.g. endothelin antagonists, iloprost, sildenafil, calcium channel blockers, anticoagulants, diuretics and supplemental oxygen) for ≥ 3 months before entering study; WHO Functional Class II to III Exclusion criteria: no recent syncope, and no skeletal or muscle abnormalities prohibiting participation in an exercise training programme Pretreatment: none | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | Morbidity – adverse events Disease progression Precluded from training 6MWD | |
| Identification | Country: Germany Setting: inpatient rehabilitation Comments: – Author's name: Sebastian Ley Institution: University Hospital Heidelberg Email: ley@gmx.de Address: Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Im Neuenheimer Feld 430,69120 Heidelberg, Germany | |
| Notes | Funding: supported by German National Research Agency (DFG): "Image‐based V/Q analysis" (FOR 474‐2). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "patients were randomly assigned to either a training or a control group using a permuted block randomisation procedure." |
| Allocation concealment (selection bias) | Unclear risk | Comment: method of allocation not specified. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: unable to blind participants or personnel due to intervention. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Assessment of 6MWD and MR [magnetic resonance] examination were performed by investigators who were blinded to the clinical data and group assignment of the patients. Evaluation of the MR data was done blinded to the clinical setting and in random order." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: all randomised participants were analysed. |
| Selective reporting (reporting bias) | Low risk | Comment: unclear whether trial was registered but reporting did not appear selective. |
| Other bias | Low risk | Comment: no other bias identified. |
Mereles 2006.
| Study characteristics | ||
| Methods | Study design: RCT Study grouping: parallel | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: people with severe chronic PH who were stable and compensated under optimised medical therapy (e.g. endothelin antagonists, iloprost, sildenafil, calcium channel blockers, anticoagulants, diuretics and supplemental oxygen) for ≥ 3 months before entering study; aged 18–75 years; WHO Functional Class II–IV Exclusion criteria: no recent syncope; no skeletal or muscle abnormalities prohibiting participation in an exercise programme Pretreatment: none evident | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | 6MWD VO2peak Wpeak Morbidity – adverse events Disease progression Precluded from training Anaerobic threshold HRQoL (SF‐36): Physical Functioning HRQoL (SF‐36): Role Physical HRQoL (SF‐36): Bodily Pain HRQoL (SF‐36): General Health HRQoL (SF‐36): Vitality HRQoL (SF‐36): Social Function HRQoL (SF‐36): Role Emotional HRQoL (SF‐36): Mental Health HRQoL (SF‐36): Physical Component Summary HRQoL (SF‐36): Mental Component Summary HRQoL (CAMPHOR): QoL NYHA Class Discontinued training | |
| Identification | Country: Germany Setting: inpatient rehabilitation Author's name: Derliz Mereles Institution: University Hospital Heidelberg Email: ekkehard_gruenig@med.uni‐heidelberg.de Address: Department of Cardiology and Pneumology, University Hospital Heidelberg, INF 410, D‐69120 Heidelberg, Germany | |
| Notes | Funding: grant from the German Pulmonary Hypertension Group, Pulmonale Hypertonie e.V., Rheinstetten, Germany. Adverse outcomes: all participants tolerated training and had no adverse events during training and no progression of disease as defined by progression of symptoms, PH or right heart failure. 2 participants perceived a short episode of dizziness without fainting immediately after bicycle ergometer training. In 1 participant, oxygen saturation dropped from 88% to 74% during exercise, although training was performed with an oxygen mask. Continuous outcomes: 6MWD reported as a change from baseline after inpatient and after outpatient time points | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: participants were randomly assigned to either a primary training group or a sedentary control group using a permuted block randomisation procedure |
| Allocation concealment (selection bias) | Unclear risk | Comment: allocation concealment not reported. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: unable to blind participants and personnel due to nature of intervention. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The completed questionnaire at baseline was compared with the results after 15 weeks by investigators who were blinded to the patients' clinical data and group assignment. To avoid bias as far as possible in this study, all measurements and/or offline readings were performed by investigators who were blinded to patient data and group assignment." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | No dropouts reported. |
| Selective reporting (reporting bias) | Low risk | Comment: protocol was not registered or published; however, outcome reporting was comprehensive. |
| Other bias | High risk | Comment: no CONSORT diagram so not possible to determine how many people were assessed in order to recruit the sample. |
Rakhmawati 2020.
| Study characteristics | ||
| Methods | Study design: RCT | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: adults with uncorrected atrial septal defects and PAH; already undergone RHC; receiving stable PAH‐targeted therapy (i.e. constant doses of sildenafil or beraprost (or both) for ≥ 3 months before randomisation); WHO Functional Class I–II; signed informed consent forms. Exclusion criteria: left ventricular systolic dysfunction, determined by left ventricular ejection fraction ≤ 45% measured using transthoracic echocardiography; mitral and aortic valve abnormalities, namely, any regurgitation and stenosis irrespective of severity; lung disease (chronic obstructive pulmonary disease, bronchial asthma and tuberculosis); using supplemental oxygen therapy; unable to walk normally (i.e. musculoskeletal abnormalities that impeded exercise and evaluation (6MWT), e.g. ankle, knee or hip problems, and poststroke sequel). | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | 6MWD HRQoL: EQ‐5D‐3L (EuroQol) Utility Index NT‐proBNP | |
| Identification | ||
| Notes | Funding: supported by Research Grant Penelitian Dasar 2019 (No. 2798/UN1.DITLIT/DIT‐LIT/LT/2019) from Direktorat Riset dan Pengabdian Masyarakat, Direktorat Jenderal Penguatan Riset dan Pengembangan Pengembangan, Kementerian Riset, Teknologi dan Pendidikan Tinggi of Indonesia via Universitas Gadjah Mada, Jogjakarta, Indonesia. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Subjects were allocated randomly through simple random sampling into the control and exercise groups. We assigned random numbers for the groups and the number of subjects. Subjects were randomly allocated by drawing lots of closed envelopes containing the number." |
| Allocation concealment (selection bias) | Unclear risk | Comment: insufficient information on concealment (e.g. who managed the process, opaque envelopes?) |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: no information reported. Not possible to blind intervention. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Outcomes were assessed by blinded investigators. The evaluations of 6MWT, EQ‐5D‐3L QoL questionnaire, and other parameters were done by investigators blinded to group allocations." |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: unbalanced withdrawals but minimal; intervention: 5%; control: 15% dropout. |
| Selective reporting (reporting bias) | Unclear risk | Comment: no trial registration reported. |
| Other bias | Unclear risk | Comment: data found not to be normally distributed but unclear which outcome data. |
Wilkinson 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study grouping: parallel | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: people with clinically stable PH from a single centre Exclusion criteria: unclear | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | Incremental Shuttle Walk Test Endurance Shuttle Walk Test Assessed at baseline and 3 months | |
| Identification | Author's name: Anna Wilkinson Institution: Royal Hallamshire Hospital, Sheffield, UK | |
| Notes | Funding: unclear Reported as 2 abstracts: theThorax abstract did not specify the number in each group, only that 40 were randomised. The European Respiratory Society abstract states 18 in each group. Neither specifies age by allocated group. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: abstract only, does not specify how sequence was generated. |
| Allocation concealment (selection bias) | Unclear risk | Comment: abstract only, does not specify. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: not possible to blind participants to intervention. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Blind assessment was undertaken pre intervention and following 3 months." |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: dropouts unclear. 2007 abstract specified 40 participants and 2008 abstract specified 36 participants. |
| Selective reporting (reporting bias) | High risk | Comment: abstract only, not all outcomes reported. |
| Other bias | High risk | Comment: abstract only. |
Wojciuk 2021.
| Study characteristics | ||
| Methods | Study design: RCT | |
| Participants | Baseline characteristics Exercise training
Control
Inclusion criteria: diagnosis of PAH (Group 1 in the comprehensive clinical classification of PH according to the ERS/ESC guidelines) based on right‐heart catheterisation (mPAP ≥ 25 mmHg, pulmonary arterial wedge pressure ≤ 15 mmHg); WHO Functional Class II or III; stable during last 3 months of study; echocardiography, a perfusion lung scan, respiratory function tests and computed tomography performed prior to the initiation of specific treatment to rule out other causes of PH. During the period of study there were no changes in specific PAH therapy. Exclusion criteria: significant modification in the treatment of the main disease within 3 months of study commencement; severe lung disease, such as chronic obstructive pulmonary disease or asthma; loss of consciousness within 3 months of study commencement; active neoplastic disease with poor prognosis; acute inflammation up to 4 weeks before enrolment; anaemia (haemoglobin < 11 g/dL for males, < 10 g/dL for females); electrolyte and hormonal disorders within 4 weeks before enrolment; other clinical situations that made it impossible for participation in rehabilitation programme; contraindications in accordance with the applicable standards of Comprehensive Cardiac Rehabilitation; intellectual disability. | |
| Interventions | Intervention characteristics Exercise training
Control
| |
| Outcomes | 6MWD Max inspiratory pressure (PImax) Max expiratory pressure (PEmax) Grip strength HRQoL (SF‐36): Physical Functioning HRQoL (SF‐36): Role Physical HRQoL (SF‐36): Bodily Pain HRQoL (SF‐36): General Health HRQoL (SF‐36): Vitality HRQoL (SF‐36): Social Function HRQoL (SF‐36): Role Emotional HRQoL (SF‐36): Mental Health HRQoL (SF‐36): Physical Component Summary HRQoL (SF‐36): Mental Component Summary | |
| Identification | ||
| Notes | Funding: grant from the Medical University of Bialystok, Bialystok, Poland (Grant No. N/ST/MN/16/002/1153). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization was performed using Research Randomizer (Version 4.0) by an investigator who was not involved in the assessment of study outcomes." |
| Allocation concealment (selection bias) | Unclear risk | Comment: no information reported. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Comment: no information reported. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: no information reported. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: high and unbalanced dropout rate (7 (30%) in exercise; 23 (100%) in control). Not all participants were included in the final analysis. |
| Selective reporting (reporting bias) | High risk | Comment: following clinical outcomes listed in registry, not reported in paper.
|
| Other bias | Low risk | Comment: no other bias identified. |
6MWD: six‐minute walk distance; 6MWT: Six‐Minute Walk Test; bpm: beats per minute; CAMPHOR: Cambridge Pulmonary Hypertension Outcome Review; CPET: cardiopulmonary exercise test; CTEPH: chronic thromboembolic pulmonary hypertension; double: participants received two pharmacotherapies; FEV1: forced expired volume in one second; FVC: forced vital capacity; HADS: Hospital Anxiety Depression Scale; HR: heart rate; HRQoL: health‐related quality of life; IPAH: idiopathic pulmonary artery hypertension; ITT: intention‐to‐treat; max: maximum; min: minute; mPAP: mean pulmonary arterial pressure; NYHA: New York Heart Association; PAH: pulmonary arterial hypertension; PASP: pulmonary arterial systolic pressure; PH: pulmonary hypertension; PImax: maximal inspiratory pressure; PLB: pursed lip breathing; PVR: pulmonary vascular resistance; QoL: quality of life; RCT: randomised controlled trial; rep: repetition; RHC: right heart catheterisation; RPE: rating of perceived exertion; SD: standard deviation; SF‐36: Short‐form 36; single: participants received one pharmacotherapy; SpO2: oxygen saturation; triple: participants received three pharmacotherapies; VE: pulmonary ventilation; VCO2: carbon dioxide production; VO2peak: peak oxygen capacity; Wpeak: peak power; WHO: World Health Organization.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Albarrati 2021 | Ineligible population, inspiratory muscle training |
| Aslan 2020 | Inspiratory muscle training only |
| Babu 2013 | Review paper |
| Babu 2014 | Not an RCT |
| Babu 2019 | Unsupervised exercise |
| Barbosa 2011 | No exercise training |
| Becker‐Grunig 2013 | Not an RCT |
| Bernheim 2007 | Wrong patient population |
| Bhasipol 2018 | Non‐randomised |
| Chia 2017 | Protocol, unsupervised exercise |
| Dowman 2017 | Ineligible patient population |
| Ehlken 2014 | Not an RCT |
| Farias da Fontoura 2018 | Inspiratory muscle training only |
| Fox 2011 | Not an RCT |
| Fukui 2016 | Study design |
| Gerhardt 2017 | Passive vibration therapy, no exercise |
| Grunig 2011 | Not an RCT |
| Grunig 2012 | Not an RCT |
| Iliuta 2019 | No right heart catheter diagnosis of pulmonary hypertension |
| jRCT1030210240 | Single arm study |
| Kabitz 2014 | Not an RCT |
| Kahraman 2020 | Intervention (neuromuscular electrical stimulation) |
| Karapolat 2019 | No non‐exercise control group |
| Kolesnikova 2011a | Wrong intervention |
| Kolesnikova 2011b | Wrong intervention |
| Mackenzie 2017 | Non‐randomised allocation |
| Marvisi 2013 | No exercise training |
| Missana 2020 | Single arm study |
| Morris 2020 | Non‐randomised trial |
| Nagel 2012 | Not an RCT |
| NCT03186092 | Inspiratory muscle training |
| NCT03476629 | Unsupervised exercise, incomplete trial |
| NCT04254289 | Unsupervised exercise, incomplete trial |
| NCT04559516 | Unsupervised exercise, incomplete trial |
| NCT04683822 | Unsupervised exercise, incomplete trial |
| Ontiyuelo 2019 | Non‐randomised |
| Robalo Cordeiro 2011 | No exercise training |
| Rokach 2019 | non‐randomised |
| Skibarkienė 2019 | Unsure if any participants had pulmonary hypertension |
| Tran 2020 | Inspiratory muscle training only |
| Yilmaz 2020 | No control group |
RCT: randomised controlled trial.
Characteristics of studies awaiting classification [ordered by study ID]
NCT00477724.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria A Screening
B Training See A + all patients who showed a restricted physical capacity in the screening
Exclusion criteria
|
| Interventions | Conventional rehabilitation (control group with no specific training) Rehabilitation with exercise and respiratory therapy (exercise and respiratory therapy for 3 weeks in‐hospital and 15 weeks at home) |
| Outcomes | Primary outcome: 6MWD; quality of life Secondary outcomes: physical capacity in the ergometer test; change of lung function during 6‐Minute Walking Test; non‐invasive haemodynamic parameters; systolic pulmonary arterial pressure at rest and during exercise; WHO Functional Class; perfusion parameters (magnetic resonance imaging); respiratory muscle function; NT‐proBNP |
| Notes | Trial first registered in 2007; intervention components unclear |
NCT00491309.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Symptomatic PAH (WHO Functional Class II–IV) invasively diagnosed by right heart catheterisation
Exclusion criteria
|
| Interventions | Exercise and respiratory therapy (specific programme for PH including respiratory therapy, dumbbell training, ergometer training, mental training) Control group without exercise training (continuation of sedentary lifestyle without advice for specific exercise training) |
| Outcomes | Primary outcomes: 6MWD; quality of life (SF‐36) Secondary outcomes: physical capacity in the CPET (watts); peak oxygen consumption and other parameters of CPET; haemodynamic parameters: dimension and pump function of right and left ventricle; systolic pulmonary arterial pressure at rest and during exercise; echocardiography |
| Notes | Trial first registered in 2017; intervention components unclear |
NCT02558582.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Immediate rehabilitation: bicycle ergometer training, respiratory training, dumbbell‐training and (mental) gait training. Immediate rehabilitation with oxygen: bicycle ergometer training, respiratory training, dumbbell‐training and (mental) gait training. Patients who are not already under long‐term oxygen therapy due to daytime hypoxaemia will additionally be randomised to receive standardised supplemental oxygen therapy during training and nights. Delayed rehabilitation: waiting group that participates in the rehabilitation programme after 3 months. Delayed rehabilitation with oxygen: waiting group that participates in the rehabilitation programme after 3 months. Patients who are not already under long‐term oxygen therapy due to daytime hypoxaemia will additionally be randomised to receive standardised supplemental oxygen therapy during training and nights. |
| Outcomes | Primary outcomes: 6MWD; constant CPET change in endurance time Secondary outcomes: quality of life (Minnesota Living with Heart Failure Questionnaire, CAMPHOR, SF‐36); Sit‐to‐Stand (number performed in 1 minute); stair ascent (force, power and time needed to climb 5 steps); haemodynamic (pulmonary arterial pressure, cardiac output); Functional Class; lung function (FVC in litres per 1 second, total lung capacity, diffusion of carbon dioxide); actigraphy (daily activity (energy expenditure, steps per day, sleep time and efficiency, lying down time, physical activity level, metabolic equivalent units)); hospitalisation days |
| Notes | Intervention components unclear |
NCT02579954.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Supervised rehabilitation Control group |
| Outcomes | Primary outcome: endurance time at 75% of the maximal workout (determined during CPET) Secondary outcomes: right ventricular ejection fraction evaluated by RMN; pulmonary haemodynamics: measurements at right heart catheterisation (cardiac index, L/min/m²); pulmonary haemodynamics: measurements at right heart catheterisation (pressure in the right atrium, mmHg); pulmonary haemodynamics: measurements at right heart catheterisation (pulmonary resistance, uw); pulmonary haemodynamics: measurements at right heart catheterisation (mPAP, mmHg); Functional Class (NYHA classification); 6MWD; functional exercise capacity (oxygen consumption measurement during test); quality of life (SF‐36); time to clinical worsening (months) |
| Notes | Interventions unclear |
NCT03045666.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Intervention: exercise twice a week for 12 weeks supervised by physiotherapists. Programme includes aerobic and strength exercises, at 2‐ to 3‐minute intervals Control: no exercise |
| Outcomes | Primary outcomes: CPET: measurements of VO2, anaerobic threshold, respiratory exchange ratio, oxygen pulse, ventilatory reserve, heart rate, end‐tidal carbon dioxide and oxygen, work rate, ventilation (VE), VCO2 during exercise test Secondary outcomes: echocardiography (dimensions and pressure of left and right ventricles; cardiac output; systolic, diastolic and mPAP, PCWP); disease‐specific quality of life (EmPHasis‐10 questionnaire); quality of life (SF‐36); NT‐proBNP; WHO Functional Class; 6MWD |
| Notes | Trial registered 2017; recruitment status: "Unknown." |
NCT03288025.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Intervention: 5 days/week of moderate exercise and biweekly diet counselling on low glycaemic index/Mediterranean diet for 12 weeks Control: counselling at baseline on diet as recommended by US Department of Agriculture and on the benefits of regular aerobic exercise |
| Outcomes | Primary outcome: insulin sensitivity Secondary outcome: right ventricular global peak longitudinal strain (echocardiography) |
| Notes | Exercise component unclear |
NCT03955016.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Intervention: 15‐week pulmonary rehabilitation programme consisting of 2 weeks' inpatient (supervised training 5 times/week), 2 weeks' outpatient (supervised sessions 3 times/week) and 11 weeks' home‐based exercise training (weekly telephone call). During the inpatient phase, participants will receive on top of the supervised training sessions a consultation of the dietitian, PH psychologist, social worker and specialised nurse. During ambulatory rehabilitation phase, patients will have 2 sessions with the occupational therapist. Every supervised training session contains: interval training on a cyclo‐ergometer, strength training of the upper and lower extremities and guided walks Control: usual care |
| Outcomes | Primary outcome: 6MWD, Borg Scale at end of the 6MWD test at baseline, 4 weeks, 15 weeks Secondary outcomes: HRQoL (SF‐36, EmPHasis‐10); WHO Functional Class; dyspnoea and fatigue (Borg Scale) at end of 6MWT; maximal incremental cycling test (peak workload, oxygen consumption (VO2max), heart rate, blood pressure, oxygen saturation, ventilation and VE/VCO2); objectively measured physical activity; symptoms of anxiety and depression (Hospital Anxiety and Depression Scale); isometric quadriceps force; haemodynamics (echocardiography): tricuspid annular plane systolic excursion, tissue Doppler imaging, left ventricular pump function, right ventricular pump function, thickness of interventricular septum, size of inferior vena cava, systolic pulmonary arterial pressure, left ventricular eccentricity index, Tei index, right ventricular area, right atrial area; heart function as measured by magnetic resonance imaging (optional) at rest and during exercise combined with right heart catheterisation; adverse events |
| Notes | Recruitment status: "Unknown" |
NCT04188756.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Intervention (exercise): high‐intensity interval training (rehabilitation) over 15 weeks. Participants will be guided by physicians for exercise training in PH Control: standard care according to current guidelines |
| Outcomes | Primary outcome: end systolic elastance Secondary outcomes: global longitudinal strain (CMRI measures of function); PVR (right heart catheter measures of afterload); 6MWD; TAPSE (echocardiography measure of function); mPAP (pressure in right heart catheter); cardiac output; T1 mapping (CMRI parameter); fractional area change (echocardiography measure of function) |
| Notes | Exercise intervention unclear; trial design unclear: parallel vs crossover; not yet recruiting; trial registered in 2019 |
NCT04224012.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Intervention (training): specialised exercise and respiratory therapy for people with PH. 3 weeks in‐hospital rehabilitation programme with continuation of exercise training at home Control: usual care |
| Outcomes | Primary outcome: right heart catheterisation index during exercise Secondary outcomes: PVR at rest; 6MWD; peak oxygen consumption (CPET); peak workload in watts (CPET); peak respiratory equivalent during CPET; echocardiography: right atrial area; right ventricular pump function, tricuspid annular plane systolic excursion; Physical Summation Score (SF‐36); Mental Summation score (SF‐36); WHO Functional Class; NT‐proBNP; oxygen saturation; magnetic resonance tomography: right heart size; right heart function; clinical worsening during study period |
| Notes |
NCT04909008.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Exercise training: 10 weeks of supervised exercise training, 3 sessions/week at the cardiac rehabilitation clinic Control: standard medical care |
| Outcomes | Primary outcome: maximal oxygen uptake Secondary outcomes: mPAP; PVR; right ventricular contractile function measured as % fractional area change; left ventricular contractile function measured as % fractional area change; slope of the relationship between mPAP and cardiac output |
| Notes |
NCT05242380.
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Intervention (kettle bell exercise): 8‐week, 3 days/week supervised training. 1 session of education on pathophysiology of PAH, benefits of physical activity and energy conservation techniques during activities of daily living. Pharmacological treatment will be continued. Exercise training consists of 4 stages. Each stage lasts 2 weeks and consist of 5 kettle bell exercises. Exercises will continue from basic (single movement training) to advanced (comprehensive movement training) and is geared towards functional training. Participants will perform 2 sets of 12 repetitions of each exercise. Each training session is planned to last 45 minutes Control: 1 session of education on the pathophysiology of PAH, benefits of physical activity and energy conservation techniques during activities of daily living. Pharmacological treatment will be continued. |
| Outcomes | Primary outcomes: participants will perform the following activities with mobile CPET: putting on socks on both feet (sitting on a chair), putting on both shoes (sitting on a chair), putting on a coat (while standing), lifting material (placing 6 × 400 g jars at chest height), sweeping the floor for 4 minutes, washing dishes for 4 minutes, go up and down stairs for 1 floor; 6MWD; isometric muscle strength will be measured with a handheld dynamometer for elbow flexion, knee extension, knee flexion, shoulder flexion, shoulder abduction, hip flexion and musculus serratus anterior; handgrip strength Secondary outcomes: activity status (Duke Activity Status Index); HRQoL (EmPHasis‐10); activities of daily living (London Chest Activity of Daily Living Scale); sleep quality (Pittsburgh Sleep Quality Index) |
| Notes |
6MWD: six‐minute walk distance; β‐hCG: beta‐human chorionic gonadotrophin; BNP: brain natriuretic peptide; CAMPHOR: Cambridge Pulmonary Hypertension Outcome Review; CMRI: cardiac magnetic resonance imaging; CPET: cardiopulmonary exercise test; CTEPH: chronic thromboembolic pulmonary hypertension; EQ‐5D‐5L: European Quality of Life 5 Dimensions 5 Level Version; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; HRQoL: health‐related quality of life; mPAP: mean pulmonary arterial pressure; NT‐proBNP: N‐terminal pro‐brain natriuretic peptide; NYHA: New York Heart Association; PAH: pulmonary arterial hypertension; PCWP: pulmonary capillary wedge pressure; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; RMN: remote magnetic navigation; SF‐36: 36‐item Short Form; ULN: upper limit of normal; VE: pulmonary ventilation; VCO2: carbon dioxide production; VO2: oxygen consumption; WHO: World Health Organization.
Characteristics of ongoing studies [ordered by study ID]
McGregor 2020.
| Study name | SPHERe |
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria (as of 29 March 2021) Adults with confirmed PH (groups 1–5) as detailed in ESC/ERS guidelines; clinically stable; WHO Functional Class II, III or IV; fluent in spoken English to allow engagement with intervention and physical outcome measures; live within reasonable travelling distance (as defined by participant) of a SPHERe exercise rehabilitation centre (outcome assessments only); ability to provide informed consent; access to appropriate technology infrastructure (computer, laptop, tablet, smart phone, email and internet connection); ability to make suitable travel arrangements to attend clinic (outcome assessments only) Exclusion criteria (as of 29 March 2021) Absolute contraindications to exercise as per international clinical guidelines; PH‐related complications, or comorbidities severe enough to prevent attendance at a SPHERe centre, or participation in exercise rehabilitation; any mental health issue that will prevent engagement with study procedures; previous randomisation in the present trial; pregnancy Previous inclusion criteria Adults with confirmed PH (groups 1–5) as detailed in ESC/ERS guidelines; clinically stable; WHO Functional Class II, III or IV; fluent in spoken English to allow engagement with intervention and physical outcome measures; live within reasonable travelling distance (as defined by participant) of a SPHERe exercise rehabilitation centre; ability to provide informed consent Previous exclusion criteria Absolute contraindications to exercise as per international clinical guidelines; PH‐related complications, or comorbidities severe enough to prevent attendance at a SPHERe centre, or participation in exercise rehabilitation; any mental health issue that will prevent engagement with study procedures; unable to make suitable travel arrangements; previous randomisation in the present trial; pregnancy |
| Interventions | Intervention (as of 29 March 2021) Setting: remotely supervised exercise rehabilitation Components: exercise training; psychological and motivational support Training dose (frequency): twice/week: home exercise bike programme; once/week: remotely supervised exercise, psychological and motivational support Training dose (intensity): not reported Training dose (duration): total: 8 weeks Control (as of 29 March 2021): single (online) session of 1‐to‐1 advice on safe and effective lifestyle physical activity, but not take part in the exercise programme Intervention (previous): 8 weeks of twice‐weekly supervised outpatient exercise rehabilitation Usual care (previous): general physical activity advice, but not supervised exercise |
| Outcomes | Primary outcome
Secondary (as of 29 March 2021)
|
| Starting date | September 2019 |
| Contact information | |
| Notes |
Morris 2018.
| Study name | ExTra_PH |
| Methods | Randomised controlled trial |
| Participants | Inclusion criteria: age > 18 years, confirmed diagnosis of PH based on the results of right heart catheterisation procedure (mPAP > 25 mmHg and pulmonary capillary wedge pressure < 15 mmHg) and NYHA Functional Class II–III. Eligible participants also will be on stable PH medical therapies and have had no exacerbations in previous 3 months Exclusion criteria: change in PH medication regimen in last 3 months or have significant comorbidities including left‐sided heart failure, pregnancy, recent history of light‐headedness during exercise or syncope episodes in last month and significant musculoskeletal and neurological conditions likely to adversely impact exercise performance, any contraindications to exercise as per the American College of Sports Medicine guidelines |
| Interventions | Intervention Setting: outpatient rehabilitation followed by standard home exercise training programme Components: exercise training Training dose (frequency): twice/week Training dose (intensity): treadmill: 70–90% 6MWT speed, cycling: 60% of the estimated peak work rate from 6MWT Training dose (duration): total: 8 weeks, sessions: 20 min each for cycling and treadmill Control: routine medical care and physical activity regimens for 8‐week study period without additional exercise training intervention |
| Outcomes | Primary outcome: 6MWD Secondary outcomes: CPET: peak minute mean values for oxygen uptake (VO2), carbon dioxide production (VCO2), ventilation (VE) and heart rate; breathing efficiency (VE\VCO2), end‐tidal carbon dioxide (PETCO2) and anaerobic threshold; health‐related quality of life: CAMPHORSF and SF‐36; cardiac function (using both CMRI and echocardiography, with CMRI serving as the principal method): left and right ventricular end‐diastolic volume and end systolic volume (1.5 T Scanner, MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany) from which stroke volume, ejection fraction, cardiac output and contractile reserve will be derived; measures of both right and left ventricular mass at rest and during 2 submaximal exercise intensities (at 30% and 60% of their respective peak workload determined from incremental exercise test); right ventricular systolic pressure estimated from the tricuspid regurgitation velocity; right ventricular systolic function by assessing the tricuspid annular plane systolic excursion; adverse responses or events including syncope, dizziness or marked worsening in oxygen desaturation during exercise; survival and time to clinical worsening during routine follow‐up clinic visits (every 3–6 months for a 2‐year period following the participant's commencement of the study); for the purpose of this study clinical worsening will be defined as PH‐related death or listing for/completed lung transplantation or hospitalisation for PH or clinical worsening leading to initiation of new PH‐specific treatment or WHO Functional Class deterioration and a > 15% decrease in 6MWT from baseline. Participants will be assessed for clinical worsening every 3–6 months following randomisation during routine clinical visits. |
| Starting date | April 2017 |
| Contact information | n.morris@griffith.edu.au |
| Notes |
6MWT: Six‐Minute Walk Test; CAMPHOR(SF): Cambridge Pulmonary Hypertension Outcome Review (Short Form); CPET: cardiopulmonary exercise test; EQ‐5D‐5L: European Quality of Life 5 Dimensions 5 Level Version; ERS: European Respiratory Society; ESC: European Society of Cardiology; ISWT: incremental Shuttle Walk Test; mPAP: mean pulmonary arterial pressure; NHS: National Health Service; NYHA: New York Heart Association; PH: pulmonary hypertension; VE: pulmonary ventilation; VCO2: carbon dioxide production; VO2: oxygen uptake; WHO: World Health Organization.
Differences between protocol and review
As per our protocol (Morris 2014), we had intended to perform a subgroup analysis according to severity of PH, but there were insufficient data available.
As the changes in exercise capacity were heterogeneous, we performed an additional subgroup analysis based on the setting (inpatient versus outpatient) for exercise‐based rehabilitation. We hypothesised that inpatient exercise‐based rehabilitation may have allowed closer supervision and the prescription of higher intensity exercise compared to outpatient‐based programmes. However, the improvement in exercise capacity remained heterogeneous for the inpatient‐based programmes and remained high for outpatient‐based programmes (I² = 53%, P = 0.06), suggestive of other factors contributing to the heterogeneous response.
Contributions of authors
NM drafted the protocol with the assistance from AH and FK.
NM and AH identified studies for the initial (2017) review, extracted data from the studies and drafted the review.
AJ and JL identified studies for the 2022 review, extracted data from the studies and drafted the review.
All review authors provided critical feedback on the review.
Contributions of editorial team
Sally Spencer (Co‐ordinating Editor) edited the review; advised on methodology, interpretation and content; approved the review prior to publication.
Christian Osadnik (Contact Editor): edited the review; advised on methodology, interpretation and content.
Kayleigh Kew (Freelance Editorial Support); advised on methodology, interpretation and content, and edited the review.
Emma Jackson (Managing Editor): co‐ordinated the editorial process; conducted peer review; obtained translations, and edited the references and other sections of the review.
Elizabeth Stovold (Information Specialist): designed the search strategy and ran the searches.
Vittoria (Freelance Information Specialist): edited the search methods section.
Sources of support
Internal sources
Griffith University, Australia
Salary support, Norman Morris
Queensland Health, Australia
Salary support, Fiona Kermeen
Alfred Health and Monash University, Australia
Salary support, Anne Holland
Monash University, Australia
Salary support, Arwel Jones and Joanna Lee
External sources
National Institute for Health and Care Research (NIHR), UK
Cochrane Infrastructure funding to Cochrane Airways Group
Declarations of interest
NM: none.
FK: none.
AJ: none.
JL: none.
AH: declared membership of the Cochrane Airways Editorial Board. AH was not involved in the editorial process for this review.
New search for studies and content updated (conclusions changed)
References
References to studies included in this review
Atef 2021 {published data only}
- Atef H, Abdeen H. Effect of exercise on sleep and cardiopulmonary parameters in patients with pulmonary artery hypertension. Sleep and Breathing 2021;25(4):1953-60. [DOI: 10.1007/s11325-020-02286-9] [DOI] [PubMed] [Google Scholar]
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Butane 2021 {published data only}
- Butāne L, Šablinskis M, Skride A, Šmite D. Individually tailored 12-week home-based exercise program improves both physical capacity and sleep quality inpatients with pulmonary arterial hypertension. Medicina (Kaunas) 2021;58(5):662. [DOI: 10.3390/medicina58050662] [DOI] [Google Scholar]
Chan 2013 {published data only}
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Ehlken 2016 {published data only}
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Ertan 2022 {published data only}
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Ganderton 2013 {published data only}
- Ganderton L, Gain K, Fowler R, Lunt D, Winship P, Bostock S, et al. Effects of exercise training on exercise capacity and quality of life in pulmonary arterial hypertension. Respirology 2013;18(Suppl 2):74 (P146). [DOI] [PMC free article] [PubMed] [Google Scholar]
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González‐Saiz 2017 {published data only}
- González-Saiz L, Fiuza-Luces C, Sanchis-Gomar F, Santos-Lozano A, Quezada-Loaiza CA, Flox-Camacho A, et al. Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: the WHOLEi+12 trial. International Journal of Cardiology 2017;15(231):277-83. [DOI] [PubMed] [Google Scholar]
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- Santos-Lozano AC, Fiuza-Luces D, Fernández-Moreno F, Llavero J, Arenas JA, López J, et al. Exercise benefits in pulmonary hypertension. Journal of the American College of Cardiology 2019;73:2906-7. [DOI] [PubMed] [Google Scholar]
Grünig 2020 {published data only}
- Grünig E, MacKenzie A, Peacock AJ, Eichstaedt CA, Benjamin N, Nechwatal R, et al. Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial. European Heart Journal 2020;14(23):2284-95. [DOI] [PubMed] [Google Scholar]
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Kagioglou 2021 {published data only}
- Kagioglou O, Mouratoglou SA, Giannakoulas G, Kapoukranidou D, Anifanti M, Deligiannis A, et al. Long-term effect of an exercise training program on physical functioning and quality of life in pulmonary hypertension: a randomized controlled trial. Biomedical Research International 2021;2021:8870615. [DOI: 10.1155/2021/8870615] [DOI] [PMC free article] [PubMed] [Google Scholar]
Ley 2013 {published data only}
- Ley S, Fink C, Risse F, Ehlken N, Fischer C, Ley-Zaporozhan J, et al. Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension. European Radiology 2013;23(2):324-31. [DOI: 10.1007/s00330-012-2606-z] [DOI] [PubMed] [Google Scholar]
Mereles 2006 {published data only}
- Ehlken N, Mereles D, Kreuscher S, Ghofrani S, Hoeper MM, Halank M, et al. Exercise and respiratory training to improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. European Respiratory Journal 2006;28(Suppl 50):372s (2220). [DOI] [PubMed] [Google Scholar]
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Rakhmawati 2020 {published data only}
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Wilkinson 2007 {published data only}
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- Wilkinson A, Elliot CA, Mawson S, Armstrong I, Billings C, Kiely DG. A randomised controlled trial to investigate the effects of a physiotherapist-led rehabilitation programme on exercise capacity and quality of life measures in patients with pulmonary hypertension. Thorax 2007;62(Suppl iii):A16. [Google Scholar]
Wojciuk 2021 {published data only}
- Wojciuk M, Ciolkiewicz M, Kuryliszyn-Moskal A, Chwiesko-Minarowska S, Sawicka E, Ptaszynska-Kopczynska K, et al. Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study. BMC Sports Science Medical Rehabilitation 2021;13(1):79. [DOI] [PMC free article] [PubMed] [Google Scholar]
References to studies excluded from this review
Albarrati 2021 {published data only}
- Albarrati A, Taher M, Nazer R. Effect of inspiratory muscle training on respiratory muscle strength and functional capacity in patients with type 2 diabetes mellitus: a randomized clinical trial. Journal of Diabetes 2021;13(4):292-8. [DOI] [PubMed] [Google Scholar]
Aslan 2020 {published data only}
- Aslan GK, Akıncı B, Yeldan I, Okumus G. A randomized controlled trial on inspiratory muscle training in pulmonary hypertension: effects on respiratory functions, functional exercise capacity, physical activity, and quality of life. Heart and Lung 2020;49:381-7. [DOI] [PubMed] [Google Scholar]
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- NCT03385733. Inspiratory muscle training in pulmonary hypertension [The effects of inspiratory muscle training on exercise capacity, physical activity and quality of life in pulmonary hypertension]. clinicaltrials.gov/ct2/show/NCT03385733 (first received 28 December 2017).
Babu 2013 {published data only}
- Babu AS, Padmakumar R, Maiya AG. A review of ongoing trials in exercise based rehabilitation for pulmonary arterial hypertension. Indian Journal of Medical Research 2013;137(5):900-6. [PMC free article] [PubMed] [Google Scholar]
Babu 2014 {published data only}
- Babu AS, Padmakumar R, Maiya AG. Effects of the pulmonary hypertension manual (PulHMan) on awareness of exercise among patients with pulmonary hypertension. World Congress of Cardiology Scientific Sessions; 2014 May 4-7; Melbourne, Australia.
Babu 2019 {published data only}
- Babu A, Maiya AG, Padmakumar R. Effects of home based exercise training on functional capacity and quality of life in group 1 pulmonary hypertension: a sub-analysis from a randomized trial. Journal of Cardiopulmonary Rehabilitation and Prevention 2018;38(6):E23. [Google Scholar]
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Barbosa 2011 {published data only}
- Barbosa PB, Ferreira EM, Arakaki JS, Takara LS, Moura J, Nascimento RB, et al. Kinetics of skeletal muscle O2 delivery and utilization at the onset of heavy-intensity exercise in pulmonary arterial hypertension. European Journal of Applied Physiology 2011;111(8):1851-61. [DOI: 10.1007/s00421-010-1799-6] [DOI] [PubMed] [Google Scholar]
Becker‐Grunig 2013 {published data only}
- Becker-Gruenig T, Ehlken N, Gorenflo M, Hager A, Halank M, Lichtblau M, et al. Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease. ESC Congress; 2012 25-28 Aug; Munich, Germany. [DOI] [PubMed]
- Becker-Grunig T, Klose H, Ehlken N, Lichtblau M, Nagel C, Fischer C, et al. Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease. International Journal of Cardiology 2013;168(1):375-81. [DOI] [PubMed] [Google Scholar]
Bernheim 2007 {published data only}
- Bernheim AM, Kiencke S, Fischler M, Dorschner L, Debrunner J, Mairbäurl H, et al. Acute changes in pulmonary artery pressures due to exercise and exposure to high altitude do not cause left ventricular diastolic dysfunction. Chest 2007;132(2):380-7. [DOI: 10.1378/chest.07-0297] [DOI] [PubMed] [Google Scholar]
Bhasipol 2018 {published data only}
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Chia 2017 {published data only}
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Dowman 2017 {published data only}
- Dowman LM, McDonald CF, Hill CJ, Lee AL, Barker K, Boote C, et al. The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial. Thorax 2017;72:210-9. [DOI] [PubMed] [Google Scholar]
Ehlken 2014 {published data only}
- Ehlken N, Verduyn C, Tiede H, Staehler G, Karger G, Nechwatal R, et al. Economic evaluation of exercise training in patients with pulmonary hypertension. Lung 2014;192(3):359-66. [DOI: 10.1007/s00408-014-9558-9] [DOI] [PubMed] [Google Scholar]
Farias da Fontoura 2018 {published data only}
- Farias da Fontoura F, Roncato G, Watte G, Brum Spilimbergo F, Bohns Meyer GM, Rigatto K, et al. Effects of inspiratory muscle training on the sensation of dyspnea in patients with pulmonary hypertension group I and IV – randomized controlled clinical trial. European Respiratory Journal 2018;62:PA1718. [Google Scholar]
Fox 2011 {published data only}
- Fox BD, Kassirer M, Weiss I, Raviv Y, Peled N, Shitrit D, et al. Ambulatory rehabilitation improves exercise capacity in patients with pulmonary hypertension. Journal of Cardiac Failure 2011;17(3):196-200. [DOI] [PubMed] [Google Scholar]
Fukui 2016 {published data only}
- Fukui S, Ogo T, Takaki H, Ueda J, Tsuji A, Morita Y, et al. Efficacy of cardiac rehabilitation after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. Heart 2016;102(17):1403-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Gerhardt 2017 {published data only}
- Gerhardt F, Dumitrescu D, Gartner C, Beccard R, Viethen T, Kramer T, et al. Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: a randomised clinical study. Heart 2017;103(8):592-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- NCT01763112. Training with whole body vibration in patients with PAH (GALILEO-PAH). clinicaltrials.gov/ct2/show/NCT01763112 (first received 8 January 2013).
Grunig 2011 {published data only}
- Grunig E, Ehlken N, Ghofrani A, Staehler G, Meyer FJ, Juenger J, et al. Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension. Respiration 2011;81(5):394-401. [DOI] [PubMed] [Google Scholar]
Grunig 2012 {published data only}
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Iliuta 2019 {published data only}
- Iliuta L. Effects of cardiac rehabilitation as independent predictor for favourable long term postoperative evolution in patients undergoing coronary artery bypass grafting. European Heart Journal 2019;40(Issue Suppl 1):ehz747.0244. [DOI: 10.1093/eurheartj/ehz747.0244] [DOI] [Google Scholar]
jRCT1030210240 {unpublished data only}
- jRCT1030210240. Examination of safety and efficacy of pulmonary rehabilitation for patients with pulmonary hypertension: appropriate exercise prescription on pulmonary hypertension during exercise. rctportal.niph.go.jp/en/detail?trial_id=jRCT1030210240 (first received 13 August 2021).
Kabitz 2014 {published data only}
- Kabitz HJ, Bremer HC, Schwoerer A, Sonntag F, Walterspacher S, Walker DJ, et al. The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension. Lung 2014;192(2):321-8. [DOI] [PubMed] [Google Scholar]
Kahraman 2020 {published data only}
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Karapolat 2019 {published data only}
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Kolesnikova 2011a {published data only}
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Kolesnikova 2011b {published data only}
- Kolesnikova EA, Arutyunov GP, Rylova NV, Rylova AK. Rehabilitation of patients with severe heart failure and pulmonary hypertension. EuroPRevent; 2011 Apr 14-16; Geneva, Switzerland.
Mackenzie 2017 {published data only}
- Mackenzie A, Ford J, Jayasekera G, Pollok V, Crowe T, Peacock A, et al. The role of exercise therapy in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine 2017;195:A3099. [DOI: 10.1164/ajrccm-conference.2017.B28] [DOI] [Google Scholar]
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- NCT02961023. The effect of adding exercise training to optimal therapy in PAH. Clinicaltrials.gov/show/NCT02961023 (first received 10 November 2016).
Marvisi 2013 {published data only}
- Marvisi M, Herth FJ, Ley S, Poletti V, Chavannes NH, Spruit MA, et al. Selected clinical highlights from the 2012 ERS congress in Vienna. European Respiratory Journal 2013;41(5):1219-27. [DOI] [PubMed] [Google Scholar]
Missana 2020 {unpublished data only}
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Morris 2020 {published data only}
- Morris ZV, Chin LM, Chan C, Guccione AA, Ahmad A, Keyser RE. Cardiopulmonary exercise test indices of respiratory buffering before and after aerobic exercise training in women with pulmonary hypertension: differentiation by magnitudes of change in six-minute walk test performance. Respiratory Medicine 2020;164:105900. [DOI] [PMC free article] [PubMed] [Google Scholar]
Nagel 2012 {published data only}
- Nagel C, Prange F, Guth S, Herb J, Ehlken N, Fischer C, et al. Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension. PLOS One 2012;7(7):e41603. [DOI] [PMC free article] [PubMed] [Google Scholar]
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NCT03186092 {unpublished data only}
- NCT03186092. Effects of training in pulmonary hypertension [Effects of respiratory muscle training on respiratory muscle strength, functional capacity and quality of life in pulmonary hypertension]. clinicaltrials.gov/show/nct03186092 (first received 14 June 2017).
NCT03476629 {published data only}
- NCT03476629. Effects of different types of physical training in patients with pulmonary arterial hypertension (PAH) [Effects of combined training versus aerobic training versus respiratory muscle training in patients with pulmonary hypertension: a randomized, controlled clinical trial]. clinicaltrials.gov/ct2/show/NCT03476629 (first received 26 March 2018).
NCT04254289 {published data only}
- NCT04254289. Pilot randomized trial of ambulatory exercise in pulmonary hypertension (PaRTAkE-PH) [Pilot randomized trial of ambulatory exercise in pulmonary hypertension]. clinicaltrials.gov/ct2/show/NCT04254289 (first received 5 February 2020).
NCT04559516 {published data only}
- NCT04559516. Remote exercise program delivery using a mobile application for pulmonary arterial hypertension (REVAMP). www.clinicaltrials.gov/ct2/show/NCT04559516 (first received 23 September 2020).
NCT04683822 {published data only}
- NCT04683822. Telerehabilitation in patients with pulmonary hypertension [Investigation of the effectiveness of a home exercise program combined with telerehabilitation in pulmonary hypertension patients]. clinicaltrials.gov/ct2/show/NCT04683822 (first received 24 December 2020).
Ontiyuelo 2019 {published data only}
- Ontiyuelo M, Anna Rodó Pin C, Blanco I, Blasco H, Molina Ferragut L, Piccari L, et al. Evolution of patients with pulmonary arterial hypertension (PAH) six months after an exercise training program. European Respiratory Journal 2019;54(Suppl 63):PA4753. [Google Scholar]
Robalo Cordeiro 2011 {published data only}
- Robalo Cordeiro C, Singh S, Herth FJ, Ley S, Chavannes NH, Clini E, et al. Selected clinical highlights from the 2010 ERS Congress in Barcelona. European Respiratory Journal 2011;38(1):209-17. [DOI] [PubMed] [Google Scholar]
Rokach 2019 {published data only}
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Skibarkienė 2019 {published data only}
- Skibarkienė J, Milinavičienė E, Kubilius R. The effectiveness of the second stage rehabilitation of patients who implanted cardiac pacemaker. 21st European Congress of Physical and Rehabilitation Medicine (ESPRM 2018); 2018 May 1-6; Vilnius, Lithuania. [hdl.handle.net/20.500.12512/21072]
Tran 2020 {published data only}
- Tran D, Munoz P, Lau E, Alison J, Brown M, Zheng Y, et al. Inspiratory muscle training improves six-minute walk distance in adults with pulmonary arterial hypertension . Journal of the American College of Cardiology 2020;75(11):2085. [Google Scholar]
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Yilmaz 2020 {published data only}
- Camcioglu B, Guclu MB, Keles MN, Tacoy GA, Cengel A. Effects of upper extremity aerobic exercise training on functional exercise capacity, respiratory muscle strength and dyspnea in patients with pulmonary arterial hypertension: a preliminary report. European Respiratory Journal 2017;50(Suppl 61):PA2540. [Google Scholar]
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References to studies awaiting assessment
NCT00477724 {published data only}
- NCT00477724. Incidence of latent pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension after endarterectomy and influence of exercise and respiratory therapy. clinicaltrials.gov/show/NCT00477724 (first received 24 May 2007).
NCT00491309 {published data only}
- NCT00491309. Exercise and respiratory therapy in patients with rheumatoid arthritis / collagenosis and pulmonary hypertension. clinicaltrials.gov/ct2/show/NCT00491309 (first received 26 June 2007).
NCT02558582 {published data only}
- NCT02558582. Effect of exercise training in patients with pulmonary hypertension [Effect of exercise training in arterial and chronic thromboembolic pulmonary hypertension in Switzerland and standardization with European countries]. clinicaltrials.gov/ct2/show/nct02558582 (first received 24 September 2015).
NCT02579954 {published data only}
- NCT02579954. Cardiac function and exercise capacity in pulmonary arterial hypertension (FONCE-HTAP). clinicaltrials.gov/ct2/show/nct02579954 (first received 20 October 2015).
NCT03045666 {published data only}
- NCT03045666. Impact of rehabilitation program on PAH patients treated with macitentan. clinicaltrials.gov/ct2/show/NCT03045666 (first received 7 February 2017).
NCT03288025 {published data only}
- NCT03288025. Pulmonary arterial hypertension improvement with nutrition and exercise (PHINE) [Pulmonary arterial hypertension improvement with nutrition and exercise (PHINE): a randomized controlled trial]. clinicaltrials.gov/ct2/show/NCT03288025 (first received 19 September 2017).
NCT03955016 {published data only}
- NCT03955016. Rehabilitation for patients with pulmonary hypertension [A randomized controlled trial to evaluate the effect of a rehabilitation program on the exercise capacity of patients with pulmonary hypertension]. clinicaltrials.gov/ct2/show/nct03955016 (first received 17 May 2019).
NCT04188756 {published data only}
- NCT4188756. RV systolic and diastolic function and contractile reserve under acute exercise and in response to chronic exercise-based rehabilitation (Reserve). clinicaltrials.gov/show/NCT04188756 (first received 6 December 2019).
NCT04224012 {published data only}
- NCT04224012. Effect of exercise and respiratory therapy on right ventricular function in severe pulmonary hypertension. clinicaltrials.gov/show/NCT04224012 (first received 13 January 2020.
NCT04909008 {published data only}
- NCT04909008. Exercise training to improve cardiopulmonary hemodynamics in heart failure patients [Exercise training to improve pulmonary haemodynamic and right ventricular function in heart failure patients with pulmonary hypertension]. clinicaltrials.gov/show/NCT04909008 (first received 1 June 2021).
NCT05242380 {published data only}
- NCT05242380. Exercise training in patients with pulmonary arterial hypertension [The effects of kettlebell exercise training in patients with pulmonary arterial hypertension]. ClinicalTrials.gov/show/NCT05242380 (first received 16 February 2022).
References to ongoing studies
McGregor 2020 {published data only}
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