Exercise programme to improve quality of life for patients with end-stage kidney disease receiving haemodialysis: the PEDAL RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 12/23/09. The contractual start date was in April 2014. The draft report began editorial review in June 2020 and was accepted for publication in January 2021. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

Copyright © 2021 Greenwood et al. This work was produced by Greenwood et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2021 Greenwood et al.

Scientific background

Haemodialysis (HD) is a major treatment option for patients with end-stage kidney failure. Over 27,000 patients receive dialysis for chronic kidney disease (CKD) in the UK and 80% of these are treated with HD. 2 Improved dialysis techniques and management of co-existing disease have made HD more tolerable, and many new patients can anticipate a longer life expectancy,3 although not always with a good quality of life (QoL).

Both physical inactivity and impaired physical function are strongly associated with increased morbidity, mortality and reduced QoL in patients on HD. 3,4 Reduced QoL is also independently associated with mortality in patients on HD. Reports indicate that Short Form questionnaire-36 items (SF-36) physical component summary (PCS) scores of < 25 arbitrary units (AU) were associated with a 93% increased risk of death and a 56% increased risk of hospitalisation in HD patients, and a 10-point decrease in PCS score translated into a 25% increased risk of death within 2 years. 5 Conversely, a 1-point increase in PCS score was associated with a 3.5% improvement in the odds of death. 6 Interventions designed to increase physical function and reduce sedentary behaviour in patients on HD may mitigate cardiovascular disease risk, improve physical functioning, improve fitness for potential future kidney transplantation, lower levels of fatigue and, in turn, improve QoL. A non-randomised controlled trial (RCT) by Painter et al. 7 reported an average 4-point increase in PCS score in the intervention group (in-centre intradialytic cycling or individualised home exercise programme) and an average 6-point decrease in PCS score in the non-intervention group. A study by DeOreo8 reported that for every increase in PCS score of 5 AU there is an ≈ 10% increase in the probability of survival.

Evidence from several systematic reviews9–22 indicates that a range of exercise training interventions show potential to improve exercise capacity and physical function in patients with dialysis-dependent CKD. The greatest effects were reported after 6 months of exercise and were associated with both supervised exercise and higher intensities of exercise. However, most of the studies reviewed were small trials, many of which were not methodologically robust, and non-intradialytic interventions were occasionally included in the evidence synthesis. 16 Relatively few of the reviewed studies on intradialytic exercise training were appropriately powered to detect QoL outcomes, and none included a cost-effectiveness analysis. Moreover, adverse events (AEs) in the published literature were recorded in only a minority of studies17 or were poorly reported. 16 A recent systematic review22 on intradialytic exercise training suggests that aerobic and resistance exercise programmes, delivered alone, can improve aerobic capacity, but that a combination of both can improve a greater range of outcomes, including exercise capacity, depression and some elements of QoL. By contrast, a recent systematic review by Young et al. 18 indicated that there was insufficient evidence demonstrating whether or not cycling exercise during HD improves patient outcomes. The recommendations emerging from these systematic reviews indicated the need for (1) high-quality, adequately powered RCTs of intradialytic exercise and (2) routine collection and reporting of AE data associated with participation in these trials. The generation of this information may help to more fully identify recommendations for an exercise delivery pathway for HD patients and, ultimately, its clinical implementation. 21

The PEDAL (PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease) trial was designed in response to a National Institute for Health Research (NIHR)-commissioned call to evaluate the clinical benefit and cost-effectiveness of exercise during HD (intradialytic exercise) in patients with end-stage kidney disease. At the time of planning and developing the PEDAL trial (2012) there was extremely limited evidence on the effectiveness of intradialytic cycling on patient-centred outcomes such as QoL indices. In CKD stages 2–5, overall QoL was improved with exercise training. 9 Improved scores in the self-reported physical function subscales of the questionnaires appeared to be the main drivers for the overall improvement. 9 Other elements of QoL, such as vitality, social function and general health, did not show a systematic change. 9 Short-term (2–6 months), structured and supervised moderate-intensity aerobic training programmes (mainly cycling) have been reported to induce a systematic and large improvement in cardiorespiratory fitness (VO_2 peak) of 17–50%, with an overall mean difference between treatment and control groups of 5.22 ml/kg/minute. Such improvements exceed the clinically important criterion of 1 metabolic equivalent (MET) (3.5 ml/kg/minute). Thus, we utilised the evidence base promoting intradialytic cycling for improved cardiorespiratory fitness to investigate whether or not the physiological benefits derived from cycling could extend to perceived enhanced QoL. Furthermore, as inconsistent improvements have been noted for objectively measured functional capacity indices (walking speed/distance, sit-to-stand 60 performance) from previous intradialytic cycling studies, we chose to evaluate key secondary outcome measures of objective physical function.

The rationale for intradialytic exercise is both intuitively and pragmatically appealing because the environment of unit-based HD provides a platform for longer-term sustainable implementation of exercise rehabilitation programmes and, thus, could promote exercise-enhancing behaviours in HD patients. The current requirement for HD patients to attend 4-hour HD sessions three times per week provides a practical opportunity to deliver a structured and supervised rehabilitation programme with an enhanced potential for participation, associated with a substantially reduced patient burden in terms of time, effort and travel cost.

Objectives

Trial design

We conducted this prospective, multicentre RCT in five regions of the UK.

Ethics approval and research governance

The trial protocol was approved by the relevant health authorities and institutional review boards, and all patients provided written informed consent. London Fulham Research Ethics Committee approved the protocol (reference 14/LO/1851). The study was prospectively registered as ISRCTN83508514. An independent data and safety monitoring committee performed regular safety surveillance. Data were entered into an electronic case report form by the investigators and were analysed at the Robertson Centre for Biostatistics, University of Glasgow.

Patient and public involvement

The planning and delivery of the PEDAL trial was facilitated by close engagement with people living with CKD and utilising HD therapy. Patients contributed directly to both the development of trial materials (e.g. participant information leaflets and consent forms) and the way the trial was conducted. INVOLVE good practice guidelines23 were followed to ensure service-user leadership in the trial delivery and dissemination of the findings. INVOLVE is a national advisory group established and funded by the NIHR to support active public involvement in NHS, public health and social care research. 23

Participants

Screening and eligibility

The majority of potential participants for the PEDAL trial were identified during routine HD clinical consultations and concurrent evaluation of clinical records to confirm eligibility for participation. Patients already established on HD for > 3 months were eligible and easily identified from hospital databases and dialysis logs. If considered eligible for the study, they were approached by a member of the renal health-care team who discussed the study and provided them with a participant information sheet with further details. After allowing the patient a minimum of 24 hours to read and consider the information in the participant information sheet, and to consult with family members, the research team approached the patient (usually during the next dialysis session) to answer any questions. If the patient agreed to proceed, an appointment was made for familiarisation and baseline outcome assessment sessions. Written informed consent was obtained by a member of the research team prior to any study assessments.

Randomisation and blinding

Randomisation was conducted using a centrally controlled, web-based randomisation system run by the Glasgow Clinical Trials Unit (GCTU). To ensure balanced assignment across critical variables, a minimisation algorithm was employed, taking into account baseline age, sex and diabetes status. It was impossible to blind the ‘treating’ physiotherapy assistants or the participants and, thus, the study implemented a blinded outcome assessment and analysis.

Intervention

Adherence

We attempted to minimise the loss to follow-up in this study by (1) emphasising to participants the importance of their attendance at follow-up assessments even if they were no longer compliant with the intervention, (2) reducing outcome assessment appointments to a maximum of two non-dialysis day visits, (3) using a reminder protocol for non-dialysis day assessment appointments that utilised prompts by the dialysis unit staff, letters and telephone contact, (4) providing travel remuneration (including, where necessary, taxi costs), and (5) the provision of training in issues related to compliance for all study staff who came into contact with the participants.

Primary and secondary outcomes

Sample size

Statistical analyses

A full statistical analysis plan was signed off prior to database lock and study unblinding. Descriptive statistics of clinical and sociodemographic variables at baseline are presented split by treatment group.

Data monitoring and quality assurance

The trial was coordinated by a Trial Management Group (TMG), consisting of the chief investigator, GCTU Assistant Director and senior clinical trial manager and a statistician. The trial manager co-ordinated the study and was accountable to the chief investigator. The central trial office (King’s College Hospital and GCTU) provided support to each site. The central trial office was responsible for randomisation, collection of data in collaboration with the research co-ordinator, data processing and analysis. Publication and dissemination of the study results was co-ordinated by the trial office in collaboration with the chief investigator and investigators. A Trial Steering Committee was established to oversee the conduct and progress of the trial. The study’s funder – the NIHR Health Technology Assessment (HTA) programme – formally appointed the chairperson and members after the nominations from the TMG. A charter was drawn up to describe membership, roles and responsibilities of the Trial Steering Committee. The Independent Data Monitoring Committee was an independent group of experts, consisting of a nephrologist, physiotherapist, lay member and a statistician, who monitored patient safety and treatment efficacy data while the clinical trial was ongoing; the primary mandate of this committee was to protect patient safety.

Recruitment and retention

Patient flow, including recruitment to and retention in the trial, is detailed in Figure 1. The trial recruited prevalent patients with stage 5 CKD receiving HD therapy from June 2015 to June 2019 in five regional kidney units in the UK. In total, the trial recruited 379 participants. A total of 335 participants attended a baseline study visit: 175 participants who were randomised to the exercise intervention and 160 participants who were randomised to usual care. Participants were informed of group allocation only after completing all baseline assessments. Fifty-nine patients allocated to the exercise intervention and 60 participants allocated to usual care did not complete the 6-month assessment. In total, seven participants died during the study: three participants from the intervention group and four participants from the usual-care group. In the intervention group, 40 participants were withdrawn and 16 did not attend for the final 6-month assessment. In the usual-care group, 15 participants were withdrawn and 14 participants did not attend the 6-month assessment. Participants were more likely to withdraw from the trial if they were older and female. Analysis to establish how participants who withdrew differed from those who remained in the trial, stratified by arm, did not reveal significant differences in age, sex or weight, but it does appear that participants were more likely to drop out of the exercise arm if they had a history of heart failure and cerebrovascular disease (Table 1). The primary outcome was therefore known for 243 (73%) participants who attended a baseline visit: 116 (66%) participants in the intervention group and 127 (79%) participants in the usual-care group (see Figure 1).

FIGURE 1.

The PEDAL trial Consolidated Standards of Reporting Trials (CONSORT) diagram. Reproduced with permission from Greenwood et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Reproduced with permission from Greenwood et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Demographic and other baseline characteristics

Adherence

A total of 175 participants received the exercise intervention. A median of 47% (IQR 28–77%) of exercise training sessions were completed by participants in the intervention group at 6 months. A total of 23% of participants had dropped out of the exercise intervention at 6 months, and 58% of participants reported temporary cessation of the intervention. At 6 months, only 18% of participants were adhering to the full exercise prescription (Table 2).

Outcomes

The results for the primary and secondary outcome measures are presented in Tables 3 and 4. The mean difference in the change in PCS score from baseline to 6 months between the intervention group and control group was 2.4 AUs (95% CI –0.1 to 4.8 AUs; p = 0.055). In the whole sample, despite no statistical improvement in PCS score (p = 0.055), it is noteworthy that the absolute mean difference in change in PCS score from baseline to 6 months between the intervention group and control group was 2.4 AUs (95% CI –0.1 to 4.8 AUs).

Safety and harms

The number of hospitalisations, all-cause mortality and cardiovascular mortality were not different between the groups. Although these results should be interpreted cautiously owing to the lack of events for these secondary outcomes, there was no obvious increase in SAEs in the intervention group either (Tables 5 and 6).

Subgroup analyses

In patients who completed > 30% of their prescribed exercise sessions, the difference in the change in PCS score was ≈ 3 AUs and statistically significant (p = 0.039). The relationship between compliance (as percentage of sessions completed) and PCS score was not significant [estimated change in PCS score per 10% difference in compliance, 0.6 AUs (95% CI –0.1 to 1.3 AUs); p = 0.11] (Table 7). The relationship between compliance (as percentage of sessions completed) and VO_2 peak was weak but statistically significant [estimated change in VO_2 peak per 10% difference in compliance, 0.3 ml/kg/minute (95% CI 0.0 to 0.6 ml/kg/minute); p = 0.047] (Table 8).

Background and methods

For the health economic evaluation, we compared the PEDAL intervention as an add-on to dialysis with dialysis alone. We estimated the mean between-group difference in costs of the intervention and the mean between-group difference in QALYs accrued by participants during the study, estimated as the area under the health utility curve. All costs and QALY differences were estimated over the 6-month period from randomisation; discounting future costs and effects for societal time preference is not relevant. Total costs and 1 – QALYs were modelled using a generalised linear regression model with a Gaussian distribution and a log-link, adjusting for age, sex and diabetes at baseline. The modified Park test was used to determine the distribution family for the model.

Intervention costs included costs for purchase and maintenance of exercise equipment (pro-rated to apply to the 6-month study period), initial training and supervision of staff, staff delivery of the exercise sessions and the number of sessions. Different scenarios for staff costs have been considered, varying situation on pay band, including/excluding London allowance and varying staff–patient ratios. The scenarios have been based on the staffing assumed to be required when implementing the exercise sessions in usual care, not within the trial. All costs were in Great British pounds; no currency conversions were required.

The cost of the equipment was assumed to be £1000 and the expected lifetime was assumed to be 10 years. This is the estimated cost of the modified Monark cycle ergometer if it were to be commercially available. Equipment costs over the 6-month study period were therefore assumed to be £50. The maintenance cost was £50 per year per bike. This is the cost of a call-out fee and any reasonable wear-and-tear replacements by the manufacturer. It was assumed that one bike covers four patients; therefore, equipment cost per patient was assumed to be £18.75 [(£50 + £25) ÷ 4] when doing the expected number of exercise sessions.

The level of staff required was assumed to be Agenda for Change band 4. This would be the level of staff required in the NHS to deliver this type of exercise intervention. Annual employer costs are £25,865.7180–30,114.3716 outside London and £30,065.7180–34,786.9716 in London. Cost per hour is calculated as annual staff cost ÷ 46 work weeks per year ÷ 37.5 work hours per week. The number of staff required to cover training sessions depends on the distances between satellite units of each study centre. It was assumed that 0.6 members of staff are required to cover training sessions for 12–20 patients. Values of 12 and 20 were used in the analysis. The level of staff required to supervise exercise sessions and train staff to deliver the sessions was assumed to be paid, Agenda for Change band 8. Annual employer costs are £55,078.005–64,755.960 outside London and £61,741.005–71,418.960 in London. It was assumed that one member of staff covers 80 patients.

The expected number of sessions over 6 months was calculated as 365.25 ÷ 2 ÷ 7 × 3 (three sessions per week). The number of sessions completed was calculated as number of expected sessions × percentage compliance reported in the eCRF ÷ 100. The cost per session was derived as (equipment cost + staff cost over 6 months) ÷ number of expected sessions for 6 months. The intervention cost per patient was derived as number of sessions actually attended × cost per session.

Costs in the control group were set to 0, because they received no additional intervention and, therefore, required no additional staff time or equipment.

The area under EQ-5D-5L health utility curve was derived as follows. Only the period from study entry (i.e. randomised and baseline visit complete) to 6 months was taken into account. If the baseline visit was on the date of study entry, the EQ-5D-5L health utility score collected at that visit was used in the calculation as EQ-5D-5L health utility score at entry. If the baseline visit was before randomisation, EQ-5D-5L health utility score was derived as follows:

• if there is no follow-up visit, starting EQ-5D-5L health utility score will be the baseline EQ-5D-5L health utility score

• if there is a follow-up visit, starting EQ-5D-5L health utility score will be determined through linear interpolation between baseline and the earliest follow-up visit thereafter.

The area under curve was derived as follows:

• If the patient was not dead and had no follow-up beyond baseline, the 6-month EQ-5D-5L health utility score was assumed to be the same as the EQ-5D-5L health utility score at entry. The area under the EQ-5D-5L health utility curve was derived as 365.25 ÷ 2 × EQ-5D-5L health utility score at entry.

• If the patient had their 6-month visit after 6 months from entry, EQ-5D-5L health utility score at 6 months was derived through linear interpolation between EQ-5D-5L health utility score at entry and EQ-5D-5L health utility score at 6-month visit. The area under the EQ-5D-5L health utility curve was derived as 365.25 ÷ 2 × (EQ-5D-5L health utility score at entry + EQ-5D-5L health utility score at 6 months) ÷ 2.

• If there was no follow-up available and the patient died after 6 months, EQ-5D-5L health utility score at the time of death was set to 0 and the EQ-5D-5L health utility score at 6 months was derived through linear interpolation. The area under the curve was derived as in the point above.

• If the 6-month visit occurred before 6 months, the EQ-5D-5L health utility score at 6 months was derived through linear interpolation between the 6-month visit and the next available information after that, either EQ-5D-5L health utility score at a following visit or at death, with EQ-5D-5L health utility score at death assumed to be 0. The area under the curve was then determined as time from entry to 6-month visit × (EQ-5D-5L health utility score at entry + EQ-5D-5L health utility score at 6-month visit) ÷ 2 + time from 6-month visit to 6 months × (EQ-5D-5L health utility score at 6-month visit + EQ-5D-5L health utility score at 6 months) ÷ 2. If there was no information after 6-month visit, EQ-5D-5L health utility score at 6 months was assumed to be the same as EQ-5D-5L health utility score at 6-month visit.

Estimated between-group differences in cost and QALYs were obtained by the method of recycled prediction in 5000 bootstrap samples. The distribution of these quantities was summarised and presented graphically in the incremental cost-effectiveness plane.

To assess whether or not the effect of treatment on QALYs differed between subgroups by age, sex and diabetes, interaction effects of these variables with treatment were added to the regression model.

Results

Table 9 shows means and CIs for costs from different sources under different scenarios for staff costs. Estimates shown assume that staff are on average pay for their pay band. Average total costs per patient over 6 months range from £231.70 (95% CI £204.30 to £259.10) to £423.90 (95% CI £373.70 to £474.10), depending on location and staff–patient ratio. The main cost factor is the staff cost for delivering the exercise sessions.

The mean of the area under the EQ-5D-5L curve was 0.665 (SD 0.248) in the control group and 0.653 (SD 0.269) in the intervention group. The mean difference between the treatment group and the intervention group, obtained using the method of recycled predictions, was –0.012, indicating lower QoL in the intervention group than in the control group, although the 95% CI (–0.069 to 0.043) included no difference. No significant subgroup effects were found for age, sex or diabetes at baseline.

Figure 2 shows the estimated differences in cost and QALYs on the ICER plane for the low staff–patient ratio outside London as an example.

FIGURE 2.

Cost-effectiveness on ICER plane, 5000 bootstrap samples, low staff–patient ratio and outside London. Reproduced with permission from Greenwood et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Reproduced with permission from Greenwood et al. 1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Discussion

The economics results suggest that, over 6 months of implementation, the PEDAL intervention resulted in higher NHS costs with no gain in QoL measured with the EQ-5D-5L. A number of factors should be borne in mind; for example, the benefit from the PEDAL intervention could be avoiding cardiovascular events and other illnesses in future years, and the 6-month time horizon would not capture this. The PEDAL protocol could be refined to target different patients on dialysis and/or to include a time point at which the benefit of the intervention was assessed, with only those reporting a good QoL gain continuing; both of these could potentially improve the cost-effectiveness.

Background

A secondary aim of the PEDAL trial was to explore and document the views of participants and members of the renal care teams in relation to their experiences of usual care and usual care augmented with intradialytic exercise. The qualitative substudy used a constructivist phenomenological approach35 to provide insights into the progress and conduct of the trial in all five study regions. Views and experiences of service providers and study participants were explored, including control group participants and those who did not complete the intervention. This report describes the positive and negative impacts of participating in intradialytic exercise (where a person chose to and was able to participate). It explains individual and contextual influences on decision-making and experiences as well as influences of the RCT context.

Methods

Results

Explanatory theory and supporting thematic analysis

Analysis of the substantial quantity of data resulted in an explanatory model, depicted in Figure 3. This will be both explained and justified, supported by illustrative data. Explanation will move from the centre of the figure outwards, focusing first on the outcomes when people sustained participation in the intervention over time. The individual influences on decision-making about participation over time will then be explored, followed by contextual influences. Finally, an explanation of how the RCT context of participation affected decision-making will be addressed. Table 13 provides theme names and definitions.

FIGURE 3.

Explanatory theory relating to individual-decision-making about starting and continuing participation in exercise while on HD.

TABLE 13 - Summary of themes and definitions

Theme/subtheme	Definition
Reciprocal influences between impacts of participation and ongoing participation in cycling while receiving HD
Impacts of participation
Positive physical impacts	Positive physical impacts of intervention participation, including more energy, increased time on bike, increased strength, reduced weight, increased walking time, improved appetite, improved circulation, feeling fitter, improved stamina, reduced sickness, less breathlessness and help with restless leg syndrome
Positive functional impacts	Positive functional impacts of intervention participation, including increased mobility, improved sleep pattern and improved balance
Positive psychological impacts	Positive psychological impacts of intervention participation, including hope, feeling happier, increased self-esteem, passing the time and distraction from negative thoughts, enjoyment of routine, feeling normal again, increased confidence, feelings of improving health, sense of pride and becoming more independent
Positive impacts on participation in life	Positive impacts of the intervention on participation in life, including increased physical activity, increased social participation, increased interaction and competition with others, and perception of a safe space to exercise
Positive impacts on physical activity when outside the renal unit	Incorporating home exercise and other activity into daily routines attributed to intervention participation, including greater walking distance, cycling, getting out and about, sports participation, feeling more energy and stamina, and being able to take on more roles in the family
Enjoyment of intervention participation	Enjoying the experience of participation in the intervention
Negative experiences of intervention participation	Barriers to participation, including negative experiences of the intervention, such as exacerbation of fatigue and depression, reduced blood pressure, feeling that exercise is a ‘shock to the system’, lack of consistency in accessing the bike, feeling a lack of progression in fitness, lack of interaction with others while on the bike, musculoskeletal pain, and uncomfortable/unsafe bike
Individual influences on decision-making: physical activity culture, ability to cycle and social environment
Physical activity culture: personal views and goals and social support relating to physical activity and health status
Positive influence on continuing to cycle
Personal drive for physical activity and exercise	Motivators for ongoing participation, including a drive to participate in physical activity or exercise because of previous and/or current participation, interest in improving health, and self-discipline relating to participation (note that this was influenced by feeling that participation is making a difference and seeing improvements in the health of other participants)
Family support	Person having family support for involvement in the intervention, positive attitudes towards exercise, and feedback about positive perceptions of intervention impacts
Ability to cycle: physical ability to cycle, renal condition and comorbidities
Barriers to continuing to cycle
Renal condition: ‘bad days’	‘Bad days’, during which symptoms of the person’s renal condition feel worse and the person requires more sleep, rest and support from others
Comorbidities	Having comorbidities
Became unwell	A change in health status, for example involving blood pressure, fluid overload or musculoskeletal pain
Social environment: impacts of relationships in the renal unit
Positive impacts on continuing to cycle
Motivational role of staff	Motivational influences of staff affected by their attitudes to exercise, the trial and skills
Camaraderie in the unit relating to cycling	Camaraderie, competition and encouragement between people within the renal unit, including patients and staff
Contextual influences on decision-making: social environment, physical activity culture and ability to cycle
Social environment: supportive, proactive culture in the renal unit
Positive impacts on continuing to cycle: supportive social environment	Relationships with staff and patients in the renal unit that demonstrate a supportive culture
Attitudes towards empowering and enabling renal patients	Contrasting attitudes, approaches and barriers to empowering and enabling renal patients in relation to self-care
Renal unit proactive about change	A renal unit having a culture of being proactive about change
Physical activity culture in the renal unit: different degrees of expectation, value and empowerment of physical activity participation
Staff enthusiasm about physical activity and exercise for patients	A positive attitude to physical activity/the intervention for renal patients owing to justification/rationale, prior experiences, beliefs that it is necessary for management of renal disease, personal beliefs about physical activity/the intervention, and noticing positive impacts for people
Expectations of renal unit staff about engagement of patients with exercise	Beliefs that people who are exercising will lose interest or prefer sedentary activities
Ability to cycle: provision of cycling equipment and support for ongoing access
Barriers to ongoing participation: Lack of opportunities to cycle	Structural barriers meaning that the exercise bike has not been available at a suitable time
Themes relating to the trial context
Motives to consent: reasons that people give for their decision to consent to the trial
Giving back (positive for continuing trial participation unless allocated to intervention group)	Decisions to consent were influenced by the desire to ‘give back’ – improving knowledge and helping others, including the next generation
Social influences (positive for continuing unless allocated to intervention group)	Decisions to consent were influenced by the community in the dialysis unit and trust in the people promoting the study and family
Invested in physical activity and exercise (positive for continuing trial participation unless allocated to control group)	Decisions to consent were influenced by having been active (cycling and other) in the past and being currently invested in achieving health-related benefits, including those relating to renal condition (e.g. preparation for life-saving transplant, losing weight, reducing breathlessness) and broader needs such as increasing mobility, circulation and playing a more active role in treatment
To pass the time	Decisions to consent were influenced by a desire to find a different/more useful way to pass the time, or as a distraction
Affordable exercise (positive for trial participation unless in control group)	Decisions to consent were influenced by the fact that it presented an opportunity to exercise with no cost
Barriers to consent: explanations of negative influences on decisions to consent to trial participation
Conflicting priorities	Negative influences from conflicting priorities on a decision to consent, including a desire to protect ‘good days’ away from the renal unit and concerns about whether or not cycling would negatively affect HD
Disinterest in exercise	Negative influences from disinterest in exercise on a decision to consent, including disinterest that may have been influenced by a lack of education about exercise or a belief that exercise is not an important part of life
Not fit to exercise	Negative influences from fitness to exercise on a decision to consent (or ability to be included), including being too overloaded with fluids, having comorbidities, reduced strength or reduced mobility
Psychological barriers	Negative influences from psychological barriers on a decision to exercise, including patient perception that their condition means that they cannot exercise
Experiences of the control group: descriptions of experiences and views relating to being allocated to the control group in the trial
Little change to activities	Having made no obvious changes to physical activity levels during the trial
Willing to help	Positive descriptions of willingness/pleasure in being able to contribute because of perceptions of the trial’s value/importance, and ability to continue with prior routine physical activity
Barriers to continuing trial participation: descriptions of barriers to ongoing trial participation
Disappointment about being in the control group	Disappointment and sadness about being allocated to the control group, including because the participant was invested in increasing their physical activity, exercise and/or mobility
End of exercise period	Frustration at having to stop cycling at the end of the specified intervention period
Renal unit engagement with the trial: descriptions of influences on the renal unit’s engagement with the PEDAL trial
Negative views about the PEDAL trial/barriers to engagement described by renal unit staff	Feeling too busy or short staffed to deliver the intervention, or the intervention not being a priority owing to conflicting priorities, or there being a lack of physical space
Positive views about the PEDAL trial/facilitators of engagement described by renal unit staff	Interest in the study question and intervention and in research more generally, and hope for better patient outcomes

Discussion

Results of the qualitative substudy are largely consistent, with the few existing qualitative studies exploring health-care provider and patient experiences of intradialytic exercise. The current study findings go further in relation to theory generation; therefore, it is possible to make some more in-depth suggestions for further development. The literature search conducted early in the trial was repeated in June 2020 [searching PubMed, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo^® (American Psychological Association, Washington, DC, USA) and SPORTDiscus (EBSCO) using the search terms ‘exercise’ and ‘haemodialysis’ and ‘qualitative’, with no limiters] and no further studies were found.

Young et al. 39 conducted a study in the UK of patient and staff perceptions of intradialytic exercise. They carried out focus groups with 24 patients and 9 staff before implementation and semistructured interviews with 11 exercising patients and 8 staff members 6 months later. Thompson et al. 40 interviewed 25 patients and 11 staff in Canada to explore perceptions of intradialytic exercise. Heiwe and Tollin41 conducted individual interviews in Sweden with six men and four women who were experiencing implementation of intradialytic cycling. There was a focus in the studies of Young et al. 39 and Heiwe and Tollin41 on identifying barriers and motivators in the data; both looked at the stage of deciding whether or not to take part, and the former also looked at experiences 6 months later.

There were multiple common themes between the PEDAL trial themes and those in previous studies. In particular, Young et al. 39 found similar functional, psychological and physiological benefits, and viewed these as providing positive feedback that enhanced ongoing participation. Thompson et al. 40 found social benefits but did not focus on analysis of the impacts of exercise. Heiwe and Tollin41 conducted their interviews in the early stages of implementation and found that participants were motivated partly by a desire to pass the time and felt that this was a good opportunity for exercise. In addition, they noted that the positive experiences of well-being benefits fed into ongoing participation, which was evident in our study.

There were common barriers that revolved around staffing and workload, limited resources and concerns over roles and appropriate training or expertise. 39,40 Interestingly, these three studies delivered the intervention with existing staffing: kinesiologist and nursing staff,40 nursing staff41 and physiotherapist staff. 41 By contrast, in all but one of the renal units represented in the current study, a dedicated PEDAL trial employee delivered the intervention. The renal unit in the PEDAL trial that provided its own support for the intervention shared the workload of study implementation between staff and discussed similar barriers to the previously published studies. Staff in the other renal units commented on the necessity of dedicated staff time. This may relate also to a theme that was common to all studies: the importance of motivation, encouragement, reinforcement, feedback and support from staff to facilitate ongoing participation.

In the context of qualitative data collection and analysis, evidence of support from similar, previous studies provides further evidence of credibility and trustworthiness of the results, so the similarities in themes from different countries and contexts are encouraging. Our study was, to our knowledge, the largest of its kind by far, and had quite diverse participants, which provides valuable triangulation.

The results of this qualitative substudy clearly support the value of exercising while on dialysis for those who can. We also have useful insights about how to enable people to continue participation over time, both from feed forward of the positive impacts and through complex social and cultural dynamics in the renal unit. It is important to consider the insights of analysis for ongoing implementation of the intervention. The results suggest that a renal unit is an integrated system, with complex interdependencies and mutual influences on expectations, beliefs and attitudes. Staff and patients are intertwined as a community and, when considering changing complex behaviours, it is important to remember this. It would be useful to analyse the findings of this study in relation to current behaviour change theory as a secondary analysis, for example using the capability, opportunity, motivation, behaviour (COM-B) behaviour change model, which emerged from the behaviour change wheel of Mitchie et al. 42 Interestingly, Young et al. 39 considered the importance of influencing behaviours of staff as well as of patients; they recommended staff training and patient education to increase engagement. We suggest that the need for change goes beyond knowledge to culture; renal units with proactive and relationship-focused cultures appeared to engage people in the intervention in different ways, which may be more sustainable in the long term. In the future it would be valuable to explore ideas around ways in which providers empower and enable, how this is influenced by leadership and context and how this affects changes in the behaviours of people engaging in and sustaining interventions such as exercising while on dialysis.

Conclusions

The explanatory theory developed through the qualitative substudy of the PEDAL trial has provided in-depth insights into the influences on people’s decision-making relating to participation in both the trial and the intervention over time. Themes are supported by the few previous qualitative studies; however, our data are more extensive, and the resulting theoretical explanation goes further to enable suggestions for future implementation and intervention sustainability. A novel finding relates to the importance of culture, and leadership to enable this, in the renal unit. Providers interviewed felt that the trial did not impinge much on their jobs, which supported trial implementation; however, this may not be conducive to sustainability of the intervention beyond the trial. Moving forward beyond the PEDAL trial, it will be most important to influence the attitudes, beliefs and behaviours of providers. Where providers are engaged and empowered, they are much more likely to engage and empower patients in participating. Once a patient is participating (where capable), the numerous physical, functional, psychological and social benefits are likely to support their ongoing participation. This in itself may then feed forward into a positive, proactive culture in the renal unit. Further research is needed to explore the complexities of intervention implementation in the longer term, with a view to aspects of behaviour change and insights from implementation science.

Summary of main findings

The aim of the PEDAL trial was to assess clinical effectiveness and cost-effectiveness of a 6-month intradialytic exercise programme on QoL, compared with usual care for HD in the UK. The PEDAL trial is novel in that it is the first, to our knowledge, to evaluate intradialytic exercise as would most likely be delivered nationally, should NHS commissioning include exercise training as part of the service specification for in-centre HD. Exercise training was delivered by physiotherapy assistants (band 4 technical instructors), supported by regional co-ordinators who were physiotherapists or exercise physiologists. Thus, the PEDAL trial evaluated the most realistic yet safe exercise rehabilitation intervention possible in this population.

The baseline demographic data of the PEDAL trial cohort broadly aligns with the ‘real-world’ dialysis population in the UK as detailed in the latest data from the UK Renal Registry43 and also the PIVOTAL (Proactive IV iron Therapy in haemodiALysis patients) trial, a recent, large interventional study conducted in UK renal units. 44 Baseline age, sex, BMI, blood pressure, diabetes prevalence and the proportion of current smokers are all similar to UK Renal Registry data. 43 However, the current study included a larger proportion of black African and black Caribbean participants, and a lower proportion of white participants, than is representative of the broader prevalent dialysis population in the UK. The baseline data are similar to most dialysis populations worldwide. 45–48 There are some differences in rates of diabetes prevalence, with lower rates in our patient cohort than in dialysis populations in the USA and Asia, which may limit application of the results to all other dialysis populations.

As delivered, the PEDAL programme did not improve the QoL of the whole sample, as assessed by the KDQoL-SF PCS (p = 0.055), nor did it improve QoL as assessed by the secondary outcomes of the EuroQol-5 Dimensions, five-level version (EQ-5D-5L) or KDQoL-SF multi-item scales. In the whole sample there were no statistical or absolute changes in functional capacity, physiological variables, anthropometric measures or clinical measures. More than half (58%) of patients temporarily halted receiving their exercise intervention for a continuous period of > 2 weeks during the study; in total, patients completed less than half [47%, interquartile range 28–77%] of exercise sessions that were prescribed. These data suggest that the HD patients had poor compliance with the exercise intervention. The nested qualitative study revealed that patient views relating to change in health status, having comorbidities and having days where there was an increase in symptoms such as tiredness were possible reasons for not engaging with the exercise intervention. Because predominant themes were the ‘exercise culture’ and camaraderie that results from exercising with others, a cluster randomisation design may perhaps have fostered this camaraderie on a whole renal unit level, preventing the perception of participants feeling ‘left out’ if they were allocated to the control group.

We chose the KDQoL-SF instrument because of its validity in CKD patients49 and inclusion of a generic core that has been widely used in CKD and other populations. The lack of effectiveness of the PEDAL programme in the whole sample on PCS score warrants comparison with previous studies. A Cochrane review9 completed in 2011 concluded that exercise was beneficial for QoL in CKD patients but, unfortunately, no meta-analysis or risk-of-bias assessment was performed on this outcome measure. Furthermore, many of the included studies were not representative of the HD population because they investigated transplant,50 pre dialysis51 or ambulatory peritoneal dialysis52 patients. More recent meta-analyses have concluded positive effects of exercise but have shown significant effects on the role physical subscale only,53 showing no effect on PCS score,18 or did not analyse this outcome owing to insufficient studies. 13,54 Other meta-analyses have included non-randomised studies53 or rated studies as at high risk of bias and showing considerable heterogeneity. 14,17,19,54 Previous meta-analyses have also included extradialytic exercise programmes19,54,55 or studies that have delivered progressive resistance training as opposed to aerobic cycling alone. 10,15,16,19,20,56 In this regard, one meta-analysis22 usefully compared aerobic exercise, progressive resistance training and combined exercise; only progressive resistance training increased PCS score. Detailed analysis of the very few empirical studies included in reviews that do show positive effects of aerobic intradialytic exercise on QoL reveals that they have often utilised unrealistic interventions that would be difficult to implement in routine care. For example, Ouzouni et al. 57 investigated an exercise programme similar to the PEDAL programme [intradialytic cycling plus TheraBands (TheraBand, Akron, OH, USA) and ankle weights] but three physiologists were employed to intensely supervise only 10 patients for 10 months to obtain a significant effect. Taken together with the results reported herein, it is highly unlikely that clinically implementable intradialytic aerobic exercise training per se increases QoL, particularly at a whole-population level.

Nevertheless, there was some evidence of benefits to KDQoL-SF-assessed QoL and aerobic capacity in patients who completed > 30% of prescribed exercise sessions. Participants, clinicians and researchers continue to advocate intradialytic aerobic exercise. The PEDAL trial uniquely assessed the cost of delivery of its intervention using careful recording of harms and using health economic methods. The number of hospitalisations, all-cause mortality and cardiovascular mortality were not different between the groups. Although these results should be interpreted cautiously because of the lack of events for these secondary outcomes, there was no obvious increase in SAEs in the intervention group. The economic cost of delivering the PEDAL intervention ranged from £882 to £1866 per patient per year (depending on pay band of the physiotherapy assistant, whether or not London weighting was applied and staff–patient ratio). This calculation assumed that intradialytic exercise would be offered as part of a general physiotherapy service (with enough capacity to provide absence cover), with costs profiled throughout the programme (e.g. exercise equipment cost is shared throughout its service life), with patients who are 100% compliant and with physiotherapy assistants supervising between 6 and 10 patients per dialysis session without incurring any travel costs. For context, the cost of delivery of HD in the UK is approximately £35,023. 58 Because the PEDAL trial was not clinically effective at a whole-sample level, whether or not the cost of delivery of intradialytic exercise is justified to enhance patient choice remains a matter for debate. Because the observed benefits to KDQoL-SF-assessed QoL may be due to an experimenter effect, a similar improvement in QoL to that achieved herein could arguably be achieved with less cost and less effort through one-to-one patient interactions and provision of patient education resources on physical activity.

The PEDAL trial aimed to address a criticism of previous exercise studies that recruited only patients with high physical health status by having more inclusive inclusion criteria. Perhaps including patients with lower physical health status prevented benefits of the exercise intervention being realised. However, this explanation is unlikely because our sample is like other pragmatic exercise studies in CKD patients (e.g. in the seminal study of Painter,59 baseline PCS score was 36 AUs). Besides, poor baseline physical health status is not a reason for lack of response to exercise intervention, because patients with poorer PCS scores respond better to intervention than those with higher PCS scores. 7

Health economic evaluation

The economics evaluation suggests that, over 6 months of implementation, the PEDAL intervention resulted in higher NHS costs with no gain in QoL as measured by the EQ-5D-5L. A number of factors should be borne in mind; for example, the benefit from the PEDAL intervention could be avoiding cardiovascular events and other illnesses in future years, and the 6-month time horizon would not capture this. In addition, the PEDAL protocol could be refined to target different patients on dialysis and/or to include a time point at which the benefit of the intervention was assessed with only those reporting a good QoL gain continuing. Both of these could potentially improve the cost-effectiveness of the intervention.

Qualitative analyses of patient views

The explanatory theory developed through the qualitative substudy of the PEDAL trial has provided in-depth insights into the influences on people’s decision-making relating to participation both in the trial and in the intervention over time. Themes are supported by the few previous qualitative studies; however, our data are more extensive, and the resulting theoretical explanation goes further to enable suggestions for future implementation and intervention sustainability. A novel finding relates to the importance of culture, and leadership to enable this, in the renal unit. Providers interviewed felt that the trial did not impinge much on their jobs, which supported trial implementation; however, this may not be conducive to sustainability of the intervention beyond the trial. Moving forward beyond the PEDAL trial, it will be most important to influence the attitudes, beliefs and behaviours of providers. Where providers are engaged and empowered, they are much more likely to engage and empower patients in participating. Once a patient is participating (where capable), the numerous physical, functional, psychological and social benefits are likely to support their ongoing participation. This in itself may then feed forward into a positive, proactive culture in the renal unit. Further research is needed to explore the complexities of intervention implementation in the longer term, with a view to aspects of behaviour change and insights from implementation science.

Limitations

The study was designed to assess a pragmatic, clinically implementable intradialytic exercise intervention. By design, the study relied on a patient-reported outcome measure for its primary outcome; it is recognised that the primary limitation of this study was the lack of an attention control group. To alleviate this concern, multiple outcomes were assessed, and objective measures were obtained whenever possible; only objective measures of habitual physical activity were not of sufficient quality to be presented in this manuscript (owing to poor patient compliance with wearing accelerometers). In addition, many patients withdrew from the study (following randomisation but before baseline, and also during follow-up) or were too unwell to complete all functional capacity and physiological outcome assessments. This particularly affected the assessments of peak aerobic capacity but is to be expected in a study with inclusive inclusion criteria and arduous outcome assessments. Finally, the study was not powered to detect differences in some secondary outcomes, including mortality. Nevertheless, we reported these data to allow a balance of benefits and harms to be assessed. Future studies should address these concerns by including attention control groups and being adequately powered to investigate minimal clinically important differences of all outcome measures. Based on the findings presented herein, studies should address poor compliance by investigating exercise counselling and behaviour change interventions (such as motivational interviewing and self-determination theory) and should specifically target ways to overcome complications associated with concurrent medical events (such as fatigue). Investigators should consider alternative mechanisms of action of exercise interventions, including self-efficacy and stage of change. 43 Finally, the benefits of including progressive resistance training should be confirmed, even if extradialytic delivery is required.

Conclusion

A pragmatic intradialytic aerobic exercise programme, which could realistically be commissioned as part of routine care, did not improve QoL of this deconditioned sample of HD patients. The lack of clinical effectiveness and cost-effectiveness was probably due to poor compliance and only modest changes in aerobic capacity, particularly in a subgroup of patients with concurrent medical events and associated fatigue.

Future work

The benefits of longer interventions, including progressive resistance training, should be confirmed, even if extradialytic delivery is required. Future studies need to evaluate whether or not there are subgroups of patients that may benefit from this type of intervention, and also whether or not there is scope to optimise the exercise intervention to improve compliance and effectiveness. This should include further qualitative work.

Contributions of authors

Sharlene A Greenwood (https://orcid.org/0000-0001-9485-4645), Pelagia Koufaki (https://orcid.org/0000-0002-1406-3729), Jamie H Macdonald (https://orcid.org/0000-0002-2375-146X), Catherine Bulley (https://orcid.org/0000-0001-8338-5388), Ian Ford (https://orcid.org/0000-0001-5927-1823), Iain C Macdougall (https://orcid.org/0000-0001-9098-8611), Alice C Smith (https://orcid.org/0000-0002-9234-9060) and Thomas H Mercer (https://orcid.org/0000-0002-5078-4769) conceived and designed the study.

Catherine Bulley, Ian Ford and Claudia-Martina Messow (https://orcid.org/0000-0003-0082-9946) analysed the data.

Sharlene A Greenwood, Pelagia Koufaki and Jamie H Macdonald interpreted and contextualised the data and drafted the paper.

Sharlene A Greenwood, Pelagia Koufaki, Jamie H Macdonald, Catherine Bulley, Sunil Bhandari (https://orcid.org/0000-0002-0996-9622), James O Burton (https://orcid.org/0000-0003-1176-7592), Indranil Dasgupta (https://orcid.org/0000-0002-7448-2677), Kenneth Farrington (https://orcid.org/0000-0001-8862-6056), Ian Ford, Philip A Kalra (https://orcid.org/0000-0001-7652-1572), Mick Kumwenda (https://orcid.org/0000-0001-8343-1129), Iain C Macdougall, Claudia-Martina Messow, Chante Reid (https://orcid.org/0000-0003-2530-6025), Alice C Smith, Maarten W Taal (https://orcid.org/0000-0002-9065-212X), Peter C Thomson (https://orcid.org/0000-0003-4761-2648), David C Wheeler (https://orcid.org/0000-0003-0745-3478), Magdi Yaqoob (https://orcid.org/0000-0002-9904-127X) and Thomas H Mercer revised the paper.

Sandip Mitra (https://orcid.org/0000-0003-0389-636X) and Claire White (https://orcid.org/0000-0002-8908-8648) revised the paper.

All authors approved the final report.

Publication

Greenwood SA, Koufaki P, Macdonald JH, Bhandari S, Burton JO, Dasgupta I, et al. Randomized Trial - PrEscription of intraDialytic exercise to improve quAlity of Life (PEDAL) in patients receiving hemodialysis. Kidney Int Rep 2021; in press.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.