Protocol update for a multi-centre randomised controlled trial of exercise rehabilitation for people with pulmonary hypertension: the SPHERe trial.

BACKGROUND: The SPHERe (Supervised Pulmonary Hypertension Exercise Rehabilitation) trial is a multi-centre, pragmatic, randomised controlled trial assessing the clinical and cost-effectiveness of supervised exercise rehabilitation with psychosocial and motivational support compared to best-practice usual care for people with pulmonary hypertension (PH). The original protocol was published in BMC Pulmonary Medicine (accessible online). We randomised our first participant in January 2020. In response to the COVID-19 pandemic, the trial was stopped in March 2020. In person delivery of the SPHERe intervention to a vulnerable population was not possible during the COVID-19 pandemic. We describe here how trial procedures and intervention delivery were adapted in response to the COVID-19 pandemic. METHODS: Restrictions imposed by the COVID-19 pandemic on the clinically vulnerable PH population meant that trial delivery was changed from a centre-based rehabilitation programme to remotely delivered group online sessions. This led to minor alterations to the eligibility criteria. These changes followed a consultation process with stakeholders and people with PH and were approved by the funder and independent trial committees. CONCLUSIONS: We describe the modified SPHERe trial protocol in response to restrictions imposed by the COVID-19 pandemic. SPHERe is the first randomised controlled trial to assess the clinical and cost-effectiveness of an online group rehabilitation programme for people with PH compared to usual care. TRIAL REGISTRATION: ISRCTN no. 10608766. Prospectively registered on 18th March 2019, updated 16th August 2023.

Effects of Exercise Training Response on Quality of Life and Cardiovascular Risk Factor Profiles in People With Coronary Artery Disease: Insights From the HIIT or MISS UK Trial.

OBJECTIVE: To compare the characteristics of responders and nonresponders to 8 weeks of exercise training to determine differences in key cardiovascular disease outcomes in people with coronary artery disease (CAD). DESIGN: Secondary analysis of data from the HIIT or MISS UK trial. SETTING: Six outpatient National Health Service cardiac rehabilitation (CR) centers in the UK. In people with CAD attending CR, the HIIT or MISS UK trial reported that short-term, low-volume, high-intensity interval training (HIIT) was more effective than moderate-intensity steady state (MISS) exercise training for improving peak oxygen uptake (V̇o2peak). PARTICIPANTS: 382 participants with CAD (N=382) (mean age: 58.8±9.6y; mean body mass index: 29.0±4.3 kg/m2). MAIN OUTCOME MEASURES: We identified responders and nonresponders based on a meaningful change in V̇o2peak, using 2 established methods. Key clinical, quality of life (QoL), and cardiopulmonary exercise test (CPET)-derived outcomes were compared between groups. RESULTS: Responders were more likely to be younger (P<.05), and demonstrate greater improvement in CPET-related outcomes, for example, oxygen uptake efficiency slope, ventilatory efficiency, and peak power output (all comparisons, P<.001). Responders were more likely to observe improvements in QoL (EQ-5D-5L; mean Δ 13.6 vs mean Δ 9.4; P=.045), and high-density lipoprotein cholesterol (HDL-c) (mean Δ 0.09 mmol/L vs mean Δ 0.04 mmol/L; P=.004), compared to nonresponders. CONCLUSIONS: In people with CAD attending CR, responders to exercise training were more likely to be younger and demonstrate greater improvements in health-related QoL and HDL-c.

Inter- and intra-observer reliability and agreement of O2Pulse inflection during cardiopulmonary exercise testing: A comparison of subjective and novel objective methodology.

Cardiopulmonary exercise testing (CPET) is the 'gold standard' method for evaluating functional capacity, with oxygen pulse (O2Pulse) inflections serving as a potential indicator of myocardial ischaemia. However, the reliability and agreement of identifying these inflections have not been thoroughly investigated. This study aimed to assess the inter- and intra-observer reliability and agreement of a subjective quantification method for identifying O2Pulse inflections during CPET, and to propose a more robust and objective novel algorithm as an alternative methodology. A retrospective analysis was conducted using baseline data from the HIIT or MISS UK trial. The O2Pulse curves were visually inspected by two independent examiners, and compared against an objective algorithm. Fleiss' Kappa was used to determine the reliability of agreement between the three groups of observations. The results showed almost perfect agreement between the algorithm and both examiners, with a Fleiss' Kappa statistic of 0.89. The algorithm also demonstrated excellent inter-rater reliability (ICC) when compared to both examiners (0.92-0.98). However, a significant level (P ≤0.05) of systematic bias was observed in Bland-Altman analysis for comparisons involving the novice examiner. In conclusion, this study provides evidence for the reliability of both subjective and novel objective methods for identifying inflections in O2Pulse during CPET. These findings suggest that further research into the clinical significance of O2Pulse inflections is warranted, and that the adoption of a novel objective means of quantification may be preferable to ensure equality of outcome for patients.

Clinical effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-covid-19 condition (REGAIN study): multicentre randomised controlled trial.

OBJECTIVE: To evaluate whether a structured online supervised group physical and mental health rehabilitation programme can improve health related quality of life compared with usual care in adults with post-covid-19 condition (long covid). DESIGN: Pragmatic, multicentre, parallel group, superiority randomised controlled trial. SETTING: England and Wales, with home based interventions delivered remotely online from a single trial hub. PARTICIPANTS: 585 adults (26-86 years) discharged from NHS hospitals at least three months previously after covid-19 and with ongoing physical and/or mental health sequelae (post-covid-19 condition), randomised (1:1.03) to receive the Rehabilitation Exercise and psycholoGical support After covid-19 InfectioN (REGAIN) intervention (n=298) or usual care (n=287). INTERVENTIONS: Best practice usual care was a single online session of advice and support with a trained practitioner. The REGAIN intervention was delivered online over eight weeks and consisted of weekly home based, live, supervised, group exercise and psychological support sessions. MAIN OUTCOME MEASURES: The primary outcome was health related quality of life using the patient reported outcomes measurement information system (PROMIS) preference (PROPr) score at three months. Secondary outcomes, measured at three, six, and 12 months, included PROMIS subscores (depression, fatigue, sleep disturbance, pain interference, physical function, social roles/activities, and cognitive function), severity of post-traumatic stress disorder, general health, and adverse events. RESULTS: Between January 2021 and July 2022, 39 697 people were invited to take part in the study and 725 were contacted and eligible. 585 participants were randomised. Mean age was 56 (standard deviation (SD) 12) years, 52% were female participants, mean health related quality of life PROMIS-PROPr score was 0.20 (SD 0.17), and mean time from hospital discharge was 323 (SD 144) days. Compared with usual care, the REGAIN intervention led to improvements in health related quality of life (adjusted mean difference in PROPr score 0.03 (95% confidence interval 0.01 to 0.05), P=0.02) at three months, driven predominantly by greater improvements in the PROMIS subscores for depression (1.39 (0.06 to 2.71), P=0.04), fatigue (2.50 (1.19 to 3.81), P<0.001), and pain interference (1.80 (0.50 to 3.11), P=0.01). Effects were sustained at 12 months (0.03 (0.01 to 0.06), P=0.02). Of 21 serious adverse events, only one was possibly related to the REGAIN intervention. In the intervention group, 141 (47%) participants fully adhered to the programme, 117 (39%) partially adhered, and 40 (13%) did not receive the intervention. CONCLUSIONS: In adults with post-covid-19 condition, an online, home based, supervised, group physical and mental health rehabilitation programme was clinically effective at improving health related quality of life at three and 12 months compared with usual care. TRIAL REGISTRATION: ISRCTN registry ISRCTN11466448.

Cost-effectiveness of High-Intensity Interval Training (HIIT) vs Moderate Intensity Steady-State (MISS) Training in UK Cardiac Rehabilitation.

OBJECTIVE: To perform a cost-effectiveness analysis of high-intensity interval training (HIIT) compared with moderate intensity steady-state (MISS) training in people with coronary artery disease (CAD) attending cardiac rehabilitation (CR). DESIGN: Secondary cost-effectiveness analysis of a prospective, assessor-blind, parallel group, multi-center RCT. SETTING: Six outpatient National Health Service cardiac rehabilitation centers in England and Wales, UK. PARTICIPANTS: 382 participants with CAD (N=382). INTERVENTIONS: Participants were randomized to twice-weekly usual care (n=195) or HIIT (n=187) for 8 weeks. Usual care was moderate intensity continuous exercise (60%-80% maximum capacity, MISS), while HIIT consisted of 10 × 1-minute intervals of vigorous exercise (>85% maximum capacity) interspersed with 1-minute periods of recovery. MAIN OUTCOME MEASURES: We conducted a cost-effectiveness analysis of the HIIT or MISS UK trial. Health related quality of life was measured with the EQ-5D-5L to estimate quality-adjusted life years (QALYs). Costs were estimated with health service resource use and intervention delivery costs. Cost-utility analysis measured the incremental cost-effectiveness ratio (ICER). Bootstrapping assessed the probability of HIIT being cost-effective according to the UK National Institute for Health and Care Excellence (NICE) threshold value (£20,000 per QALY). Missing data were imputed. Uncertainty was estimated using probabilistic sensitivity analysis. Assumptions were tested using univariate/1-way sensitivity analysis. RESULTS: 124 (HIIT, n=59; MISS, n=65) participants completed questionnaires at baseline, 8 weeks, and 12 months. Mean combined health care use and delivery cost was £676 per participant for HIIT, and £653 for MISS. QALY changes were 0.003 and -0.013, respectively. For complete cases, the ICER was £1448 per QALY for HIIT compared with MISS. At a willingness-to-pay threshold of £20,000 per QALY, the probability of HIIT being cost-effective was 96% (95% CI, 0.90 to 0.95). CONCLUSION: For people with CAD attending CR, HIIT was cost-effective compared with MISS. These findings are important to policy makers, commissioners, and service providers across the health care sector.

Development of an online intervention for the Rehabilitation Exercise and psycholoGical support After covid-19 InfectioN (REGAIN) trial.

Background: Up to half of people hospitalised with COVID-19 report diverse and persistent symptoms affecting quality of life for months and sometimes years after discharge (long-COVID). We describe the development of an online group exercise and behavioural support intervention for people who continue to experience such physical and/or emotional health problems more than three months after hospital discharge. Methods: Intervention development was informed by the Medical Research Council framework for complex interventions. Our multidisciplinary team of academics, clinicians, and people with long-COVID, had collective expertise in the development and testing of complex interventions. We integrated a bio-psycho-social model of care drawing on rehabilitation literature for long-term health conditions and experiences from our pre-pilot study. Multiple stakeholder meetings were held to refine the intervention which was designed to be deliverable within the UK National Health Service. We adhere to TIDieR guidance for transparent and explicit reporting of telehealth interventions. Results: The final REGAIN online exercise and behavioural support intervention consisted of an initial 1:1 consultation with a trained practitioner, followed by eight online group exercise, and six group support, sessions delivered over eight weeks. Participants could also access an online library of on-demand exercise and support videos. Conclusions: The final REGAIN intervention, combining exercise and behavioural support, is fully manualised with clear pathways to delivery and implementation. It is currently being tested in a randomised controlled trial. The intervention, developed with extensive patient and stakeholder engagement, could be incorporated into existing NHS rehabilitation programmes, should it prove to be clinically and cost-effective for people with long-COVID. Trial registration: International Standard Randomised Controlled Trial Number (ISRCTN) 11466448: Rehabilitation exercise and psychological support after COVID-19 infection: REGAIN.

Long-COVID has many debilitating symptoms, such as breathlessness, muscle weakness and fatigue, which significantly affect peoples' physical and mental health and quality of life. Rehabilitation programmes can help people improve their quality of life in other medical conditions with similar symptoms. We developed a programme of physical and mental health rehabilitation, delivered online, specifically to support people with ongoing long-COVID symptoms more than three months after hospital discharge. The programme was developed by people with long-COVID along with clinicians and researchers. The programme described in this article is now being tested in a large research trial to see if it can help people with long-COVID.

Development of a complex exercise rehabilitation intervention for people with pulmonary hypertension: the supervised pulmonary hypertension exercise rehabilitation (SPHERe) trial.

BACKGROUND: People with pulmonary hypertension (PH) are not routinely referred for exercise rehabilitation despite the potential for reducing breathlessness and improving quality of life. We describe the development of a supervised pulmonary hypertension exercise rehabilitation (SPHERe) programme for people with PH. METHODS: Development was completed in three phases: (1) systematic review, (2) stakeholder engagement with consensus from patients and experts and (3) prepilot intervention acceptability testing. We completed systematic reviews to identify international cardiopulmonary rehabilitation guidance and trials of exercise-based interventions for people with PH. Evidence from systematic reviews and stakeholder consensus shaped the SPHERe intervention, including addition of individual behavioural support sessions to promote exercise adherence. The draft SPHERe intervention was ratified through discussions with multidisciplinary professionals and people living with PH. We acceptability tested the centre-based intervention with eight participants in a prepilot development phase which identified a number of condition-specific issues relating to safety and fear avoidance of activity. Comprehensive intervention practitioner training manuals were produced to ensure standardised delivery. Participant workbooks were developed and piloted. Trial recruitment began in January 2020 but was subsequently suspended in March 2020 further to COVID-19 pandemic 'lockdowns'. In response to the pandemic, we undertook further development work to redesign the intervention to be suitable for exclusively home-based online delivery. Recruitment to the revised protocol began in June 2021. DISCUSSION: The final SPHERe intervention incorporated weekly home-based online group exercise and behavioural support 'coaching' sessions supervised by trained practitioners, with a personalised home exercise plan and the optional loan of a stationary exercise bike. The intervention was fully manualised with clear pathways for assessment and individualised exercise prescription. The clinical and cost-effectiveness of the SPHERe online rehabilitation intervention is currently being tested in a UK multicentre randomised controlled trial. TRIAL REGISTRATION NUMBER: ISCRTN10608766.

Rising arterial stiffness with accumulating comorbidities associates with heart failure with preserved ejection fraction.

AIMS: Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular-vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing. METHODS AND RESULTS: Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near-normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = -0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e') on echocardiography (r = -0.307, P = 0.014). CONCLUSIONS: This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at-risk intermediate phenotypes (e.g. pre-HFpEF) before overt HFpEF occurs.

High-intensity interval training in cardiac rehabilitation: a multi-centre randomized controlled trial.

BACKGROUND: There is a lack of international consensus regarding the prescription of high-intensity interval training (HIIT) for people with coronary artery disease (CAD) attending cardiac rehabilitation (CR). AIMS: To assess the clinical effectiveness and safety of low-volume HIIT compared with moderate-intensity steady-state (MISS) exercise training for people with CAD. METHODS AND RESULTS: We conducted a multi-centre RCT, recruiting 382 patients from 6 outpatient CR centres. Participants were randomized to twice-weekly HIIT (n = 187) or MISS (n = 195) for 8 weeks. HIIT consisted of 10 × 1 min intervals of vigorous exercise (>85% maximum capacity) interspersed with 1 min periods of recovery. MISS was 20-40 min of moderate-intensity continuous exercise (60-80% maximum capacity). The primary outcome was the change in cardiorespiratory fitness [peak oxygen uptake (VO2 peak)] at 8 week follow-up. Secondary outcomes included cardiovascular disease risk markers, cardiac structure and function, adverse events, and health-related quality of life. At 8 weeks, VO2peak improved more with HIIT (2.37 mL.kg-1.min-1; SD, 3.11) compared with MISS (1.32 mL.kg-1.min-1; SD, 2.66). After adjusting for age, sex, and study site, the difference between arms was 1.04 mL.kg-1.min-1 (95% CI, 0.38 to 1.69; P = 0.002). Only one serious adverse event was possibly related to HIIT. CONCLUSIONS: In stable CAD, low-volume HIIT improved cardiorespiratory fitness more than MISS by a clinically meaningful margin. Low-volume HIIT is a safe, well-tolerated, and clinically effective intervention that produces short-term improvement in cardiorespiratory fitness. It should be considered by all CR programmes as an adjunct or alternative to MISS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02784873. https://clinicaltrials.gov/ct2/show/NCT02784873.

Cardiac rehabilitation exercise training can improve cardiorespiratory fitness and quality of life for people with coronary artery disease, but sometimes, it is not effective. The intensity of the exercise training may be important. We conducted a randomized controlled trial to test if moderate-intensity exercise or high-intensity exercise was better.High-intensity interval training was more effective than moderate-intensity exercise training for improving cardiorespiratory fitness in people with coronary artery disease attending cardiac rehabilitation.High-intensity interval training was safe and well tolerated.

Hypoxia during maintenance hemodialysis-the critical role of pH.

Background: The impact and management of subclinical hypoxia during hemodialysis is a significant medical challenge. As key determinants of O2 availability and delivery, proposed mechanisms contributing to hypoxia include ischemia, alkalemia and pulmonary leukocyte sequestration. However, no study has comprehensively investigated and compared these interrelated mechanisms throughout a typical hemodialysis treatment week. This study aimed to comprehensively assess the physiological mechanisms that contribute to hypoxia during hemodialysis. Methods: In 76 patients, we measured arterial blood gases and pH at four time-points during hemodialysis (start, 15 min, 60 min, end) over the course of a standard treatment week. For the mid-week hemodialysis session, we additionally measured central hemodynamics (non-invasive cardiac output monitoring) and white blood cell count. Results: Linear regression modelling identified changes in pH, but not central hemodynamics or white blood cell count, to be predictive of changes in PaO2 throughout hemodialysis (e.g. at 60 min, ß standardized coefficient pH = 0.45, model R2 = 0.25, P < .001). Alkalemia, hypokalemia, decreased calcium and increased hemoglobin-O2 affinity (leftward shift in the oxyhemoglobin dissociation curve) were evident at the end of hemodialysis. pH and hemoglobin-O2 affinity at the start of hemodialysis increased incrementally over the course of a standard treatment week. Conclusion: These data highlight the important role of pH in regulating O2 availability and delivery during hemodialysis. Findings support routine pH monitoring and personalized dialysate bicarbonate prescription to mitigate the significant risk of alkalemia and subclinical hypoxia.

Digital Peer-Supported Self-Management Intervention Codesigned by People With Long COVID: Mixed Methods Proof-of-Concept Study.

BACKGROUND: There are around 1.3 million people in the United Kingdom with the devastating psychological, physical, and cognitive consequences of long COVID (LC). UK guidelines recommend that LC symptoms be managed pragmatically with holistic support for patients' biopsychosocial needs, including psychological, emotional, and physical health. Self-management strategies, such as pacing, prioritization, and goal setting, are vital for the self-management of many LC symptoms. OBJECTIVE: This paper describes the codevelopment and initial testing of a digital intervention combining peer support with positive psychology approaches for self-managing the physical, emotional, psychological, and cognitive challenges associated with LC. The objectives of this study were to (1) codesign an intervention with and for people with LC; (2) test the intervention and study methods; (3) measure changes in participant well-being, self-efficacy, fatigue, and loneliness; and (4) understand the types of self-management goals and strategies used by people with LC. METHODS: The study used a pre-post, mixed methods, pragmatic, uncontrolled design. Digital intervention content was codeveloped with a lived-experience group to meet the needs uncovered during the intervention development and logic mapping phase. The resulting 8-week digital intervention, Hope Programme for Long COVID, was attended by 47 participants, who completed pre- and postprogram measures of well-being, self-efficacy, fatigue, and loneliness. Goal-setting data were extracted from the digital platform at the end of the intervention. RESULTS: The recruitment rate (n=47, 83.9%) and follow-up rate (n=28, 59.6%) were encouraging. Positive mental well-being (mean difference 6.5, P<.001) and self-efficacy (mean difference 1.1, P=.009) improved from baseline to postcourse. All goals set by participants mapped onto the 5 goal-oriented domains in the taxonomy of everyday self-management strategies (TEDSS). The most frequent type of goals was related to activity strategies, followed by health behavior and internal strategies. CONCLUSIONS: The bespoke self-management intervention, Hope Programme for Long COVID, was well attended, and follow-up was encouraging. The sample characteristics largely mirrored those of the wider UK population with LC. Although not powered to detect statistically significant changes, the preliminary data show improvements in self-efficacy and positive mental well-being. Our next trial (ISRCTN: 11868601) will use a nonrandomized waitlist control design to further examine intervention efficacy.

Effectiveness and Safety of Early Initiation of Poststernotomy Cardiac Rehabilitation Exercise Training: The SCAR Randomized Clinical Trial.

Importance: Guidelines recommend that cardiac rehabilitation (CR) exercise training should not start until 6 weeks after sternotomy, although this is not evidence based. Limited data suggest that starting earlier is not detrimental, but clinical trials are needed. Objective: To compare the effectiveness and safety of CR exercise training started either 2 weeks (early CR) or 6 weeks (usual-care CR) after sternotomy. Design, Setting, and Participants: This was an assessor-blind, noninferiority, parallel-group, randomized clinical trial that conducted participant recruitment from June 12, 2017, to March 17, 2020. Participants were consecutive cardiac surgery sternotomy patients recruited from 2 outpatient National Health Service rehabilitation centers: University Hospital, Coventry, UK, and Hospital of St Cross, Rugby, UK. Interventions: Participants were randomly assigned to 8 weeks of twice-weekly supervised CR exercise training starting either 2 weeks (early CR) or 6 weeks (usual-care CR) after sternotomy. Exercise training adhered to existing guidelines, including functional strength and cardiovascular components. Main Outcomes and Measures: Outcomes were assessed at baseline (inpatient after surgery), after CR (10 or 14 weeks after sternotomy), and 12 months after randomization. The primary outcome was the change in 6-minute walk test distance from baseline to after CR. Secondary outcomes included safety, functional fitness, and quality of life. Results: A total of 158 participants (mean [SD] age, 63 [11.5] years, 133 male patients [84.2%]) were randomly assigned to study groups; 118 patients (usual-care CR, 61 [51.7%]; early CR, 57 [48.3%]) were included in the primary analysis. Early CR was not inferior to usual-care CR (noninferiority margin, 35 m); the mean change in 6-minute walk distance from baseline to after CR was 28 m greater in the early CR group (95% CI, -11 to 66; P = .16). Mean differences for secondary outcomes were not statistically significant, indicating noninferiority of early CR. There were 46 vs 58 adverse events and 14 vs 18 serious adverse events in usual-care CR and early CR, respectively. There was no difference between the groups in the likelihood of participants having an adverse or serious adverse event. Conclusions and Relevance: Starting exercise training from 2 weeks after sternotomy was as effective as starting 6 weeks after sternotomy for improving 6-minute walk distance. With appropriate precautions, clinicians and CR professionals can consider starting exercise training as early as 2 weeks after sternotomy. Trial Registration: ClinicalTrials.gov Identifier: NCT03223558.

Rehabilitation Exercise and psycholoGical support After covid-19 InfectioN' (REGAIN): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objective is to determine which of two interventions: 1) an eight week, online, home-based, supervised, group rehabilitation programme (REGAIN); or 2) a single online session of advice (best-practice usual care); is the most clinically and cost-effective treatment for people with ongoing COVID-19 sequelae more than three months after hospital discharge. TRIAL DESIGN: Multi-centre, 2-arm (1:1 ratio) parallel group, randomised controlled trial with embedded process evaluation and health economic evaluation. PARTICIPANTS: Adults with ongoing COVID-19 sequelae more than three months after hospital discharge Inclusion criteria: 1) Adults ≥18 years; 2) ≥ 3 months after any hospital discharge related to COVID-19 infection, regardless of need for critical care or ventilatory support; 3) substantial (as defined by the participant) COVID-19 related physical and/or mental health problems; 4) access to, and able/supported to use email and internet audio/video; 4) able to provide informed consent; 5) able to understand spoken and written English, Bengali, Gujarati, Urdu, Punjabi or Mandarin, themselves or supported by family/friends. EXCLUSION CRITERIA: 1) exercise contraindicated; 2) severe mental health problems preventing engagement; 3) previous randomisation in the present study; 4) already engaged in, or planning to engage in an alternative NHS rehabilitation programme in the next 12 weeks; 5) a member of the same household previously randomised in the present study. INTERVENTION AND COMPARATOR: Intervention 1: The Rehabilitation Exercise and psycholoGical support After covid-19 InfectioN (REGAIN) programme: an eight week, online, home-based, supervised, group rehabilitation programme. Intervention 2: A thirty-minute, on-line, one-to-one consultation with a REGAIN practitioner (best-practice usual care). MAIN OUTCOMES: The primary outcome is health-related quality of life (HRQoL) - PROMIS® 29+2 Profile v2.1 (PROPr) - measured at three months post-randomisation. Secondary outcomes include dyspnoea, cognitive function, health utility, physical activity participation, post-traumatic stress disorder (PTSD) symptom severity, depressive and anxiety symptoms, work status, health and social care resource use, death - measured at three, six and 12 months post-randomisation. RANDOMISATION: Participants will be randomised to best practice usual care or the REGAIN programme on a 1:1.03 basis using a computer-generated randomisation sequence, performed by minimisation and stratified by age, level of hospital care, and case level mental health symptomatology. Once consent and baseline questionnaires have been completed by the participant online at home, randomisation will be performed automatically by a bespoke web-based system. BLINDING (MASKING): To ensure allocation concealment from both participant and REGAIN practitioner at baseline, randomisation will be performed only after the baseline questionnaires have been completed online at home by the participant. After randomisation has been performed, participants and REGAIN practitioners cannot be blind to group allocation. Follow-up outcome assessments will be completed by participants online at home. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 535 participants will be randomised: 263 to the best-practice usual care arm, and 272 participants to the REGAIN programme arm. TRIAL STATUS: Current protocol: Version 3.0 (27th October 2020) Recruitment will begin in December 2020 and is anticipated to complete by September 2021. TRIAL REGISTRATION: ISRCTN:11466448 , 23rd November 2020 FULL PROTOCOL: The full protocol Version 3.0 (27th October 2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.

Supervised pulmonary hypertension exercise rehabilitation (SPHERe): study protocol for a multi-centre randomised controlled trial.

BACKGROUND: Supervised cardio-pulmonary rehabilitation may be safe and beneficial for people with pulmonary hypertension (PH) in groups 1 (pulmonary arterial hypertension) and 4 (chronic thromboembolic disease), particularly as a hospital in-patient. It has not been tested in the most common PH groups; 2 (left heart disease), 3 (lung disease), or 5 (other disorders). Further it has not been evaluated in the UK National Health Service (NHS) out-patient setting, or with long-term follow-up. The aim of this randomised controlled trial (RCT) is to test the clinical and cost-effectiveness of a supervised exercise rehabilitation intervention with psychosocial support compared to best practice usual care for people with PH in the community/outpatient setting. METHODS: This multi-centre, pragmatic, two-arm RCT with embedded process evaluation aims to recruit 352 clinically stable adults with PH (groups 1-5) and WHO functional class II-IV. Participants will be randomised to either the Supervised Pulmonary Hypertension Exercise Rehabilitation (SPHERe) intervention or control. The SPHERe intervention consists of 1) individual assessment and familiarisation sessions; 2) 8-week, twice-weekly, supervised out-patient exercise training; 3) psychosocial/motivational support and education; 4) guided home exercise plan. The control intervention consists of best practice usual care with a single one-to-one practitioner appointment, and general advice on physical activity. Outcomes will be measured at baseline, 4 months (post-intervention) and 12 months by researchers blinded to treatment allocation. The primary outcome is the incremental shuttle walk test at 4 months. Secondary outcomes include health-related quality of life (HRQoL), time to clinical worsening and health and social care use. A purposive sample of participants (n = 20 intervention and n = 20 control) and practitioners (n = 20) will be interviewed to explore experiences of the trial, outcomes and interventions. DISCUSSION: The SPHERe study is the first multi-centre clinical RCT to assess the clinical and cost effectiveness of a supervised exercise rehabilitation intervention compared to usual care, delivered in the UK NHS, for people in all PH groups. Results will inform clinicians and commissioners as to whether or not supervised exercise rehabilitation is effective and should be routinely provided for people with PH. TRIAL REGISTRATION: ISRCTN no. 10608766, prospectively registered on 18th March 2019.

Heart failure with preserved ejection fraction (HFpEF) pathophysiology study (IDENTIFY-HF): does increased arterial stiffness associate with HFpEF, in addition to ageing and vascular effects of comorbidities? Rationale and design.

AIMS: There has been a paradigm shift proposing that comorbidities are a major contributor towards the heart failure with preserved ejection fraction (HFpEF) syndrome. Furthermore, HFpEF patients have abnormal macrovascular and microvascular function, which may significantly contribute towards altered ventricular-vascular coupling in these patients. The IDENTIFY-HF study will investigate whether gradually increased arterial stiffness (in addition to ageing) as a result of increasing common comorbidities, such as hypertension and diabetes, is associated with HFpEF. METHODS AND ANALYSIS: In our observational study, arterial compliance and microvascular function will be assessed in five groups (Groups A to E) of age, sex and body mass index matched subjects (age ≥70 years in all groups):Group A; normal healthy volunteers without major comorbidities such as hypertension and diabetes mellitus (control). Group B; patients with hypertension without diabetes mellitus or heart failure (HF). Group C; patients with hypertension and diabetes mellitus without HF. Group D; patients with HFpEF. Group E; patients with heart failure and reduced ejection fraction (parallel group). Vascular function and arterial compliance will be assessed using pulse wave velocity, as the primary outcome measure. Further outcome measures include cutaneous laser Doppler flowmetry as a measure of endothelial function, transthoracic echocardiography and exercise tolerance measures. Biomarkers include NT-proBNP, high-sensitivity troponin T, as well as serum galectin-3 as a marker of fibrosis. ETHICS AND DISSEMINATION: The study was approved by the regional research ethics committee (REC), West Midland and Black Country 17/WM/0039, UK, and permission to conduct the study in the hospital was also obtained from the RDI, UHCW NHS Trust. The results will be published in peer-reviewed journals and presented in local, national and international medical society meetings. TRIAL REGISTRATION NUMBER: NCT03186833.

Low frequency electrical muscle stimulation and endothelial function in advanced heart failure patients.

AIM: Obtain initial estimates of the change in brachial artery endothelial function and maximal oxygen uptake (VO2peak ) with 8 weeks of low-frequency electrical muscle stimulation (LF-EMS) or sham in patients with advanced chronic heart failure. METHODS AND RESULTS: Using a double blind, randomized design, 35 patients with chronic heart failure (New York Heart Association class III-IV) were assigned to 8 weeks (5 × 60 min per week) of either LF-EMS (4 Hz, continuous) or sham (skin level stimulation only) of the quadriceps and hamstrings muscles. Four of the five sessions were at home and one under supervision. Ultrasound images of resting brachial artery diameter and post 5 min occlusion to determine flow-mediated dilation (FMD), a marker of vascular function and peak oxygen uptake (VO2peak ) during cardiopulmonary exercise test, were measured before and after LF-EMS (n = 20) and sham (n = 15) interventions. FMD improved by 2.56% (95% confidence interval: 0.69 to 3.80) with LF-EMS compared with sham (P = 0.07). There were no notable changes in VO2peak . CONCLUSIONS: Improvements in FMD with LF-EMS may have a clinically meaningful effect as higher FMD is associated with better prognosis. This is a preliminary finding, and a larger trial is warranted.

Feasibility and effects of intra-dialytic low-frequency electrical muscle stimulation and cycle training: A pilot randomized controlled trial.

BACKGROUND AND OBJECTIVES: Exercise capacity is reduced in chronic kidney failure (CKF). Intra-dialytic cycling is beneficial, but comorbidity and fatigue can prevent this type of training. Low-frequency electrical muscle stimulation (LF-EMS) of the quadriceps and hamstrings elicits a cardiovascular training stimulus and may be a suitable alternative. The main objectives of this trial were to assess the feasibility and efficacy of intra-dialytic LF-EMS vs. cycling. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Assessor blind, parallel group, randomized controlled pilot study with sixty-four stable patients on maintenance hemodialysis. Participants were randomized to 10 weeks of 1) intra-dialytic cycling, 2) intra-dialytic LF-EMS, or 3) non-exercise control. Exercise was performed for up to one hour three times per week. Cycling workload was set at 40-60% oxygen uptake (VO2) reserve, and LF-EMS at maximum tolerable intensity. The control group did not complete any intra-dialytic exercise. Feasibility of intra-dialytic LF-EMS and cycling was the primary outcome, assessed by monitoring recruitment, retention and tolerability. At baseline and 10 weeks, secondary outcomes including cardio-respiratory reserve, muscle strength, and cardio-arterial structure and function were assessed. RESULTS: Fifty-one (of 64 randomized) participants completed the study (LF-EMS = 17 [77%], cycling = 16 [80%], control = 18 [82%]). Intra-dialytic LF-EMS and cycling were feasible and well tolerated (9% and 5% intolerance respectively, P = 0.9). At 10-weeks, cardio-respiratory reserve (VO2 peak) (Difference vs. control: LF-EMS +2.0 [95% CI, 0.3 to 3.7] ml.kg-1.min-1, P = 0.02, and cycling +3.0 [95% CI, 1.2 to 4.7] ml.kg-1.min-1, P = 0.001) and leg strength (Difference vs. control: LF-EMS, +94 [95% CI, 35.6 to 152.3] N, P = 0.002 and cycling, +65.1 [95% CI, 6.4 to 123.8] N, P = 0.002) were improved. Arterial structure and function were unaffected. CONCLUSIONS: Ten weeks of intra-dialytic LF-EMS or cycling improved cardio-respiratory reserve and muscular strength. For patients who are unable or unwilling to cycle during dialysis, LF-EMS is a feasible alternative.

Is exercise-based cardiac rehabilitation effective? A systematic review and meta-analysis to re-examine the evidence.

OBJECTIVES: To determine the contemporary effectiveness of exercise-based cardiac rehabilitation (CR) in terms of all-cause mortality, cardiovascular mortality and hospital admissions. DATA SOURCES: Studies included in or meeting the entry criteria for the 2016 Cochrane review of exercise-based CR in patients with coronary artery disease. STUDY ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) of exercise-based CR versus a no-exercise control whose participants were recruited after the year 2000. STUDY APPRAISAL AND SYNTHESIS METHODS: Two separate reviewers independently screened the characteristics of studies. One reviewer quality appraised any new studies and assessed their risk of bias using the Cochrane Collaboration's recommended risk of bias tool. Data were reported as the risk difference (95% CI). RESULTS: We included 22 studies with 4834 participants (mean age 59.5 years, 78.4% male). We found no differences in outcomes between exercise-based CR and a no-exercise control at their longest follow-up period for: all-cause mortality (19 studies; n=4194; risk difference 0.00, 95% CI -0.02 to 0.01, P=0.38) or cardiovascular mortality (9 studies; n=1182; risk difference -0.01, 95% CI -0.02 to 0.01, P=0.25). We found a small reduction in hospital admissions of borderline statistical significance (11 studies; n=1768; risk difference -0.05, 95% CI -0.10 to -0.00, P=0.05). CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Our analysis indicates conclusively that the current approach to exercise-based CR has no effect on all-cause mortality or cardiovascular mortality, when compared with a no-exercise control. There may be a small reduction in hospital admissions following exercise-based CR that is unlikely to be clinically important. PROSPERO REGISTRATION NUMBER: CRD42017073616.

Early initiation of post-sternotomy cardiac rehabilitation exercise training (SCAR): study protocol for a randomised controlled trial and economic evaluation.

INTRODUCTION: Current guidelines recommend abstinence from supervised cardiac rehabilitation (CR) exercise training for 6 weeks post-sternotomy. This practice is not based on empirical evidence, thus imposing potentially unnecessary activity restrictions. Delayed participation in CR exercise training promotes muscle atrophy, reduces cardiovascular fitness and prolongs recovery. Limited data suggest no detrimental effect of beginning CR exercise training as early as 2 weeks post-surgery, but randomised controlled trials are yet to confirm this. The purpose of this trial is to compare CR exercise training commenced early (2 weeks post-surgery) with current usual care (6 weeks post-surgery) with a view to informing future CR guidelines for patients recovering from sternotomy. METHODS AND ANALYSIS: In this assessor-blind randomised controlled trial, 140 cardiac surgery patients, recovering from sternotomy, will be assigned to 8 weeks of twice-weekly supervised CR exercise training commencing at either 2 weeks (early CR) or 6 weeks (usual care CR) post-surgery. Usual care exercise training will adhere to current UK recommendations. Participants in the early CR group will undertake a highly individualised 2-3 week programme of functional mobility, strength and cardiovascular exercise before progressing to a usual care CR programme. Outcomes will be assessed at baseline (inpatient), pre-CR (2 or 6 weeks post-surgery), post-CR (10 or 14 weeks post-surgery) and 12 months. The primary outcome will be change in 6 min walk distance. Secondary outcomes will include measures of functional fitness, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: Recruitment commenced on July 2017 and will complete by December 2019. Results will be disseminated via national governing bodies, scientific meetings and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03223558; Pre-results.