Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol

cardiac rehabilitation, mental health, coronary artery disease, heart failure, randomised controlled trial, low and middle income country. ALL Metrics - Views Downloads How to cite this article Taylor RS, Chaudhry IB, Faraque M et al. Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.13957.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente Select a format first ▬ ✚ Study Protocol [version 1; peer review: 1 approved, 2 approved with reservations] Rod S Taylor https://orcid.org/0000-0002-3043-6011 1, Imran Bashir Chaudhry2-4, Mithila Faraque5, [...] Panniyammakal Jeemon6, Amy Blakemore3, Karina Lovell3, Nusrat Husain3, Tahir Saghir7, Saidur Rahman Mashreky https://orcid.org/0000-0001-7892-798X 8, Sivadasanpillai Harikrishnan6, Chaudhury Meshkat Ahmed9, Abraham Samuel Babu10, Alex McConnachie https://orcid.org/0000-0002-7262-7000 1, Emma McIntosh https://orcid.org/0000-0001-6340-3083 1, Rakhshi Memon11, Sally Singh12,13, Alastair Leyland1, Bhautesh Jani1, Walter Flores14, ACROSS Collaborative GroupRod S Taylor https://orcid.org/0000-0002-3043-6011 1, Imran Bashir Chaudhry2-4, [...] Mithila Faraque5, Panniyammakal Jeemon6, Amy Blakemore3, Karina Lovell3, Nusrat Husain3, Tahir Saghir7, Saidur Rahman Mashreky https://orcid.org/0000-0001-7892-798X 8, Sivadasanpillai Harikrishnan6, Chaudhury Meshkat Ahmed9, Abraham Samuel Babu10, Alex McConnachie https://orcid.org/0000-0002-7262-7000 1, Emma McIntosh https://orcid.org/0000-0001-6340-3083 1, Rakhshi Memon11, Sally Singh12,13, Alastair Leyland1, Bhautesh Jani1, Walter Flores14, ACROSS Collaborative Group PUBLISHED 06 May 2025 Author details Author details 1 School of Health and Wellbeing, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, Scotland, G12 8TA, UK 2 Pakistan Institute of Living and Learning, Karachi, Sindh, Pakistan 3 The University of Manchester, Division of Psychology and Mental Health, Manchester, England, UK 4 University of Karachi, Karachi, Sindh, Pakistan 5 Bangladesh University of Health Sciences, Dhaka, Dhaka Division, Bangladesh 6 Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India 7 National Institute of Cardiovascular Diseases, National Institute of Cardiovascular Diseases, Karachi, Sindh, Pakistan 8 Department of Public Health, North South University, Dhaka, Dhaka Division, Bangladesh 9 Bangabandhu Sheikh Mujib Medical University, Dhaka, Dhaka Division, Bangladesh 10 Department of Physiotherapy, Manipal College of Health Professions, Manipal, Karnataka, India 11 University College London, Faculty of Population Health Sciences, London, England, UK 12 Respiratory Sciences, University of Leicester, Leicester, England, UK 13 University Hospitals of Leicester NHS Trust, Leicester, England, UK 14 Accountability Research Center, American University Washington College of Law, Washington, District of Columbia, USA 2 Pakistan Institute of Living and Learning, Karachi, Sindh, Pakistan 3 The University of Manchester, Division of Psychology and Mental Health, Manchester, England, UK 4 University of Karachi, Karachi, Sindh, Pakistan 5 Bangladesh University of Health Sciences, Dhaka, Dhaka Division, Bangladesh 6 Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India 7 National Institute of Cardiovascular Diseases, National Institute of Cardiovascular Diseases, Karachi, Sindh, Pakistan 8 Department of Public Health, North South University, Dhaka, Dhaka Division, Bangladesh 9 Bangabandhu Sheikh Mujib Medical University, Dhaka, Dhaka Division, Bangladesh 10 Department of Physiotherapy, Manipal College of Health Professions, Manipal, Karnataka, India 11 University College London, Faculty of Population Health Sciences, London, England, UK 12 Respiratory Sciences, University of Leicester, Leicester, England, UK 13 University Hospitals of Leicester NHS Trust, Leicester, England, UK 14 Accountability Research Center, American University Washington College of Law, Washington, District of Columbia, USA Rod S Taylor Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Imran Bashir Chaudhry Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Writing – Review & Editing Mithila Faraque Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Panniyammakal Jeemon Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Amy Blakemore Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Karina Lovell Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Nusrat Husain Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Tahir Saghir Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Saidur Rahman Mashreky Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Sivadasanpillai Harikrishnan Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Chaudhury Meshkat Ahmed Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Abraham Samuel Babu Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Alex McConnachie Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Emma McIntosh Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Rakhshi Memon Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Sally Singh Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Alastair Leyland Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Bhautesh Jani Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Walter Flores Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS The evidence and infrastructure needed to access and deliver cardiac rehabilitation (CR) services are absent or lacking in low and middle-income countries (LMICs), resulting in a substantial loss of potential health and socio-economic benefits. Home-based programmes provide an affordable model of delivery that can leverage a scalable increase in CR access in LMICs. ACROSS (Affordable Cardiac Rehabilitation: An Outreach Inter-disciplinary Strategic Study) seeks to co-develop (with patients, caregivers, clinicians, and service commissioners) a culturally and contextually applicable and affordable home-based programme for people with the multimorbidity of coronary heart disease and/or heart failure with co-existing depression and/or anxiety and evaluate the acceptability, clinical effectiveness, and cost-effectiveness of its implementation in Bangladesh, India, and Pakistan and to determine its scalability and sustainability. Four linked work packages (WPs). WP1 (cultural adaptation/refinement of home-based rehabilitation): examine rehabilitation implementation barriers/enablers from multiple stakeholder perspectives and co-develop a feasible and acceptable culturally & contextually adapted home-based programme, extended to take account of co-existing depression and/or anxiety; WP2 (external pilot): assess feasibility/acceptability of the co-developed rehabilitation intervention and study design and processes necessary for a full-scale trial; WP3: (multicentre/multi-country hybrid effectiveness and implementation randomised trial) determine the clinical and cost-effectiveness of a culturally adapted home-based rehabilitation intervention for people with coronary heart disease and/or heart failure and depression and/or anxiety; WP4 (capacity building): build research and rehabilitation delivery capacity. The ACROSS programme overarching goal is to develop a clinically and cost-effective CR model in low-resource settings for people in Bangladesh, India, and Pakistan with a multimorbidity of heart disease and depression and/or anxiety with the potential for substantial health and socio-economic benefits. The combination of heart disease alongside depression and anxiety is a common and profound unmet need for global health systems, especially in low and middle-income country settings. It affects people of working age, causing them ill-health and major financial loss. Cardiac rehabilitation is recommended as a core component of health services and includes exercise, education, and psychological support. It has been shown to reduce death rate and hospital admissions and improve the quality of life. However, cardiac rehabilitation services in low- and middle-income countries are virtually absent. Working with partners in Bangladesh, Pakistan, and India, the ‘Affordable Cardiac Rehabilitation: An Outreach Interdisciplinary Strategic Study’ (ACROSS) programme seeks to develop and evaluate the implementation of a clinically effective, affordable, and culturally and contextually appropriate model of home-based rehabilitation. ACROSS has four work packages: (1) Engagement events with those with lived-disease experience, their families, healthcare staff, and service providers to co-develop a culturally and contextually adapted home-based rehabilitation ('ACROSS') programme and training materials for providers; (2) A pilot study to understand if the ACROSS programme is acceptable and practical for patients and staff and whether a full-scale trial is doable; (3) A trial in 3000 patients with multiple long-term conditions that include heart disease and depression and anxiety across several sites in each country to tell us whether the programme improves health outcomes at 12-months and what its affordability is; and (4) Develop a sustainable model of workforce training and implementation to enable long-term programme delivery as well as build partner research capacity. People with lived-disease experience, clinicians, community leaders, and healthcare policymakers have been extensively involved in the planning of ACROSS. Our stakeholder meetings have consistently emphasised the importance of this research and supported the development of our research plans. Patients and stakeholders in each partner country will provide ongoing advice. cardiac rehabilitation, mental health, coronary artery disease, heart failure, randomised controlled trial, low and middle income country. Corresponding Author(s) Rod S Taylor ([email protected]) Grant information: This project is funded by the National Institute for Health Research (NIHR) under its Research and Innovation for Global Health Transformation (RIGHT) Programme (Grant reference - NIHR205540). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2025 Taylor RS et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Taylor RS, Chaudhry IB, Faraque M et al. Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.13957.1) First published: 06 May 2025, 5:41 (https://doi.org/10.3310/nihropenres.13957.1) Latest published: 06 May 2025, 5:41 (https://doi.org/10.3310/nihropenres.13957.1) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. In January 2024, the National Institute for Health and Care Research (NIHR) on Interventions for Global Health Transformation (RIGHT) programme approved the funding of ‘Affordable Cardiac Rehabilitation: An Outreach Inter-disciplinary Strategic Study (ACROSS)’. ACROSS is a global research programme that seeks to address the question of whether the implementation of an adapted home-based rehabilitation programme for people with multimorbidity that includes coronary heart disease and/or heart failure with a co-existence of depression and/or anxiety in Bangladesh, India and Pakistan, is clinically effective and cost-effective compared to usual care alone. This paper presents the rationale, study design and protocol for the ACROSS programme. Burden of heart disease & a mental health disorder. Cardiovascular disease (CVD) is the most prevalent non-communicable disease, the leading cause of global mortality, and a major contributor to premature disability and ill-health. CVD causes an estimated 17.8 million deaths worldwide, corresponding to 330 million years of life lost and another 35.6 million years lived with disability1,2. By 2030, it is estimated that >80% of CVD-related disability and death will occur in low and middle-income countries (LMICs) due to increasing risk factors (e.g., hypertension, smoking, diabetes, obesity)2,3. South Asia contributes to the highest proportion of CVD burden compared to other regions globally4. Socio-economic effects are particularly marked in LMICs, where CVD more frequently affects those of working age and is estimated to result in a decrease in gross domestic product of approximately 7%5. The burden of CVD is further exacerbated by the co-presence of one or more chronic diseases - so-called ‘multimorbidity’6. A common and burdensome multimorbidity is the combination of heart disease and depression or anxiety. Depression and anxiety act both as a risk factor for the development of heart disease and substantially increase the burden of heart disease7. Recent data show depression and anxiety to be highly prevalent in people with heart disease and may even be higher in South Asian populations (e.g., 70.4% depression in heart failure)8–10. The addition of a mental health problem is associated with a 40–50% increased risk of mortality and major cardiac events and a 30–50% reduction in health-related quality of life (HRQoL) in people with heart disease11,12. Need for cardiac rehabilitation (CR). Cardiac rehabilitation (CR) is a complex secondary prevention intervention that aims to improve HRQoL, optimise functioning and disease self-management, and minimise the risk of recurrent cardiac events in people with heart disease13. It comprises of core components that include exercise training, medication management, risk factor management, and psychological support delivered by multidisciplinary teams, including nurses, physiotherapists, dieticians, and physicians. There is strong evidence supporting the effectiveness and safety of CR programmes, especially for people with CHD and heart failure. The 2021 Cochrane review of 85 randomised trials of CR in CHD (23,430 patients) reported a 12% reduction (relative risk (RR): 0.88; 95% confidence interval (CI): 0.68 to 1.04) in cardiovascular mortality and a 42% reduction (relative risk: 0.58; 95% CI 0.43 to 0.77) in hospital admissions compared to usual care14. The 2024 Cochrane review of 60 randomised trials of CR in heart failure (8,728 patients) shows a 31% reduction (RR 0.69; 95% CI: 0.56 to 0.86) in hospital admissions15. Both Cochrane reviews show CR participation is associated with substantial improvements in exercise/functional capacity, patient HRQoL, and mental well-being14,15. For those who develop a mental health diagnosis before or following their cardiac event, meta-analyses have shown significant and consistent improvements in their levels of depression and anxiety following CR participation16. Despite its clinical and cost-effectiveness and international guidelines recommending its use, CR remains globally underutilised17. This is particularly the case in LMICs, where there are typically few CR programmes due to a lack of public health funding and healthcare professional capacity18,19. An international survey published in 2019, reported that some 50% of countries currently have CR programmes, with the lowest availability in LMICs19. Similar findings were also observed in the Southeast Asian region20. Furthermore, most evidence supporting CR has come from high-income countries14,15. The potential of home-based CR delivery. Given constraints in their healthcare infrastructure, LMICs require affordable, scalable, and context-appropriate CR approaches21. These include home and community-based programmes supported by accessible digital technologies (e.g., internet and mobile phones) and training for healthcare staff to ensure quality of CR delivery. Home-based programmes can also reduce barriers to CR access and uptake, reducing the need for travel to hospital centres and flexibility to allow rehabilitation to fit around employment commitments17. There is strong evidence that home-based programmes delivering the core components of rehabilitation and supported by healthcare staff can improve patient outcomes to those seen in more traditional centre/hospital-based programmes22. For example, the REACH-HF (Rehabilitation EnAblement in Chronic Heart Failure) trial in the UK showed that home-based rehabilitation significantly improved HRQoL and was cost-effective23,24. The adjunct use of mobile technology (e.g., app-based delivery of education material/wearables such as accelerometers to track behaviour changes/web-based consultations) to a home-based programme provides a key opportunity to further enhance rehabilitation access and cost-effectiveness25. The COVID-19 pandemic resulted in a sea change in CR delivery26. Since then, CR has pivoted to home-based models and mobile technology (phone and web consultations replacing home visits plus provision of online facilitator training for healthcare staff)26,27. An interdisciplinary programme of implementation research is now needed to test whether a culturally and contextually appropriate affordable home-based delivery model of rehabilitation can be developed (alongside the necessary increases in healthcare staff delivery capacity) to be sufficiently scalable and sustainable to meet the vast current unmet secondary preventive burden of LMICs. A cost-effective CR model in low resource settings for people with multimorbidity that includes the high unmet need of heart disease, and a mental health condition has the potential to accrue substantial health and socio-economic benefits. The wider implementation of such an alternative affordable rehabilitation model also offers an important strategic opportunity to overcome suboptimal rehabilitation access and uptake experienced in high-income settings. The overarching aim of the ACROSS programme is the evaluation and implementation of a sustainable and scalable culturally and contextually adapted and affordable model of home-based rehabilitation for people with the multimorbidity that includes heart disease and a mental health disorder. Specific research objectives: 1. To co-design with key stakeholders a culturally and contextually adapted affordable home-based rehabilitation (‘ACROSS’) programme with low intensity inventions for depression and anxiety (Work Package 1 (WP1)). 2. To co-design ACROSS delivery training for health professionals including a train-the-trainer programme to enable the cascade of training (WP1). 3. To assess the feasibility and acceptability of implementing the ACROSS programme and trial design and examine the parameters and processes of a full-scale trial, including recruitment, randomisation, and retention (WP2). 4. To determine the clinical effectiveness (hierarchical primary outcome of mortality, hospital admission, and health-related quality of life) of the ACROSS programme (WP3). 5. To determine cost-effectiveness of the ACROSS programme in terms of an incremental cost per quality adjusted life year (WP3). Cross-cutting objectives: 6. To build research and clinical delivery capacity and capability and support south-south partnership and learning to underpin the scalable and sustainable country-wide provision of rehabilitation services (WP4). 7. To embed community and stakeholder engagement to inform the route to impact of the project outputs and findings (WPs1–4). Through our PhDs (see details in WP4 ‘Training & Capacity Building’ section below), to embed specific methodological research questions into the ACROSS programme. e.g., adapting complex intervention/co-design & co-development of interventions in the LMIC settings. Figure 1 provides a graphical summary of the timing and sequencing of the ACROSS WPs. All research will be performed in accordance with the principles stated in the Declaration of Helsinki. Prior to starting the programme of research (Q2/3 2025), ethical approval will be obtained for all individual protocols from the local institutional review board (IRB) or other appropriate ethics committee to confirm the study meets national and international guidelines for research on humans. Written participant informed consent for all studies will be obtained. From the outset of the ACROSS programme, we have embedded Community Engagement and Involvement (CEI)/Patient and Public Involvement and Engagement (PPIE) groups in each of our three LMIC countries. Our research plans (research questions/design and conduct of the study/outcomes measures/recuitment strategy) have been developed alongside patients and the public in our partner countries. Our communications manager will coordinate a project dissemination plan with our partner PPIE/CEI stakeholder and patient groups. All materials will be available in local languages and given potential challenges of patient/family literacy, we will seek to ensure materials are appropriately visual and to improve accessibility. Adapting and implementing existing evidence-based interventions to new contexts can introduce new services into new environments that are cost-effectively and timely, with reasonable prospects of successful outcomes28. A goal of adaptation is to maintain the effectiveness of the intervention by preserving core features that account for success while delivering an intervention that is responsive to the new cultural and contextual setting. WP1 aims to co-design and co-adapt a feasible, culturally acceptable and contextually adapted, affordable home-based rehabilitation (‘ACROSS’) programme (based on Heart Manual29,30 and REACH-HF23,24) developed and proven in the UK and tested in principle in a single centre trial in Bangladesh31. It will now be adapted for people with CHD or heart failure in Bangladesh, India, and Pakistan and extended to take account of multimorbidity, including depression and anxiety. We will incorporate and co-adapt low-intensity cognitive behaviour therapy interventions for depression and anxiety (including behavioural activation/cognitive restructuring/problem solving) into the Heart Manual and REACH-HF interventions. In addition, we will develop a facilitator training programme for healthcare practitioners and an associated train-the-trainer programme, to enable the upscaling of delivery capacity.

Examine the population, patient, and provider contexts in which the home-based rehabilitation would be delivered in our three partner countries. Co-design and co-adapt a feasible, culturally acceptable and contextually adapted home-based rehabilitation (‘ACROSS’) programme developed for people with multimorbidity that includes coronary heart disease and heart failure and depression or anxiety. Co-design an interactive facilitator training package that can be delivered remotely to ensure scalability and sustainability of the ACROSS programme delivery. Co-produce a train-the-trainer facilitator and supervision package for ACROSS. To achieve our objectives, we will conduct two interrelated studies: 1. Study 1A - Patient and Provider Contexts: This qualitative study will explore implementation barriers and enablers through semi-structured interviews with national health informants and focus groups with health professionals and patients. The aim is to understand the local healthcare contexts and prepare for a broader trial. The Consolidated Framework for Implementation Research (CFIR)32 will guide data collection, focusing on factors like the perceived advantages of the intervention, leadership engagement, and existing care pathways. 2. Study 1B - Intervention Co-Design: This study will use Normalisation Process Theory33 to co-design the ACROSS rehabilitation programme. Collaborating with patients, healthcare workers, and professionals, the team will adapt existing interventions and create new training resources. Consensus processes will ensure the programme aligns with the cultural and contextual needs of the target population. WP2 aims to determine the feasibility/acceptability of the ACROSS intervention (co-designed in WP1) and study design and to gather information to examine the parameters and processes of a full-scale trial (WP3), including recruitment, randomisation, and retention.

Assess participant recruitment and retention. Assess the ACROSS programme feasibility and acceptability, exploring barriers and facilitators to uptake and engagement from both participant and healthcare provider perspectives. Assess the fidelity and reach of the ACROSS programme and, if necessary, further refine the intervention. Assess the feasibility and acceptability of data collection tools and obtain estimates of key cost drivers. Assess whether progression criteria are met, and a full randomised trial (WP3) is warranted. Study Design: A randomised external pilot study with embedded process and economic evaluations. The overarching aim of the external pilot is to implement the co-adapted ACROSS programme developed in WP1 across two sites in each of Bangladesh, India, and Pakistan and to assess the feasibility of a full randomised trial (WP3). Target population & Setting: see WP3. Sample Size and Randomisation: To address the objectives of this pilot trial, 100 patients34 from two centres in each of the three partner countries will be recruited over 5 months and randomised as outlined in WP3. Intervention: ACROSS programme (see WP1), alongside usual care. Control: No rehabilitation; usual care alone. Outcomes & Progression Criteria: Key outcomes will focus on whether progression criteria are met to proceed to a definitive trial. Patient data will be collected at baseline (pre-randomisation) and 4 months post-randomisation, and economic evaluations will measure key cost drivers like healthcare utilisation and social care. Process Evaluation: This will assess the feasibility and acceptability of the intervention and study design, following MRC guidelines35. Data will include fidelity checks of intervention delivery, interviews with patients and staff, and analysis of barriers to engagement36. Data Analyses: The study will be reported according to the CONSORT extension for pilot and feasibility studies33. Quantitative data will be analysed descriptively, while qualitative data will undergo thematic analysis. Themes related to intervention delivery will be interpreted through Normalisation Process Theory (NPT)37. This multicentre, multi-country study evaluates the clinical and cost-effectiveness of the ACROSS rehabilitation programme for individuals with multimorbidity, including heart disease and mental health disorders, across three South Asian countries. It also investigates factors influencing wider implementation in low- and middle-income countries (LMICs).

1. Assess the clinical effectiveness of ACROSS alongside usual care compared to standard treatment alone. 2. Evaluate cost-effectiveness in the three participating countries. 3. Conduct an implementation analysis to understand scalability. Study Design: Type 1 hybrid effectiveness-implementation randomised controlled trial (RCT) with an embedded economic evaluation37,38. Participants will be individually randomised (1:1) to receive ACROSS plus usual care or usual care alone. The study will take place in publicly and privately funded healthcare settings. Participants & inclusion criteria: Adults (≥18 years) hospitalised for acute myocardial infarction, unstable angina, coronary intervention, or heart failure (ejection fraction <45%) with co-existing mild-to-severe depression (Patient Health Questionnaire-9 [PHQ-9] score ≥5) and/or anxiety (General Anxiety Disorder-7 [GAD-7] ≥5) are eligible39,40. Exclusions include contraindications to exercise, advanced dementia, or conditions preventing safe home-based rehabilitation. Intervention & Control: It is anticipated that intervention CHD patients will receive an adapted ACROSS version of the Heart Manual intervention29–31, and heart failure patients will receive an adapted ACROSS version of the REACH-HF intervention23,24. The final details of the ACROSS program intervention will be confirmed following an extensive co-design process (in WP1) and feasibility testing (in WP2). All participants, including controls, will receive usual medical management by national guidelines. Primary outcome: A composite of mortality, hospital days, and HRQoL (HeartQoL questionnaire) at 12 months, and analysed using the Win Ratio method41,42. To calculate the Win Ratio, each intervention group participant is compared with each control group participant. If the intervention group participant has a “better” outcome, it is called a “win”, whereas if the control group participant does better, it is a “loss.” Otherwise, it is a “tie”. Secondary & implementation outcomes: Includes individual elements of the primary outcome, depression, anxiety, exercise capacity, physical activity, risk factors, and safety events. Implementation outcomes assess reach, adherence, and acceptability. Sample size: the study employs a simulation-based approach for sample size calculations in Win Ratio analyses, assuming a 12-month mortality rate of 13% and hospitalisation rate of 0.2 per person per year. The intervention is expected to reduce all-cause mortality (hazard ratio 0.85) and hospitalisations (incidence rate ratio 0.75)14,15. Simulations indicate that a two-level Win Ratio analysis provides comparable power to a non-parametric analysis of days alive out of hospital (DAOH). However, achieving sufficient power requires incorporating health-related quality of life improvements as third level (see Figure 2). A sample size of 1000 patients per country ensures >89% power, accounting for a 20% loss to follow-up. Recruitment: will span 12 months, with a 4-month internal pilot to check recruitment feasibility, aiming for 336 participants per country. Data collection will take place at baseline, and 4- and 12 months post-randomisation. Data analysis: The Statistical Working Group will develop a common Statistical Analysis Plan, which will be approved before unblinded analysis. Primary analyses will estimate the Win Ratio considering mortality, hospital days, and HRQoL. Additional regression models and subgroup analyses will be conducted. Missing data will be handled through multiple imputations in sensitivity analyses. Economic evaluation: will assess cost-effectiveness in low-resource settings, incorporating direct and indirect costs using EQ-5D-5L data. Sensitivity analyses will explore cost variations. Within-trial results will be reported and presented as an incremental cost-utility ratio with the joint distribution of cost/utility pairs being represented on the cost-effectiveness plane and with a cost-effectiveness acceptability curve43 employing cost-effectiveness thresholds based on country per capita gross domestic product (GDP) values and benchmark values (e.g., World Health Organisation [WHO]). Analyses will explore cost effectiveness in subgroups as defined earlier. Recent guidance on conducting economic evaluations in LMIC settings reported by the National Institute of Care Excellence (NICE) International44 will be adhered to as well as reporting standards such as the Consolidated Health Economic Evaluation Reporting Standards statement45. Qualitative analyses: will assess intervention fidelity and contextual factors through interviews and thematic coding. The primary goal of WP4 is to enhance research capacity in our LMICs and foster knowledge exchange between the UK and LMICs. The ACROSS project partners with three organisations: the International Council of Cardiovascular Prevention and Rehabilitation (ICCPR), the Heart Manual Office UK, and the Global Health Network (TGHN). These organisations provide expertise in online rehabilitation training and global health research support.

Supporting PhD studentships. Building research and rehabilitation delivery capacity in partner countries. Enhancing understanding of complex intervention trials in LMICs. Developing a virtual training hub hosted on the ACROSS website. Key challenges identified by LMIC partners involve the need for training in large-scale research, particularly RCTs, and scaling up rehabilitation services. The project aims to develop equitable partnerships, enabling knowledge transfer between the UK and LMICs and facilitating south-to-south learning. The project will follow the WHO’s ESSENCE principles to strengthen research capacity46. WP4's training plan includes both face-to-face and virtual activities. In-person training activities will involve researchers from LMIC countries visiting the UK for methodological training and UK trainers visiting LMIC countries to run rehabilitation training and ‘train the trainer’ courses. To maximise accessibility and minimise the carbon footprint of ACROSS, these activities may be adapted to virtual formats. A core element of WP4 is to establish a virtual training hub, providing access to online materials and courses in global health research. The capacity building efforts already underway include several virtual events including workshops on research theory, mental health forums, and seminars on adapting interventions. ACROSS will promote accreditation for training to enhance the professional development of participants and facilitate future research collaborations. Research and methodological training will focus on building capacity for RCTs and intervention development, which is essential for the project’s other work packages. This will include training approximately 45 researchers from partner countries in areas including patient-public involvement (PPI), qualitative research, trial methods, health economics, and data analysis. The Glasgow Clinical Trial Unit will coordinate the training and will be supported by materials from global health research networks, including the MRC Research Trials Methodology Partnership. Rehabilitation service capacity will be built through partnerships with ICCPR and the Heart Manual Office, which will deliver training on home-based rehabilitation programmes. This will include an online ‘train the trainer’ programme, enabling sustainable rehabilitation practices. A key part of WP4 is the PhD training programme, supporting 8 studentships across the three LMIC countries. These students will work on projects related to the ACROSS programme, global trial methodology, mental health, and rehabilitation. The PhD students will be supported by local LMIC and UK supervisor teams, with access to training materials from the ACROSS hub and opportunities to attend webinars and workshops. To support postdoctoral research, WP4 plans to include activities such as grant writing workshops to help early career researchers submit high-quality grant applications. Community engagement involvement/patient public involvement engagement (CEI/PPIE) has been embedded into the ACROSS research programme development. Going forward we will seek the following key areas of CEI/PPIE direction: (i) participation in co-development/co-adaptation of our home-based rehabilitation intervention/training materials (WP1); (ii) ongoing advice on all aspects of our research including development of all participant facing documentation (e.g. participant information leaflets), participant recruitment strategies, patient interview guide, and interpretation of qualitative data, writing lay summaries etc; (iii) direction on dissemination/targeting of impact, and (iv) increasing community awareness about comorbidity and decreasing stigma attached to mental health conditions. Our partner countries have each established local CEI/PPIE that includes: (i) ‘stakeholder group’: regional/national healthcare policymakers, key clinical opinion leaders, representatives of key healthcare professional groups (nursing/physiotherapy/ cardiology/psychology/psychiatry), community/regional leaders (including religious scholars), and senior healthcare providers/managers and (ii) ‘patient involvement group’: people with lived experience of heart disease and depression/anxiety and their families, facilitated by one of our local project team with fluency in local language(s). We expect our CEI/PPIE groups will meet on 3-4 occasions/year, with meetings facilitated by an experienced CEI/PPIE researcher from each country team. To identify any gaps in skills/training CEI/PPIE contributors may require, we will develop/deliver an induction programme (as part of WP4) to clarify roles/expectations and build trust and rapport with the group members. Together with our CEI/PPIE group we have developed the ACROSS programme theory of change (see Figure 3). The overarching aim of the ACROSS programme to develop a clinically and cost-effective CR model in low resource settings for people with a multimorbidity of heart disease and depression and/or anxiety, offers huge potential health and socio-economic benefits in Bangladesh, India, and Pakistan. The wider implementation of such an affordable intervention model also offers an important strategic opportunity to overcome the problem of suboptimal rehabilitation access experienced in other low- and middle-income countries. We will seek to disseminate our findings widely, using a variety of approaches, supported by our stakeholder and patient advisory groups. ACROSS Programme collaboration Rezaul Karim, Ibrahim Cardiac Hospital & Research Institute, 122 Kazi Nazrul Islam Ave, Dhaka 1000, Bangladesh. Email: [email protected] ORCID: 0000-0002-8439-2499 Zia Ul Haq, Khayber Medical University, Peshawar, Pakistan. Email: [email protected] ORCID: 0000-0001-5124-2171 Nabila Soomro, Sindh Institute of Physical Medicine and Rehabilitation, Karachi. Email: [email protected] ORICD: 0000-0001-5022-8829 Zainab F. Zadeh, Pakistan Institute of Learning and Living, Karachi, PK, Email: [email protected] ORCID: 0000-0002-3043-6011 Sehrish Tofique Ameer B. Khoso, Pakistan Institute of Learning and Living, Karachi, PK, Email: [email protected] ORCID: 0000-0003-2026-7952 Jamal Uddin Sehrish Tofique, Pakistan Institute of Learning and Living, Karachi, PK, Email: [email protected] ORCID: 0000-0002-8027-054X Farhat Jafri, Karachi Medical and Dental College, Karachi. Email: [email protected] ORCID: 0000-0003-2466-7283 Riffat Sultana, Karachi Institute of Heart Disease, Karachi. Email: [email protected] Huma Naeem, Sheikh Mohamed Bin Zayed Al Nahyan Institute of Cardiology- Baluchistan, Quetta. Email: [email protected] ORCID: 0000-0003-1998-2772 Palash Chandra Banik, Bangladesh University of Health Sciences (BUHS), 125/1, Darus Salam, Mirpur-1, Dhaka-1216, Bangladesh, Email: [email protected] ORCID: 0000-0003-2395-9049 Sohel Choudhury, Department of Epidemiology & Research, National Heart Foundation Hospital & Research Institute, Plot-7/2, Section-2, Mirpur Dhaka, Dhaka, 1216 Bangladesh, Email: [email protected] ORCID: 0000-0002-7498-4634 Louise Taylor, The Heart Manual Department, NHS Lothian, Astley Ainslie Hospital, 133 Grange Loan, Edinburgh, UK. Email: [email protected] ORCID: 0009-0003-4207-8105 Jamal Uddin, MRC/CSO Social and Public Health Sciences Unit & Robertson Centre for Biostatistics, School of Health and Wellbeing, University of Glasgow, Clarice Pears Building, 90 Byres Road, Glasgow G12 8TB, UK, Email: [email protected] ORCID: 0000-0001-5964-6381 Claire Copping, MRC/CSO Social and Public Health Sciences Unit School of Health and Wellbeing, University of Glasgow, Clarice Pears Building, 90 Byres Road, Glasgow G12 8TB, UK, Email: [email protected] ORCID: N/a David Innes, MRC/CSO Social and Public Health Sciences Unit, School of Health and Wellbeing, University of Glasgow, Clarice Pears Building, 90 Byres Road, Glasgow G12 8TB, UK, Email: [email protected] ORCID: 0009-0002-0954-3792 Sunil Roy TN, Consultant Cardiologist, Aster Medcity, Cochin, Kerala, India, Email: [email protected] ORCID: 0000-0003-4123-3313 Stigi Joseph, Consultant Cardiologist, Little Flower Hospital, Angamali, Kerala, India, Email: [email protected] Vijayan Ganesan, Consultant Cardiologist, Aster MIMS Hospital, Kannur, Kerala, India, Email: [email protected] Mukund A Prabhu, Associate Professor, Department of Cardiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India, Email: [email protected] Jyothi Vijay MS, Assistant Professor, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum, Thiruvananthapuram - 695 011, Kerala, India, Email: [email protected] Ramya Das NK, Assistant Professor, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum, Thiruvananthapuram - 695 011, Kerala, India, Email: [email protected] We thank our Community Engagement and Involvement (CEI)/Patient and Public Involvement and Engagement (PPIE) groups for their contributions to date. 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Reference Source Author details Author details 1 School of Health and Wellbeing, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, Scotland, G12 8TA, UK 2 Pakistan Institute of Living and Learning, Karachi, Sindh, Pakistan 3 The University of Manchester, Division of Psychology and Mental Health, Manchester, England, UK 4 University of Karachi, Karachi, Sindh, Pakistan 5 Bangladesh University of Health Sciences, Dhaka, Dhaka Division, Bangladesh 6 Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India 7 National Institute of Cardiovascular Diseases, National Institute of Cardiovascular Diseases, Karachi, Sindh, Pakistan 8 Department of Public Health, North South University, Dhaka, Dhaka Division, Bangladesh 9 Bangabandhu Sheikh Mujib Medical University, Dhaka, Dhaka Division, Bangladesh 10 Department of Physiotherapy, Manipal College of Health Professions, Manipal, Karnataka, India 11 University College London, Faculty of Population Health Sciences, London, England, UK 12 Respiratory Sciences, University of Leicester, Leicester, England, UK 13 University Hospitals of Leicester NHS Trust, Leicester, England, UK 14 Accountability Research Center, American University Washington College of Law, Washington, District of Columbia, USA 2 Pakistan Institute of Living and Learning, Karachi, Sindh, Pakistan 3 The University of Manchester, Division of Psychology and Mental Health, Manchester, England, UK 4 University of Karachi, Karachi, Sindh, Pakistan 5 Bangladesh University of Health Sciences, Dhaka, Dhaka Division, Bangladesh 6 Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India 7 National Institute of Cardiovascular Diseases, National Institute of Cardiovascular Diseases, Karachi, Sindh, Pakistan 8 Department of Public Health, North South University, Dhaka, Dhaka Division, Bangladesh 9 Bangabandhu Sheikh Mujib Medical University, Dhaka, Dhaka Division, Bangladesh 10 Department of Physiotherapy, Manipal College of Health Professions, Manipal, Karnataka, India 11 University College London, Faculty of Population Health Sciences, London, England, UK 12 Respiratory Sciences, University of Leicester, Leicester, England, UK 13 University Hospitals of Leicester NHS Trust, Leicester, England, UK 14 Accountability Research Center, American University Washington College of Law, Washington, District of Columbia, USA Rod S Taylor Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Imran Bashir Chaudhry Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Project Administration, Writing – Review & Editing Mithila Faraque Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Panniyammakal Jeemon Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Amy Blakemore Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Karina Lovell Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing Nusrat Husain Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Tahir Saghir Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Saidur Rahman Mashreky Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Sivadasanpillai Harikrishnan Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Chaudhury Meshkat Ahmed Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Abraham Samuel Babu Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Alex McConnachie Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Emma McIntosh Roles: Funding Acquisition, Methodology, Writing – Review & Editing Roles: Funding Acquisition, Methodology, Writing – Review & Editing Rakhshi Memon Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Sally Singh Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Alastair Leyland Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Roles: Conceptualization, Funding Acquisition, Writing – Review & Editing Bhautesh Jani Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Walter Flores Roles: Funding Acquisition, Writing – Review & Editing Roles: Funding Acquisition, Writing – Review & Editing Competing interests RST is currently co-Chair of the NIHR Research on Interventions for Global Health Transformation (RIGHT) Funding Committee. NH has been a past Trustee of the Pakistan Institute of Living and Learning (PILL), Abaseen Foundation UK, Lancashire Mind UK and Manchester Global Foundation (MGF). He is a member of the Academic Faculty at the Royal College of Psychiatrists (RCPsych), London. He is a National Institute for Health and Care Research (NIHR) Senior Investigator. He has attended educational events organised by various pharmaceutical industries. RM is CEO of Manchester Global Foundation (UK Charity Number 116841) and trustee of UK Association for Medical Aid to Pakistan (UK Charity Number 1123929). IBC has given lectures or advice to Eli Lilly, Bristol Myers Squibb, Lundbeck, Astra Zeneca, and Janssen pharmaceuticals for which he or his employing institution have been reimbursed, outside the submitted work. Prof Chaudhry was previously a trustee of the Pakistan Institute of Living and Learning (PILL). Other authors declare no conflicts of interest. Grant information This project is funded by the National Institute for Health Research (NIHR) under its Research and Innovation for Global Health Transformation (RIGHT) Programme (Grant reference - NIHR205540). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright © 2025 Taylor RS et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. metrics VIEWS $counts.viewCount downloads Citations CITE how to cite this article Taylor RS, Chaudhry IB, Faraque M et al. Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.13957.1) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. track receive updates on this article Track an article to receive email alerts on any updates to this article. Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 06 May 2025 Views 0 How to cite this report: Merriman NA. Reviewer Report For: Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.15169.r35712) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35712 https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35712 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 16 Jun 2025 Approved with Reservations VIEWS 0 The authors present a well written protocol for a programme of work assessing home-based cardiac rehabilitation in LMICs. I would recommend some minor amendments to improve clarity:

How much of a role ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close I would recommend some minor amendments to improve clarity:

How much of a role ... Continue reading The authors present a well written protocol for a programme of work assessing home-based cardiac rehabilitation in LMICs. I would recommend some minor amendments to improve clarity:

How much of a role will digital technology play in the proposed intervention? Who will be responsible for developing, implementing, and maintaining the digital technologies utilised? Will access to internet in the home be an inclusion criterion? It would be useful to discuss this as both a strength and a limitation. The CFIR was updated in 2022, so I suggest using the updated version Damschroder LJ et. al (2022)- Ref 1. For WP2 and WP3, usual care can differ massively from one site to another. Do the authors intend to collect detailed information on healthcare utilisation across the control and intervention groups to account for any differences? More information on the sample size estimation for the pilot trial is needed. What is the timeframe for recruitment to the pilot trial (i.e., how long post-diagnosis) and where will they be recruited from? Who will be responsible for recruiting participants to the pilot trial? Will the acceptability of randomisation also be assessed? Who will conduct the randomisation and how will it be done? What are the progression criteria for the full RCT? What if these criteria aren’t achieved? The CONSORT statement was updated in 2025, I suggest using the updated version https://www.equator-network.org/reporting-guidelines/consort/ Will control participants be offered the opportunity to avail of the intervention once the trial is completed? Is a further process evaluation planned for the full RCT in WP3? If so, will it follow the same framework as the process evaluation in WP2? More detail is needed here. General comments I wish the authors the best of luck with this very worthwhile project. I would recommend some minor amendments to improve clarity:

How much of a role will digital technology play in the proposed intervention? Who will be responsible for developing, implementing, and maintaining the digital technologies utilised? Will access to internet in the home be an inclusion criterion? It would be useful to discuss this as both a strength and a limitation. The CFIR was updated in 2022, so I suggest using the updated version Damschroder LJ et. al (2022)- Ref 1. For WP2 and WP3, usual care can differ massively from one site to another. Do the authors intend to collect detailed information on healthcare utilisation across the control and intervention groups to account for any differences? More information on the sample size estimation for the pilot trial is needed. What is the timeframe for recruitment to the pilot trial (i.e., how long post-diagnosis) and where will they be recruited from? Who will be responsible for recruiting participants to the pilot trial? Will the acceptability of randomisation also be assessed? Who will conduct the randomisation and how will it be done? What are the progression criteria for the full RCT? What if these criteria aren’t achieved? The CONSORT statement was updated in 2025, I suggest using the updated version https://www.equator-network.org/reporting-guidelines/consort/ Will control participants be offered the opportunity to avail of the intervention once the trial is completed? Is a further process evaluation planned for the full RCT in WP3? If so, will it follow the same framework as the process evaluation in WP2? More detail is needed here. General comments I wish the authors the best of luck with this very worthwhile project. - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Yes - Are sufficient details of the methods provided to allow replication by others? Partly - Are the datasets clearly presented in a useable and accessible format? Not applicable

1. Damschroder L, Reardon C, Widerquist M, Lowery J: The updated Consolidated Framework for Implementation Research based on user feedback. Implementation Science. 2022; 17 (1). Publisher Full TextCompeting Interests: No competing interests were disclosed. Reviewer Expertise: I have expertise in the area of complex intervention development CITE HOW TO CITE THIS REPORT Merriman NA. Reviewer Report For: Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.15169.r35712) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35712 https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35712 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Views 0 How to cite this report: Arjunan P. Reviewer Report For: Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.15169.r35708) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35708 https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35708 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 09 Jun 2025 Porkodi Arjunan, King Faisal University, Al Hofuf, Saudi Arabia Approved with Reservations VIEWS 0 Your Report Please provide a full report, expanding on your answers to the questions above. In particular, if you answered “no” or “partly” to any of the questions, please give constructive and specific details as to how ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close Please provide a full report, expanding on your answers to the questions above. In particular, if you answered “no” or “partly” to any of the questions, please give constructive and specific details as to how ... Continue reading Your Report Please provide a full report, expanding on your answers to the questions above. In particular, if you answered “no” or “partly” to any of the questions, please give constructive and specific details as to how the authors can address any criticisms. Please indicate clearly which points must be addressed to make the article scientifically sound. (50 words min.)

The researchers have given clear information in the background of the study; however need to give more information regarding the list of multimorbidity with heart failure/ coronary heart disease. What is the reason for selecting Depression and anxiety as one of the most common multimorbidities with heart failure or coronary heart disease?. Also, the researchers have mentioned in the title as home-based cardiac rehabilitation. Need more information about home-based CR is this protocol implemented after discharge or before discharge from the hospital? Justify the reason for adding home-based CR. Please write research questions

Please explain in detail the setting for each work package and also the role of interdisciplinary team members in the home-based CR?. Population: Please clearly specify the population. In phase 3, it is mentioned that a patient with heart failure or coronary heart disease. Clearly specify in the inclusion criteria about the line of treatment, eg, Medical management or surgical management (the treatment protocol will differ for both lines of treatment). Moreover, the treatment decision will differ according to the primary physician, from admission until discharge. Explain the protocol implementation in various centres and countries. Specify the inclusion criteria regarding the cognitive status of the participants- Explain Protocol- Explain the validity of the protocol. Who has approved the protocol? Based on what guidelines this protocol developed Work package 1: Who will do the screening for depression and anxiety? Explain the process of recruitment, whether the participants will be recruited from the community or hospital. Outcome: Please state the time points the outcome assessment will be used for analysis Sample: Define the control group and the difference between treatment groups. Please provide a full report, expanding on your answers to the questions above. In particular, if you answered “no” or “partly” to any of the questions, please give constructive and specific details as to how the authors can address any criticisms. Please indicate clearly which points must be addressed to make the article scientifically sound. (50 words min.)

The researchers have given clear information in the background of the study; however need to give more information regarding the list of multimorbidity with heart failure/ coronary heart disease. What is the reason for selecting Depression and anxiety as one of the most common multimorbidities with heart failure or coronary heart disease?. Also, the researchers have mentioned in the title as home-based cardiac rehabilitation. Need more information about home-based CR is this protocol implemented after discharge or before discharge from the hospital? Justify the reason for adding home-based CR. Please write research questions

Please explain in detail the setting for each work package and also the role of interdisciplinary team members in the home-based CR?. Population: Please clearly specify the population. In phase 3, it is mentioned that a patient with heart failure or coronary heart disease. Clearly specify in the inclusion criteria about the line of treatment, eg, Medical management or surgical management (the treatment protocol will differ for both lines of treatment). Moreover, the treatment decision will differ according to the primary physician, from admission until discharge. Explain the protocol implementation in various centres and countries. Specify the inclusion criteria regarding the cognitive status of the participants- Explain Protocol- Explain the validity of the protocol. Who has approved the protocol? Based on what guidelines this protocol developed Work package 1: Who will do the screening for depression and anxiety? Explain the process of recruitment, whether the participants will be recruited from the community or hospital. Outcome: Please state the time points the outcome assessment will be used for analysis Sample: Define the control group and the difference between treatment groups. - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Partly - Are sufficient details of the methods provided to allow replication by others? Partly - Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: I have expertise in the area of heart failure and Cardiac rehabilitation CITE HOW TO CITE THIS REPORT Arjunan P. Reviewer Report For: Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.15169.r35708) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35708 https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35708 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. - Author Response 10 Sep 2025Rod Taylor, School of Health and Wellbeing, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, G12 8TA, UK10 Sep 2025Author ResponseWe thank the reviewer #2 for their positive feedback on our ACROSS research programme protocol publication. We provide a response to each of their specific queries below. Details & rationale ... Continue reading We thank the reviewer #2 for their positive feedback on our ACROSS research programme protocol publication. We provide a response to each of their specific queries below. Details & rationale of multimorbidity – as we present in the Introduction section of our paper, the ACROSS programme the rationale for targeting people with a combined diagnosis of heart disease (coronary artery disease and/or heart failure) plus a mental health disorder (anxiety and/or depression) is because of their particularly poor health outcomes (i.e. reduced survival, high risk of morbidity, and marked loss of health-related of quality of life). The co-diagnosis of heart disease and a mental health disorder is also a common one [1]. Timing of home-based CR – for hospitalised patients, they will receive home-based CR following discharge. Additionally, patients, who may not have been acutely hospitalised, but attending for hospital outpatient management visits will also be eligible for home-based CR. Further details of each work package - the dual purpose of this present protocol paper was to provide a detailed description of the rationale and research aims of the ACROSS programme together with a high-level summary of methods of each work package. We will separately develop and publish a (master – cross country ) detailed protocol for each work package (WP 1, 2 and 3). For WP2 and WP3, this will include details of the trial population inclusion and exclusion criteria, patient screening and recuitment procedure, intervention and control condition description (including the health professionals who will deliver the home-based CR programme) and outcome collection. Protocol approval – the detailed protocol and participant facing documents (e.g. participant information sheet, consent form) for each work package will be submitted for assessment and approval by R&D teams and ethics committees in each of the participating countries and their relevant institutions. Timepoints of outcome assessment – as outlined in our paper, outcomes will be assessed in WP3 trial participants at baseline (prior to randomisation) and 4 and 12-months post randomisation.

1. Farmer C, Fenu E, O'Flynn N, Guthrie B. Clinical assessment and management of multimorbidity: summary of NICE guidance. BMJ. 2016;354:i4843.We thank the reviewer #2 for their positive feedback on our ACROSS research programme protocol publication. We provide a response to each of their specific queries below.Competing Interests: None Close Details & rationale of multimorbidity – as we present in the Introduction section of our paper, the ACROSS programme the rationale for targeting people with a combined diagnosis of heart disease (coronary artery disease and/or heart failure) plus a mental health disorder (anxiety and/or depression) is because of their particularly poor health outcomes (i.e. reduced survival, high risk of morbidity, and marked loss of health-related of quality of life). The co-diagnosis of heart disease and a mental health disorder is also a common one [1]. Timing of home-based CR – for hospitalised patients, they will receive home-based CR following discharge. Additionally, patients, who may not have been acutely hospitalised, but attending for hospital outpatient management visits will also be eligible for home-based CR. Further details of each work package - the dual purpose of this present protocol paper was to provide a detailed description of the rationale and research aims of the ACROSS programme together with a high-level summary of methods of each work package. We will separately develop and publish a (master – cross country ) detailed protocol for each work package (WP 1, 2 and 3). For WP2 and WP3, this will include details of the trial population inclusion and exclusion criteria, patient screening and recuitment procedure, intervention and control condition description (including the health professionals who will deliver the home-based CR programme) and outcome collection. Protocol approval – the detailed protocol and participant facing documents (e.g. participant information sheet, consent form) for each work package will be submitted for assessment and approval by R&D teams and ethics committees in each of the participating countries and their relevant institutions. Timepoints of outcome assessment – as outlined in our paper, outcomes will be assessed in WP3 trial participants at baseline (prior to randomisation) and 4 and 12-months post randomisation.

1. Farmer C, Fenu E, O'Flynn N, Guthrie B. Clinical assessment and management of multimorbidity: summary of NICE guidance. BMJ. 2016;354:i4843. COMMENTS ON THIS REPORT - Author Response 10 Sep 2025Rod Taylor, School of Health and Wellbeing, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, G12 8TA, UK10 Sep 2025Author ResponseWe thank the reviewer #2 for their positive feedback on our ACROSS research programme protocol publication. We provide a response to each of their specific queries below. Details & rationale ... Continue reading We thank the reviewer #2 for their positive feedback on our ACROSS research programme protocol publication. We provide a response to each of their specific queries below. Details & rationale of multimorbidity – as we present in the Introduction section of our paper, the ACROSS programme the rationale for targeting people with a combined diagnosis of heart disease (coronary artery disease and/or heart failure) plus a mental health disorder (anxiety and/or depression) is because of their particularly poor health outcomes (i.e. reduced survival, high risk of morbidity, and marked loss of health-related of quality of life). The co-diagnosis of heart disease and a mental health disorder is also a common one [1]. Timing of home-based CR – for hospitalised patients, they will receive home-based CR following discharge. Additionally, patients, who may not have been acutely hospitalised, but attending for hospital outpatient management visits will also be eligible for home-based CR. Further details of each work package - the dual purpose of this present protocol paper was to provide a detailed description of the rationale and research aims of the ACROSS programme together with a high-level summary of methods of each work package. We will separately develop and publish a (master – cross country ) detailed protocol for each work package (WP 1, 2 and 3). For WP2 and WP3, this will include details of the trial population inclusion and exclusion criteria, patient screening and recuitment procedure, intervention and control condition description (including the health professionals who will deliver the home-based CR programme) and outcome collection. Protocol approval – the detailed protocol and participant facing documents (e.g. participant information sheet, consent form) for each work package will be submitted for assessment and approval by R&D teams and ethics committees in each of the participating countries and their relevant institutions. Timepoints of outcome assessment – as outlined in our paper, outcomes will be assessed in WP3 trial participants at baseline (prior to randomisation) and 4 and 12-months post randomisation.

1. Farmer C, Fenu E, O'Flynn N, Guthrie B. Clinical assessment and management of multimorbidity: summary of NICE guidance. BMJ. 2016;354:i4843.We thank the reviewer #2 for their positive feedback on our ACROSS research programme protocol publication. We provide a response to each of their specific queries below.Competing Interests: None Close Details & rationale of multimorbidity – as we present in the Introduction section of our paper, the ACROSS programme the rationale for targeting people with a combined diagnosis of heart disease (coronary artery disease and/or heart failure) plus a mental health disorder (anxiety and/or depression) is because of their particularly poor health outcomes (i.e. reduced survival, high risk of morbidity, and marked loss of health-related of quality of life). The co-diagnosis of heart disease and a mental health disorder is also a common one [1]. Timing of home-based CR – for hospitalised patients, they will receive home-based CR following discharge. Additionally, patients, who may not have been acutely hospitalised, but attending for hospital outpatient management visits will also be eligible for home-based CR. Further details of each work package - the dual purpose of this present protocol paper was to provide a detailed description of the rationale and research aims of the ACROSS programme together with a high-level summary of methods of each work package. We will separately develop and publish a (master – cross country ) detailed protocol for each work package (WP 1, 2 and 3). For WP2 and WP3, this will include details of the trial population inclusion and exclusion criteria, patient screening and recuitment procedure, intervention and control condition description (including the health professionals who will deliver the home-based CR programme) and outcome collection. Protocol approval – the detailed protocol and participant facing documents (e.g. participant information sheet, consent form) for each work package will be submitted for assessment and approval by R&D teams and ethics committees in each of the participating countries and their relevant institutions. Timepoints of outcome assessment – as outlined in our paper, outcomes will be assessed in WP3 trial participants at baseline (prior to randomisation) and 4 and 12-months post randomisation.

1. Farmer C, Fenu E, O'Flynn N, Guthrie B. Clinical assessment and management of multimorbidity: summary of NICE guidance. BMJ. 2016;354:i4843. Views 0 How to cite this report: Rovere MTL. Reviewer Report For: Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.15169.r35547) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35547 https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35547 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Reviewer Report 03 Jun 2025 Maria Teresa La Rovere, Istituti Clinici Scientifici Maugeri IRCCS, Montescano, Italy Approved VIEWS 0 Thank you for giving me the opportunity to revise this study protocol, which outlines a research programme on the implementation of cardiac rehabilitation in low- and middle-income countries (LMICs). The proposed study comprises four well-considered work packages: 1) ... Continue reading I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close The proposed study comprises four well-considered work packages: 1) ... Continue reading Thank you for giving me the opportunity to revise this study protocol, which outlines a research programme on the implementation of cardiac rehabilitation in low- and middle-income countries (LMICs). The proposed study comprises four well-considered work packages: 1) Stakeholder engagement events to co-develop a suitable home-based rehabilitation programme and training materials for providers; 2) An acceptability and feasibility pilot study; 3) A trial involving 3,000 patients with heart disease and comorbid anxiety and depression to evaluate improvement in outcomes over 12 months; 4) Development of a sustainable model for research and rehabilitation delivery. The study aims to address the significant disparity in cardiac rehabilitation provision between high-income countries and LMICs. It seeks to transfer the proven benefits of cardiac rehabilitation to LMICs, which are expected to experience a substantial increase in cardiovascular disease in the coming years. A key strength of the study is its focus on populations with the comorbid conditions of heart disease — anxiety and depression — which are highly prevalent in LMICs. The proposed cardiac rehabilitation approach is clinically This study is important, timely and relevant. My only observation is that the study does not address gender issues in relation to the development of the rehabilitation programme, the involvement of healthcare staff or the sample size of the effectiveness trial. Is the rationale for, and objectives of, the study clearly described? Yes The authors provide a precise and comprehensive description of the background to the study and explain how new technologies and the momentum of the pandemic make it possible to implement sustainable rehabilitation programmes, even in LMICs. The study's overall objective and its specific research objectives are clearly stated. Is the study design appropriate for the research question? Yes A key aspect of the study design is engaging a wide range of stakeholders, including healthcare professionals, providers, patients, and their families, to co-develop culturally sensitive programmes that consider the local context. This co-development process provides the basis for answering the research question regarding the feasibility and acceptability of scaling up the programme to conduct an effectiveness trial. The co-developed home-based rehabilitation program incorporates interventions that have previously been tested in people in the UK. The assessment of feasibility/acceptability within the randomised pilot study includes economic evaluations. Strength in the effectiveness trial lies in the adoption of the Win Ratio approach for the analysis of the composite primary outcome. The proposed study comprises four well-considered work packages: 1) Stakeholder engagement events to co-develop a suitable home-based rehabilitation programme and training materials for providers; 2) An acceptability and feasibility pilot study; 3) A trial involving 3,000 patients with heart disease and comorbid anxiety and depression to evaluate improvement in outcomes over 12 months; 4) Development of a sustainable model for research and rehabilitation delivery. The study aims to address the significant disparity in cardiac rehabilitation provision between high-income countries and LMICs. It seeks to transfer the proven benefits of cardiac rehabilitation to LMICs, which are expected to experience a substantial increase in cardiovascular disease in the coming years. A key strength of the study is its focus on populations with the comorbid conditions of heart disease — anxiety and depression — which are highly prevalent in LMICs. The proposed cardiac rehabilitation approach is clinically This study is important, timely and relevant. My only observation is that the study does not address gender issues in relation to the development of the rehabilitation programme, the involvement of healthcare staff or the sample size of the effectiveness trial. Is the rationale for, and objectives of, the study clearly described? Yes The authors provide a precise and comprehensive description of the background to the study and explain how new technologies and the momentum of the pandemic make it possible to implement sustainable rehabilitation programmes, even in LMICs. The study's overall objective and its specific research objectives are clearly stated. Is the study design appropriate for the research question? Yes A key aspect of the study design is engaging a wide range of stakeholders, including healthcare professionals, providers, patients, and their families, to co-develop culturally sensitive programmes that consider the local context. This co-development process provides the basis for answering the research question regarding the feasibility and acceptability of scaling up the programme to conduct an effectiveness trial. The co-developed home-based rehabilitation program incorporates interventions that have previously been tested in people in the UK. The assessment of feasibility/acceptability within the randomised pilot study includes economic evaluations. Strength in the effectiveness trial lies in the adoption of the Win Ratio approach for the analysis of the composite primary outcome. - Is the rationale for, and objectives of, the study clearly described? Yes - Is the study design appropriate for the research question? Yes - Are sufficient details of the methods provided to allow replication by others? Yes - Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cardiac rehabilitation CITE HOW TO CITE THIS REPORT Rovere MTL. Reviewer Report For: Affordable Cardiac Rehabilitation An Outreach Inter-Disciplinary Strategic Study (ACROSS) – Research Programme Protocol [version 1; peer review: 1 approved, 2 approved with reservations]. NIHR Open Res 2025, 5:41 (https://doi.org/10.3310/nihropenres.15169.r35547) The direct URL for this report is: https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35547 https://openresearch.nihr.ac.uk/articles/5-41/v1#referee-response-35547 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Alongside their report, reviewers assign a status to the article: - Approved - Approved with reservations - Not approved | Invited Reviewers | ||| |---|---|---|---| | 1 | 2 | 3 | | | Version 1 06 May 25 | read | read | read | Sign up for content alerts You are now signed up to receive this alert Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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