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

Background

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.

Rationale

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 disability^1,2. 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 disease^11,12.

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-being^14,15. 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 capacity^18,19. 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 countries^14,15.

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-effective^23,24. 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.

Aims and objectives

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:

Cross-cutting objectives:

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.

Figure 1. Summary of ACROSS WP.

Patient and Public Involvement

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.

WP1 - Cultural and contextual adaptation of rehabilitation intervention

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 Manual^29,30 and REACH-HF^23,24) 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.

Objectives:

To achieve our objectives, we will conduct two interrelated studies:

WP2 - External pilot trial

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.

Objectives:

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.

WP3 - Hybrid effectiveness-implementation trials of ACROSS rehabilitation

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).

Objectives:

Study Design: Type 1 hybrid effectiveness-implementation randomised controlled trial (RCT) with an embedded economic evaluation^37,38. 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 eligible^39,40. 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 intervention^29–31, and heart failure patients will receive an adapted ACROSS version of the REACH-HF intervention^23,24. 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 method^41,42. 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.

Figure 2. Sample size estimation for WP3.

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.

WP4 - Capacity building

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.

Objectives:

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 & public involvement

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).

Figure 3. ACROSS Theory of Change model.