Overview of Cochrane Systematic Reviews on Interventions for Rehabilitation in People with Ischemic Heart Disease: A Mapping Synthesis

Objectives: This overview of Cochrane Systematic Reviews (CSRs) reports on current evidence and its certainty of the effectiveness of interventions for the rehabilitation of people with ischemic heart disease (IHD), included in the World Health Organization Rehabilitation Programme Package of Interventions for Rehabilitation. Methods: We included all the CSRs relevant to people with IHD. We used a mapping synthesis to group outcomes and comparisons of included CSRs, indicating the effectiveness of interventions for rehabilitation and the certainty of evidence. Results: The evidence map included a total of 13 CSRs. The effect of the interventions varied across comparisons, and the certainty of evidence was inconsistent, ranging from high to very low. We found the best evidence for exercise-based cardiac rehabilitation in the reduction of fatal and non-fatal myocardial infarction and all-cause hospital admission up to 12 months follow-up. Also, combined interventions (work-directed interventions, physical conditioning interventions, and psychological interventions) reduce the days needed for returning to work. Conclusions: The current effect and certainty of evidence for several comparisons investigated support the role of exercise-based cardiac rehabilitation in the management of people with IHD, specifically reducing the risk of fatal and non-fatal myocardial infarction and hospitalisation. However, our findings highlight the lack of high-certainty evidence about hard endpoints, particularly total mortality. Future research should prioritise these primary endpoints to enhance the credibility of cardiac rehabilitation.


Introduction
In 2017, the World Health Organization (WHO) launched the "Rehabilitation 2030: a call for action" initiative to strengthen rehabilitation in health systems and integrate it into all levels of health care [1].Within this initiative, the WHO Rehabilitation Programme developed a Package of Interventions for Rehabilitation (WHO PIR) that was launched at the third Rehabilitation 2030 meeting held in Geneva in July 2023 [2].This package responds to the global need for rehabilitation services, which should be integrated into primary health care to reach more people in need.The development of the PIR was composed of six consecutive phases.In the first phase, the WHO Rehabilitation Programme Advisory Board selected 20 health conditions in the summer of 2018 based on the disability statistics of the Global Burden of Disease (GBD) Study 2016 [3] and expert opinion, according to two criteria: (1) to be amenable to rehabilitation and (2) to cover different disease areas (e.g., musculoskeletal, cardiovascular, nervous system).In addition, the level of disability associated with these health conditions and their prevalence estimates were considered [4].Phase 2, called "Best-Evidence for Rehabilitation (be4rehab)", aimed to identify the best quality evidence concerning the effectiveness of interventions for rehabilitation for 20 key health conditions, including ischemic heart disease.
Ischemic heart disease (IHD), also called coronary heart disease or coronary artery disease, is the single most common cause of death globally, with over 9 million deaths per year worldwide [5].According to the American Heart Association, the annual incidence of new coronary events is approximately 720,000 cases per year, and the current prevalence of IHD is approximately 18.2 million cases in the United States alone [6].The morbidity has social and economic implications.According to the study of Leal et al. 2006 [7], it is estimated that for the European Union, the total costs were around EUR 45 billion in 2003, broken down as follows: 51% incurred in health care, 34% in productivity losses, and 15% in informal care.In addition, anxiety and depression commonly occur after IHD, affecting the quality of life (QoL) and return to work of the persons concerned.
Rehabilitation plays an important role in the overall management of people with IHD.Exercise training is commonly recommended in the management of people with IHD as a core element of a Cardiac Rehabilitation Program [8][9][10].
Cochrane Reviews are the reference standard among systematic reviews for their methodological rigour and quality [11].The evidence gathered from these reviews is the strongest available and was consequently considered by the WHO as highly relevant for PIR development.Due to the methodological rigour and quality of the CSRs, this paper aims to describe the research performed and the Cochrane evidence found on interventions for the rehabilitation of people with IHD.The results provide an overall description of the available evidence in the field through a specific methodology still not widely used in medicine-an evidence map [12].

Materials and Methods
The methods for developing the content of the WHO PIR have been established and published collaboratively by the WHO Rehabilitation Programme and Cochrane Rehabilitation under the guidance of the WHO's guideline review committee [4].A first search of the Cochrane Systematic Reviews (CSRs) relevant to the WHO PIR for IHD was carried out in August 2019 on the Cochrane Rehabilitation database of tagged CSRs [13], according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Guidelines [14].The data were extracted and communicated to the WHO for the development of the PIR.In a second instance, to overcome the limitations of the rapid overview of reviews requested by the WHO, we performed a search on the full Cochrane Library on 11 December 2023, according to the protocol submitted on OSF registers (10.17605/OSF.IO/TPABF).We included only CSRs that examined interventions for rehabilitation in people with IHD.Studies focusing on interventions that are not related to rehabilitation were excluded.

Search Strategy
The first search was performed according to the methodology developed by the WHO and Cochrane Rehabilitation for the WHO PIR [4,15].In the second search, we identified studies from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library.Detailed search strategies have been developed by an author with experience in bibliographic searches (MJDF), using the terms "myocardial ischemia" and "myocardial revascularisation".The database was searched on 11 December 2023.The full search strategy is shown in Table 1.(myocard* NEAR/1 isch*mi*):ti,ab,kw 3.

Study Selection and Data Extraction
Two independent authors (CK, GC) screened articles for eligibility at the title/abstract stage and the full-text stage.They selected the CSRs relevant to rehabilitation, considering all reviews on interventions provided or prescribed by rehabilitation professionals.In case of disagreement, a third author was involved (CA).One author (MJDF) performed data extraction, and two authors (CK, GC) verified the accuracy of the process.We extracted all rehabilitation-relevant interventions from the table of findings published in each CSR and collated them into an Excel file datasheet the PICO (population, intervention, comparison, outcome) information, as follows: type of outcomes and outcome measures, number of included studies, sample size, population, intervention, comparison, effect (in favour of intervention, in favour of control, no effect), and the certainty of evidence judgement for each comparison and outcome.

Assessment of Methodological Quality of Included Reviews
To assess the methodological quality of the included reviews, we used the 16-item AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews), published in 2007 and updated in 2017 [16].The tool consists of binary (yes or no) questions and does not produce an overall score.The overall rating is determined based on weaknesses identified in seven critical domains.To evaluate the weaknesses, two independent authors (MJDF, CK) critically appraised the included reviews.If there was a disagreement, a third author was consulted to reach a consensus (CA).

Certainty of Evidence Appraisal
We extracted the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) judgement of each CSR.When CSRs lacked this information, two authors independently applied the standard GRADE approach to evaluate the quality of evidence for the primary outcomes [17,18].This post hoc GRADE process comprised the retrieval of the original primary studies included in each CSR and tabulation of the judgments in Summary of Findings tables using the GRADEPro software.

Summarising Evidence within a Map
After the data extraction, we summarised the results into an evidence map, a specific methodology used to identify the literature within a research field to provide a comprehensive view of what is known and where evidence gaps exist [12,19].An Excel sheet was used to map the evidence, grouping outcomes, and comparison of included CSRs indicating the effect (no, in favour of intervention, in favour of control) and the quality of evidence (very low, low, moderate, and high).

Results
Among the 977 CSRs, 13 met the inclusion criteria set by the WHO (see Figure 1).Table 2 shows the characteristics of the included CSRs.The results of the AMSTAR 2 assessment indicated a high methodological quality of all the CSRs (see Table S1).Nine reviews reported the certainty of evidence using the GRADE approach [20][21][22][23][24][25][26][27][28], while the other four did not report GRADE judgement [29][30][31][32].The included CSRs investigated interventions for the treatment of the rehabilitation needs in patients with IHD on 28 outcomes analysed within 13 comparisons in inpatient and outpatient settings.The findings were grouped by outcome and arbitrarily classified according to the most appropriate International Classification of Functioning Disability and Health (ICF) category [33].The results were reported into an evidence map to ensure easy readability of the information (Figure 2).
After the data extraction, we summarised the results into an evidence map, a specific methodology used to identify the literature within a research field to provide a comprehensive view of what is known and where evidence gaps exist [12,19].An Excel sheet was used to map the evidence, grouping outcomes, and comparison of included CSRs indicating the effect (no, in favour of intervention, in favour of control) and the quality of evidence (very low, low, moderate, and high).

Results
Among the 977 CSRs, 13 met the inclusion criteria set by the WHO (see Figure 1).Table 2 shows the characteristics of the included CSRs.The results of the AMSTAR 2 assessment indicated a high methodological quality of all the CSRs (see Table S1).Nine reviews reported the certainty of evidence using the GRADE approach [20][21][22][23][24][25][26][27][28], while the other four did not report GRADE judgement [29][30][31][32].The included CSRs investigated interventions for the treatment of the rehabilitation needs in patients with IHD on 28 outcomes analysed within 13 comparisons in inpatient and outpatient settings.The findings were grouped by outcome and arbitrarily classified according to the most appropriate International Classification of Functioning Disability and Health (ICF) category [33].The results were reported into an evidence map to ensure easy readability of the information (Figure 2).[24].It is uncertain whether internet-based interventions, compared to usual care or no care, have an effect on systolic and diastolic blood pressure (not estimable, low-certainty evidence) [22].Home-based CR may have no effect on exercise capacity ≤ 12 months, compared to centrebased treatment (low-certainty evidence) [22].It is uncertain whether music therapy with standard care, compared to standard care only, may have an effect on heart rate, respiratory rate, pain, and systolic blood pressure (very-low-certainty evidence) [21].Psychological treatment, including cognitive behavioural therapy, psychodynamic psychotherapy, interpersonal therapy (IPT), non-directive or supportive therapy, and counselling, compared with usual care, may have an effect on depression symptoms, while no difference was found in depression remission (low-certainty evidence), with potentially no effect.It is uncertain whether music therapy may have an effect on psychological distress and anxiety compared to standard care (low-certainty evidence) [21,28].

Low-and Very-Low-Certainty Evidence
Psychological interventions, compared to usual care, may not increase the proportion of participants returning to work in the long term (>1 to <5 years) (low certainty), while it is uncertain whether psychological interventions may increase the proportion of participants returning to work in the short (up to 6 months) and medium term (6 months-1 year) or whether it may lower the days needed to return to work (very low certainty).Workdirected counselling compared to usual care may not reduce the days needed to return to work (low certainty).Physical conditioning interventions, compared to usual care, may increase the proportion of participants returning to work in the very long term (≥5 years) (low certainty evidence), without effects in the medium (6 months-1 year) and long term (>1 to <5 years), and on the days needed to return to work (low-certainty evidence).It is uncertain whether physical conditioning interventions may reduce the proportion of participants returning to work in the short term (up to 6 months) (very-low-certainty evidence).Combined interventions, defined as all work-directed interventions, exercisebased CR, and psychological interventions or any combination, compared to usual care, may increase the proportion of participants returning to work in the short term (up to 6 months) (low-certainty evidence) without raising the proportion of participants returning to work in the medium term (6 months-1 year) (low-certainty evidence).It is uncertain whether combined interventions may increase the proportion of participants returning to work in the long term (very-low-certainty evidence) [24].

Pharmacological Therapy Optimisation
The certainty of evidence of the effects of pharmacological treatment is summarised in Figure 2.

Discussion
In July 2023, the WHO launched the Package of Interventions for Rehabilitation (WHO PIR), which aimed to identify the best quality evidence concerning the effectiveness of interventions for rehabilitation of cardiopulmonary conditions [2].The PIR individualised the interventions for rehabilitation as crucial to achieve, restore, and maintain optimal levels of functioning and to prevent additional cardiac events.In this paper, we mapped the Cochrane evidence on the effectiveness of rehabilitation interventions for people with IHD, addressing all core components included in the PIR: exercise training, patient education, psychological intervention, and pharmacological optimisation, including different modes of delivery such as internet-based, home-based, or centre-based.Our data show that exercise-based CR, compared to no exercise treatment, provides a large reduction in fatal and non-fatal myocardial infarction up to 12 months of follow-up and probably reduces all-cause hospital admissions up to 12 months of follow-up, while combined interventions (work-directed interventions, physical conditioning interventions, and psychological interventions) provide a reduction in the days needed for returning to work.These findings align with those of a recently published network meta-analysis, which indicates a decrease in the risk of non-fatal myocardial infarction [34].
However, our overview shows that CR has no effect on both total and cardiovascular mortality, considering exercise-based CR, patient education or psychological treatment alone.Moreover, exercise-based CR shows no effect on CABG revascularisation and risk of PCI revascularisation up to 12 months.Patient education alone provides uncertain effects on health-related QoL and the reduction of fatal and non-fatal MI compared to no treatment, while it may reduce other fatal or non-fatal cardiovascular events.Finally, when evaluating CR settings, home-based CR, compared to centre-based CR, gives uncertain effects on the health-related QoLup to 24 months follow-up, and very-low-certainty evidence exists on the effect on mortality up to 12 months.Similarly, low-certainty evidence exists about internet-based interventions, compared to usual care or no intervention.
Our data support recent international guidelines and meta-analyses.The 2023 AHA/ ACC/ACCO/ASPC/NLA/PCNA Guidelines for the management of patients with chronic coronary disease [10] recommend all patients with chronic coronary disease to be referred to a CR program to improve outcomes.A CR programme is generally considered a multidisciplinary intervention with exercise training as a pivotal part.General physical activity recommendations are reported, including a combination of regular aerobic physical activity and resistance exercise throughout the week, without any data about outcomes specifically after exercise-based CR.The 2023 ESC Guidelines for the management of acute coronary syndromes [9] in the "Long treatment" Section recommend that all acute coronary syndrome patients participate in a comprehensive CR programme to reduce CV hospitalisations, MI (in line with our data) and CV mortality.Regarding the outcome of mortality, it is specified "in some studies", suggesting the paucity of data supporting this last hard endpoint.Our data show with moderate certainty that exercise-based CR versus non-treatment or other treatment has no effect on cardiovascular and total mortality.Evaluating CR settings, both European and American guidelines report telerehabilitation as an alternative for patients who cannot attend facility-based CR, being equivalent to traditional CR in terms of achieving functional improvement, managing risk factors and increasing well-being.In line with our data, few data are available about the effect of telerehabilitation on recurrent events and only one meta-analysis showed no significant difference between mortality following telehealth intervention and centre-based supervised CR.
Finally, a recently published meta-analysis [35] focusing on exercise-based CR for coronary heart disease (CHD) reported data about 85 RCTs involving 23,430 patients with a median 12-month follow-up.Perfectly in line with our findings, exercise-based CR was associated with significant risk reductions in hospitalisations and MI without significant impact on all-cause mortality and the need for coronary artery bypass graft or percutaneous coronary intervention.The take-home message of the important benefit of exercise-based CR to reduce risk of cardiovascular mortality, apparently contrary to our data, is not detected at short-term follow-up (6-12 months), and the certainty/quality of data is not reported.
Our findings reinforce the current national and international clinical directives emphasising that effective CR for those with CHD should be comprehensive and include educational interventions in conjunction with exercise and psychological therapy [36].The current landscape, as highlighted in the articles by Vilela et al. and Beatty et al. [37,38], underscores the evolving role of CR in managing CHD.Prospects suggest a shift towards personalised, patient-centred approaches that integrate technology, behavioural interventions, and novel exercise modalities tailored to individual needs.Additionally, there is a growing emphasis on addressing research gaps, such as optimising modes of delivery, understanding the impact of psychosocial factors on rehabilitation outcomes, and exploring innovative strategies to improve adherence to long-term programmes.Advancements in wearable technology, telemedicine, and data analytics are expected to play a pivotal role in monitoring and optimising patient progress outside clinical settings, thereby enhancing the overall effectiveness of cardiac rehabilitation.Collaboration between multidisciplinary teams, including cardiologists, rehabilitation physicians, exercise physiologists, physiotherapists, psychologists, dietitians, and technology experts, will likely drive the development of comprehensive and adaptive rehabilitation programmes.Ultimately, the future of CR research holds promise in redefining and optimising the standard of care for individuals with CHD, paving the way for more effective, accessible, and personalised rehabilitation approaches.

Strengths and Limitations
Our findings result from selecting CSRs according to the methods framed by the WHO Rehabilitation Programme and Cochrane Rehabilitation.We included CSRs exclusively as they represent the gold standard among systematic reviews due to their high-quality methodology; however, this could limit the generalizability of the findings and investigated interventions.Nevertheless, the uniformity of the Cochrane methodology gives coherence to the overview and is currently suggested by the WHO.Not providing a full evidence map that should start from an "a priori" grid developed according to a specific methodology, including all the possible outcomes and interventions, is a limitation.Moreover, according to the reported interventions and outcomes, we provided only the GRADE evidence of the current CSRs.Although beyond the scope of this paper, the authors acknowledge that this did not allow them to identify the evidence gaps fully.Given the heterogeneity in the interventions for rehabilitation observed in the included studies, further research to refine the optimal cardiac rehabilitation approach for individuals with IHD is needed.Also, as discussed in the CSRs, well-designed and adequately reported RCTs more representative of usual clinical practise are still needed.Additionally, to ensure improved comparability between trials, it will be important to define a core set of outcomes to be included in all rehabilitation studies for IHD patients.Finally, with a view towards personalised treatment, it will be crucial to examine the effectiveness of various rehabilitation interventions in IHD patients, taking into account diverse clinical phenotypes, disease severity, and comorbidities.

Conclusions
In this paper we provided the most reliable evidence on rehabilitation interventions for persons with IHD, which is included in the WHO PIR.The current effect and certainty of evidence for several comparisons investigated in this population support the role of exercise-based cardiac rehabilitation in the management of people with IHD.However, our data highlight the lack of high-certainty evidence about hard endpoints, in particular CV and all-cause mortality, which must be the main priority of future research to improve the credibility of CR, which should be much more integrated into primary health care and the overall management of people with IHD.Moreover, many different aspects, such as modes of delivery, the impact of psychosocial factors on rehabilitation outcomes, innovative strategies to improve adherence to long-term programmes, wearable technology, and telemedicine, should be included in future studies.

Figure 1 .Figure 1 .
Figure 1.PRISMA flow diagram of the study.** If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

3. 5 .
Return to Work (Proportion of Participants Returning to Work, Days Until Return to Work) [Remunerative Employment d850; Non-Remunerative Employment d855] 3.5.1.High-and Moderate-Certainty Evidence Combined interventions (work-directed interventions, physical conditioning interventions, and psychological interventions), compared to usual care, probably show a reduction in the days needed to return to work (moderate certainty) [24].Finally, combined interventions described as work-directed interventions, person-directed interventions as psychological interventions, and physical conditioning interventions likely result in littleto no difference in adverse events, and physical conditioning interventions, compared to usual care, probably do not increase adverse events (such as cardiac deaths or reinfarction) (moderate certainty) if combined with psychological interventions[24].

Table 2 .
Characteristics of the Cochrane Systematic Reviews included.

Table 2 .
Cont. : coronary artery disease: CAD; coronary heart disease: CHD; cardiac rehabilitation: CR; Coronary Artery Bypass Grafting: CABG; myocardial infarction: MI; Not Available: NA; Number: Nr; Not Reported: NR; Numeric Rating Scale: NRS; percutaneous coronary intervention: PCI; Spielberger State-Trait Anxiety Inventory: STAI; Usual care: UC; Visual Analogue Scale: VAS.hospital admission ('no exercise' control); 12: total mortality (no patient education); 13: fatal and/or non-fatal MI at the end of the follow-up period (no patient education); 14: other fatal and/or non-fatal cardiovascular events (no patient education); 15: HRQoL (no patient education); 16: total revascularisations, including CABG and PCI (no patient education); 17: hospitalisations-cardiac-related-at end of follow-up period (no patient education); 18: all-cause withdrawal at follow-up (no patient education); 19: all-cause mortality-short term (usual care); 20: cardiovascular mortality-long term (usual care); 21: depression symptoms-short term (usual care); 22: depression remission-short term (usual care); 23: depression symptoms-short term (end of treatment) (other psychological treatment); 24: depression remission-short term (end of treatment) (other psychological treatment); 25: proportion of participants returning to work in the short term-up to 6 months (lesser forms of cardiovascular rehabilitation); 26: proportion of participants returning to work in the medium term-from 6 months to 1 year (lesser form of cardiovascular rehabilitation); 27: proportion of participants at work in the long term-from >1 to <5 years (lesser forms of cardiovascular rehabilitation); 28: days until return to work (lesser forms of cardiovascular rehabilitation); 29: all-cause mortality-short term, end of treatment (other pharmacological intervention); 30: myocardial infarction-short term, end of treatment (other pharmacological intervention); 31: depression symptoms-short , physical conditioning interventions, and psychological interventions) may have no effect on health-related QoL compared to usual care (low certainty) Legend: coronary artery disease: CAD; coronary heart disease: CHD; cardiac rehabilitation: CR; Coronary Artery Bypass Grafting: CABG; myocardial infarction: MI; Not Available: NA; Number: Nr; Not Reported: NR; Numeric Rating Scale: NRS; percutaneous coronary intervention: PCI; Spielberger State-Trait Anxiety Inventory: STAI; Usual care: UC; Visual Analogue Scale: VAS.LegendFigure 2. Evidence map for interventions for persons with ischemic heart disease.Map colours: green: favour intervention; yellow: no effect; grey: not estimable; Abbreviations for certainty of evidence: VL: very low; L: low; M: moderate; H: high; NA: not available.Other abbreviations: ischemic heart disease: IHD; myocardial interventions