Cardiac rehabilitation is a complex intervention that seeks to improve the functional capacity, wellbeing and health-related quality of life of patients with heart disease. A substantive evidence ...base supports cardiac rehabilitation as a clinically effective and cost-effective intervention for patients with acute coronary syndrome or heart failure with reduced ejection fraction and after coronary revascularization. In this Review, we discuss the major contemporary challenges that face cardiac rehabilitation. Despite the strong recommendation in current clinical guidelines for the referral of these patient groups, global access to cardiac rehabilitation remains poor. The COVID-19 pandemic has contributed to a further reduction in access to cardiac rehabilitation. An increasing body of evidence supports home-based and technology-based models of cardiac rehabilitation as alternatives or adjuncts to traditional centre-based programmes, especially in low-income and middle-income countries, in which cardiac rehabilitation services are scarce, and scalable and affordable models are much needed. Future approaches to the delivery of cardiac rehabilitation need to align with the growing multimorbidity of an ageing population and cater to the needs of the increasing numbers of patients with cardiac disease who present with two or more chronic diseases. Future research priorities include strengthening the evidence base for cardiac rehabilitation in other indications, including heart failure with preserved ejection fraction, atrial fibrillation and congenital heart disease and after valve surgery or heart transplantation, and evaluation of the implementation of sustainable and affordable models of delivery that can improve access to cardiac rehabilitation in all income settings.
Peripheral neuropathic pain, including painful diabetic neuropathy (PDN), is associated with marked negative impact on health-related quality of life (HRQoL). The magnitude of reduction of HRQoL ...experienced by individual PDN patients appears to be strongly associated with their level of pain and disease severity. In spite of the availability of a range of pharmacotherapy, a substantive proportion of PDN patients continue to experience suboptimal HRQoL. Such patients are potential candidates for spinal cord stimulation (SCS) devices. Three randomised controlled trials in over 300 patients with refractory PDN have shown that the addition of SCS to standard of care therapy results in important health gains, including pain reduction and enhancement of HRQoL. Sham-controlled RCTs that enable blinding of patients, clinicians and researchers are needed to confirm the role of SCS in PDN.
Background
Coronary heart disease (CHD) is the single most common cause of death globally. However, with falling CHD mortality rates, an increasing number of people live with CHD and may need support ...to manage their symptoms and prognosis. Exercise‐based cardiac rehabilitation (CR) aims to improve the health and outcomes of people with CHD. This is an update of a Cochrane systematic review previously published in 2011.
Objectives
To assess the effectiveness and cost‐effectiveness of exercise‐based CR (exercise training alone or in combination with psychosocial or educational interventions) compared with usual care on mortality, morbidity and HRQL in patients with CHD.
To explore the potential study level predictors of the effectiveness of exercise‐based CR in patients with CHD.
Search methods
We updated searches from the previous Cochrane review, by searching Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 6, 2014) from December 2009 to July 2014. We also searched MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCO) and Science Citation Index Expanded (December 2009 to July 2014).
Selection criteria
We included randomised controlled trials (RCTs) of exercise‐based interventions with at least six months’ follow‐up, compared with a no exercise control. The study population comprised men and women of all ages who have had a myocardial infarction (MI), coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), or who have angina pectoris, or coronary artery disease. We included RCTs that reported at least one of the following outcomes: mortality, MI, revascularisations, hospitalisations, health‐related quality of life (HRQL), or costs.
Data collection and analysis
Two review authors independently screened all identified references for inclusion based on the above inclusion and exclusion criteria. One author extracted data from the included trials and assessed their risk of bias; a second review author checked data. We stratified meta‐analysis by the duration of follow up of trials, i.e. short‐term: 6 to 12 months, medium‐term: 13 to 36 months, and long‐term: > 3 years.
Main results
This review included 63 trials which randomised 14,486 people with CHD. This latest update identified 16 new trials (3872 participants). The population included predominantly post‐MI and post‐revascularisation patients and the mean age of patients within the trials ranged from 47.5 to 71.0 years. Women accounted for fewer than 15% of the patients recruited. Overall trial reporting was poor, although there was evidence of an improvement in quality of reporting in more recent trials.
As we found no significant difference in the impact of exercise‐based CR on clinical outcomes across follow‐up, we focused on reporting findings pooled across all trials at their longest follow‐up (median 12 months). Exercise‐based CR reduced cardiovascular mortality compared with no exercise control (27 trials; risk ratio (RR) 0.74, 95% CI 0.64 to 0.86). There was no reduction in total mortality with CR (47 trials, RR 0.96, 95% CI 0.88 to 1.04). The overall risk of hospital admissions was reduced with CR (15 trials; RR 0.82, 95% CI 0.70 to 0.96) but there was no significant impact on the risk of MI (36 trials; RR 0.90, 95% CI 0.79 to 1.04), CABG (29 trials; RR 0.96, 95% CI 0.80 to 1.16) or PCI (18 trials; RR 0.85, 95% CI 0.70 to 1.04).
There was little evidence of statistical heterogeneity across trials for all event outcomes, and there was evidence of small study bias for MI and hospitalisation, but no other outcome. Predictors of clinical outcomes were examined across the longest follow‐up of studies using univariate meta‐regression. Results show that benefits in outcomes were independent of participants' CHD case mix (proportion of patients with MI), type of CR (exercise only vs comprehensive rehabilitation) dose of exercise, length of follow‐up, trial publication date, setting (centre vs home‐based), study location (continent), sample size or risk of bias.
Given the heterogeneity in outcome measures and reporting methods, meta‐analysis was not undertaken for HRQL. In five out of 20 trials reporting HRQL using validated measures, there was evidence of significant improvement in most or all of the sub‐scales with exercise‐based CR compared to control at follow‐up. Four trial‐based economic evaluation studies indicated exercise‐based CR to be a potentially cost‐effective use of resources in terms of gain in quality‐adjusted life years.
The quality of the evidence for outcomes reported in the review was rated using the GRADE method. The quality of the evidence varied widely by outcome and ranged from low to moderate.
Authors' conclusions
This updated Cochrane review supports the conclusions of the previous version of this review that, compared with no exercise control, exercise‐based CR reduces the risk of cardiovascular mortality but not total mortality. We saw a significant reduction in the risk of hospitalisation with CR but not in the risk of MI or revascularisation. We identified further evidence supporting improved HRQL with exercise‐based CR. More recent trials were more likely to be well reported and include older and female patients. However, the population studied in this review still consists predominantly of lower risk individuals following MI or revascularisation. Further well conducted RCTs are needed to assess the impact of exercise‐based CR in higher risk CHD groups and also those presenting with stable angina. These trials should include validated HRQL outcome measures, explicitly report clinical event outcomes including mortality and hospital admissions, and assess costs and cost‐effectiveness.
Although recommended in guidelines for the management of coronary heart disease (CHD), concerns have been raised about the applicability of evidence from existing meta-analyses of exercise-based ...cardiac rehabilitation (CR).
The goal of this study is to update the Cochrane systematic review and meta-analysis of exercise-based CR for CHD.
The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and Science Citation Index Expanded were searched to July 2014. Retrieved papers, systematic reviews, and trial registries were hand-searched. We included randomized controlled trials with at least 6 months of follow-up, comparing CR to no-exercise controls following myocardial infarction or revascularization, or with a diagnosis of angina pectoris or CHD defined by angiography. Two authors screened titles for inclusion, extracted data, and assessed risk of bias. Studies were pooled using random effects meta-analysis, and stratified analyses were undertaken to examine potential treatment effect modifiers.
A total of 63 studies with 14,486 participants with median follow-up of 12 months were included. Overall, CR led to a reduction in cardiovascular mortality (relative risk: 0.74; 95% confidence interval: 0.64 to 0.86) and the risk of hospital admissions (relative risk: 0.82; 95% confidence interval: 0.70 to 0.96). There was no significant effect on total mortality, myocardial infarction, or revascularization. The majority of studies (14 of 20) showed higher levels of health-related quality of life in 1 or more domains following exercise-based CR compared with control subjects.
This study confirms that exercise-based CR reduces cardiovascular mortality and provides important data showing reductions in hospital admissions and improvements in quality of life. These benefits appear to be consistent across patients and intervention types and were independent of study quality, setting, and publication date.
To undertake a systematic review and meta-analysis to assess the impact of cardiac rehabilitation (CR) on physical activity (PA) levels of patients with heart disease and the methodological quality ...of these studies.
Databases (MEDLINE, EMBASE, CENTRAL, CINAHL, PsychINFO and SportDiscus) were searched without language restriction from inception to January 2017 for randomised controlled trials (RCTs) comparing CR to usual care control in adults with heart failure (HF) or coronary heart disease (CHD) and measuring PA subjectively or objectively. The direction of PA difference between CR and control was summarised using vote counting (ie, counting the positive, negative and non-significant results) and meta-analysis.
Forty RCTs, (6480 patients: 5825 CHD, 655 HF) were included with 26% (38/145) PA results showing a statistically significant improvement in PA levels with CR compared with control. This pattern of results appeared consistent regardless of type of CR intervention (comprehensive vs exercise-only) or PA measurement (objective vs subjective). Meta-analysis showed PA increases in the metrics of steps/day (1423, 95% CI 757.07 to 2089.43, p<0.0001) and proportion of patients categorised as physically active (relative risk 1.55, 95% CI 1.19 to 2.02, p=0.001). The included trials were at high risk of bias, and the quality of the PA assessment and reporting was relatively poor.
Overall, there is moderate evidence of an increase in PA with CR participation compared with control. High-quality trials are required, with robust PA measurement and data analysis methods, to assess if CR definitely leads to important improvements in PA.
Preoperative corneal neovascularization (CNV) is thought to be associated with an increased rate of corneal graft failure and potentially also graft rejection.
New therapeutic options that offer ...differential influence on the ingrowths or regression of either corneal blood or lymphatic vessels force us to re-evaluate the known data about the role of CNV in keratoplasty.
Electronic databases and corneal registries were searched (up through September 2008). Results were reported both descriptively for each study and using random effects meta-analysis. Potential moderating factors for the association between vascularization and graft failure and rejection were examined using metaregression analysis.
Nineteen studies reporting on a total of 24,944 grafts undergoing keratoplasty were included. An increase in the risk of graft failure and rejection in the presence of pathologic CNV was seen in studies with a pooled risk ratio of 1.32 (95% confidence interval CI, 1.15-1.49) for graft failure and 2.07 (95% CI, 0.98-3.15) for graft rejection. There was evidence of incremental increase of risk for graft failure and rejection as more corneal quadrants were affected by neovascularization. The 2 factors predictive of increased risk of neovascularization and graft failure were increased recipient age (P = 0.003) and male gender (P = 0.046).
Graft failure and rejection risk increase with an increasing number of corneal quadrants affected by neovascularization before keratoplasty. These data support the study of novel topical antiangiogenic therapies at the cornea to precondition such a cornea for future corneal grafting.
Proprietary or commercial disclosure may be found after the references.
Biopsy-confirmed liver fibrosis is a prognostic factor for patients with nonalcoholic fatty liver disease (NAFLD). We performed a systematic review to quantify the prognostic value of fibrosis stage ...in patients with NAFLD and the subgroup of patients with nonalcoholic steatohepatitis (NASH) and to assess the evidence that change in fibrosis stage is a surrogate endpoint.
We searched the MEDLINE, Embase, Cochrane Library, and trial registry databases through August 2018 for prospective or retrospective cohort studies of liver-related clinical events and outcomes in adults with NAFLD or NASH. We collected data on mortality (all cause and liver related) and morbidity (cirrhosis, liver cancer, and all liver-related events) by stage of fibrosis, determined by biopsy, for patients with NAFLD or NASH. Using fibrosis stage 0 as a reference population, we calculated fibrosis stage-specific relative risk (RR) and 95% confidence interval (CI) values for mortality and morbidities. We performed fixed-effect and random-effect model meta-analyses. Metaregression was used to examine associations among study design (prospective vs retrospective cohort), overall risk of bias (medium or high), and mean duration of follow-up (in years).
Our meta-analysis included 13 studies, comprising 4428 patients with NAFLD; 2875 of these were reported to have NASH. Compared with no fibrosis (stage 0), unadjusted risk increased with increasing stage of fibrosis (stage 0 vs 4): all-cause mortality RR, 3.42 (95% CI, 2.63–4.46); liver-related mortality RR, 11.13 (95% CI, 4.15–29.84); liver transplant RR, 5.42 (95% CI, 1.05–27.89); and liver-related events RR, 12.78 (95% CI, 6.85–23.85). The magnitude of RR did not differ significantly after adjustment for confounders, including age or sex in the subgroup of NAFLD patients with NASH. Three studies examined the effects of increasing fibrosis on quality of life had inconsistent findings.
In a systematic review and meta-analysis, we found biopsy-confirmed fibrosis to be associated with risk of mortality and liver-related morbidity in patients with NAFLD, with and without adjustment for confounding factors and in patients with reported NASH. Further studies are needed to assess the association between fibrosis stage and patient quality of life and establish that change in liver fibrosis stage is a valid endpoint for use in clinical trials.
Background
Despite advances in treatment, the increasing and ageing population makes heart failure an important cause of morbidity and death worldwide. It is associated with high healthcare costs, ...partly driven by frequent hospital readmissions. Disease management interventions may help to manage people with heart failure in a more proactive, preventative way than drug therapy alone. This is the second update of a review published in 2005 and updated in 2012.
Objectives
To compare the effects of different disease management interventions for heart failure (which are not purely educational in focus), with usual care, in terms of death, hospital readmissions, quality of life and cost‐related outcomes.
Search methods
We searched CENTRAL, MEDLINE, Embase and CINAHL for this review update on 9 January 2018 and two clinical trials registries on 4 July 2018. We applied no language restrictions.
Selection criteria
We included randomised controlled trials (RCTs) with at least six months' follow‐up, comparing disease management interventions to usual care for adults who had been admitted to hospital at least once with a diagnosis of heart failure. There were three main types of intervention: case management; clinic‐based interventions; multidisciplinary interventions.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. Outcomes of interest were mortality due to heart failure, mortality due to any cause, hospital readmission for heart failure, hospital readmission for any cause, adverse effects, quality of life, costs and cost‐effectiveness.
Main results
We found 22 new RCTs, so now include 47 RCTs (10,869 participants). Twenty‐eight were case management interventions, seven were clinic‐based models, nine were multidisciplinary interventions, and three could not be categorised as any of these. The included studies were predominantly in an older population, with most studies reporting a mean age of between 67 and 80 years. Seven RCTs were in upper‐middle‐income countries, the rest were in high‐income countries.
Only two multidisciplinary‐intervention RCTs reported mortality due to heart failure. Pooled analysis gave a risk ratio (RR) of 0.46 (95% confidence interval (CI) 0.23 to 0.95), but the very low‐quality evidence means we are uncertain of the effect on mortality due to heart failure. Based on this limited evidence, the number needed to treat for an additional beneficial outcome (NNTB) is 12 (95% CI 9 to 126).
Twenty‐six case management RCTs reported all‐cause mortality, with low‐quality evidence indicating that these may reduce all‐cause mortality (RR 0.78, 95% CI 0.68 to 0.90; NNTB 25, 95% CI 17 to 54). We pooled all seven clinic‐based studies, with low‐quality evidence suggesting they may make little to no difference to all‐cause mortality. Pooled analysis of eight multidisciplinary studies gave moderate‐quality evidence that these probably reduce all‐cause mortality (RR 0.67, 95% CI 0.54 to 0.83; NNTB 17, 95% CI 12 to 32).
We pooled data on heart failure readmissions from 12 case management studies. Moderate‐quality evidence suggests that they probably reduce heart failure readmissions (RR 0.64, 95% CI 0.53 to 0.78; NNTB 8, 95% CI 6 to 13). We were able to pool only two clinic‐based studies, and the moderate‐quality evidence suggested that there is probably little or no difference in heart failure readmissions between clinic‐based interventions and usual care (RR 1.01, 95% CI 0.87 to 1.18). Pooled analysis of five multidisciplinary interventions gave low‐quality evidence that these may reduce the risk of heart failure readmissions (RR 0.68, 95% CI 0.50 to 0.92; NNTB 11, 95% CI 7 to 44).
Meta‐analysis of 14 RCTs gave moderate‐quality evidence that case management probably slightly reduces all‐cause readmissions (RR 0.92, 95% CI 0.83 to 1.01); a decrease from 491 to 451 in 1000 people (95% CI 407 to 495). Pooling four clinic‐based RCTs gave low‐quality and somewhat heterogeneous evidence that these may result in little or no difference in all‐cause readmissions (RR 0.90, 95% CI 0.72 to 1.12). Low‐quality evidence from five RCTs indicated that multidisciplinary interventions may slightly reduce all‐cause readmissions (RR 0.85, 95% CI 0.71 to 1.01); a decrease from 450 to 383 in 1000 people (95% CI 320 to 455).
Neither case management nor clinic‐based intervention RCTs reported adverse effects. Two multidisciplinary interventions reported that no adverse events occurred. GRADE assessment of moderate quality suggested that there may be little or no difference in adverse effects between multidisciplinary interventions and usual care.
Quality of life was generally poorly reported, with high attrition. Low‐quality evidence means we are uncertain about the effect of case management and multidisciplinary interventions on quality of life. Four clinic‐based studies reported quality of life but we could not pool them due to differences in reporting. Low‐quality evidence indicates that clinic‐based interventions may result in little or no difference in quality of life.
Four case management programmes had cost‐effectiveness analyses, and seven reported cost data. Low‐quality evidence indicates that these may reduce costs and may be cost‐effective. Two clinic‐based studies reported cost savings. Low‐quality evidence indicates that clinic‐based interventions may reduce costs slightly. Low‐quality data from one multidisciplinary intervention suggested this may be cost‐effective from a societal perspective but less so from a health‐services perspective.
Authors' conclusions
We found limited evidence for the effect of disease management programmes on mortality due to heart failure, with few studies reporting this outcome. Case management may reduce all‐cause mortality, and multidisciplinary interventions probably also reduce all‐cause mortality, but clinic‐based interventions had little or no effect on all‐cause mortality. Readmissions due to heart failure or any cause were probably reduced by case‐management interventions. Clinic‐based interventions probably make little or no difference to heart failure readmissions and may result in little or no difference in readmissions for any cause. Multidisciplinary interventions may reduce the risk of readmission for heart failure or for any cause. There was a lack of evidence for adverse effects, and conclusions on quality of life remain uncertain due to poor‐quality data. Variations in study location and time of occurrence hamper attempts to review costs and cost‐effectiveness.
The potential to improve quality of life is an important consideration but remains poorly reported. Improved reporting in future trials would strengthen the evidence for this patient‐relevant outcome.
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