Exercise‐based cardiac rehabilitation for people with implantable ventricular assist devices
Abstract
Background
Heart failure is the end stage of heart disease, and the prevalence and incidence of the condition is rapidly increasing. Although heart transplantation is one type of surgical treatment for people with end‐stage heart failure, donor availability is limited. Implantable ventricular assist devices (VADs) therefore offer an alternative treatment to heart transplantation. Although two studies reported the beneficial effects of exercise‐based cardiac rehabilitation (CR) on functional capacity and quality of life (QOL) by performing systematic reviews and meta‐analyses, both systematic reviews included studies with limited design (e.g. non‐randomised, retrospective studies) or participants with implantable or extracorporeal VADs.
Objectives
To determine the benefits and harms of exercise‐based CR for people with implantable VADs.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, PsycINFO, Conference Proceedings Citation Index‐Science (CPCI‐S) on Web of Science, CINAHL, and LILACS on 3 October 2017 with no limitations on date, language, or publication status. We also searched two clinical trials registers on 10 August 2017 and checked the reference lists of primary studies and review articles.
Selection criteria
Randomised controlled trials (RCTs) regardless of cluster or individual randomisation, and full‐text studies, those published as abstract only, and unpublished data were eligible. However, only individually RCTs and full‐text publications were included.
Data collection and analysis
Two review authors independently extracted outcome data from the included studies. We double‐checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. We had no dichotomous data to analyse and used mean difference or standardised mean difference with 95% confidence intervals (CIs) for continuous data. Furthermore, we assessed the quality of evidence as it relates to those studies that contribute data to the meta‐analyses for the prespecified outcomes, using GRADEpro software.
Main results
We included two studies with a total of 40 participants in the review. Exercise‐based CR consisted of aerobic or resistance training or both three times per week for six to eight weeks. Exercise intensity was 50% of oxygen consumption (VO2) reserve, or ranged from 60% to 80% of heart rate reserve. Two serious adverse events were observed in one trial, in which participants did not complete the study due to infections. Furthermore, a total of four participants in each group required visits to the emergency department, although these participants did complete the study. Summary scores from the 36‐item Short Form Health Survey (SF‐36) and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were measured as quality of life. One trial reported that the KCCQ summary score improved by 14.4 points in the exercise group compared with 0.5 points in the usual care group. The other trial reported that the SF‐36 total score improved by 29.2 points in the exercise group compared with 16.3 points in the usual care group. A large difference in quality of life was observed between groups at the end of follow‐up (standardised mean difference 0.88, 95% CI ‐0.12 to 1.88; 37 participants; 2 studies; very low‐quality of evidence). However, there was no evidence for the effectiveness of exercise‐based CR due to the young age of the participants, high risk of performance bias, very small sample size, and wide confidence intervals, which resulted in very low‐quality evidence. Furthermore, we were not able to determine the effect of exercise‐based CR on mortality, rehospitalisation, heart transplantation, and cost, as these outcomes were not reported.
Authors' conclusions
The evidence is currently inadequate to assess the safety and efficacy of exercise‐based CR for people with implantable VADs compared with usual care. The amount of RCT evidence was very limited and of very low quality. In addition, the training duration was very short term, that is from six to eight weeks. Further high‐quality and well‐reported RCTs of exercise‐based CR for people with implantable VADs are needed. Such trials need to collect data on events (mortality and rehospitalisation), patient‐related outcomes (including quality of life), and cost‐effectiveness.
PICOs
Plain language summary
Exercise‐based cardiac rehabilitation for people with implantable ventricular assist devices
Background
People with heart failure have a decreased capacity to undertake physical exercise, which has a negative impact on their health and quality of life. Recent research has shown that exercise‐based cardiac rehabilitation (CR) may improve exercise capacity and quality of life in people with implantable ventricular assist devices (VADs), which are a type of mechanical pump that supports heart function. It was therefore considered important to systemically review randomised controlled trials (a type of study in which participants are assigned to a treatment group using a random method) to determine the benefits and harms of exercise‐based CR in people with implantable VADs.
Purpose
To assess the effects of exercise‐based CR in people with implantable VADs.
Methods
We searched the scientific literature for randomised controlled trials that assessed the effectiveness of exercise in people with heart failure who have implantable VADs by comparing participants receiving the exercise intervention with those receiving usual care, where the intervention consisted of a single type of exercise or more. We excluded participants with total artificial hearts. The evidence is current to 3 October 2017.
Results
We included only two randomised controlled trials and a total of 40 participants in this review. Exercise‐based CR consisted of aerobic or resistance training or both three times per week for six to eight weeks. Two serious adverse events (i.e. participants who did not complete the study due to infections) occurred in one of the two trials. Furthermore, four participants in each study group required visits to the emergency department, although these participants did complete the study. Neither study evaluated the outcomes of death, rehospitalisation, heart transplantation, and cost. Due to the very low quality of the evidence, the effectiveness of exercise‐based CR on quality of life was uncertain.
Quality of the evidence
We assessed the quality of the evidence for quality of life as very low due to the young age of the participants, Insufficient blinding, small number of participants, and imprecision because of wide range of confidence intervals. The effects of exercise‐based CR for people with implantable VADs were not clear.
Conclusion
The current evidence is inadequate to assess the benefits and harms of exercise‐based CR for people with implantable VADs compared with usual care. The amount of randomised controlled trial evidence was very limited and of very low quality. In addition, the training duration was very short term. High‐quality randomised controlled trials are needed to collect data on events (death and rehospitalisation), patient‐related outcomes (including quality of life), and cost.
Authors' conclusions
Summary of findings
| Exercise‐based cardiac rehabilitation compared to usual care for people with implantable ventricular assist devices | ||||||
| Patient or population: people with implantable ventricular assist devices | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with usual care | Risk with exercise‐based cardiac rehabilitation | |||||
| Mortality due to all causes ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Mortality due to cardiovascular event ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Rehospitalisation due to cardiovascular event ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Serious adverse events: infection | ‐ | ‐ | ‐ | ‐ | ‐ | 1 trial reported no adverse events. The other trial reported 2 serious adverse events: 1 participant in the cardiac rehabilitation group had a driveline infection, and 1 participant in the usual care group had an infection. These 2 participants did not complete the study. A total of 2 serious adverse events were observed across the 1 trial. |
| Health‐related quality of life | ‐ | SMD 0.88 SD higher | ‐ | 37 | ⊕⊝⊝⊝ | A higher score means better quality of life. |
| Heart transplantation ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Cost ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Blinding of participants and personnel, or other potential sources bias (not intention‐to‐treat analysis) were poorly described in the included studies, therefore quality of evidence was downgraded by one level for risk of bias. | ||||||
Background
Description of the condition
Heart failure is the end stage of heart disease. The global prevalence of heart failure was reported at approximately 40 million by the Global Burden of Disease study (Vos 2016). Ischaemic heart disease is a major cause of heart failure, and the most common cause of death in the world, with an incidence of 8.76 million deaths in 2015 according to Global Health Observatory data reported by the World Health Organization (WHO 2017). In many countries, 1% to 2% of adults and more than 10% of elderly people have heart failure (Mosterd 2007), with a one‐year survival rate of only 30% to 40% (Mozaffarian 2015). Furthermore, the number of people with heart failure has rapidly increased in the past few decades, and is estimated to continue increasing until 2035 (Mozaffarian 2015; Okura 2008). People with heart failure have symptoms such as fatigue, exertional breathlessness, and lethargy (McMurray 2012). In addition, these symptoms may induce a vicious cycle of deconditioning that leads to decreased quality of life (QOL) and increased disability (Hatta 2009). The classification of severity in heart failure is based on these symptoms and exercise capacity, and can be determined using tools from the New York Heart Association (NYHA) (ranging from class I to IV) and the American Heart Association (AHA)/American College of Cardiology (ACC) stages (ranging from stage A to D) (Fletcher 2001; Hunt 2005). End‐stage heart failure is evaluated as NYHA IV or AHA/ACC stage D, which describes people who have severe symptoms at rest, despite maximal medical therapy. People with end‐stage heart failure therefore have very low QOL and high disability (Hatta 2009).
Although heart transplantation is one type of surgical treatment for people with end‐stage heart failure, donor availability is limited (AST and ASTS 2012). Ventricular assist devices (VADs) offer an alternative treatment to heart transplantation. Often used as a bridge to recovery, cardiac transplantation or destination therapy, VADs consist of a surgically implanted mechanical pump that increases cardiac output and maintains sufficient blood flow to the peripheral organs (Heart Failure Society of America 2010; Peura 2012). The majority of people with end‐stage heart disease are managed with medications and devices (cardiac resynchronisation therapy pacemakers), and only the minority get transplants or VADs; indeed, these are particularly scarce outside wealthy health economies such as the United States (Kirklin 2018; Stehlik 2013). However, it is possible that the use of VADs may grow in time as the technology improves and costs fall.
There are two types of flow in VADs: continuous flow or pulsatile flow. While pulsatile‐flow VADs are physically large with a short battery life, continuous‐flow VADs are lightweight with better durability (Hrobowski 2013; Slaughter 2009). A large‐scale prospective non‐randomised observational study of VAD implantation therapy (ROADMAP trial) showed that VAD implantation dramatically increased survival rate, and improved QOL and NYHA classes of people with end‐stage heart failure (Starling 2017). The ROADMAP study reported a two‐year survival rate of 70% and 41% (70% versus 63% in intention‐to‐treat survival rate) in people with VADs versus optimal medical management, respectively. However, the following challenges still remain in the use of VAD implantation therapy (Starling 2017). First, although the QOL scores are significantly better in people with VADs than in people with optimal medical management, the QOL of people with VADs is lower than that of healthy people living in the community (Rose 2001; Ware 1993). Previous studies have suggested that lower QOL was closely correlated with impaired physical function and emotional status (Hoekstra 2013; Oh 2014). Second, the frequency of adverse events in people with VADs is approximately twice as high as that in people with optimal medical management. In particular, the rate of neurological events in people with VADs is approximately four times higher than that of optimal medical management. The ROADMAP study reported that 12% of people experienced pump thrombus and 11.7% experienced neurological events after VAD implantation (Starling 2017). People with VADs therefore require anticoagulant therapy to prevent potential embolism after VAD implantation (Peura 2012). However, such therapy could increase the risk of cerebral haemorrhage.
Description of the intervention
The AHA strongly recommends cardiac rehabilitation (CR) for people with heart failure to improve functional capacity and QOL and to reduce mortality (Yancy 2017). According to several guidelines, exercise‐based CR decreases cardiovascular events (ACSM 2009; Canadian Cardiovascular Society 2014; Fletcher 2013). Furthermore, CR for people with VADs is safe and effective according to two previous systematic reviews and meta‐analyses (Ganga 2017; Mahfood 2017). This type of therapy includes exercise training, risk‐factor education, behaviour change, and psychological support for the purpose of primary or secondary prevention of disease. Exercise training consists of 30‐ to 60‐minute exercise sessions on a treadmill or bicycle ergometer, which are performed more than 3 times per week over a period of 6 to 12 months, at a training intensity of 50% to 80% of peak oxygen consumption. Resistance training, such as weight training or machine training, is also performed as a type of CR for people with heart failure (Taylor 2014).
How the intervention might work
A Cochrane Review found that exercise‐based CR was associated with a 25% reduction in mortality and a 39% reduction in hospital readmission for people with heart failure (Taylor 2014). Well‐established evidence shows that exercise training improves physical function and emotional status in people with heart failure, resulting in improved QOL (Taylor 2014). It has been reported that exercise training can reduce coagulation potential and enhance fibrinolytic potential in both healthy people and people with heart disease (Womack 2003). Furthermore, exercise‐based CR has been shown to improve the risk factor parameter of neurological events such as triglycerides, high‐density lipoprotein cholesterol, and nitric oxide in people with heart disease (Rankovic 2012). However, there is little evidence describing the effects of exercise training on mortality, morbidity, or QOL in people with implantable VADs (Allen 2010).
Why it is important to do this review
The European Society of Cardiology does not provide guidance on whether exercise‐based CR is likely to be an effective intervention for people with VADs (Ponikowski 2016). Recently, two studies reported the beneficial effects of exercise‐based CR on functional capacity and QOL by performing systematic reviews and meta‐analyses (Ganga 2017; Mahfood 2017). However, these two systematic reviews have some limitations relating to study design. First, both systematic reviews included studies with study designs that produce inherent limitations (e.g. non‐randomised, retrospective studies). Second, the participants were people with implantable or extracorporeal VADs, which need to be considered separately. A meta‐analysis of RCTs was therefore needed to examine the effects of exercise‐based CR in people with implantable VADs. As the use of VADs will continue to rise due to the growing number of people with end‐stage heart failure, it is necessary to clarify the effectiveness of exercise‐based CR for people with VADs (Corra 2012). This review aimed to determine the benefits and harms of exercise‐based CR for people with implantable VADs.
Objectives
To determine the benefits and harms of exercise‐based cardiac rehabilitation (CR) for people with implantable ventricular assist devices (VADs).
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) regardless of cluster or individual randomisation were eligible, but only individually randomised trials were included, as no relevant cluster RCTs were identified. In addition, full‐text studies, those published as abstract only, and unpublished data were eligible. However, the only relevant studies identified were full‐text publications.
Types of participants
We included participants 18 years of age or older, with a diagnosis of heart failure with an implantable VAD. We excluded participants with an extracorporeal VAD or total artificial heart.
Types of interventions
We included trials comparing exercise‐based CR with usual care. Exercise‐based CR is defined as a supervised or unsupervised inpatient, outpatient, community‐ or home‐based intervention that includes some form of exercise training applied to a cardiac patient population. The intervention could be exercise training alone or exercise training in addition to psychosocial and/or educational interventions (i.e. 'comprehensive CR'). Usual care could include standard medical care such as drug therapy, but without any form of structured exercise training or advice.
Types of outcome measures
Primary outcomes
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Mortality: all‐cause and cardiovascular
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Rehospitalisation: all‐cause and cardiovascular events
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Serious adverse events: defined as participants who could not complete the study due to device‐ and non‐device‐related adverse events
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Heart transplantation
Secondary outcomes
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Exercise capacity: peak oxygen consumption (peak VO2: mL/kg/min) or other measures, e.g. 6‐minute walking distance (6MWD: m)
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Health‐related QOL assessed by validated questionnaires, e.g. 36‐item Short Form Health Survey (SF‐36) (points), Minnesota Living with Heart Failure Questionnaire (points)
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Cost
The reporting of one or more of the outcomes listed here in the trial was not an inclusion criterion for the review.
Search methods for identification of studies
Electronic searches
We identified trials through systematic searches of the following bibliographic databases on 3 October 2017.
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Cochrane Central Register of Controlled Trials (CENTRAL) Issue 9 of 12, 2017 in the Cochrane Library
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Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, MEDLINE Daily and MEDLINE (Ovid, 1946 to 3 October 2017)
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Embase (Ovid, 1980 to 2017 Week 40)
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PsycINFO (Ovid, 1806 to September Week 4 2017)
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Conference Proceedings Citation Index‐S (CPCI‐S) on the Web of Science (Thomson Reuters, 1990 to 3 October 2017)
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CINAHL (Cumulative Index of Nursing and Allied Health Literature) (EBSCO, 1937 to 3 October 2017)
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LILACS (Latin American and Caribbean Health Sciences Literature) (BIREME, 1982 to 3 October 2017)
The search strategy for MEDLINE (Ovid) (Appendix 1) was adapted for use in the other databases. The Cochrane sensitivity‐maximising RCT filter was applied to MEDLINE (Ovid) (Lefebvre 2011), and adaptations of the filter were applied to the other databases, except CENTRAL. See Appendix 1 for all of the search strategies used.
We also conducted a search of ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/) on 10 August 2017.
We searched all databases from their inception to the present, and we imposed no restriction on the language of publication or publication status.
Searching other resources
We checked the reference lists of all primary studies and review articles for additional references. We furthermore contacted experts in the field to ask if they knew of any ongoing or unpublished trials.
Data collection and analysis
Selection of studies
Two review authors (SY and KH) independently screened the titles and abstracts of all potentially relevant studies identified as a result of the search, and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. In case of disagreements, other review authors were asked to arbitrate (EO and RM). SY and KH retrieved the full‐text reports/publications, and independently screened the full texts and identified studies for inclusion. SY and KH also identified and recorded reasons for the exclusion of ineligible studies. Any disagreements were resolved through discussion or by consulting other review authors (EO and RM) when necessary. The review authors identified and excluded duplicates, and collated multiple reports of the same study so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table.
Data extraction and management
A data collection form that had been piloted on at least one study in the review was used to record study characteristics and outcome data. Two review authors (SY and KH) extracted characteristics from the included studies, as follows.
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Methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and location, study setting, and date of study.
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Participants: the number of people randomised, the number of people completing treatment, the number of people who withdrew or were lost to follow‐up, mean age, age range, gender, severity of condition, diagnostic criteria, inclusion criteria, and exclusion criteria.
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Interventions: intervention, comparison, concomitant medications, and excluded medications.
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Outcomes: primary and secondary outcomes specified and collected, and time points reported.
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Notes: funding for trial, and notable conflicts of interest of trial authors.
Two review authors (SY and KH) independently extracted outcome data from the included studies and checked each other's data extraction. One review author (SY) transferred data into the Review Manager 5 file (RevMan 2014). SY and KH double‐checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (KH) spot‐checked study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Two review authors (SY and KH) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreements were resolved by discussion, by involving other review authors (EO and RM), or by contacting the authors of the included studies. We assessed risk of bias according to the following domains.
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Random sequence generation
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Allocation concealment
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Blinding of participants and personnel
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Blinding of outcome assessment
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Incomplete outcome data
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Selective outcome reporting
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Other bias, e.g. industry funding
We graded each potential source of bias as high, low, or unclear risk, and provided a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We summarised the 'Risk of bias' judgements across different studies for each of the domains listed. Where information on risk of bias was related to unpublished data or correspondence with a trialist, we noted this in the 'Risk of bias' table.
When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome.
Assessment of bias in conducting the systematic review
We conducted the review according to the published protocol (Yamamoto 2016a).
Measures of treatment effect
We planned to analyse dichotomous data as risk ratios (RR) with 95% confidence intervals (CIs) but no such data was available to analyse.
We analysed continuous data as mean difference (MD) or standardised mean difference (SMD) with 95% CIs. The MD was the absolute difference between the mean value in two groups in a trial. The SMD was used as a summary statistic in the meta‐analysis when the studies all assessed the same outcome but measured it in a variety of ways. We entered data presented as a scale with a consistent direction of effect. When the standard deviation (SD) for change from the baseline was not available, we calculated the SDs using the Review Manager 5 calculator. Where appropriate, we combined the results from included studies for each outcome to give an overall estimate of treatment effect.
Unit of analysis issues
We included only individually randomised trials and synthesised the relevant information.
Dealing with missing data
We planned to contact investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study was identified as abstract only). Where this was not possible, and the missing data were thought to introduce serious bias, we would have explored the impact of including such studies in the overall assessment of results by sensitivity analysis. However, this was not applicable to this review. The denominator for each outcome in each study was the number randomised minus any participants whose outcomes were known to be missing.
Assessment of heterogeneity
We used I² and Chi² statistics to measure heterogeneity among the trials in each analysis. If we identified substantial heterogeneity (e.g. I² score of > 50% and P < 0.05), we reported it and explored possible causes using prespecified subgroup analysis. However, we did not perform subgroup analyses because all results of I² scores were less than 50%.
Assessment of reporting biases
We planned that if we were able to pool more than 10 trials, we would create and examine a funnel plot to explore publication bias by assessing funnel plot asymmetry visually. However, we did not perform this analysis due to the small number of included trials.
Data synthesis
We undertook meta‐analyses only where this was meaningful, that is if the treatments, participants, and the underlying clinical questions were similar enough for pooling to make sense. We pooled data from each study using random‐effects modelling where appropriate, as we needed to consider the difference between the interventions in the two studies.
'Summary of findings' table
We created a 'Summary of findings' table using the following outcomes.
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Mortality due to all causes
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Mortality due to cardiovascular event
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Rehospitalisation due to cardiovascular event
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Serious adverse events
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Health‐related QOL
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Heart transplantation
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Cost
One author (SY) used the five GRADE domains (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of evidence as it relates to those studies that contribute data to the meta‐analyses for the prespecified outcomes. We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), employing GRADEpro software (GRADEproGDT 2017). We justified all decisions to downgrade the quality of studies using footnotes, and made comments to aid readers' understanding of the review where necessary. A second review author (KH) checked the assessment.
Subgroup analysis and investigation of heterogeneity
We planned to carry out the following subgroup analyses for primary outcomes if we obtained an I² score of greater than 50%.
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Length of follow‐up (< 12 months or ≧ 12 months)
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Types of VAD (continuous flow or pulsatile flow)
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Exercise setting (hospital only, home only, or both settings)
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Type of rehabilitation (exercise only or comprehensive CR)
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Year of publication (before 2000, or in or after 2000)
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Prospective trial registration (there is proof that trials actually took place, or none).
We planned to use the formal test for subgroup interactions in Review Manager 5 (RevMan 2014), as well as adding the year of publication in order to assess the influence of usual care. The standard of usual care has changed with the times: beta‐blockers, angiotensin‐receptor blockers, and angiotensin‐converting enzyme inhibitors became standard therapy for heart failure after the year 2000 according to a meta‐analysis, Shekelle 2003, and guideline (Hunt 2001). We furthermore checked if the trial was prospectively registered or obtained registration information from the ethics committee that approved the trial. We thereafter planned to conduct a subgroup analysis according to whether the trial was registered/approved or not. However, we did not perform subgroup analyses because all results of I² scores were less than 50%.
Sensitivity analysis
We planned to carry out a sensitivity analysis for primary outcomes if the high risk of bias of some of the included studies affected the results. We defined 'high risk' as a study having: a high risk in terms of random sequence generation; inadequate allocation concealment; and greater than 20% of data missing (Tierney 2005). We planned to carry out the following sensitivity analyses.
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Only including studies with a low risk of bias
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Excluding trials with 10 or fewer events
However, trials were not at high risk of bias (i.e. random sequence generation: low; inadequate allocation concealment: low; and less than 20% of data missing). Furthermore, there were no adverse events in one trial, and two serious adverse events in the other trial. We therefore did not perform a sensitivity analysis.
Results
Description of studies
See: Characteristics of included studies and Characteristics of excluded studies.
Results of the search
We identified a total of 478 records after removal of duplicates, and retrieved the full texts of 22 records after screening titles and abstracts (Figure 1). Of the remaining records, we excluded a further 14 after full‐text review: 7 studies were non‐randomised; 2 studies were review articles; 2 studies had inappropriate interventions; and 3 studies had inappropriate participants. One of the remaining records was an RCT (Adamopoulos 2013), however it was not clear which types of VAD (i.e. implantable or extracorporeal) were assessed, and the details of the results were unclear. We tried to contact the author, but were unable to obtain the author's address. We therefore classified this trial as awaiting classification (see Characteristics of studies awaiting classification). We included a total of two trials (seven reports) in this review.
Study flow diagram.
Included studies
We included two studies with a total of 40 participants in this review. Both trials had small sample sizes and were single‐centre studies. The duration of follow‐up was six to eight weeks. One trial included people with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels 1 and 2 (Hayes 2012), and the other trial included levels 1 to 4 (Kerrigan 2014). INTERMACS levels of 1 to 7 describe people who have severe symptoms at rest before VAD implantation. Although one trial was undertaken in the United States and the other in Australia, neither trial provided details on the ethnicity of participants. The mean age of participants in the included studies ranged from 40 to 60 years. Seventy‐five per cent of recruited participants were men. Both trials evaluated exercise capacity (e.g. peak VO2 or 6MWD) and QOL, although neither reported mortality and major adverse cardiovascular events (MACE). Exercise‐based cardiac rehabilitation was aerobic exercise training using a treadmill, in Hayes 2012, or treadmill and cycle ergometer, in Kerrigan 2014, and one study also included resistance training (Hayes 2012). Exercise‐based training was performed approximately three times per week for six to eight weeks. Exercise intensity was 50% of VO2 reserve, or ranged from 60% to 80% of heart rate reserve. In one trial (Kerrigan 2014), usual care did not include an individualised exercise prescription, but participants were told to continue to follow their physician's instructions regarding care, including daily walking. In the other trial (Hayes 2012), usual care included a prescribed exercise regimen of regular walking. Details of the included studies are provided in the Characteristics of included studies table. Both trials were
supported by internal grants.
Excluded studies
We excluded 14 studies for the reasons provided in the Characteristics of excluded studies table. Many studies were excluded because they were not RCTs.
Risk of bias in included studies
'Risk of bias' assessments are indicated in Figure 2 and Figure 3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Both trials reported that a computerised algorithm was used to randomly assign participants, and the allocation sequence was concealed using opaque envelopes.
Blinding
All participants were divided into an exercise group and a usual care group, and were instructed not to discuss their intervention. Due to the nature of the exercise intervention, blinding was not possible. However, as assessors were blinded in both trials, we considered the risk of detection bias to be low.
Incomplete outcome data
One trial reported no loss to follow‐up or missing data in the study (Hayes 2012). The other trial reported that two participants in the exercise group did not complete the study: one participant moved away and the other experienced a driveline infection (dropout rate 11%), and one participant in the usual care group did not complete the study due to an infection (dropout rate 13%) (Kerrigan 2014).
Selective reporting
Both trials were registered with a clinical trial registry and reported on all outcomes.
Other potential sources of bias
There were no significant differences between the groups at baseline in both trials. However, one trial underwent analysis against only included participants whose results were known (Kerrigan 2014). The other trial underwent analysis against all participants (no dropouts) (Hayes 2012).
Effects of interventions
See summary of findings Table for the main comparison.
Data from 2 trials involving a total of 40 participants were available for assessing the effects of interventions.
Primary outcomes
Mortality
Neither trial reported on mortality.
Rehospitalisation
Neither trial reported on rehospitalisation.
Serious adverse events
One trial reported no adverse events (Hayes 2012). The other trial reported two serious adverse events: one participant in the exercise group had a driveline infection after a case of acute cholecystitis, and one participant in the usual care group had an infection (Kerrigan 2014). These two participants did not complete the study. A total of two serious adverse events were observed across the one trial. Furthermore, a total of four participants in each group required visits to the emergency department, although these participants did complete the study. One participant was transferred to the emergency department due to a syncopal episode immediately after an exercise session. Three other participants in the exercise group visited the emergency department more than three hours after completing their last exercise session, and one of them required overnight hospitalisation due to epistaxis. Four participants in the usual care group visited the emergency department, three of whom required overnight hospitalisation due to oedema, infection, and anaemia.
Heart transplantation
No trial reported on heart transplantation.
Secondary outcomes
Exercise capacity
Peak VO2 and 6MWD were measured to assess exercise capacity in both trials. In both trials, peak VO2 was measured using a respiratory gas analyser, and 6MWD was performed using the American Thoracic Society guidelines (ATS Committee 2002).
For peak VO2, we included 2 studies involving 37 participants in the analysis. Exercise capacity was measured at baseline and at six weeks in one trial (Kerrigan 2014), and baseline and eight weeks in the other trial (Hayes 2012). One trial reported that the increase in peak VO2 was significant in the exercise group only (Kerrigan 2014), and the other trial reported a significant increase in peak VO2 in both groups (Hayes 2012). In a pooled analysis of the two studies, there was no evidence of a difference in peak VO2 at the end of follow‐up between the groups when comparing the exercise group with usual care (mean difference (MD) 2.05 mL/kg/min, 95% confidence interval (CI) ‐1.72 to 5.82) (Analysis 1.1). Similarly, one trial reported that the increase in 6MWD was significant in the exercise group only (Kerrigan 2014), and the other trial reported a significant increase in 6MWD in both groups (Hayes 2012). In a pooled analysis of the two studies, there was no evidence of a difference in 6MWD at the end of follow‐up between groups when comparing the exercise group with the usual care group (MD 45.56 m, 95% CI ‐6.72 to 97.85) (Analysis 1.2).
Health‐related quality of life
Summary scores from the SF‐36 and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were measured as QOL. We included 2 trials involving 37 participants in this analysis. One trial reported that the KCCQ summary score improved by 14.4 points in the exercise group compared with 0.5 points in the usual care group (Kerrigan 2014). The other trial reported that the SF‐36 total score improved by 29.2 points in the exercise group compared with 16.3 points in the usual care group (Hayes 2012). We calculated the SDs using the Review Manager 5 calculator because we did not obtain the SDs for changes from baseline for one study (Kerrigan 2014). In a pooled analysis of the two studies, there was a large difference in QOL between groups when comparing the exercise group with usual care (standardised mean difference (SMD) 0.88, 95% CI ‐0.12 to 1.88; 37 participants; 2 studies; very low‐quality evidence; Analysis 1.3). This SMD size is considered to be a large effect according to the Cohen paper (Cohen 1988), as cited in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). However, the young age of the participants, high risk of performance bias, small sample size, and wide confidence intervals resulted in an assessment of very low‐quality evidence for this outcome (summary of findings Table for the main comparison).
Cost
Neither trial reported on cost analysis.
Subgroup analysis
We did not perform subgroup analyses because all results of I² scores were less than 50%.
Discussion
Summary of main results
We included 2 RCTs involving a total of 40 participants in this review. Exercise‐based CR consisted of aerobic or resistance training or both three times per week for six to eight weeks. The studies were conducted in the United States, Kerrigan 2014, and Australia, Hayes 2012. One trial showed improvements in exercise capacity (peak VO2 and 6MWD) and QOL in the exercise group but not in the usual care group (Kerrigan 2014). The other trial reported that exercise capacity and QOL were improved in both groups (Hayes 2012). Pooled analyses of the two studies showed no evidence that CR improved exercise capacity, and a large difference in QOL between groups. However, the evidence for QOL was limited due to the young age of the participants, high risk of performance bias, small sample size, and wide confidence intervals, which resulted in very low‐quality evidence.
Furthermore, we identified several problems in these trials. First, the period of exercise for people with implantable VADs was very short at 1.5 to 2 months compared with other systematic reviews on exercise‐based cardiac rehabilitation that included studies of more than 3 months' duration (Anderson 2016; Taylor 2014; Yamamoto 2016). Second, the usual care group in one trial did not receive an individualised exercise prescription (Kerrigan 2014), but were told to continue to follow their physician's instructions regarding care including daily walking. In the other trial (Hayes 2012), the usual care group received an exercise programme. The frequency of exercise sessions or adherence in the Kerrigan study might therefore be lower than that in the Hayes study (Hayes 2012; Kerrigan 2014), although both control groups received similar care. Third, the CR group was prescribed a bicycle training programme in the gym, whereas the usual care group received a walking programme (Hayes 2012). It was possible that the method of measuring the peak VO2 by bicycle ergometer is biased towards showing improvement in the CR group (Hayes 2012). Furthermore, a total of two serious adverse events associated with infection was observed in one of the two trials (CR group: 1/25 (4%) versus usual care: 1/15 (7%)) (Kerrigan 2014). In addition, a total of four participants in each group required visits to the emergency department. Although exercise‐based CR might have no effect on adverse events, we could not show that exercise‐based CR is safe for people with implantable VADs because the quality of the evidence for serious adverse events was very low. Furthermore, due to a lack of data we were not able to assess the effect of exercise‐based CR on our primary outcomes of mortality and rehospitalisation, and the secondary outcome of cost.
Overall completeness and applicability of evidence
The generalisability of this review is limited by the low average age and the very low number of participants. Data from the Centers for Medicare & Medicaid Services in the United States reported that the mean age of people with VADs was 61.8 years, and males accounted for 80.2% of people with VADs (Khazanie 2014). In our meta‐analysis, one trial set in Australia reported the mean age of participants as less than 50 years, with males making up 85% of people with implantable VADs (Hayes 2012). The other trial set in the United States reported that the mean age of participants was 55 years, and 73% of participants were male (Kerrigan 2014). Participants in these studies were therefore a little younger compared with previous data. Types of intervention (aerobic and resistance training) in trials was properly prescribed according to AHA guidelines (Fletcher 2013). However, the term of exercise‐based CR was very short compared with previous studies (Anderson 2016; Taylor 2014; Yamamoto 2016). For this reason, it is possible that the effect of the intervention is not sufficiently shown in this meta‐analysis.
Quality of the evidence
Both of the included trials reported sequence generation, allocation concealment, and outcomes according to the registered protocol, and were judged to be at low risk of bias.
However, as the blinding of participants and personnel, or other potential sources of bias (not intention‐to‐treat analysis), were poorly described, we downgraded the quality of evidence by one level for the study limitations domain in serious adverse events and QOL outcomes. We judged the consistency of the effect domain as non‐serious due to low heterogeneity in both outcomes. For the indirectness domain, we downgraded the quality of evidence by one level in both outcomes because the mean age of participants was a little younger compared with previous data. For the imprecision domain, we downgraded the quality of evidence by two levels in both outcomes because the sample size was very small, and 95% CIs were very wide in both outcomes. In addition, serious adverse events were not reported in one trial. Lastly, as there were only two trials, we could not assess the publication bias domain. For these reasons, we judged the quality of evidence to be very low.
Potential biases in the review process
The number of people with VADs has increased rapidly in recent years, with a relative increase of 324% from 2006 to 2011, and a 460% increase among elderly people (Khazanie 2014; Lampropulos 2014). For this reason, further systematic reviews and meta‐analysis could be utilised in this field.
We conducted this review according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Furthermore, we undertook a comprehensive electronic search to identify published and unpublished studies, and synthesised and analysed data according to our review protocol (Yamamoto 2016a). We also searched conference abstracts. However, most abstracts focused on the same trials, or lacked sufficient data including authors' contact information (Adamopoulos 2013). It is therefore possible that we did not obtain all relevant data.
Agreements and disagreements with other studies or reviews
Our findings demonstrated that the effectiveness of exercise‐based CR was very uncertain due to very low‐quality evidence. The previous meta‐analysis of exercise‐based CR for people with implantable VADs reported that exercise‐based CR significantly increased peak VO2 by 3.00 mL/kg/min and 6MWD by 60.06 meters, and improved QOL (Mahfood 2017). The other review also reported similar results (Ganga 2017). However, some problems existed in these previous reviews, which included participants with either implantable or extracorporeal VADs, or that they were not RCTs. Furthermore, in our review the length of the training period was very short (i.e. from six to eight weeks). Future research therefore needs to address the long‐term benefits of exercise training after VADs implantation. In addition, only one trial in this analysis featured an exercise‐based CR of both aerobic training and resistance training (Hayes 2012). Resistance training alone has been found to improve exercise capacity (i.e. peak VO2 and 6MWD) (Jewiss 2016; Yamamoto 2016).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Comparison 1 Exercise‐based cardiac rehabilitation versus usual care, Outcome 1 Exercise capacity: peak VO2 (mL/kg/min).
Comparison 1 Exercise‐based cardiac rehabilitation versus usual care, Outcome 2 Exercise capacity: 6‐minute walking distance (m).
Comparison 1 Exercise‐based cardiac rehabilitation versus usual care, Outcome 3 Quality of life.
| Exercise‐based cardiac rehabilitation compared to usual care for people with implantable ventricular assist devices | ||||||
| Patient or population: people with implantable ventricular assist devices | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with usual care | Risk with exercise‐based cardiac rehabilitation | |||||
| Mortality due to all causes ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Mortality due to cardiovascular event ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Rehospitalisation due to cardiovascular event ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Serious adverse events: infection | ‐ | ‐ | ‐ | ‐ | ‐ | 1 trial reported no adverse events. The other trial reported 2 serious adverse events: 1 participant in the cardiac rehabilitation group had a driveline infection, and 1 participant in the usual care group had an infection. These 2 participants did not complete the study. A total of 2 serious adverse events were observed across the 1 trial. |
| Health‐related quality of life | ‐ | SMD 0.88 SD higher | ‐ | 37 | ⊕⊝⊝⊝ | A higher score means better quality of life. |
| Heart transplantation ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| Cost ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Blinding of participants and personnel, or other potential sources bias (not intention‐to‐treat analysis) were poorly described in the included studies, therefore quality of evidence was downgraded by one level for risk of bias. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Exercise capacity: peak VO2 (mL/kg/min) Show forest plot | 2 | 37 | Mean Difference (IV, Random, 95% CI) | 2.05 [‐1.72, 5.82] |
| 2 Exercise capacity: 6‐minute walking distance (m) Show forest plot | 2 | 37 | Mean Difference (IV, Random, 95% CI) | 45.56 [‐6.72, 97.85] |
| 3 Quality of life Show forest plot | 2 | 37 | Std. Mean Difference (IV, Random, 95% CI) | 0.88 [‐0.12, 1.88] |
