Exercise-based cardiac rehabilitation for adults with atrial fibrillation

  • Protocol
  • Intervention

Authors

  • Signe S Risom,

    Corresponding author
    1. Rigshospitalet, Copenhagen University Hospital, Department of Cardiology, The Heart Centre, Copenhagen, Denmark
    2. Copenhagen University, Faculty of Health and Medical Sciences, Copenhagen, Denmark
    • Signe S Risom, Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, 2100, Denmark. signe.stelling.risom@rh.regionh.dk.

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  • Ann-Dorthe Zwisler,

    1. Rigshospitalet, Copenhagen University Hospital, Department of Cardiology, The Heart Centre, Copenhagen, Denmark
    2. National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
    3. Holbaek Hospital, Department of Cardiology, Holbaek, Denmark
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  • Pernille Palm Johansen,

    1. Rigshospitalet, Copenhagen University Hospital, Department of Cardiology, The Heart Centre, Copenhagen, Denmark
    2. Copenhagen University Hospital Bispebjerg, Department of Cardiology, Copenhagen, Denmark
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  • Kirstine L Sibilitz,

    1. Rigshospitalet, Copenhagen University Hospital, Department of Cardiology, The Heart Centre, Copenhagen, Denmark
    2. Copenhagen University, Faculty of Health and Medical Sciences, Copenhagen, Denmark
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  • Jane Lindschou,

    1. Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, Denmark
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  • Rod S Taylor,

    1. University of Exeter Medical School, Institute of Health Research, Exeter, UK
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  • Christian Gluud,

    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark
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  • Jesper H Svendsen,

    1. Rigshospitalet, Copenhagen University Hospital, Department of Cardiology, The Heart Centre, Copenhagen, Denmark
    2. The Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), Copenhagen, Denmark
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  • Selina K Berg

    1. Rigshospitalet, Copenhagen University Hospital, Department of Cardiology, The Heart Centre, Copenhagen, Denmark
    2. Gentofte Hospital, Department of Cardiology, Gentofte, Denmark
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The aim of this review is to assess the benefits and harms of rehabilitation programmes consisting of a physical exercise component that focuses on increasing exercise capacity, and may include a psychoeducational intervention that focuses on improving mental health and the patient’s self management skills, compared with no intervention or treatment as usual in adults who currently have AF or have been treated for AF.

Background

Description of the condition

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia (irregular heart beat). It affects 1.5% to 2% of the population in Europe and North America (Ball 2013; Camm 2012; Nguyen 2013). The incidence of AF is increasing, mainly due to an ageing population (Ball 2013; Camm 2012; Go 2001; Ruigomez 2005; Stewart 2001). AF is associated with increased mortality, incidence of stroke and other thromboembolic events, and heart failure (Camm 2010; Kirchhof 2007; Stewart 2002). As such, AF has now become a health, social, and economic burden (Brenyo 2011) and is set to worsen over the coming decades (Camm 2012).

Patients with AF can experience palpitations, shortness of breath, fatigue, dizziness, and syncope (fainting) (Camm 2010). An American observational study of 655 individuals found that AF symptoms are a negative predictor for patients' physical capacity (Atwood 2007). Symptoms and duration of AF episodes vary within the individual and from individual to individual (Camm 2010). Five different types of AF exist: first-diagnosed AF, paroxysmal AF, persistent AF, long-standing persistent AF, and permanent AF (Camm 2010). First-diagnosed AF is the term given to the condition when a patient presents with AF for the first time, irrespective of the duration of the arrhythmia or the presence and severity of AF-related symptoms. Paroxysmal AF is self terminating, and usually the rhythm converts spontaneously to sinus rhythm within 48 hours. In persistent AF, the AF episode lasts longer than seven days or requires cardioversion to terminate the episode. When AF duration exceeds one year, AF is considered long-standing persistent. Permanent AF is when AF is accepted without further attempts of conversion, or these attempts have been shown to be unsuccessful or short-lasting (Camm 2010; Lafuente-Lafuente 2012).

Treatment of AF focuses on re-establishing and maintaining sinus rhythm (so-called rhythm control) and protecting the patient against thromboembolic complications (Camm 2010). When AF is longer-lasting (as in persistent AF, long-standing persistent AF and permanent AF) the therapeutic goal is to control the heart rate in the range of 60 to 80 beats/minute at rest and 90 to 115 beats/minute when active (rate control). This is achieved by treatment with antiarrhythmic drugs which block the function of the atrioventricular node (Brenyo 2011; Camm 2010). In addition, treatment should aim at reducing symptoms and discomfort related to AF (Brenyo 2011).

Acute management of patients with AF includes acute conversion to sinus rhythm, protection against thromboembolic events and acute improvement of cardiac function. However, AF recurrence is common despite administration of antiarrhythmic drugs to maintain normal sinus rhythm after cardioversion (Camm 2010).

Radiofrequency ablation is sometimes used to treat AF. It is an invasive treatment developed to cure AF. In a Cochrane systematic review, Chen et al found that ablation has a better effect in inhibiting recurrence of AF compared with medical therapies, but there is limited evidence demonstrating that sinus rhythm is maintained after ablation and after long-term follow-up (Chen 2012). Despite the results of the systematic review, ablation seems to have an increasingly accepted role in the treatment of AF (Brenyo 2011; Calkins 2009; Camm 2010).

Studies have found that quality of life is impaired in individuals with AF compared with healthy controls, the general population, or patients with coronary heart disease in the western world (Dabrowski 2010; Kang 2004; Thrall 2006). Studies have suggested that maintaining sinus rhythm improves quality of life and may be associated with improved survival (Dabrowski 2010; Dorian 2000; Dorian 2002; Kang 2004; McCabe 2011; Thrall 2006). Patients’ lack of self management skills causes distress when trying to handle symptoms of AF such as palpitations, dyspnoea, and fatigue. Seemingly, patients with AF report that they have not received education or help from health professionals regarding how to live with AF (McCabe 2011).

Taken together, the consequences of AF are reduced quality of life and physical capacity, increased healthcare costs, readmission to hospital, loss of income, increased morbidity, and mortality.

Description of the intervention

Cardiac rehabilitation seemingly benefits patients with coronary heart disease and those with heart failure in terms of physical, mental, cognitive, and social function; and a reduction in morbidity, mortality, and healthcare costs (Taylor 2014; Heran 2011; Piepoli 2010).

Cardiac rehabilitation is a comprehensive intervention that includes the components of exercise training, education, psychosocial management, and a behavioural modification programme designed to improve the physical and emotional conditions of patients with heart disease (Piepoli 2010). Cardiac rehabilitation for patients with coronary heart disease can also include patient assessment, nutritional counselling, and risk factor management focusing on lipids, blood pressure, weight, diabetes mellitus, and smoking cessation (Piepoli 2010).

Studies regarding rehabilitation for patients with AF have employed varies training protocols which show the uncertainty as to what kind of physical exercise patients with AF should perform. In a review of 36 studies (of which 6 were randomised controlled trials (RCTs); in total 1512 patients) the following exercise programme was recommended: (1) physical exercise training should include three or more weekly sessions of moderate intensity whole-body aerobic activities (such as walking, jogging, cycling, or rowing); (2) training should include at least 60 minutes per session and continue for a minimum of three months; and (3) physical exercise training sessions should also include segments of stretching, balance exercises, resistance training, and callisthenics (Giacomantonio 2013). Seemingly, the review included studies with a variety of different designs and did not include any rehabilitation components other than exercise training. Further, there was no protocol published before the review was conducted, and risk of bias and risk of random errors were not assessed in trial sequential analyses.

While current recommendations for rehabilitation for patients with coronary heart disease, heart failure and heart valve replacement suggest that a psychosocial or educational support, or both, should be offered (National Board of Health 2013), this has not been explored in patients with AF. A systematic review including 30 studies of mixed designs exploring rehabilitation for patients living with permanent AF, reported that no studies had included psychosocial support or education, or both, with the aim of improving the patient’s self management skills (Lowres 2013).

How the intervention might work

A RCT of 30 patients showed that exercise capacity and heart rate variability improved after two months of exercise training in those with permanent AF (Hegbom 2006; Hegbom 2007). A prospective pilot study of 10 patients, found that regular moderate physical activity among older individuals with AF decreases the ventricular rate at rest and during exercise, while increasing exercise capacity (Plisiene 2008). A prospective study of 20 patients showed that patients' physical capacity increases significantly after physical exercise (a 15% increase measured by VO2 max) (Mertens 1996). In a RCT of 49 patients with permanent AF, Osbak and colleagues concluded that exercise capacity measured by VO2 max improved significantly after 12 weeks of exercise training (Osbak 2011).

In a systematic review, Giacomantonio and colleagues showed that routine moderate intensity physical activity can improve exercise capacity, the capacity to carry out activities of daily living, and overall quality of life for persons living with AF (Giacomantonio 2013).

At the same time a qualitative study concluded that many patients with AF are less likely to perform sports activities because they are afraid to use their body (Hansson 2004).

Possible harmful effects of physical exercise in patients with AF have not been investigated in RCTs but Mertens 1996 found in a small clinical trial that it is safe for patients with permanent AF to participate in exercise training programmes, although patients could experience AF specific adverse events during training, e.g. AF and other arrhythmias (Mertens 1996).

We have not been able to find examples of integrated rehabilitation programmes for patients with AF or guidelines outlining recommendations for rehabilitation for patients with AF, but Hendriks 2012 found in a RCT, that follow-up in a nurse-led AF clinic reduced cardiovascular hospitalisations and mortality significantly compared with usual care. In addition, they found that the AF-related knowledge level was higher in the nurse-led group at one year follow-up compared with the control group that received usual care (Hendriks 2014).

In summary, studies show that exercise training has a positive effect on patients' heart rate and exercise capacity, and quality of life increases after exercise training.

Why it is important to do this review

As described, we find that rehabilitation for patients with AF is an under-researched area and to our knowledge there are no international or national guidelines regarding rehabilitation for patients with AF. Nevertheless, studies suggest that rehabilitation consisting of physical exercise plus a psychoeducational component would increase patients’ physical and mental health.

The benefits and harms of rehabilitation programmes, including an exercise component or a psychoeducational component, or both, for adults with AF are unclear. We have not been able to identify any meta-analysis or systematic reviews that have summarised the evidence in a systematic manner.

Objectives

The aim of this review is to assess the benefits and harms of rehabilitation programmes consisting of a physical exercise component that focuses on increasing exercise capacity, and may include a psychoeducational intervention that focuses on improving mental health and the patient’s self management skills, compared with no intervention or treatment as usual in adults who currently have AF or have been treated for AF.

Methods

Criteria for considering studies for this review

Types of studies

We will include RCTs investigating rehabilitation versus no intervention or treatment as usual for AF patients. We will include trials irrespective of language, publication year, publication type, and publication status.

Types of participants

Adult patients (18 years old or older) of both sexes and of all ethnicities with current AF, or who have been treated for AF, are eligible for the review. We will include patients irrespective of the type of AF and the treatment of the arrhythmia.

Types of interventions

Experimental intervention

The experimental intervention is classified as: any rehabilitation programme in an inpatient, outpatient, community-based or home-based setting that is applied to an AF patient. The rehabilitation programme must include a physical exercise component, and it may include a psychoeducational component. The exercise component must focus on strengthening the patient's exercise capacity and preferably improve rate control (i.e. reduced maximum heart rate during exercise). There will be no restrictions in the length, intensity, or content of the training programme. The psychoeducational component must focus on psychosocial support or education, aiming to improve the patient's self management skills.

Control intervention

We will include the following control interventions.

  • Treatment as usual (e.g. standard medical care, such as drug and ablation therapy).

  • No intervention.

Co-interventions

We will allow any type of co-interventions as long as they are equally delivered in the experimental group and in the control group. Co-interventions can include: drug delivery, ablation techniques, or diet interventions.

Types of outcome measures

We will assess all outcomes at two time points:

  • end of intervention (as defined by the trialists); and

  • longest available follow-up.

Primary outcomes
  1. Mortality: all-cause mortality and cardiovascular mortality.

  2. Serious adverse events: defined as any untoward medical occurrence that is life threatening, resulting in death, or is persistent or leads to significant disability; or any medical event, which has jeopardised the patient or required intervention to prevent it; or any hospital admission or prolongation of existing hospital admission.

  3. Health-related quality of life using generic or disease specific validated instruments, e.g. Short Form-36 and Heart-Related Quality of Life.

Secondary outcomes
  1. Exercise capacity: any measure of exercise capacity including direct measurement of VO2 peak or VO2 max or indirect measures such as exercise time, walking distance, etc.

  2. Mean number of symptoms including palpitations, dyspnoea, dizziness, and attacks during the intervention period (Camm 2010).

  3. Proportion of participants that experience loss of employment.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases to identify trials.

  1. The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library.

  2. The Database of Abstracts of Reviews of Effectiveness (DARE) on The Cochrane Library.

  3. MEDLINE (OVID).

  4. EMBASE (OVID).

  5. CINAHL (EBSCO).

  6. PsycINFO (OVID).

  7. LILACS (Bireme).

  8. Conference Proceedings Citation Index-S (CPCI-S) on Web of Science (Thomson Reuters).

We will translate the preliminary search strategy for MEDLINE (OVID) (Appendix 1) for use in the other databases. We will apply the Cochrane sensitivity-maximising RCT filter to MEDLINE (Lefebvre 2011) and adaptations of it to the other databases where applicable. We will search the databases from their inception to the search date.

Searching other resources

In addition, we will search the following clinical trial registries to identify ongoing studies.

  1. ClinicalTrials.gov (www.clinicaltrials.gov).

  2. The World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/).

We will check the reference lists of relevant publications for any unidentified randomised trials. We will not impose any language restrictions. We will organise translation of studies that are written in languages that we do not comprehend.

Data collection and analysis

Selection of studies

Two authors (SSR and PPJ) will independently screen titles and abstracts of all publications obtained from searches to decide which studies meet the inclusion criteria according to types of studies, types of participants, and types of interventions. If in doubt, we will read the full article. We will exclude studies that do not meet the inclusion criteria. To help standardise this process, the authors will use the same checklist to register the study inclusion criteria. We will retrieve full text copies of all potentially relevant studies and store these electronically. The authors will resolve disagreements by discussion, and where necessary a third author (SKB) will be consulted.The study selection process will be documented using a PRISMA study selection flow chart, which will be presented in the review.

Data extraction and management

Two authors (SSR and PPJ) will independently extract data from the identified trials using standardised data extraction forms. Where data are presented both numerically (in tables or text) and graphically (in figures), we will use numeric data because of possible measurement error when estimating from graphs. A third author (SKB) will confirm all numeric calculations and extractions from graphs or figures. We will resolve any discrepancies by consensus. SSR will enter data into The Cochrane Collaboration's statistical software Review Manager (RevMan 2012). In those cases where there are not sufficient data or data are unclear in the published trial reports, we will contact authors, requesting them to clarify the missing information.

We will extract the following data.

  1. General information: published/unpublished, title, authors’ names, source, country, contact address, language of publication, year of publication, duplicate publication, funding.

  2. Study characteristics: design and duration.

  3. Interventions: type of physical exercise, type of rehabilitation programme (comprehensive and what elements or physical exercise only), setting (e.g. inpatient, outpatient, community-based or home-based setting), time after hospitalisation, type of control intervention/conventional care.

  4. Participants: inclusion and exclusion criteria, number of participants in intervention and control group, patient demographics such as sex and age, baseline characteristics including type of AF and symptoms, and losses to follow-up.

  5. Outcomes: mortality (all-cause mortality, cardiovascular mortality), serious adverse events defined as above, health-related quality of life using generic or disease specific validated instruments. Exercise capacity measured by, e.g. VO2 peak, or VO2 max, or walking distance. Mean number of symptoms including palpitations, dyspnoea, dizziness, and attacks during the intervention period, and proportion of participants that experience loss of employment.

  6. Risk of bias: please see Assessment of risk of bias in included studies below.

We will compare data from each intervention group of each parallel group trial. If any cross-over RCTs are identified, we will only use data from the first phase of the trial (i.e. before the cross-over).

Assessment of risk of bias in included studies

We will utilise The Cochrane Collaboration’s tool for assessing risk of bias to judge the risk of bias in the included trials. Two authors (SSR and PPJ) will independently assess the risk of bias and disagreements will be resolved by discussion (Higgins 2011a). We will provide assessments of risk of bias in the 'Risk of bias' table for each trial.

Overall risk of bias

We will categorise a trial as overall 'low risk of bias' if the trial is rated 'low risk of bias' in all the risk of bias domains listed below. Likewise, we will categorise a trial as overall 'high risk of bias' if the risk of bias is rated either 'uncertain risk of bias' or 'high risk of bias' in any domain out of all of the risk of bias domains listed below. We expect all trials to be categorised as 'overall high risk of bias' as it is not possible to blind participants and personnel (Savovic 2012; Wood 2008). We will therefore also categorise trials as overall 'lower risk of bias', if a trial is categorised as overall 'lower risk of bias' the trial is rated 'low risk of bias' in all the risk of bias domains listed below except ‘blinding of participants and personnel‘.

Generation of allocation sequence

Low risk of bias: Sequence generation is achieved using computer generated random numbers or a table of random numbers. Drawing lots, tossing a coin, shuffling cards, and throwing dice are adequate if performed by an independent adjudicator, or the method is unlikely to introduce selection bias.

• Uncertain risk of bias: Insufficient information to assess whether the method used could cause bias.

High risk of bias: The method used is improper and likely to be confounding (e.g. the sequence generation is not random).

Allocation concealment

• Low risk of bias: The method used will probably not cause bias on the final observed effect (e.g. allocation is controlled by a central and independent randomisation unit).

• Uncertain risk of bias: There is not enough information to assess whether the method used could cause bias on the estimate of effect.

• High risk of bias: The method used will probably cause bias on the final observed effect (e.g. the allocation sequence is known to the investigators).

Blinding of participants and personnel

Low risk of bias: Any intervention is delivered blinded to the patient or personnel and neither the patient nor the personnel are aware of which group the patient is allocated to.

Uncertain risk of bias: There is insufficient information to assess whether the patient or the personnel is blinded to the intervention.

High risk of bias: Neither the patient nor the personnel are blinded to the intervention.

Due to the type of intervention we will expect a high level of bias for this bias domain. This will apply to all studies as it is impossible to blind patients when the intervention consist of physical exercise and may include a psychoeducational intervention as well.

Blinding of outcome assessment

• Low risk of bias: If the trial investigators performing the outcome assessments, analyses, and calculations are blinded to the treatment allocation and this is described.

• Uncertain risk of bias: If the procedure of blinding is insufficiently described.

• High risk of bias: If blinding is not performed or the procedure cannot be classified as 'low risk of bias'.

Performance bias

Low risk of bias: Any co-interventions are delivered equally across intervention and control groups.

• Uncertain risk of bias: There is insufficient information to access whether co-interventions were present or equally delivered across groups, and that could put the trial at a risk of bias.

• High risk of bias: The co-interventions are not delivered equally across intervention and control groups.

Incomplete outcome data

• Low risk of bias: The number and reasons for dropouts and withdrawals are described and valid methods have been used to handle missing data, e.g. multiple imputations.

• Uncertain risk of bias: The trial gave the impression that there have been no dropouts or withdrawals, but that was not sufficiently described.

• High risk of bias: The crude estimate of effects will be biased if the effects are concluded on missing or incomplete data (e.g. dropouts or withdrawals), and the methods which have been used to handle missing data are unsatisfactory, e.g. last observation carried forward.

Selective outcome reporting

Low risk of bias: All the primary and clinically relevant outcomes of the trial have been reported, and the hierarchy of the outcomes are documented in a protocol before launch of randomisation.

• Uncertain risk of bias: Not all primary or clinically relevant outcomes are reported, or are not reported fully, or it is unclear whether data on these outcomes were reported or not.

• High risk of bias: Not all primary or clinically relevant outcomes have been reported, or if there is incongruence between the original protocol and the outcome measures used in the results.

For-profit-bias

Low risk of bias: The trial appears to be free of industry sponsorship or other kind of for-profit support by an organisation that may have an interest in a given result.

Uncertain risk of bias: it is unclear how the trial is funded.

High risk of bias: The trial is sponsored by the industry or has received other kind of for-profit support by an organisation that may have an interest in a given result.

Measures of treatment effect

We will express results of dichotomous outcomes as a risk ratio (RR) with 95% confidence intervals (CIs). For continuous outcomes we will estimate the mean difference (MD) between intervention groups. We prefer not to calculate effect size measures (standardised mean difference, SMD) (Higgins 2011b). However if different instruments are reported across trials that assess the same outcome (e.g. quality of life) we will calculate and pool effect sizes using SMD and transform the effect back to the units of one or more of the specific instruments.

Unit of analysis issues

If any cluster-RCTs are included, we will contact the trial authors to obtain an estimate of the intra-cluster correlation (ICC) where appropriate adjustments for the correlation between participants within clusters have not been made, or impute it using estimates from the other included trials, or from similar external trials.

Dealing with missing data

We will obtain missing data by contacting the authors of the trials if possible. If data remain unavailable, we will assess and discuss the impact of the missing data.

We will analyse dichotomous outcomes according to the intention-to-treat method (Higgins 2011c; Sterne 2011), which includes all participants irrespective of compliance or follow-up. For the primary analyses, we will assume that participants lost to follow-up are alive, have no serious adverse events, and have not experienced loss of employment. We will conduct a Sensitivity analysis (see below). For continuous outcomes we will analyse available patient data and include data only on those for whom results are known (Sterne 2011). If standard deviations (SDs) are missing, and if it is not possible to obtain SDs either from authors or by calculation, we will impute the missing data by using SDs from other included trials, specifically trials with a low risk of bias (Savovic 2012).

Assessment of heterogeneity

We will explore clinical heterogeneity by comparing the population, experimental intervention and control intervention. We will observe statistical heterogeneity in the trials both by visual inspection of a forest plot and by using a standard Chi2 value with a significance level of P = 0.10. We will assess heterogeneity using the I2 statistic. We will interpret an I2 estimate greater than or equal to 50% and a statistically significant Chi2 statistic as evidence of a substantial problem with heterogeneity (Higgins 2011b). If this is the case, we will explore reasons for heterogeneity. If there is high inconsistency, and a clear reason is found, we will present data separately.

Assessment of reporting biases

Small study (publication) bias

We will construct funnel plots for each outcome to establish the potential influence of small study effects and potential publication bias. We will not use funnel plots for outcomes where there are ten or fewer trials, or where all trials are of similar sizes (Furukawa 2006).

Data synthesis

We will perform data synthesis according to recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), and statistical analyses using the latest version of Review Manager (RevMan 2012), and the software Trial Sequential Analysis (TSA 2011). We will use a random-effects model and a fixed-effect model for meta-analyses (Deeks 2011; DeMets 1987; DerSimonian 1986). In case of discrepancies between results from the two models, we will present results from both models, otherwise we will report the results from the random-effects model only. Should it be inappropriate or not possible to do a meta-analysis, we will perform a narrative assessment.

Trial sequential analysis

'Trial sequential analysis' is the planned application to control risks of random errors because cumulative meta-analyses are at risk of producing such errors due to sparse data and repetitive testing on the accumulating data (Thorlund 2009a; Thorlund 2009b; TSA 2011; Wetterslev 2009). The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta-analysis. To minimise random errors, calculation of the required information size is planned (i.e. the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) (Wetterslev 2008). The information size calculation should also account for the diversity present in the meta-analysis (Wetterslev 2009). We will add the trials according to the year of publication, and if more than one trial was published in a year, we will add trials alphabetically according to the last name of the first author (Wetterslev 2008).

In our meta-analysis, the required information size for binary outcomes will be based on the assumption of a plausible relative risk reduction (RRR) of 20% from the proportion with the outcome in the control group or on the RRR observed in the included trials with low risk of bias (Wetterslev 2008). For continuous outcomes, we will test a difference of 0.5 SDs using SD in the control groups. As default, a type I error of 5%, type II error of 20%, and adjusted information size for diversity will be used unless otherwise stated (Wetterslev 2008; Wetterslev 2009).

Trial sequential monitoring boundaries can be constructed on the basis of the required information size and the risks for type I and type II errors (TSA 2011; Wetterslev 2008). These boundaries will determine the statistical inference that can be drawn regarding the cumulative meta-analysis. If the monitoring boundaries for benefits or harms are crossed before the diversity-adjusted required information size is reached it is possible that firm evidence may be established and further trials may turn out to be superfluous. If the monitoring boundary for futility is crossed, it is possible that further trials may turn out to be superfluous, at least for the postulated intervention effect. On the other hand, if the boundaries are not surpassed, it is most probably necessary to continue conducting trials in order to detect or reject a certain intervention effect.

Subgroup analysis and investigation of heterogeneity

We plan to perform subgroup analyses on the primary outcomes using stratified meta-analysis. We will perform subgroup analyses on the following.

  • Trials with overall ’low risk of bias’ compared to trials with overall ‘high risk of bias’. If no trials are categorised as overall ‘low risk of bias’, we will perform subgroup analyses on trials with overall ‘lower risk of bias’ compared with trials with overall ‘high risk of bias’.

  • Trials including women compared with trials including men.

  • Trials including younger patients compared with trials including older patients, defined by the trialists or by mean age.

  • Trials with exercise intervention only, compared with trials with exercise intervention plus any other co-intervention, such as psychoeducational intervention.

  • Participants with persistent AF compared with participants with paroxysmal AF.

  • Hospitalisation after rehabilitation because of AF compared with no hospitalisation because of AF.

Sensitivity analysis

For the primary outcomes, we plan to perform the following sensitivity analyses.

Dichotomous outcomes
Best/worse-case scenario

For this analysis we will assume that all participants lost to follow-up in the experimental group have not experienced the outcome (e.g. death); and all those with missing outcomes in the control group have experienced the outcome (e.g. death).

Worst/best-case scenario

For this analysis we will assume that all participants lost to follow-up in the experimental group have experienced the outcome (e.g. death); and all those with missing outcomes in the control group have not experienced the outcome (e.g. death).

Continuous data
Assumptions for lost data

Where assumptions have to be made for lost data (see Dealing with missing data), we will compare the findings from our assumptions with data only from those participants who completed the trials.

Summary of findings

We will use the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with each of the major outcomes in our review and we will present the findings in 'Summary of findings' tables using the GRADE software. The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The quality measure of a body of evidence considers: within study risk of bias; the directness of the evidence; heterogeneity of the data; precision of effect estimates; and risk of publication bias.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.

Appendices

Appendix 1. search strategy

1. Atrial Fibrillation/
2. atrial fibrillation*.tw.
3. auricular fibrillation*.tw.
4. atrium fibrillation*.tw.
5. Catheter Ablation/
6. atrial ablation*.tw.
7. (electric* adj2 ablation*).tw.
8. catheter ablation*.tw.
9. (radiofrequency adj2 ablation*).tw.
10. pulmonary vein isolation*.tw.
11. or/1-10
12. exp Exercise/
13. exp Exercise Therapy/
14. Exercise Tolerance/
15. exp Sports/
16. Physical Exertion/
17. exercis*.tw.
18. sport*.tw.
19. Physical Fitness/
20. exp "Physical Education and Training"/
21. (fitness or fitter or fit).tw.
22. (muscle* adj3 (train* or activ*)).tw.
23. (train* adj5 (strength* or aerobic* or exercise*)).tw.
24. ((aerobic or resistance) adj3 (train* or activ*)).tw.
25. (physical* adj5 (fit* or train* or therap* or activ* or strength or endur* or exert* or capacit*)).tw.
26. ((exercise* or fitness) adj3 (treat* or interven* or program* or train* or physical or activ*)).tw.
27. Exercise Tolerance/
28. (exercis* adj2 (toleran* or capacity)).tw.
29. Rehabilitation/
30. "Activities of Daily Living"/
31. Dance Therapy/
32. Rehabilitation Centers/
33. rehabilitat*.tw.
34. kinesiotherap*.tw.
35. danc*.tw.
36. walk*.tw.
37. run*.tw.
38. jog*.tw.
39. (("lifestyle" or life-style) adj5 activ$).tw.
40. (("lifestyle" or life-style) adj5 physical$).tw.
41. Patient Education as Topic/
42. (patient* adj5 educat*).tw.
43. ((lifestyle or life-style) adj5 (interven* or program* or treatment*)).tw.
44. Self Care/
45. (self adj5 (manag* or care or motivate*)).tw.
46. exp Psychotherapy/
47. psychotherap*.tw.
48. (psycholog* adj5 intervent*).tw.
49. Counseling/
50. (counselling or counseling).tw.
51. ((behavior* or behaviour*) adj5 (modify or modificat* or therap* or change)).tw.
52. (psycho-educat* or psychoeducat*).tw.
53. (motivat* adj5 (intervention or interv*)).tw.
54. Health Education/
55. (health adj5 educat*).tw.
56. (psychosocial or psycho-social).tw.
57. (cognitive adj2 behav*).tw.
58. or/12-57
59. 11 and 58
60. randomized controlled trial.pt.
61. controlled clinical trial.pt.
62. randomized.ab.
63. placebo.ab.
64. drug therapy.fs.
65. randomly.ab.
66. trial.ab.
67. groups.ab.
68. 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67
69. exp animals/ not humans.sh.
70. 68 not 69
71. 59 and 70

Contributions of authors

Signe S Risom drafted the protocol.
All authors have revised and contributed to the drafting of the protocol, and all have approved the final version of the protocol for publication.

Declarations of interest

Signe S Risom, Selina K Berg, Kirstine L Sibilitz , Christian Gluud, Jane Lindschou, Jesper Hastrup Svendsen, and Ann-Dorthe Zwisler are involved in conducting three RCTs, investigating the effect of cardiac rehabilitation for 1) people with atrial fibrillation treated with radiofrequency ablation, 2) people treated for infective endocarditis, and 3) people after heart valve surgery.

Pernille Palm Johansen and Rod S Taylor have no known conflicts of interest.

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