Interventions for improving adherence to dietary salt and fluid restrictions in people with chronic kidney disease (stage 4 and 5)

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

This review aims to look at the benefits and harms of non‐pharmacological interventions to improve adherence to dietary salt and fluid restriction in people with CKD (stages 4 and 5).

Background

Description of the condition

Chronic kidney disease (CKD) is a chronic condition characterised by progressive loss of kidney function that may lead to kidney failure (Levey 2020). CKD is divided into five stages, with stages 1 and 2 representing early kidney disease, stage 3 representing moderate disease, stage 4 representing severe kidney disease, and stage 5 CKD indicating kidney failure.

The global prevalence of CKD is increasing rapidly and is currently estimated to be 9.1% (GBD Chronic Kidney Disease Collaboration 2020). CKD is also a major public health issue and causes significant morbidity and death (Jager 2017), as well as being a risk factor for other conditions such as cardiovascular disease (Jankowski 2021) and COVID‐19 (Gansevoort 2020).

Chronic fluid overload is a common complication in people with stage 4 and 5 CKD (Zoccali 2017). The degree of fluid overload experienced depends on several factors, including salt and fluid intake, cardiac function, residual kidney function, dialysate composition, ultrafiltration volume and diuretic therapy (K/DOQI 2005). Restricting salt and fluid is especially important in advanced CKD when kidney function has declined and sodium excretion is impaired (Khandelwal 2003). The result of excessive accumulation of sodium is an increase in extracellular osmolality and movement of water from the intracellular to the extracellular compartment. Thirst is also stimulated. This combination of factors results in blood volume expansion and chronic fluid overload and is the rationale for dietary salt and fluid restriction.

There are numerous negative side effects from chronic fluid overload. These include shortness of breath, oedema, hypertension, and left ventricular hypertrophy (Khan 2016; Shin 2021). In the longer term, chronic volume overload is associated with increased cardiovascular events and death (Tsai 2015; Zoccali 2017). In addition to medical treatments, non‐pharmacological interventions such as restriction of salt and fluid intake are critical to correcting volume status and managing chronic fluid overload. Unfortunately, estimates of adherence to salt and fluid restrictions indicate that only ~60% of people are adherent (Lambert 2017; Vr 2022). These estimates vary widely, and some studies have reported adherence rates of 0% for fluid (Sharp 2005) to as high as 96.6% (Hecking 2004). Adherence to reduced salt diets is also highly variable and can range from 32% (Mason 2014) to 87% (Md Yusop 2013). 

Description of the intervention

The main goals of non‐pharmacological approaches to chronic fluid overload are to reduce dietary sodium and fluid. Sodium intake should be reduced to less than 100 mmol/day (< 2.3 g) (Ikizler 2020). Fluid intake targets are individualised in stages 4 and 5 CKD and depend on the amount of residual kidney function, type of dialysis undertaken, and diuretic therapy. When prescribed, fluid restrictions are typically 1000 to 1500 mL/day. Interventions to achieve these goals may target the individual, the environment they reside in, and/or the healthcare system they interact with. 

How the intervention might work

Adherence refers to the extent that a person's behaviour corresponds with agreed recommendations (WHO 2003). Dietary salt and fluid restriction adherence in CKD is complex and is influenced by social, individual, cultural and environmental factors (Lambert 2017). Interventions that are targeted at the individual may be designed to improve knowledge about the condition or of the consequences of fluid overload to elicit behaviour change. In contrast, individual counselling and behavioural interventions may be based on theoretical models of behaviour change and may address behaviours or skills needed to reduce salt and fluid intake. Other interventions targeted at the individual may address the emotions or feelings of self‐efficacy or empowerment to encourage adherence to the diet and fluid restriction. 

Why it is important to do this review

The World Health Organization (WHO) has stated that interventions to improve adherence may have a far greater impact on health than any improvements to medical treatment (WHO 2003). There are several reasons why it is important to conduct this review. Firstly, the burden of ill health from chronic fluid overload is immense (Zoccali 2017). Chronic fluid overload also results in poor quality of life (QoL) for patients. Secondly, there is evidence that interventions to improve adherence to reduced salt and fluid diets may improve health outcomes.  For example, recent evidence indicates that reducing salt intake in people with CKD results in reduced blood pressure (BP) and protein in the urine (McMahon 2021). Similarly, interventions to reduce inter‐dialytic weight gain (IDWG) can result in small but significant improvements to volume status (Murali 2019). Third, non‐pharmacological interventions are attractive to patients with CKD (Hemmelgarn 2017), partly because of the high level of polypharmacy (Okpechi 2021), and may be more cost‐effective in the long term to manage the challenges of chronic volume overload. To date, there have been no other systematic reviews completed on this topic. Finally, there have been significant improvements in recent years in trial design and outcome reporting thus, it is timely and important to review the evidence on this topic. 

Objectives

This review aims to look at the benefits and harms of non‐pharmacological interventions to improve adherence to dietary salt and fluid restriction in people with CKD (stages 4 and 5).

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs), quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods), and cluster RCTs looking at non‐pharmacological interventions to improve adherence to dietary salt or fluid restriction in people with CKD (stage 4 and 5) will be included.

Cross‐over studies will be included, and data from the first phase only will be used for analyses.

Studies in any healthcare setting will be included. 

Excluded study designs: cohort studies, non‐RCTs, commentaries, editorials, abstracts, clinical observations or case studies, and single‐arm studies.

Types of participants

Adults aged ≥ 18 years with stage 4 or 5 CKD (Levey 2005), including those who are receiving haemodialysis (HD) or peritoneal dialysis (PD).

Inclusion criteria

• Adults with severe CKD (stage 4 or 5), including those undertaking dialysis or conservative management

• Adults undertaking HD or PD on a permanent basis 

• Studies with populations at various stages of CKD will be included if the data can be analysed separately for those with severe kidney disease (i.e. stage 4 and 5 CKD).

Exclusion criteria

• Studies of children (< 18 years)

• Individuals receiving dialysis for acute kidney injury.

Types of interventions

We will include studies assessing interventions to improve adherence to dietary salt or fluid restriction compared to a control arm. Direct head‐to‐head comparisons of interventions or comparisons to routine care are acceptable. Any intensity, mode of delivery, duration and frequency of intervention will be considered. 

The types of interventions at the patient level that may be included are adapted from De Bleser 2009 and include (but are not limited to): 

• Educational or cognitive interventions that convey information or knowledge, either individually or in a group setting, and are delivered either verbally, in written form, audiovisually or via a mobile application

• Counselling or behavioural interventions which target, shape, and/or reinforce behaviour and empower patients to participate in their care, or change a patient's skill level or normal routine

• Psychological or affective interventions that appeal to the feelings or emotions of patients, their social relationships,  and social supports.

• Biomedical feedback which uses biological data to provide feedback on adherence 

• Mixed interventions that involve a combination of the above intervention types. 

Eligible comparator groups include inactive controls (such as placebo, no treatment, standard or usual care or a waitlist control) or active control (such as a variation of the same intervention). All variations of the intervention will be included. 

Types of outcome measures

We will not exclude studies based on non‐reporting of outcomes of interest.

The outcomes selected include the relevant SONG core outcome sets as specified by the Standardised Outcomes in Nephrology initiative (SONG 2017). These include fatigue from the SONG HD outcome set and PD‐related infection and technique survival from the PD outcome set. 

Primary outcomes

• Death and cause‐specific death

• Major adverse cardiovascular events: sudden death, fatal and non‐fatal myocardial infarction, stroke, congestive heart failure, arrhythmias

• QoL using any validated scale such as the EQ‐5D‐5L (Herdman 2011), Short Form 36 (SF‐36) Health Survey (Ware 1992) or KDQOL (Hays 1994).

Secondary outcomes

Clinical parameters (volume status or changes in body volume)

• Weight gain (absolute weight gain, IDWG or percentage of post‐dialysis weight at end of intervention or change between the beginning and end of intervention)

• Bioimpedance spectroscopy (BIS) or bioimpedance analysis (BIA) measurements of extracellular fluid volume (ECV) expressed as litres, excess volume in litres or percentage above normal ECV, at end of intervention or change between the beginning and end of the intervention.

• Blood volume monitoring of weight either at end of the intervention or change between the beginning and end of the intervention.

• Other measures of volume status or body volume using any other validated assessment, technique or tool.

Clinical parameters (blood pressure control)

• Symptomatic intradialytic hypotension: defined as a decrease in systolic BP (SBP) ≥ 20 mm Hg or a decrease in mean arterial pressure (MAP) ≥ 10 mm Hg, associated with abdominal discomfort, muscle cramps, nausea, vomiting, restlessness, dizziness, fainting, anxiety, yawning or sighing (K/DOQI 2005). This outcome will record both the number of events and the number of patients with events.

• BP control, including SBP and diastolic BP (DBP), predialysis and post‐dialysis BP and antihypertensive medication changes

• Other measures of BP control using any other validated assessment, technique or tool.

Other clinical parameters

• Proteinuria and albuminuria 

• Left ventricular mass (g/m²) at the end of intervention or change between the beginning and end of the intervention 

• Nutritional status using any validated measure such as the Subjective Global Assessment 

• Weight

• Urine volume, urine sodium or chloride levels.

Patient centred outcomes

• Validated tools or self‐reported data: adherence to treatment, dietary intake and diet quality, life participation, fatigue, PD‐related infection and PD technique survival. 

Adverse effects

• Hospitalisation and adverse patient outcomes associated with each intervention type (including those collected using patient‐reported experience or outcome measures).

Search methods for identification of studies

Electronic searches

We will search the Cochrane Kidney and Transplant Register of Studies through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources:

1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

2. Weekly searches of MEDLINE OVID SP

3. Searches of kidney and transplant journals and the proceedings and abstracts from major kidney and transplant conferences

4. Searching the current year of EMBASE OVID SP

5. Weekly current awareness alerts for selected kidney and transplant journals

6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website under CKT Register of Studies.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

1. Reference lists of review articles, relevant studies and clinical practice guidelines.

2. Contacting relevant individuals/organisations seeking information about unpublished or incomplete studies.

3. Grey literature sources (e.g. abstracts, dissertations and theses), in addition to those already included in the Cochrane Kidney and Transplant Register of Studies, will not be searched.

Data collection and analysis

Selection of studies

The search strategy will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however, studies and reviews that might include relevant data or information on studies will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfy the inclusion criteria. Disagreements will be resolved in consultation with a third author.

Data extraction and management

Data extraction will be carried out independently by two authors using standard data extraction forms. Disagreements will be resolved in consultation with a third author. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together, and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions, these data will be used. Any discrepancy between published versions will be highlighted.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2022) (see Appendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately prevented during the study?

  • Participants and personnel (performance bias)

  • Outcome assessors (detection bias)

• Were incomplete outcome data adequately addressed (attrition bias)?

• Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could put it at risk of bias?

For studies involving Indigenous people, we will consider using the CONSIDER statement (Huria 2019) to evaluate reporting of health research and the CREATE quality appraisal tool (Harfield 2020) to evaluate study quality. 

Measures of treatment effect

For dichotomous outcomes  (death, major cardiovascular events, episodes of intradialytic hypotension), results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (IDWG, BP, left ventricular mass index, quality of life measures), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. Where possible, we will use the mean change score from baseline. If data are reported at more than one time point during the study, all data will be extracted (Deeks 2022).

Unit of analysis issues

For RCTs, we will examine randomisation of the individual participant. If a study has more than two intervention arms, the control group sample size will be split by the number of subgroup comparisons for that study. For cross‐over studies, we will evaluate the potential for carry‐over or period effects and, if appropriate, adopt a conservative approach and use data from the first phase only (Higgins 2022).  

If outcome data for a study are reported for more than one period of follow‐up, we will perform sub‐group analyses for different periods of follow‐up (≤ 6 weeks, > 6 to 12 weeks, > 12 weeks). 

Cluster RCTs will be analysed in one of two ways:

1. Using a statistical analysis that properly accounts for the cluster design. Some examples of these are based on a ‘multi level model’, a ‘variance components analysis’ or may use ‘generalised estimating equations’ (Higgins 2011)

2. Conduct the analysis treating the sample size as the number of clusters and proceed as if the study were individually randomised, treating the clusters as individuals.

When considering studies with multiple treatment groups, we will combine all relevant experimental intervention groups of the study into a single group and combine all relevant control intervention groups into a single group to enable a single pair‐wise comparison.

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing and/or writing to the corresponding author), and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data, such as screened, randomised patients, intention‐to‐treat, as‐treated and per‐protocol population, will be carefully performed. Attrition rates, for example, drop‐outs, losses to follow‐up and withdrawals, will be investigated. Issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) will be critically appraised (Higgins 2022). 

Assessment of heterogeneity

We will first assess the heterogeneity by visual inspection of the forest plot. We will quantify statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values will be as follows:

• 0% to 40%: might not be important

• 30% to 60%: may represent moderate heterogeneity

• 50% to 90%: may represent substantial heterogeneity

• 75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test or a CI for I²) (Higgins 2022).

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2022).

Data synthesis

Data will be pooled using the random‐effects model, but the fixed‐effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, interventions, type of dialysis, stage of CKD and study quality). If outcome data for a study are reported for more than one period of follow‐up, we will perform sub‐group analyses for different periods of follow‐up (≤ 6 weeks, > 6 to 12 weeks, > 12 weeks). Heterogeneity among participants could be related to age, type of dialysis and renal pathology. Heterogeneity in treatments could be related to prior interventions experienced and the mode, format, intensity, duration and frequency of interventions. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various interventions provided. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.

Planned subgroups where sufficient data are available are as follows:

• Dialysis modality: HD, PD, not receiving dialysis

• Stage 4 CKD and non‐dialysis stage 5 CKD versus dialysis

• Type of intervention: educational, cognitive, counselling, behavioural,  psychological, affective, biomedical or mixed 

• Endpoint measurement at different time points: ≤ 6 weeks; > 6 weeks to 12 weeks, > 12 weeks

• Age: ≤ 65 years versus > 65 years 

• Sex: males versus females

• Education level: > 12 years versus ≤ 12 years of education

• Diabetes status: those with diabetes versus those without and proportion of patients with diabetes in the study

• Hypertensive  status: those with SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg versus non‐hypertensive patients and the proportion of patients with hypertension in the study

• Dialysis vintage: those who have undertaken dialysis ≤ 6 months versus those with > 6 months experience on dialysis

• Studies with high versus low risk of bias

• Geographical area: North America, Latin America, Asia, Europe, Australasia

• Health literacy level: inadequate or adequate health literacy.

Sensitivity analysis

We will perform sensitivity analyses to explore the influence of the following factors on effect size:

• Repeating the analysis, excluding unpublished studies

• Repeating the analysis taking account of the risk of bias

• Repeating the analysis, excluding any very long or large studies to establish how much they dominate the results

• Repeating the analysis by excluding cluster randomised studies 

• Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country 

• Repeating the analysis excludes studies with mixed populations who cannot be separated but are predominantly those with CKD stage 4 or 5.

Summary of findings and assessment of the certainty of the evidence

We will present the main results of the review in 'Summary of findings' tables. These tables present key information concerning the certainty of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2022a). The 'Summary of findings' tables also includes an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the certainty of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. This will be assessed by two authors. The certainty of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, the precision of effect estimates and risk of publication bias (Schunemann 2022b). We plan to present the following outcomes in the 'Summary of findings' tables.

• Adverse events, including hospitalisation for emergency dialysis, hypertension and hypotension

• Major adverse cardiovascular events

• Death 

• IDWG

• Quality of Life. 

Appendices

Appendix 1. Electronic search strategies

Database	Search terms
CENTRAL	dialysis:ti,ab,kw (hemodialysis or haemodialysis):ti,ab,kw (hemofiltration or haemofiltration):ti,ab,kw (hemodiafiltration or haemodiafiltration):ti,ab,kw (CAPD or CCPD or APD):ti,ab,kw kidney next failure:ti,ab,kw ("end‐stage kidney" or "end‐stage renal" or "endstage kidney" or "endstage renal"):ti,ab,kw (ESKD or ESKF or ESRD or ESRF):ti,ab,kw {or #1‐#8} adherence:kw compliance:kw "water‐electrolyte imbalance":ti,ab,kw ((fluid* or water) near/5 (restrict* or adher* or nonadher* or compliance or comply* or overload or balance or intake or diet* or control or regulat* or reduc* or decreas* or manag*)):ti,ab,kw sodium next chloride:kw ((sodium or salt) near/5 (low or reduc* or restrict* or adher* or nonadher* or compliance or comply* or intake* or diet* or control or decreas* or regulat* or manag*)):ti,ab,kw "interdialytic weight gain":ti,ab,kw {or #10‐#16} #9 and #17 ((cognitive next behavio*ral next therapy) or CBT):ti,ab,kw "acceptance and commitment therapy":ti,ab,kw behavio*ral next contract*:ti,ab,kw (self next efficacy near/2 train*):ti,ab,kw "patient education":ti,ab,kw "health coaching":ti,ab,kw hypnosis:ti,ab,kw "peer support":ti,ab,kw "peer group":kw motivational next interview*:ti,ab,kw #29"bioimpedance spectroscopy":ti,ab,kw #30biofeedback near/5 fluid:ti,ab,kw #31"blood volume":ti,ab,kw #32(dialysis next prescription* near/2 adjust*):ti,ab,kw #33{or #19‐#32} #34#18 and #33 in Trials
MEDLINE	exp Renal Dialysis/ Hemofiltration/ Kidney Failure, Chronic/ dialysis.tw. (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. (CAPD or CCPD or APD).tw. (end‐stage kidney or end‐stage renal or endstage kidney or endstage renal).tw. (ESKD or ESKF or ESRD or ESRF).tw. or/1‐10 exp "Treatment Adherence and Compliance"/ Water‐Electrolyte Imbalance/ Drinking/ ((fluid* or water) adj5 (restrict* or adher* or nonadher* or compliance or comply* or overload or balance or intake or diet* or control or regulat* or reduc* or decreas* or manag*)).tw. Sodium, Dietary/ Diet, Sodium‐Restricted/ ((sodium or salt) adj5 (low or reduc* or restrict* or adher* or nonadher* or compliance or comply* or intake* or diet* or control or decreas* or regulat* or manag*)).tw. interdialytic weight gain.tw. or/12‐19 and/11,20 exp Cognitive Behavioral Therapy/ Patient Education as Topic/ Behavior Therapy/ Self Efficacy/ Health Promotion/ Hypnosis/ Peer Group/ exp Social Support/ Motivational Interviewing/ Electric Impedance/ and Body Composition/ Blood Volume/ (cognitive behavio?ral therapy or CBT).tw. "acceptance and commitment therapy".tw. behavio?ral contract*.tw. (self‐efficacy adj2 train*).tw. health coaching.tw. hypnosis.tw. peer support.tw. motivational interview*.tw. bioimpedance spectroscopy.tw. (biofeedback adj3 fluid).tw. (blood volume adj2 monitor*).tw. (dialysis prescription* adj2 adjust*).tw. or/22‐44 and/21,45
EMBASE	exp Renal Replacement Therapy/ (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. dialysis.tw. (CAPD or CCPD or APD).tw. Chronic Kidney Disease/ Kidney Failure/ Chronic Kidney Failure/ (end‐stage renal or end‐stage kidney or endstage renal or endstage kidney).tw. (ESRF or ESKF or ESRD or ESKD).tw. or/1‐11 441536 patient compliance/ dietary compliance/ fluid balance/ fluid intake/ ((fluid* or water) adj5 (restrict* or adher* or nonadher* or compliance or comply* or overload or balance or intake or diet* or control or regulat* or reduc* or decreas* or manag*)).tw. sodium chloride/ sodium restriction/ sodium intake/ ((sodium or salt) adj5 (low or reduc* or restrict* or adher* or nonadher* or compliance or comply* or intake* or diet* or control or decreas* or regulat* or manag*)).tw. interdialytic weight gain.tw. or/13‐22 and/12,23 cognitive behavioral therapy/ "acceptance and commitment therapy"/ behavior therapy/ patient education/ self concept/ health promotion/ hypnosis/ peer group/ motivational interviewing/ impedance/ and spectroscopy/ biofeedback/ blood volume/ (cognitive behavio?ral therapy or CBT).tw. "acceptance and commitment therapy".tw. behavio?ral contract*.tw. (self‐efficacy adj2 train*).tw. health coaching.tw. hypnosis.tw. peer support.tw. motivational interview*.tw. bioimpedance spectroscopy.tw. (biofeedback adj3 fluid).tw. (blood volume adj2 monitor*).tw. (dialysis prescription* adj2 adjust*).tw. or/25‐48 and/24,49 1192

Appendix 2. Risk of bias assessment tool

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

1. Draft the protocol: KL, EN, AW, SJ

2. Study selection: KL, EN, DB, JI

3. Extract data from studies: KL, EN, DB

4. Enter data into RevMan: KL, EN, DB

5. Carry out the analysis: KL, EN, LN, LC, RB, DB, JI

6. Interpret the analysis: KL, EN, SJ, AW, LN, LC, RB, DB, JI

7. Draft the final review: KL, EN, SJ, AW

8. Disagreement resolution: JI

9. Update the review: KL

Sources of support

Internal sources

• No sources of support provided

External sources

• No sources of support provided

Declarations of interest

• KL: has received consultancy fees from Abbott Australasia, Otsuka and AstraZeneca. None of these are related to the current study.

• EN: no relevant interests were disclosed

• JI: no relevant interests were disclosed

• AW: no relevant interests were disclosed

• LN: no relevant interests were disclosed

• LC: no relevant interests were disclosed

• RB: no relevant interests were disclosed

• DB: no relevant interests were disclosed

• SJ: no relevant interests were disclosed

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