Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta‐analysis

Abstract

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

To assess the effects of different prophylactic antibiotics on exacerbations, quality of life and serious adverse events in people with COPD.

Background

Description of the condition

Chronic obstructive pulmonary disease (COPD) is a common and preventable disease, which is characterised by persistent respiratory symptoms and airways obstruction, with or without alveolar abnormalities usually caused by significant exposure to noxious particles or gases (GOLD 2018). Tobacco smoking is considered the main risk factor for COPD but other factors, such as biomass fuel and air pollution, can also contribute to individuals developing the disease. In addition, individuals with genetic abnormalities, abnormal lung development, and accelerated ageing are likely to be susceptible to COPD (GOLD 2018). Common respiratory symptoms include dyspnoea, cough with or without sputum production and recurrent lower respiratory tract infections. People with COPD may experience intermittent worsening of symptoms, known as exacerbations. Exacerbations are associated with increased mortality (Soler‐Cataluña 2005), higher healthcare costs (Pasquale 2012), a more rapid decline in lung function (Donaldson 2002), as well as negatively impacting quality of life for the individual (Seemungal 1998).

Description of the intervention

The ECLIPSE study has shown that frequent exacerbations (two or more exacerbations per year, or one or more exacerbations requiring hospitalisation per year) are associated with a moderate to severe COPD phenotype and as disease severity increases the frequency of exacerbations also increases (Hurst 2010). One attempt to reduce the frequency of exacerbations of COPD and reverse this potential ‘vicious cycle' of inflammation is by using antibiotics long‐term as prophylaxis. Prophylatic antibiotics are usually given by mouth but may also be delivered via other routes, including inhalation. Depending on the type of antibiotic, regimens include daily, three times a week, or ‘pulsed' administration ('pulsed' antibiotic may be given, for example, daily for several days followed by a break) (Herath 2018).

A Cochrane Review analysed 3932 patients in 14 RCTs from 2001 to 2015 (Herath 2018). The authors investigated the effects of macrolides (azithromycin, erythromycin, clarithromycin) and moxifloxacin (a fourth‐generation synthetic fluoroquinolone) compared with placebo. The use of long‐term prophylactic antibiotics was associated with significantly fewer patients who experienced an exacerbation of COPD (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.42 to 0.78) compared with those receiving placebo. However, patients on prophylactic antibiotics were more likely to experience adverse effects, such as hearing loss with azithromycin and gastrointestinal symptoms with moxifloxacin.

How the intervention might work

The effect of prophylactic antibiotics is not completely understood. Antibiotics may offer both antibacterial and anti‐inflammatory effects (Martinez 2008), and therefore may reduce both bacterial load and inflammation as a result of exacerbations from bacteria, viruses, and environmental pollution. Studies have suggested that the lungs of people with COPD may be colonised with more pathogenic bacteria than found in healthy lungs (Sethi 2004). Bacteria are identified in the sputum of approximately 40% to 60% of people experiencing an acute exacerbation (Sethi 2004), and their overgrowth may be a precipitant of exacerbations (Sze 2014). Antibiotics may also reduce neutrophilic airway inflammation by reducing bacterial loads, with potential clinical benefits (Siva 2014). Choice of prophylactic antibiotic may be guided by factors including clinician and patient preference and prior experience, previously isolated bacteria, and side effect profile. Organisms isolated from exacerbating patients include Haemophilus influenzae (11% of all patients), Streptococcus pneumoniae (10%), Moraxella catarrhalis (10%), Haemophilus parainfluenzae (10%), and Pseudomonas aeruginosa (4%) (Sapey 2006).

Prophylactic antibiotics may be of greatest benefit in a subset of patients (Miravittles 2015). Compared to placebo, azithromycin (a macrolide antibiotic) reduces exacerbations most markedly in older patients, non‐smokers, and those not using oral or inhaled steroids at baseline, which may reflect suboptimal treatment (Albert 2011). We have specified several subgroup analyses which we will conduct to explore this in the context of head‐to‐head antibiotics, if we identify sufficient evidence to do so.

Why it is important to do this review

This Cochrane review will include a network meta‐analysis that will accompany the head‐to‐head pairwise meta‐analyses review of prophylactic antibiotics (Threapleton 2018), and will be supplemented with the addition of antibiotic versus placebo data (Herath 2018). As there are limited comparisons of antibiotics for reducing exacerbations and improving quality of life of patients with COPD, a NMA is therefore important to identify which antibiotic is better for improving these outcomes.

Objectives

To assess the effects of different prophylactic antibiotics on exacerbations, quality of life and serious adverse events in people with COPD.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs), regardless of language or publication status. We will include trials of minimum 12 weeks intervention duration. We will exclude cross‐over trials due to carry‐over effects.

Types of participants

We will include adults aged 18 years and older who have been diagnosed with COPD according to validated criteria (e.g. European Respiratory Society, American Thoracic Society, or GOLD criteria). We will include study populations with mild, moderate, severe, or very severe COPD according to the GOLD criteria for airflow limitation (GOLD 1: ≥ 80% predicted forced expiratory volume in one second (FEV1); GOLD 2: 50 to 79%; GOLD 3: 30 to 49; GOLD 4 < 30%). We anticipate that trials will likely recruit participants with moderate to severe or very severe COPD (GOLD stages 2 to 4). If we identify trials recruiting a milder COPD population (GOLD stage 1), we will consider how compatible the data is before combining in the network. If the data is not compatible, we will report the results from these trials narratively. We will include trials that recruit participants with or without a recent history of exacerbations and will explore this as a potential source of heterogeneity. We will exclude participants with the following co‐morbidities or characteristics: a primary diagnosis of bronchiectasis, asthma, or genetic diseases, such as cystic fibrosis or primary ciliary dyskinesia.

Types of interventions

We will include any prophylactic oral antibiotic classes given for at least 12 weeks continuously, intermittently (e.g. three times per week), or pulsed, in keeping with the linked pairwise meta‐analyses (Herath 2018; Threapleton 2018). Pulsed antibiotics must be given for a minimum of five consecutive days every eight weeks.

We will include trials in which participants have access to the following background treatments provided that they are not part of the randomised study treatments.

• Short‐acting and long‐acting bronchodilators

• Inhaled corticosteroids

• Oral corticosteroids

• Oxygen

• Pulmonary rehabilitation

• Smoking cessation interventions

• Any other standard treatment for COPD

Types of outcome measures

Primary outcomes

• COPD exacerbation^a (we will extract hazard ratio (HR) data as a preference, followed by rate ratio data and the number of participants with one or more exacerbations)

• Quality of life (St George's respiratory questionnaire)

• All‐cause serious adverse events (number of participants with one or more adverse event)

• Drug resistance/microbial sensitivity (we will not perform NMA on this outcome, but we will report results for this outcome from trials narratively)

• Mortality (we anticipate that events will be rare, so we will not perform NMA on this outcome, but we will report results for this outcome from trials narratively)

We will report endpoint data for dichotomous outcomes. Continuous outcomes will be extracted and reported at the closest time point to six and 12 months.

^aModerate and severe exacerbations: defined as worsening of respiratory status requiring treatment with systemic corticosteroids with or without antibiotics; severe exacerbations defined as requiring hospitalisation.

Search methods for identification of studies

Electronic searches

We will identify studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist of the Cochrane Airways Group. The Cochrane Airways Trials Register contains studies identified from several sources.

• Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL), through the Cochrane Register of Studies Online (crso.cochrane.org)

• Weekly searches of MEDLINE Ovid SP (1946 to date)

• Weekly searches of Embase Ovid SP (1974 to date)

• Monthly searches of PsycINFO Ovid SP (1967 to date)

• Monthly searches of CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature) (1937 to date)

• Monthly searches of AMED EBSCO (Allied and Complementary Medicine)

• Handsearches of the proceedings of major respiratory conferences

Studies contained in the Cochrane Airways Trials Register are identified through search strategies based on the scope of Cochrane Airways. Details of these strategies, as well as a list of handsearched conference proceedings, are in Appendix 1. See Appendix 2 for search terms used to identify studies for this review.

We will search the following trials registries.

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov)

• World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch)

We will search the Cochrane Airways Trials Register and additional sources from inception to present, with no restriction on language of publication.

Searching other resources

We will check the reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for study information.

We will search for errata or retractions from included studies published in full text on PubMed (www.ncbi.nlm.nih.gov/pubmed), and will report the date this was done within the review.

Data collection and analysis

This review is built on two existing Cochrane Reviews (Herath 2018; Threapleton 2018), in which data from included studies in each of the reviews has already been extracted by two pairs of independent authors. For studies already identified from the two existing Cochrane reviews that report exacerbations outcome data, we will check and extract hazard ratio data if it is available. If we find studies that are not included in Herath 2018 and Threapleton 2018, we will select and extract data as outlined below.

Selection of studies

Two review authors (SJ and CT) will independently screen the titles and abstracts of the search results and will code them as either ‘retrieve' (eligible or potentially eligible/unclear) or ‘do not retrieve'. We will retrieve the full‐text study reports of all potentially eligible studies. Two review authors (SJ and CT) will independently assess these for inclusion and will record the reasons for exclusion of ineligible studies. We will select studies that evaluate the clinical efficacy and safety of any prophylactic antibiotic treatments in patients with COPD (e.g. macrolides/quinones, macrolides/tetracyclines, quinones/tetracyclines, and combined macrolide plus tetracycline/macrolide). We will resolve any disagreement through discussion or, if required, we will consult a third review author (RN). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and ‘Characteristics of excluded studies' table (Moher 2009).

Data extraction and management

We will use Microsoft Excel to manage outcome data for the NMA, which will be piloted on at least one trial included in the review. One review author (SJ) will extract the following study characteristics from included trials that have not already been included in the two existing Cochrane reviews (Herath 2018; Threapleton 2018).

• Methods: study design, total duration of study, details of any ‘run‐in' period, number of study centres and location, study setting, withdrawals, and date of study

• Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria

• Interventions: intervention, comparison, concomitant medications, and excluded medications

• Outcomes: primary and secondary outcomes specified and collected, and time points reported

• Notes: funding for studies and notable conflicts of interest of trial authors

Two review authors (SJ and CT) will independently extract outcome data from included trials that have not already been identified by the two existing Cochrane reviews (Herath 2018; Threapleton 2018), which they will manage in Microsoft Excel. We will note in the ‘Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third review author (RN). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (CT) will spot‐check study characteristics for accuracy against the study report. We will incorporate data extracted from previous Cochrane Reviews that are relevant for this NMA in the data extraction sheet.

Assessment of risk of bias in included studies

Studies that have been identified from Herath 2018 and Threapleton 2018 have already been assessed for risk of bias previously by two pairs of independent authors. If we find trials that are not included in Herath 2018 and Threapleton 2018, we will assess the risk of bias as outlined below:

Two review authors (SJ and CT) will independently assess risk of bias for each included trial using the criteria outlined in the recently updated Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2018). We will resolve any disagreements by discussion or by consulting a third review author (RN). We will assess the risk of bias according to the following domains.

• Random sequence generation

• Allocation concealment

• Blinding of participants and personnel

• Blinding of outcome assessment

• Incomplete outcome data

• Selective outcome reporting

• Other bias

We will judge each potential source of bias as either ‘high', ‘low', or ‘unclear' and will provide a quote from the study report together with a justification for our judgement in the ‘Risk of bias' table. We will summarise the ‘Risk of bias' judgements across different trials for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trial author, we will note this in the ‘Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the trials that contribute to that outcome.

Assessment of bias in conducting the systematic review

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

Measures of treatment effect

Network meta‐analysis

We will conduct a NMA of clinical trials to compare all prophylactic antibiotics with each other and with placebo. We will conduct the NMA using a Bayesian Markov chain Monte Carlo method implemented in WinBUGS 1.4.3 (WinBUGS 2007). We will use a hierarchical model with classes of antibiotics composed of individual treatments which will allow each treatment effect to be estimated as well as the overall class mean (Kew 2014; Dias 2018). We will use intention‐to‐treat (ITT) data where they are reported. We will combine dichotomous data that takes into account exposure time with rate and HR data for exacerbations; whereas we will pool other dichotomous outcomes as OR. Dichotomous data can be combined with HR or rate ratio data assuming that all exacerbations occur at the same rate (i.e. a patient is not more likely to have a second exacerbation if they have had a previous exacerbation). If available, we will extract HR as a preference since it accounts for time at risk and censoring. We will use mean difference for continuous outcomes.

Direct pairwise meta‐analysis

Two Cochrane Reviews will undertake pairwise meta‐analyses (Herath 2018; Threapleton 2018).

Unit of analysis issues

For dichotomous outcomes, we will use participants as the unit of analysis to eliminate risk of multiple counting of participants (i.e. number of COPD patients with one exacerbation). If exacerbation data are provided as rate ratios or HRs, we will extract this data and analyse it accordingly. We will include data from cluster‐randomised trials provided the data has been, or can be, adjusted to take into account clustering.

Dealing with missing data

We will contact investigators or trial sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a trial is identified as an abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will perform a sensitivity analysis to determine whether the missing data could introduce serious bias to the overall results of the NMA.

Assessment of heterogeneity

Assessment of similarity of participants, interventions, and trial methods

We will assess trials according to similarity of participants, interventions, trial methods, including any confounding factors that may affect the analysis including different patient populations and inconsistency. If we find that differences between trials do not allow pooling of data, we will identify potential subgroups and analyse them separately.

Assessment of heterogeneity and statistical consistency

For the NMA, we will assess consistency by comparing the model fit and between‐trial heterogeneity from NMA models versus those from an unrelated effects (inconsistency) model (Dias 2013a; Dias 2013b). We will use this to determine the presence and area of inconsistency. If we identify substantial inconsistency (i.e. the extent to which different sources of evidence are compatible in a ‘closed loop' or path in which three or more trials are connected, starting and ending at the same node), we will explore factors, including participant and design characteristics, that may contribute to inconsistency. We will qualitatively compare the results from direct pairwise meta‐analysis versus NMA estimates to check for broad agreement.

Assessment of reporting biases

We will minimise reporting bias from unpublished trials or selective outcome reporting by using a broad search strategy, and by checking references of included trials and relevant systematic reviews. For each outcome, we will estimate and present the proportion of trials that contribute to the NMA. Where possible, we will combine exacerbations data reported as HR, rate ratio, or number of participants with at least one exacerbation to minimise reporting bias.

Data synthesis

We will consider all treatment dosages as individual treatments. We will use a class‐model approach for the NMA (Kew 2014; Dias 2018). We will prespecify five classes of interventions in the network: macrolides (e.g. azithromycin, erythromycin, roxithromycin), quinolones (ciprofloxacin, moxifloxacin), tetracyclines (doxycycline), combined tetracycline/macrolide (e.g. roxithromycin/doxycyline), and placebo. We will compare models that assume all interventions within a class have the same effect to models where effects within a class are exchangeable (i.e. similar) using the deviance information criterion and taking into account any changes in the estimated heterogeneity. We will present estimates for within‐class variability in treatment effects, as well as between‐class variability in treatment effects where applicable. We will also present the ranking of each class in one of the five positions (from best to worst).

‘Summary of findings' table

We will create a ‘Summary of findings' table using all four primary outcomes. We will judge the quality of the evidence based on the ‘Risk of bias' assessment of included trials, estimates of heterogeneity, and assessment of model fit inconsistency.

Sensitivity analysis

We plan to undertake a flexible and exploratory approach to investigation of heterogeneity, depending on the data we find. If we identify significant heterogeneity in the NMA, we will explore heterogeneity using prespecified factors, if extractable.

• Exacerbation history: trials that recruit participants with a group mean of <1 versus 2‐3 or 4 or more exacerbations in the preceding year

• COPD severity: participants predominately classed as GOLD 1 or 2 versus those predominantly GOLD 3 or 4

• Trials with > 70% participants on long‐acting β‐agonists (LABA) or long‐acting muscarinic receptor agonists (LAMA) or inhaled corticosteroid (ICS) at baseline

• Pseudomonas colonisation: trials that recruit participants colonised with Pseudomonas at baseline versus those not colonised with Pseudomonas at baseline

• Methodological issues with randomisation, allocation concealment, participant/personnel blinding, outcome assessor blinding, and attrition

If there is insufficient data to assess the prespecified factors, we will investigate differences (if any) by extracting key severity criteria for each trial, and will summarise data across pairwise comparisons.

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group's Specialised Register (CAGR)

Electronic searches: core databases

Database	Frequency of search
CENTRAL (the Cochrane Library)	Monthly
MEDLINE (Ovid)	Weekly
Embase (Ovid)	Weekly
PsycINFO (Ovid)	Monthly
CINAHL (EBSCO)	Monthly
AMED (EBSCO)	Monthly

Handsearches: core respiratory conference abstracts

Conference	Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)	2001 onwards
American Thoracic Society (ATS)	2001 onwards
Asia Pacific Society of Respirology (APSR)	2004 onwards
British Thoracic Society Winter Meeting (BTS)	2000 onwards
Chest Meeting	2003 onwards
European Respiratory Society (ERS)	1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)	2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)	1999 onwards

Condition search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti‐asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1‐15

17. exp Aspergillosis, Allergic Bronchopulmonary/

18. lung diseases, fungal/

19. aspergillosis/

20. 18 and 19

21. (bronchopulmonar$ adj3 aspergillosis).mp.

22. 17 or 20 or 21

23. 16 or 22

24. Lung Diseases, Obstructive/

25. exp Pulmonary Disease, Chronic Obstructive/

26. emphysema$.mp.

27. (chronic$ adj3 bronchiti$).mp.

28. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

29. COPD.mp.

30. COAD.mp.

31. COBD.mp.

32. AECB.mp.

33. or/24‐32

34. exp Bronchiectasis/

35. bronchiect$.mp.

36. bronchoect$.mp.

37. kartagener$.mp.

38. (ciliary adj3 dyskinesia).mp.

39. (bronchial$ adj3 dilat$).mp.

40. or/34‐39

41. exp Sleep Apnea Syndromes/

42. (sleep$ adj3 (apnoea$ or apnoea$)).mp.

43. (hypopnoea$ or hypopnoea$).mp.

44. OSA.mp.

45. SHS.mp.

46. OSAHS.mp.

47. or/41‐46

48. Lung Diseases, Interstitial/

49. Pulmonary Fibrosis/

50. Sarcoidosis, Pulmonary/

51. (interstitial$ adj3 (lung$ or disease$ or pneumon$)).mp.

52. ((pulmonary$ or lung$ or alveoli$) adj3 (fibros$ or fibrot$)).mp.

53. ((pulmonary$ or lung$) adj3 (sarcoid$ or granulom$)).mp.

54. or/48‐53

55. 23 or 33 or 40 or 47 or 54

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1‐7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify studies in other electronic databases.

Appendix 2. Search strategy to identify relevant studies from the Cochrane Airways Trials Register

#1 MeSH DESCRIPTOR Pulmonary Disease, Chronic Obstructive Explode All

#2 MeSH DESCRIPTOR Bronchitis, Chronic

#3 (obstruct*) near3 (pulmonary or lung* or airway* or airflow* or bronch* or respirat*)

#4 COPD:MISC1

#5 (COPD OR COAD OR COBD OR AECOPD):TI,AB,KW

#6 #1 OR #2 OR #3 OR #4 OR #5

#7 MESH DESCRIPTOR Anti‐Bacterial Agents EXPLODE ALL

#8 (antibiotic* or antibacterial or anti‐bacterial):ti,ab,kw

#9 (prophylactic or prophylaxis or prevent*):ti,ab,kw

#10 (long‐term OR "long term"):ti,ab,kw

#11 (#7 OR #8) AND (#9 OR #10)

#12 MESH DESCRIPTOR Antibiotic Prophylaxis EXPLODE ALL

#13 Penicillin or phenoxymethylpenicillin or phenethicillin or amoxicillin or amoxicillin or "clavulanic acid" or tetracycline or oxytetracycline or doxycycline or quinolone or ciprofloxacin or moxifloxacin or gemifloxacin or levofloxacin or macrolide or erythromycin or roxithromycin or azithromycin or clarithromycin or telithromycin or sulphonamide or co‐trimoxazole or sulphaphenazole or trimethoprim or sigmamycin or tetracycline or oleandomycin or sulfamethoxazole or sulfaphenazole or sulphonamide or cephalosporin

#14 #11 OR #12 OR #13

#15 #14 AND #6

#16 INREGISTER

#17 #15 AND #16

Contributions of authors

SJ drafted the Background and Methods sections of the protocol.

SD drafted the NMA methodology of the protocol.

CT drafted the Background and Methods sections of the protocol.

AGM drafted the Background and Methods sections of the protocol.

RN provided conceptual and clinical advice, and critical review of the protocol.

All review authors read and approved the final protocol version.

Sources of support

Internal sources

• The review authors declare that no such funding was received for this systematic review, Other.

External sources

• National Institute for Health Research (NIHR), UK.

  Cochrane Programme Grant 16/114/21: NHS priorities in the management of chronic respiratory disease

Declarations of interest

SJ is employed full‐time by a NIHR Programme Grant to complete work on this Cochrane Review.

SD is a co‐applicant on a grant, where Pfizer are partially sponsoring a researcher, but is not sponsored by Pfizer herself.

CT is employed part‐time by a NIHR Programme Grant to complete work on this Cochrane Review and is an Academic Clinical Fellow in Pharmacology.

AGM has received a research grant for an investigator initiated study by Boehringer Ingelheim. He has received honoraria by Boehringer Ingelheim and GlaxoSmithKline, which are not related to the content of this manuscript.

RN is employed part‐time by a NIHR Programme Grant to complete work on this Cochrane Review and is a qualified general practitioner.

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