Pharmacological and surgical interventions for the treatment of gastro‐oesophageal reflux in adults and children with asthma

Abstract

Background

Asthma and gastro‐oesophageal reflux disease (GORD) are common medical conditions that frequently co‐exist. GORD has been postulated as a trigger for asthma; however, evidence remains conflicting. Proposed mechanisms by which GORD causes asthma include direct airway irritation from micro‐aspiration and vagally mediated oesophagobronchial reflux. Furthermore, asthma might precipitate GORD. Thus a temporal association between the two does not establish that GORD triggers asthma.

Objectives

To evaluate the effectiveness of GORD treatment in adults and children with asthma, in terms of its benefits for asthma.

Search methods

The Cochrane Airways Group Specialised Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and online clinical trial databases were searched. The most recent search was conducted on 23 June 2020.

Selection criteria

We included randomised controlled trials comparing treatment of GORD in adults and children with a diagnosis of both asthma and GORD versus no treatment or placebo.

Data collection and analysis

A combination of two independent review authors extracted study data and assessed trial quality. The primary outcome of interest for this review was acute asthma exacerbation as reported by trialists.

Main results

The systematic search yielded a total of 3354 citations; 23 studies (n = 2872 participants) were suitable for inclusion. Included studies reported data from participants in 25 different countries across Europe, North and South America, Asia, Australia, and the Middle East. Participants included in this review had moderate to severe asthma and a diagnosis of GORD and were predominantly adults presenting to a clinic for treatment. Only two studies assessed effects of intervention on children, and two assessed the impact of surgical intervention. The remainder were concerned with medical intervention using a variety of dosing protocols.

There was an uncertain reduction in the number of participants experiencing one or more moderate/severe asthma exacerbations with medical treatment for GORD (odds ratio 0.53, 95% confidence interval (CI) 0.17 to 1.63; 1168 participants, 2 studies; low‐certainty evidence). None of the included studies reported data related to the other primary outcomes for this review: hospital admissions, emergency department visits, and unscheduled doctor visits.

Medical treatment for GORD probably improved forced expiratory volume in one second (FEV₁) by a small amount (mean difference (MD) 0.10 L, 95% CI 0.05 to 0.15; 1333 participants, 7 studies; moderate‐certainty evidence) as well as use of rescue medications (MD ‐0.71 puffs per day, 95% CI ‐1.20 to ‐0.22; 239 participants, 2 studies; moderate‐certainty evidence). However, the benefit of GORD treatment for morning peak expiratory flow rate was uncertain (MD 6.02 L/min, 95% CI 0.56 to 11.47; 1262 participants, 5 studies). It is important to note that these mean improvements did not reach clinical importance. The benefit of GORD treatment for outcomes synthesised narratively including benefits of treatment for asthma symptoms, quality of life, and treatment preference was likewise uncertain. Data related to adverse events with intervention were generally underreported by the included studies, and those that were available indicated similar rates regardless of allocation to treatment or placebo.

Authors' conclusions

Effects of GORD treatment on the primary outcomes of number of people experiencing one or more exacerbations and hospital utilisation remain uncertain. Medical treatment for GORD in people with asthma may provide small benefit for a number of secondary outcomes related to asthma management. This review determined with moderate certainty that with treatment, lung function measures improved slightly, and use of rescue medications for asthma control was reduced. Further, evidence is insufficient to assess results in children, or to compare surgery versus medical therapy.

Plain language summary

Treatment of gastro‐oesophageal reflux disease to help manage asthma in adults and children

Background

People with asthma are three times more likely to have reflux (where acid from the stomach comes back up the oesophagus) than healthy people. Reflux may be a trigger for asthma, or alternatively, asthma may trigger reflux. Treatments that can help reflux include drugs that reduce stomach acids or improve stomach emptying. Research studies have found inconsistent benefit for improvement in asthma symptoms or lung function. Although asthma may be improved in some people, it was not possible to predict who might benefit.

Review question

This review aimed to investigate if treatment for gastro‐oesophageal reflux disease (GORD) would benefit adults and children with asthma.

Study characteristics

To answer this question, we looked for all randomised controlled trials (RCTs) comparing GORD treatment (medical and/or surgical intervention) to placebo or no treatment in adults or children who had been diagnosed as having both asthma and GORD.

Key results

We found 23 studies for inclusion in this review. These studies focused mostly on adults, with a total of 2872 participants involved. Only two studies assessed the effects of treating GORD in children, and two investigated the benefits of using surgery for GORD to improve asthma control. According to evidence presented in this review, using medication to treat GORD in people with asthma probably reduces the amount of rescue medication needed to control asthma symptoms and also probably improves lung function to a small degree. It is important to note that these benefits may be too small to make an impact on the daily life of someone with asthma.

Based on available evidence, this review is not able to show if there was clear benefit of treatment for asthma symptoms for quality of life, or how many flare‐ups are experienced by a person with asthma. Because researchers used many different approaches to treating people who participated in their studies, it is also difficult to suggest whether a specific type of medication regimen would be best. Not many of the included studies mentioned negative effects of being involved in the research. Those that did reported that any negative effects during the research period happened equally in both treatment and placebo/no treatment groups.

We did not find any data in the included studies related to hospital admissions nor to emergency room or unscheduled doctor visits.

Certainty of evidence

Overall certainty of the evidence was assessed as moderate to low. This is mainly because the studies that were included in this review were very different in the way they approached the research, which produced variable results.

Bottom line

Moderate‐certainty evidence (as some of the included studies were poorly described) shows that with medical treatment for GORD, people with asthma may experience a small improvement in their lung function and may be able to reduce their need to use rescue medications. However, the impact of treatment for GORD on events such as asthma flare‐ups, symptoms, or the need to go to the hospital or consult a doctor is uncertain. Additionally, there was not enough evidence, with only two studies reporting on each, to assess surgical treatment or the effectiveness of GORD treatment in children.

Summary of findings

Summary of findings 1. Medical or surgical intervention, or both, for gastro‐oesophageal reflux disease compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children.

Medical or surgical intervention, or both, for gastro‐oesophageal reflux disease compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children
Patient or population: treatment for asthma in adults and children with asthma and GORD Setting: outpatient Intervention: medical or surgical intervention, or both, for gastro‐oesophageal reflux disease Comparison: nil intervention, delayed intervention control, or placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with nil intervention, delayed intervention control, or placebo	Risk with medical or surgical intervention, or both, for gastro‐oesophageal reflux disease
Number of participants with moderate/severe acute exacerbations Duration of treatment: range 24 weeks to 26 weeks	112 per 1000	63 per 1000 (21 to 171)	OR 0.53 (0.17 to 1.63)	1168 (2 RCTs)	⊕⊕⊝⊝ LOWa,b	Evidence is uncertain about the effect of medical treatment for GORD on acute exacerbations in adults. There were 60 adults with events in the experimental group (n = 732 individuals) compared to 49 adults in the control group (n = 436 individuals)
Change in FEV₁ (L) Duration of treatment: range 6 weeks to 26 weeks	Mean change in FEV₁ (L) was 0.50	MD 0.1 higher (0.05 higher to 0.15 higher)	‐	1333 (7 RCTs)	⊕⊕⊕⊝ MODERATEa	There is moderate‐certainty evidence related to the effect of medical treatment for GORD on FEV₁ (L) in adults with asthma. Pooled analysis indicates that the mean difference in treatment was a small, non‐clinically significant improvement of 0.10 L compared to control
Use of "rescue" medications and emergency action plans: B2 use puffs per day Duration of treatment: range 14 weeks to 24 weeks	Mean use of "rescue" medications and emergency action plans: B2 use puffs per day was 2.11	MD 0.71 lower (1.2 lower to 0.22 lower)	‐	239 (2 RCTs)	⊕⊕⊕⊝ MODERATEa	There is moderate‐certainty evidence related to the effect of medical treatment for GORD on use of rescue medications for people with asthma. A small reduction in average puffs per day (0.71) was detected in the treatment group (n = 115) compared to the control group (n = 124)
Change in quality of life Assessed with AQLQ Scale from 1 to 7; duration of treatment: range 8 weeks to 26 weeks	Mean change in AQLQ was 0.9244	MD 0.21 higher (0.02 lower to 0.44 higher)	‐	1595 (5 RCTs)	⊕⊕⊝⊝ LOWa,c	Evidence is uncertain related to the effect of medical treatment for GORD on change in AQLQ for people with asthma. Mean difference of 0.21 was smaller than minimum important difference of 0.5 units
Healthcare utilisation ‐ not measured			‐	‐	‐	No studies included in this review reported on this outcome
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AQLQ: Asthma Quality of Life Questionnaire; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; GORD: gastro‐oesophageal reflux disease; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aRisk of bias assessment for included studies was unclear or high for important domains of randomisation and allocation concealment (‐1 point).

^bA small number of events resulted in a wide confidence interval (‐1 point).

^cPooled effect estimate is imprecise, with confidence interval including no difference (‐1 point).

Background

This is an update of a Cochrane Review previously published in 2003 (Gibson 2003).

Description of the condition

Gastro‐oesophageal reflux disease (GORD) is the passing of gastric contents through the gastric cardia into the oesophagus. This can be a normal physiological event that occurs mainly after meals during the day in healthy people. Abnormal acid reflux occurs when there is significant exposure (pH < 4.0) to the distal oesophagus for longer than 1.2 hours (cumulative time > 5%) over a 24‐hour period as established by intra‐oesophageal pH monitoring (Johnson 1974; Johnsson 1987). Abnormal acid reflux is commonly associated with upper gastrointestinal (GI) symptoms such as heartburn, dysphagia, regurgitation, and chest pain. There has long been recognition of extra‐oesophageal manifestations including asthma, laryngitis, chronic cough, and rhinosinusitis (Hungin 2005; Mahdavinia 2016; Moore 2010).

The prevalence of GORD in people with asthma is reported to be three times that in the general population (Mauskar 2016). A study from India identified that GORD was present in 40% of people with asthma (Gaude 2016).

Asthma and GORD are common medical conditions that often co‐exist, as shown in different trials. For example, Sontag 1990 studied 104 adults with asthma and found that more than 80% had abnormal GORD on 24‐hour pH monitoring. Compared with healthy controls, people with asthma and reflux had significantly decreased lower oesophageal sphincter pressures, greater oesophageal acid exposure times, more frequent reflux episodes, and longer acid clearance, irrespective of body position and bronchodilator therapy. Studies in children with asthma similarly show a high prevalence of significant GORD (Andze 1991; Martin 1982; Tucci 1993). A systematic review of 28 studies found that symptoms of GORD and abnormal 24‐hour pH monitoring were occurring in 59% and 51% of people with asthma but concluded that data were insufficient to clarify the direction of causality in this association (Havemann 2007). The mechanism underpinning the relationship between GORD and asthma remains unclear, most likely due to the multi‐factorial nature of both conditions (Pacheco 2018).

The role of GORD as a trigger in asthma can be explained by several mechanisms: micro‐aspiration of gastric acid into the respiratory airways (Astarita 2000; Klotz 1971; Mays 1976), vagally mediated reflux inducing bronchoconstriction and airway hyper‐responsiveness (Astarita 2000; Mansfield 1989; Tuchman 1984), and direct acid stimulation of the oesophagus. However, studies in people with asthma have provided conflicting results on the effects of lower oesophageal acidification as a trigger for asthma. Furthermore, the possibility exists that asthma might precipitate GORD (Singh 1983). Thus a temporal association between the two does not conclusively establish that GORD triggers asthma symptoms.

Given recently available technological advancements, impedance‐pH monitoring enables detection of weakly acid, or non‐acid, reflux when pH exposure to the oesophagus is greater than 4 but less than 7 (Ates 2014; Sifrim 2004). It has been suggested that non‐acid reflux may contribute to persistent asthma symptoms, particularly when the individual does not respond to acid suppression treatment (Ates 2014).

Description of the intervention

Narrative reviews have identified the high frequency of GORD in people with asthma, as well as the clinical features and the spectrum of available therapy. Therapy can involve a number of measures, either medical or surgical, to improve symptoms of GORD. Examples of medical treatment include histamine (receptor type 2) antagonists in standard or high dose, proton pump inhibitors, and prokinetics. Presently, proton pump inhibitors are the gold standard treatment for gastro‐oesophageal reflux. Different types of proton pump inhibitors are available, but meta‐analyses fail to show significant differences in efficacy for symptom relief between proton pump inhibitors (Gralnek 2006). Potential surgical options for GORD include Nissen fundoplication and partial posterior semi‐fundoplication (Toupet and Lind techniques). Randomised trials have been conducted on each form of therapy, with conflicting results (Choy 1997; Field 1998; Kahrilas 1996; Simpson 1995; Winter 1997). A systematic review of antireflux surgery in people with asthma found that surgery may improve asthma symptoms but not pulmonary function (Field 1999).

How the intervention might work

Asthma has been proposed as one of the extra‐oesophageal manifestations of GORD. Proton pump inhibitor and histamine (receptor type 2) antagonist drugs aim to suppress acid production in the stomach, thus reducing the risks of acid micro‐aspiration into the airway and vagally mediated bronchoconstriction (Gracie 2016; Harding 2001). Prokinetic therapy with metoclopramide (other prokinetics ‐ domperidone and bethanechol), on the other hand, has been shown to augment gastric emptying and increase lower oesophageal sphincter pressure (Champion 1997). Currently, proton pump inhibitors are recommended as the initial approach to reflux management, and asthma guidelines recommend that, especially in severe cases, the presence of GORD should be investigated and treatment provided when appropriate to improve management of asthma symptoms (King‐Biggs 2019; Moore 2010).

In terms of surgical treatment, fundoplication is one of the most common approaches for treatment of GORD, with success rates of 80% to 90% (Patti 2015). Fundoplication is a procedure that involves wrapping the upper curve of the stomach around the lower portion of the oesophagus, thereby tightening the oesophageal sphincter. This procedure changes the way the gastro‐oesophageal junction functions to reduce the occurrence of transient lower oesophageal sphincter relaxations (Ireland 1993). The best surgical responses are seen in patients with typical symptoms of GORD that demonstrate good response to proton pump inhibitor therapy and in those who have abnormal ambulatory pH studies with good symptom correlation (Oelschlager 2008).

Why it is important to do this review

To date, clinical research trials have described mixed results on the effectiveness of GORD treatment to support management of asthma symptoms. The original publication of this Cochrane Review was unable to show improvement in asthma management‐related outcomes following treatment for GORD and identified that specific subgroups may benefit (Gibson 2003). Since 2003, several trials using different types of medical and surgical treatments for GORD have been published. Therefore, an update of the review is required to examine newly published evidence on the role of GORD treatment for asthma in adults and children.

Objectives

To evaluate the effectiveness of GORD treatment in adults and children with asthma, in terms of its benefits for asthma.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs), both parallel and cross‐over. Cluster‐randomised controlled trials were eligible, provided the data had been or could be adjusted for clustering. We included studies if they were reported as full text or were published as an abstract only, or if unpublished data were available. We included studies for which only a subset of participants met all inclusion criteria, provided disaggregated data could be obtained.

Types of participants

We included adults and children with a diagnosis of both asthma and GORD. Asthma was diagnosed according to international or national guidelines (e.g. GINA 2019), or was diagnosed by a medical practitioner with use of an objective lung function measurement. Similarly, a formal diagnosis of GORD by a medical practitioner was required based on symptoms or objective measurements such as 24‐hour pH studies/manometry or oesophagoscopy with or without biopsy.

Types of interventions

We included pharmacological and surgical interventions for treatment of patients with GORD. Pharmacological interventions consisted of: antacids (e.g. Gaviscon), proton pump inhibitors (e.g. lansoprazole, esomeprazole, omeprazole, rabeprazole, pantoprazole, dexlansoprazole, omeprazole with sodium bicarbonate), histamine 2 receptor antagonists (e.g. ranitidine), and prokinetics (e.g. baclofen, domperidone, bethanechol). We did not specify minimum dosages or duration of intervention for any of these pharmacotherapies. Surgical interventions included Nissen's fundoplication and the Bianchi procedure (i.e. total oesophagogastric disconnection). These pharmacological and surgical interventions could be evaluated on their own as individual therapy, or as a combined pharmacological and surgical package intervention.

Comparator groups included no intervention, delayed intervention control, and placebo.

Types of outcome measures

Primary outcomes

• Acute asthma exacerbations (either number of participants with events or rate) as reported by trialists

• Hospital admissions (either number of participants with events or rate) and length of stay

• Emergency room or unscheduled doctor visits (either number of participants with events or rate)

Secondary outcomes

• Lung function: spirometry, measured as forced expiratory volume in 1 second (FEV₁; litres per minute) and peak expiratory flow rate (PEFR) (morning only)

• Use of "rescue" medications and emergency action plan as reported by trialists (e.g. self‐report via diary or questionnaire, electronic monitoring, prescription monitoring, pharmacy claims data)

• Asthma symptoms score (ideally measured by a validated scale such as the Asthma Control Questionnaire (ACQ); Juniper 1999)

• Nocturnal symptoms (e.g. self‐report via a diary or questionnaire)

• Quality of life (e.g. Asthma Quality of Life Questionnaire (AQLQ)) with responder analysis (dichotomous analysis of people who achieved the minimal important difference versus those who did not)

• Treatment preferences (e.g. determined by self‐report)

• Adverse events

Search methods for identification of studies

Electronic searches

We identified studies by searching the following databases and trial registries.

• Cochrane Airways Trials Register (Cochrane Airways 2019), via the Cochrane Register of Studies (searched 23 June 2020).

• Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, via the Cochrane Register of Studies (searched to 23 June 2020).

• MEDLINE Ovid SP (ALL) 1946 to 22 June 2020 (searched 23 June 2020).

• Embase Ovid SP 1974 to 2020 week 25 (searched 23 June 2020).

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) (searched 23 June 2020).

• World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch) (searched 23 June 2020).

The database search strategies are listed in Appendix 1.

We searched all databases and trials registries from their inception to the present, with no restriction on language or type of publication. We handsearched conference abstracts and searched grey literature through the Cochrane Airways Trials Register and the CENTRAL database. Searches were conducted by the Information Specialist for Cochrane Airways.

Searching other resources

In addition, we screened reference lists of all available primary studies and review articles to identify potentially relevant citations. We contacted the authors of primary studies regarding other published and unpublished trials known to them.

Data collection and analysis

Selection of studies

We used the Cochrane Screen4Me workflow to assist with assessment of search results by matching records in the search results to records already screened in Cochrane Crowd (http://crowd.cochrane.org) and labelled as an RCT or as not an RCT (Marshall 2018; McDonald 2017; Noel‐Storr 2018; Thomas 2017), and we assessed records using the RCT Classifier, a machine learning model that distinguishes RCTs from non‐RCTs. The Cochrane Airways Group Information Specialist removed studies identified in the previous version of this review (Gibson 2003).

Following these initial assessments, we imported data into EndNote software for removal of duplicate references. Two independent review authors (ZK and KVC) screened titles and abstracts and coded them as 'potentially include: full text review required' or 'exclude'. We resolved disagreements through discussion and consensus, erring on the side of caution, with discrepancies requiring full‐text review. Two independent review authors (ZK and KVC) then reviewed full‐text articles for eligibility and coded them as 'include', 'ongoing', 'exclude but relevant', or 'exclude'. Again, we resolved disagreements through discussion and consensus. We recorded this selection process in the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses flow diagram (PRISMA; Moher 2009), as well as in the Characteristics of excluded studies table.

Data extraction and management

Two review authors independently extracted characteristics, outcome data, and risk of bias data from all included studies onto a pilot‐tested, standardised data extraction template using Microsoft Word (all review authors). We resolved any emerging conflicts by discussion and consensus or with a third review author as required. Data extracted for characteristics included:

• methods: country, design, objective/aim, study site, methods of analysis;

• participants: eligibility for study, randomisation numbers per group, participants completed per group, age, gender, comorbidities, diagnostic criteria for asthma, diagnostic criteria for GORD, association between asthma and GORD tested, major exclusion criteria, baseline severity of asthma (FEV₁ in litres, FEV₁ per cent predicted, PEFR), baseline severity of GORD, baseline complications of GORD;

• interventions: duration of intervention, type of intervention, type of control; and

• outcomes: pre‐specified outcomes, follow‐up period, outcomes measured.

Assessment of risk of bias in included studies

Two review authors (all authors) independently assessed risk of bias for each study for random sequence generation, allocation concealment, blinding of participants and outcome assessors, handling of missing data, selective outcome reporting, and other threats to validity in the studies, in line with recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). We also conducted a retrospective risk of bias assessment for all original studies included in the previous version of this review.

We judged each potential source of bias as high, low, or unclear risk, and we provided a justification for the judgement in the 'risk of bias' tables. A summary of risk of bias judgements across different studies for each of the domains listed is provided in the results. We noted information on risk of bias related to unpublished data or correspondence with trialists in the risk of bias table.

We used the pre‐specified protocol to guide review processes when assessing risk of bias associated with undertaking this systematic review and noted deviations from this protocol in the section titled Differences between protocol and review.

Measures of treatment effect

We combined data from included trials using Review Manager 5.3. We analysed continuous and dichotomous data using a fixed‐effect model for all studies deemed similar enough to be pooled. We considered a random‐effects model in the presence of substantial heterogeneity (≥ 50% based on the I² statistic). We undertook meta‐analysis only when we considered treatments, participants, and underlying clinical questions sufficiently similar to be meaningfully pooled. We described any data that could not be pooled using narrative synthesis in the Results section under Effects of interventions, and we entered any data presented as a scale with a consistent direction of effect.

When multiple trial arms were reported in a single trial, we included only the relevant arms. If two intervention arms were both relevant, when appropriate, we combined them as if they were one study arm. For studies reporting both change from baseline and endpoint scores, we used change from baseline scores. When both per‐protocol and intention‐to‐treat analyses were provided, we used the latter as a preference.

For continuous outcomes, we used mean differences (MDs) with 95% confidence intervals (CIs) or standardised mean differences (SMDs).

For dichotomous outcomes, we calculated Mantel‐Haenzsel odds ratios (ORs) with 95% CIs. In instances of rare events (calculated as ≤ 5% of the population), we used Peto ORs. For data reported as rates (e.g. exacerbations), we planned to analyse on the log scale as hazard ratios and to combine using the random‐effects model and generic inverse variance.

Unit of analysis issues

This review included a mixture of cross‐over and parallel studies, producing the potential for unit of analysis issues. We addressed unit of analysis issues by excluding cross‐over trials from meta‐analyses, unless paired data were available (e.g. paired t‐test). We analysed data from cluster‐randomised controlled trials only if available data had been or could be adjusted for potential clustering effects (Higgins 2019a). We would have made adjustments for clustering by contacting the original study authors to identify intracluster correlation coefficients. However, none of the included studies involved clusters, and ultimately, this was not necessary.

Dealing with missing data

We evaluated missing information regarding participants on an available case analysis basis, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2019). When statistics essential for analysis were missing (e.g. when group means and standard deviations for both groups were not reported) and could not be calculated from other data, we attempted to contact study authors for missing data. We assumed loss of participants that occurred before baseline measurements to have no effect on eventual outcome data of the study. We used the intention‐to‐treat approach as the measure for assessment and discussion of losses after baseline measurements. When data were presented only in abstract or protocol form and attempts to contact study authors (on two occasions) were unsuccessful, we classified studies as excluded but relevant.

Assessment of heterogeneity

We used a combination of tests, including visual inspection of data and the I² statistic to assess statistical heterogeneity. We determined thresholds for the I² statistic according to the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2019), as follows:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity; and

• 75% to 100%: considerable heterogeneity.

Funnel plots were to be applied as well if 10 or more studies had been included. We considered the Der‐Simonian and Laird method of analysis presented with a P value less than 0.05 as statistically significant. In the presence of significant heterogeneity (as per criteria above), we re‐analysed data using the random‐effects model (Der Simonian 1986).

Assessment of reporting biases

We planned to explore potential reporting biases by using a funnel plot had meta‐analysis of 10 or more studies been available. Instead, reporting biases were extrapolated within the other bias section in the risk of bias tables. Unpublished data were able to be included in the review, with their status highlighted within the references. When available, outcomes reported in protocols of studies were compared against outcomes reported in publications.

Data synthesis

We combined and analysed data from all trials using Review Manager 2014 (RevMan 5.3) software. We used a fixed‐effect model for all analyses. However, in the presence of substantial heterogeneity (I² statistic ≥ 50%), we used a random‐effects model. We performed sensitivity analyses using a fixed‐effect model.

Subgroup analysis and investigation of heterogeneity

We planned to perform subgroup analyses for adults versus children for all outcomes.

Sensitivity analysis

We performed a sensitivity analysis when results from the same studies were reported with conflicting information from different sources (see Differences between protocol and review).

Summary of findings and assessment of the certainty of the evidence

We created a summary of findings table for outcomes considered to be relevant for either clinical care and/or policy makers. We selected the following:

1. Acute exacerbations

2. Hospital admissions and length of stay

3. Emergency room or unscheduled doctor visits

4. Use of "rescue" medications

5. Asthma symptoms

We used the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence as it relates to the included studies reporting these outcomes. We then generated the Summary of findings table 1 using GRADEpro software (GRADEpro GDT) and provided all justifications for downgrading of evidence in the table footnotes.

Results

Description of studies

See Table 2 for a brief summary of the main characteristics of the 23 studies included in this review.

1. Summary of characteristics of included studies.

Study ID	Country	N	Duration (weeks)	Intervention	Control	Outcomes of interest in this review
Aiguo 1999	China	54	6	a: Jiang Ni decoction twice daily b: 150 mg ranitidine twice daily plus cisapride 10 mg 3 times daily	Placebo	FEV₁; PEFR; asthma symptoms
Dos Santos 2007	Brazil	44	12	Pantoprazole 40 mg once daily	Placebo	FEV₁; mPEFR; ePEFR; asthma symptoms; nocturnal asthma symptoms; quality of life
Ekstrom 1989	Sweden	50	4	Ranitidine 150 mg twice daily	Placebo	FEV₁; mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms; nocturnal asthma symptoms; adverse events
Fallahi 2008	Iran	36	6	Omeprazole 20 mg twice daily	Placebo	FEV₁; PEFR
Ford 1994	UK	11	4	Omeprazole 20 mg once daily	Placebo	PEF; use of beta₂‐agonists; asthma symptoms
Frison 2002	Brazil	22	8	Lansoprazole 60 mg once daily plus cisapride 30 mg once daily plus behavioural management	Placebo plus behavioural management	FEV₁; mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms; nocturnal asthma symptoms
Goodall 1981	UK	20	6	Cimetidine 200 mg 3 times daily plus 2 at night	Placebo	FEV₁; PEFR; use of beta₂‐agonists; asthma symptoms; nocturnal asthma symptoms
Jiang 2003	China	30	6	Omeprazole 20 mg once daily plus domperidone 10 mg 3 times daily	Nil intervention	FEV₁; PEFR
Kiljander 1999	Finland	57	8	Omeprazole 40 mg once daily	Placebo	FEV₁; PEFR; use of beta₂‐agonists; asthma symptoms; nocturnal asthma symptoms
Kiljander 2006	Multi‐nationala	770	16	Esomeprazole 40 mg twice daily	Placebo	Asthma exacerbations; FEV₁; mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms; nocturnal asthma symptoms; quality of life; adverse events
Kiljander 2010	Multi‐nationalb	916	26	a: Esomeprazole 40 mg once daily b: Esomeprazole 40 mg twice daily	Placebo	Asthma exacerbations, FEV₁; mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms; nocturnal asthma symptoms; quality of life; adverse events
Kjellen 1981	Sweden	62	8	Conservative treatment (head elevation, warm water after meals, avoiding food 3 hours before sleep, refraining from aspirin and anticholinergic drugs, not raising intra‐abdominal pressure)	Nil intervention	FEV₁;use of beta₂‐agonists; asthma symptoms
Larrain 1991	Chile	90	26	a: Cimetidine 300 mg 4 times daily b: Surgery, posterior gastropexy with cardiac calibration	Placebo	FEV₁; asthma symptoms
Levin 1998	USA	11	8	Omeprazole 20 mg once daily	Placebo	FEV₁; mPEFR; ePEFR; quality of life
Littner 2005	USA	207	24	Lansoprazole 30 mg twice daily	Placebo	Asthma exacerbations, FEV₁; mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms; nocturnal asthma symptoms; quality of life; adverse events
Maev 2002	Russia	64	8	Omeprazole 20 mg twice daily	Placebo	FEV₁; PEF; asthma symptoms
Meier 1994	USA	15	6	Omeprazole 20 mg twice daily	Placebo	FEV₁; PEF; use of beta₂‐agonists; asthma symptoms
Nagel 1988	UK	15	1	Ranitidine 150 mg in the morning and 300 mg at night	Placebo	mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms
Sharma 2007	India	204	16	Omeprazole 20 mg twice daily plus domperidone 10 mg 3 times daily	Placebo	FEV₁; mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms; nocturnal asthma symptoms; adverse events
Sontag 2003	USA	75	104	a: Ranitidine 150 mg 3 times daily plus conservative treatment b: Surgery, Nissen fundoplication plus conservative treatment	Symptomatic treatment as needed, Mylanta 30 mL	PEF, asthma symptoms
Stordal 2005	Norway	38	12	Omeprazole 20 mg once daily	Placebo	FEV₁; use of beta₂‐agonists; asthma symptoms; quality of life
Susanto 2008	Indonesia	36	14	Esomeprazole 40 mg daily plus conservative treatment (lifestyle modifications and antacid medication if required)	Conservative treatment (lifestyle modifications and antacid medication if required)	mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms
Teichtahl 1996	Australia	25	12	Omeprazole 40 mg once daily	Placebo	FEV₁;mPEFR; ePEFR; use of beta₂‐agonists; asthma symptoms

ePEFR: evening peak expiratory flow rate; FEV₁: forced expiratory volume in one second; mPEFR: morning peak expiratory flow rate.

^aKiljander 2006 included participants from centres in the following countries: Argentina, Brazil, Bulgaria, Canada, Czech Republic, Finland, Hungary, Italy, Mexico, Romania, Sweden, and the United States of America.

^bKiljander 2010 included participants from centres in the following countries: Argentina, Bulgaria, Canada, Czech Republic, France, Germany, Hungary, Italy, Mexico, Poland, Portugal, Slovakia, and the United States of America.

For additional details on the 23 included and 77 excluded studies, see Characteristics of included studies and Characteristics of excluded studies.

Results of the search

The previously published version of this review identified 12 RCTs for inclusion (Gibson 2003). For this update, searches were completely re‐run up to 23 June 2020 to ensure that standards reflect current Cochrane Review procedures (Lefebvre 2019). The original 12 studies were re‐screened according to updated criteria for inclusion. Of these, we excluded two as they did not include participants who fulfilled the pre‐defined diagnosis of asthma and GORD as outlined for this review (Boeree 1998; Gustafsson 1992).

Through update searches, we retrieved 3531 records and we identified one additional record through handsearching of reference lists of relevant studies. After all duplicates were removed by the information specialist, Screen4Me workflow, and EndNote software, ZK and KVC screened 1320 records. On the basis of title and abstract review, we excluded 1205 records as they were irrelevant to the review question. We obtained full text for the remaining 115 records and reviewed them for eligibility. At this stage, we excluded 77 studies, leaving 23 studies for inclusion in this review. Of these, 12 were suitable for inclusion in meta‐analyses. For further details of the screening processes, see the study flow diagram (Figure 1).

1.

PRISMA study flow diagram.

Included studies

Study design

The included studies were published between 1981 and 2010. Fourteen of the included studies were parallel studies, and eight used a cross‐over design (Ekstrom 1989; Ford 1994; Goodall 1981; Kiljander 1999; Levin 1998; Meier 1994; Nagel 1988; Teichtahl 1996). These 23 studies including international multi‐centred studies randomly assigned a total of 2872 participants. Two studies were multi‐national trials (Kiljander 2006; Kiljander 2010), and one study originated from Australia (Teichtahl 1996), one from Chile (Larrain 1991), one from Finland (Kiljander 1999), one from India (Sharma 2007), one from Iran (Fallahi 2008), one from Norway (Stordal 2005), one from Russia (Maev 2002), two from Brazil (Dos Santos 2007; Frison 2002), two from China (Aiguo 1999; Jiang 2003), two from Sweden (Ekstrom 1989; Kjellen 1981), three from United Kingdom (Ford 1994; Goodall 1981; Nagel 1988), and four from United States of America (Levin 1998; Littner 2005; Meier 1994; Sontag 2003).

Participants

A total of 2872 participants were randomly assigned across the 23 studies; 21 studies were adult studies (n = 2598 participants), and two involved a paediatric demographic (n = 274 participants) (Fallahi 2008; Stordal 2005). The total number of participants randomised across all included studies varied from 11 in Ford 1994 to 916 in Kiljander 2010. The age range for adult studies was 20 to 75 years, with a range for child/adolescent studies of 7 to 20 years. Participants from all included studies had diagnoses of both asthma and GORD based on different criteria.

Diagnosis of asthma

Different criteria had been used for asthma diagnosis; these particularly varied in clinical assessment of forced expiratory volume in 1 second (FEV₁) reversibility. Objective pulmonary function tests were required for diagnosis in 19 studies. Four studies diagnosed asthma based on doctors' assessment using symptoms and clinical grounds (Aiguo 1999; Goodall 1981; Larrain 1991; Stordal 2005). Thirteen studies reported baseline lung function as expressed in FEV₁ (Stordal 2005), peak expiratory flow rate (PEFR) (Ford 1994), or both (Aiguo 1999; Dos Santos 2007; Frison 2002; Jiang 2003; Kiljander 1999; Kiljander 2006; Kiljander 2010; Kjellen 1981; Levin 1998; Littner 2005; Sharma 2007). When baseline data were not reported, the inclusion criteria for the study had been substituted as an indicator of asthma severity (Ekstrom 1989). Five studies did not specify the severity of asthma (Fallahi 2008; Goodall 1981; Meier 1994; Nagel 1988; Teichtahl 1996), but baseline asthma symptom scores were reported by Sontag 2003 as indicators of asthma severity. Medications used in the Larrain 1991 and Maev 2002 studies also indicated the severity of asthma as moderate to severe.

Diagnosis of GORD

Different methods were used including history of symptoms, endoscopy, manometry, acid perfusion test, and 24‐hour pH monitoring. Six of the included studies described use of a dual‐lumen/channel probe (Frison 2002; Kiljander 1999; Levin 1998; Meier 1994; Nagel 1988; Stordal 2005); of these, two provided enough information to discern that impedance was also available (Levin 1998; Stordal 2005) (a dual‐lumen pH probe with impedance is the current gold standard for GORD diagnosis). All studies except three diagnosed GORD based on objective tests (Fallahi 2008; Levin 1998; Littner 2005). GORD symptoms were evident in more than 70% of the population in 17 studies (Aiguo 1999; Dos Santos 2007; Ekstrom 1989; Fallahi 2008; Ford 1994; Frison 2002; Goodall 1981; Kiljander 2006; Kiljander 2010; Larrain 1991; Levin 1998; Littner 2005; Meier 1994; Nagel 1988; Sontag 2003; Stordal 2005; Teichtahl 1996). Association of asthma and GORD was examined in seven studies (Dos Santos 2007; Ekstrom 1989; Frison 2002; Goodall 1981; Kiljander 2006; Meier 1994; Nagel 1988).

Intervention

The length of studies varied with intervention duration and ranged from 1 to 104 weeks. Types of interventions included non‐pharmacological treatment, pharmacological treatment, and surgical intervention.

Non‐pharmacological treatment

Kjellen 1981, a parallel study over eight weeks, was the only study to investigate non‐pharmacological conservative anti‐reflux therapy. Interventions involved elevating the head‐end of the bed, drinking warm water after meals, avoiding late meals three hours before bedtime, refraining from aspirin and anticholinergic medications, and avoiding procedures that were known to increase intra‐abdominal pressure.

Pharmacological treatment

Proton pump inhibitors were the mainstay of study treatment in 12 studies. Different dosages and types of proton pump inhibitors were studied, including esomeprazole (40 mg to 80 mg/d), lansoprazole (60 mg/d), omeprazole (20 to 40 mg/d), and pantoprazole (40 mg/d). H₂ antagonists were also studied in five studies (Ekstrom 1989; Goodall 1981; Larrain 1991; Nagel 1988; Sontag 2003). Four studies investigated the effectiveness of combination therapy including omeprazole and domperidone (Jiang 2003; Sharma 2007); lansoprazole and cisapride (Frison 2002); and ranitidine and cisapride (Aiguo 1999). In addition to pharmacological treatment, the study population in Frison 2002 and Sontag 2003 were provided conservative treatment.

Surgical intervention

Only two included studies used surgical intervention. Larrain 1991 randomised participants to three arms, which included medical treatment (cimetidine 300 mg four times a day), placebo, or surgery (posterior gastropexy). Sontag 2003 also randomised participants to three groups: (1) surgical approach by Nissan fundoplication; (2) medical therapy with ranitidine 150 mg three times a day; and (3) control.

Excluded studies

We excluded 77 studies (81 records) from the updated reference list following full‐text assessment against eligibility criteria (see Characteristics of excluded studies). We also excluded two of the old studies included in the previous version of this Cochrane Review. One of the excluded studies recruited patients with chronic obstructive pulmonary disease (COPD) as well as asthma, and results could not be separated (Boeree 1998), whilst another study did not require GORD as an inclusion criterion (Gustafsson 1992). The most common reason for study exclusion was no GORD diagnosis (n = 20 studies), followed by not being unable to confirm eligibility (n = 19), no relevant intervention (n = 10), inappropriate control (n = 9), no asthma diagnosis (n = 6), no control (n = 4), not randomised (n = 3), not all asthma (n = 3), and not all GORD (n = 3).

Risk of bias in included studies

Full details of our risk of bias judgements can be found under the 'Risk of bias' section at the end of each Characteristics of included studies table and in Figure 2. Many studies did not provide sufficient information to assess the risk of bias, resulting in many “unclear” judgements across domains. For unclear risk of bias, study authors were contacted for additional information. Two independent review authors (ZK and KC, HY and KT, or HY and KH) reached agreement when assessing study quality.

2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We considered generation of randomisation sequence to be adequate in five studies (Ekstrom 1989; Frison 2002; Larrain 1991; Levin 1998; Meier 1994), and it was unclear in 17 studies (Aiguo 1999; Dos Santos 2007; Fallahi 2008; Ford 1994; Goodall 1981; Jiang 2003; Kiljander 1999; Kiljander 2006; Kiljander 2010; Littner 2005; Maev 2002; Nagel 1988; Sharma 2007; Sontag 2003; Stordal 2005; Susanto 2008; Teichtahl 1996). Kjellen 1981 was assessed to have high risk of bias for using alternation for allocation of study participants to treatment or control groups.

Similarly, we judged the method of allocation concealment to be adequate in five studies (Ekstrom 1989; Frison 2002; Larrain 1991; Levin 1998; Stordal 2005), and we assigned high risk to Kjellen 1981. We judged the remaining 17 studies as having unclear risk due to lack of information about allocation concealment (Aiguo 1999; Dos Santos 2007; Fallahi 2008; Ford 1994; Goodall 1981; Jiang 2003; Kiljander 1999; Kiljander 2006; Kiljander 2010; Littner 2005; Maev 2002; Meier 1994; Nagel 1988; Sharma 2007; Sontag 2003; Susanto 2008; Teichtahl 1996).

Blinding

Adequate blinding of participants and outcome assessors was reported on the basis of information provided by study authors, such as well‐defined study protocols, identical placebo tablets or intervention, central or third party allocation of participants, and same follow‐up and outcomes measurements. Thirteen studies were deemed to have unclear risk of performance bias due to inadequate information provided (Aiguo 1999; Ekstrom 1989; Fallahi 2008; Ford 1994; Frison 2002; Goodall 1981; Kiljander 2006; Kiljander 2010; Maev 2002; Nagel 1988; Sharma 2007; Susanto 2008; Teichtahl 1996). Larrain 1991 was deemed to have unclear risk of bias as a placebo identical to the study drug was used; however, it was not possible to blind the surgical arm due to the nature of the intervention. Blinding of participants was assessed as adequate in six studies (Dos Santos 2007; Kiljander 1999; Levin 1998; Littner 2005; Meier 1994; Stordal 2005), but risk was considered high in three studies (Kjellen 1981; Jiang 2003; Sontag 2003).

We judged the risk of detection bias due to inadequate blinding of outcome assessment as high in Kjellen 1981 and low in seven studies (Dos Santos 2007; Kiljander 1999; Larrain 1991; Levin 1998; Littner 2005; Meier 1994; Stordal 2005). Fifteen studies had unclear risk of detection bias (Aiguo 1999; Ekstrom 1989; Fallahi 2008; Ford 1994; Frison 2002; Goodall 1981; Jiang 2003; Kiljander 2006; Kiljander 2010; Maev 2002; Meier 1994; Sharma 2007; Sontag 2003; Susanto 2008; Teichtahl 1996).

Incomplete outcome data

We reported high risk of attrition bias in three studies (Dos Santos 2007; Kiljander 2006; Susanto 2008). We assessed risk of attrition bias as low in 19 studies (Aiguo 1999; Ekstrom 1989; Fallahi 2008; Ford 1994; Frison 2002; Goodall 1981; Jiang 2003; Kiljander 2010; Kjellen 1981; Larrain 1991; Levin 1998; Littner 2005; Maev 2002; Meier 1994; Nagel 1988; Sharma 2007; Sontag 2003; Stordal 2005; Teichtahl 1996), and as unclear in one study (Kiljander 1999).

Selective reporting

Selective reporting (reporting bias) was deemed to be at high risk in two studies (Maev 2002; Teichtahl 1996), and was deemed to be at unclear risk in eight studies (Aiguo 1999; Dos Santos 2007; Ekstrom 1989; Goodall 1981; Larrain 1991; Meier 1994; Nagel 1988; Susanto 2008). The remaining thirteen studies were judged to have low risk for reporting bias (Fallahi 2008; Ford 1994; Frison 2002; Jiang 2003; Kjellen 1981; Kiljander 1999; Kiljander 2006; Kiljander 2010; Levin 1998; Littner 2005; Sharma 2007; Sontag 2003; Stordal 2005).

Other potential sources of bias

Twenty studies were assessed as having low risk for other potential bias (Aiguo 1999; Dos Santos 2007; Ekstrom 1989; Fallahi 2008; Frison 2002; Goodall 1981; Jiang 2003; Kiljander 1999; Kiljander 2010; Kjellen 1981; Larrain 1991; Littner 2005; Maev 2002; Meier 1994; Nagel 1988; Sharma 2007; Sontag 2003; Stordal 2005; Susanto 2008; Teichtahl 1996). Two were assessed as high risk for other potential sources of bias; both were provided with the study drug by a pharmaceutical company. In the case of Ford 1994, the company also provided assistance with statistical analyses, and the study design of Kiljander 2006 was set by the pharmaceutical company. Levin 1998 was assessed as having unclear risk for this domain; per publication, there appeared to be no washout phase between treatment periods, and the potential for contamination was not discussed.

Effects of interventions

See: Table 1

See Table 1 for the main comparison medical or surgical intervention, or both, for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children.

Of the eight cross‐over studies included in this review, only one reported results in a manner that could be considered for inclusion in meta‐analyses (Levin 1998). Outcomes from the other seven cross‐over studies were reported narratively (Ekstrom 1989; Ford 1994; Goodall 1981; Kiljander 1999; Meier 1994; Nagel 1988; Teichtahl 1996).

For ease of reading, results related to effects of interventions are collated and reported as "Pooled results" and "Individual study results".

Pooled results

Primary outcomes

Acute exacerbations

Three of the 23 included studies reported data on exacerbations. Of these, two studies reported on the number of participants who experienced a severe asthma exacerbation and could be pooled into a meta‐analysis using a random‐effects model (Kiljander 2010; Littner 2005). The difference between medical treatment with a proton pump inhibitor compared to placebo was uncertain in terms of numbers of participants experiencing a moderate/severe exacerbation (odds ratio (OR) 0.53, 95% confidence interval (CI) 0.17 to 1.63; 1168 participants, 2 studies; P = 0.27; Analysis 1.1; Figure 3; low‐certainty evidence). A sensitivity analysis was performed, as Kiljander 2010 reported different values for this outcome on the online trial registry compared to the published article. According to the sensitivity analysis, this variation does not change the outcome (Table 3).

1.1. Analysis.

Comparison 1: Medical intervention for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children, Outcome 1: Number of participants with any moderate/severe acute exacerbations

3.

Forest plot of comparison: medical intervention for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children. Analysis, Outcome: 1.1 number of participants with acute exacerbations.

2. Sensitivity analysis: number of participants with an acute exacerbation.

	Odds ratio	P value
	M‐H, Random, 95% CI
Per publication data	0.53 (0.17 to 1.63)	0.27
Per trials website data	0.54 (0.17 to 1.74)	0.30

M‐H: Mantel‐Haenszel.

Hospital admissions and emergency room or unscheduled doctor visits

Use of hospital and emergency services or unscheduled doctor visits were not reported as outcomes in any of the studies included in this review.

Secondary outcomes

Forced expiratory volume in one second (FEV₁)

Of the 19 included studies that reported on FEV₁, seven were suitable for meta‐analysis (Aiguo 1999; Frison 2002; Jiang 2003; Kiljander 2010; Kjellen 1981; Levin 1998; Littner 2005). Improvement in change in absolute FEV₁ was detected in adults with asthma and a GORD diagnosis (mean difference (MD) 0.10 L, 95% CI 0.05 to 0.15; 1333 participants, 7 studies; P < 0.0001; Analysis 1.2; moderate‐certainty evidence).

1.2. Analysis.

Comparison 1: Medical intervention for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children, Outcome 2: Change in FEV₁ (L)

Morning peak expiratory flow rate (PEFR)

Twelve included studies reported morning PEFR; of these, five were able to be pooled (Dos Santos 2007; Kiljander 2010; Levin 1998; Littner 2005; Susanto 2008). A fixed‐effect model was used to demonstrate improvement of 6 L/min with medical treatment compared to placebo (MD 6.02, 95% CI 0.56 to 11.47; 1262 participants, 5 studies; Analysis 1.3; P = 0.03).

1.3. Analysis.

Comparison 1: Medical intervention for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children, Outcome 3: Morning peak expiratory flow (L/min)

Sensitivity analysis was performed using a random‐effects model (see Table 4 for a comparison with the primary analysis).

3. Sensitivity analysis: morning peak expiratory flow rate (L/min).

	Mean difference	P value
	IV, Random, 95% CI
Random‐effects analysis	10.18 (‐1.92 to 22.28)	0.10
Fixed‐effect analysis	6.02 (0.56 to 11.47)	0.03

IV: inverse variance.

Use of "rescue" medications and emergency action plan

Two out of the 14 studies reporting on use of a beta₂‐agonist as "rescue" medication were pooled (Littner 2005; Susanto 2008). Meta‐analysis indicates a reduction in puffs per day with medical treatment for GORD in adults with asthma compared to adults given a control intervention (MD ‐0.71, 95% CI ‐1.20 to ‐0.22; P = 0.005; 239 participants, 2 studies; Analysis 1.4; moderate‐certainty evidence).

1.4. Analysis.

Comparison 1: Medical intervention for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children, Outcome 4: Use of "rescue" medications and emergency action plans: B2 use puffs per day

Change in quality of life

Quality of life was reported in seven studies (Dos Santos 2007; Frison 2002; Kiljander 2006; Kiljander 2010; Levin 1998; Littner 2005; Stordal 2005). Data for this outcome were collected using a variety of scales and questionnaires across studies. The difference in change in Asthma Quality of Life Questionnaire (AQLQ) scores between medical treatment for GORD in people with asthma compared to control was able to be meta‐analysed, although evidence of any benefit overall was uncertain (MD 0.21, 95% CI ‐0.02 to 0.44; 1595 participants, 5 studies; P = 0.07; Analysis 1.5). A responder analysis was conducted within a single study (Kiljander 2010), highlighting that more people in the intervention group experienced greater than the minimal clinically important improvement in quality of life, as measured by the AQLQ (OR 1.53, 95% CI 1.15 to 2.03; 864 participants, 1 study; P = 0.003; Analysis 1.6; low‐certainty evidence).

1.5. Analysis.

Comparison 1: Medical intervention for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children, Outcome 5: Change in AQLQ

1.6. Analysis.

Comparison 1: Medical intervention for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children, Outcome 6: AQLQ responder analysis

According to the paediatric subgroup in Analysis 1.5, any benefit in AQLQ with medical treatment compared to placebo was also uncertain (MD 0.12, 95% CI ‐0.24 to 0.48; 36 participants; 1 study; P = 0.51).

Individual study results

Primary outcomes

Acute exacerbations

Kiljander 2006 reported that fewer asthma exacerbations (n = 22) were noted in the esomeprazole group compared to the placebo group (n = 24). However, the median time to asthma exacerbation was shorter at 42 days in the treatment group compared to 67 days in the placebo group; study authors state that this comparison was not statistically significant (P = 0.70).

One additional study reported this outcome as an adverse event, noting that a participant experienced an acute asthma exacerbation whilst active in the intervention (cimetidine) group, requiring prolonged inpatient admission, and was withdrawn (Goodall 1981).

Hospital admissions and emergency room or unscheduled doctor visits

Use of hospital and emergency services or unscheduled doctor visits were not reported as outcomes in any of the studies included in this review.

Secondary outcomes

Forced expiratory volume in one second (FEV₁)

Of the studies that were not suitable for meta‐analysis, four parallel studies ‐ Maev 2002; Kiljander 2006; Dos Santos 2007; Sharma 2007 ‐ and five cross‐over studies ‐ Goodall 1981; Ekstrom 1989; Meier 1994; Teichtahl 1996; Kiljander 1999 ‐ involving adults reported on FEV₁ with conflicting results. A detailed description of the findings of these studies can be found in Appendix 2.

Morning peak expiratory flow rate (PEFR)

Of the studies not suitable for inclusion in the meta‐analysis, nine reported specifically on morning PEFR (Ekstrom 1989; Ford 1994; Frison 2002; Goodall 1981; Kiljander 1999; Kiljander 2006; Nagel 1988; Sharma 2007; Teichtahl 1996), and six reported an unspecified PEFR value (Aiguo 1999; Fallahi 2008; Frison 2002; Jiang 2003; Maev 2002; Sontag 2003). Results in both groups were conflicting; a detailed description of the findings of these studies can be found in Appendix 2.

Use of "rescue" medications and emergency action plan

Eleven included studies were not suitable for meta‐analysis (Ekstrom 1989; Ford 1994; Frison 2002; Goodall 1981; Kiljander 1999; Kiljander 2006; Kiljander 2010; Kjellen 1981; Nagel 1988; Sharma 2007; Teichtahl 1996); again, results in adults were conflicting. A detailed description of the findings of these studies can be found in Appendix 2.

Use of an emergency action plan was not reported as an outcome in any of the studies included in this review.

Change in quality of life

Two studies reporting on quality of life were not suitable for meta‐analysis (Dos Santos 2007; Frison 2002); both indicated a clinically significant improvement with treatment. Additional details are presented in Appendix 2.

Asthma symptom scores

A total of 20 studies reported on asthma symptoms (Aiguo 1999; Dos Santos 2007; Ekstrom 1989; Ford 1994; Frison 2002; Goodall 1981; Kiljander 1999; Kiljander 2006; Kiljander 2010; Kjellen 1981; Larrain 1991; Littner 2005; Maev 2002; Meier 1994; Nagel 1988; Sharma 2007; Sontag 2003; Stordal 2005; Susanto 2008; Teichtahl 1996); seven of these were cross‐over studies. Overall, results were conflicting; complete details can be found in Appendix 2.

Nocturnal symptoms

Eleven studies reported nocturnal asthma symptoms (Dos Santos 2007; Ekstrom 1989; Ford 1994; Frison 2002; Goodall 1981; Kiljander 1999; Kiljander 2006; Littner 2005; Sharma 2007; Susanto 2008; Teichtahl 1996). Again, results varied and details can be found in Appendix 2.

Treatment preferences

Treatment preferences were reported in two studies (Ford 1994; Goodall 1981), indicating that participants preferred to receive treatment over placebo. Results are described in greater detail in Appendix 2.

Adverse events

Adverse events were not a pre‐specified outcome for this review. However, for safety, we report available data from included studies related to this. Six studies reported that the incidence of adverse events was similar between intervention and control groups (Ekstrom 1989; Goodall 1981; Kiljander 2006; Kiljander 2010; Littner 2005; Sharma 2007); more detail is provided in Appendix 2.

Discussion

Summary of main results

The body of evidence to underpin treatment for gastro‐oesophageal reflux disease (GORD) in asthma has grown since the original publication of this review (Gibson 2003). This update contains evidence from 23 studies involving 2872 participants; despite this, only limited data are available to illuminate many of the pre‐specified outcomes of interest, and we concluded that certainty was low to moderate. Further, only two studies reported on effects of GORD treatment in the paediatric asthma population (Fallahi 2008; Stordal 2005), and two others reported on potential effects of surgical intervention (Larrain 1991; Sontag 2003). Meta‐analysis revealed that the benefit of medical treatment for reducing the number of people who experience a severe exacerbation of asthma is uncertain. Likewise, the benefit of medical treatment for GORD for people with asthma in relation to quality of life as measured by the Asthma Quality of Life Questionnaire (AQLQ) is uncertain. However, benefit was noted for other clinical outcomes including forced expiratory volume in one second (FEV₁; moderate‐certainty evidence) and use of rescue medication (moderate‐certainty evidence). Morning peak expiratory flow rate (PEFR) was meta‐analysed (but was not included in the Table 1), indicating improvement with medical treatment for GORD. It must be noted that the magnitude of the differences noted in pooled analyses is not clinically important.

For outcomes for which meta‐analysis was not possible, there was some uncertainty about the benefit of intervention. It was not possible to definitively conclude that asthma symptoms were improved by medical treatment for GORD; this is mainly attributable to inconsistent reporting and use of both validated and invalidated scores by trialists. Nocturnal asthma symptoms were improved with H₂ receptor agonist treatment according to the two studies included in this review; however, similar agreement was not found on review of studies evaluating the effectiveness of proton pump inhibitors.

Of the two studies that captured data on treatment preferences, there was a clear preference of participants for treatment over placebo. However, a limitation that should be considered when this result is interpreted is that it is likely that the participant‐reported preference reflected improvement in GORD symptoms, rather than improvement in asthma symptoms.

Data related to acute presentations to the healthcare system (i.e. hospital admissions and emergency room or unscheduled doctor visits) were not captured or reported in any of the included studies. Therefore, effects of treatment of GORD on acute episodes of asthma and its effect on the healthcare system could not be determined.

Adverse event reporting was generally under‐performed in the included studies, although evidence available in this review does not indicate risk with GORD treatment for asthma symptom management.

The duration of the study period in the included studies varied from only 1 week to 104 weeks. Studies consistently averaged results over the entire treatment, which might cause bias against finding a treatment effect. Further, response to GORD treatment could be underestimated due to the short duration of treatment, as the effect of treatment could be delayed or could require additional time to manifest.

Given lack of standardisation in dosing protocols, it is difficult to determine the most effective prescription to be used in practice. Likewise, head‐to‐head comparisons between different types of medical treatments and between monotherapy versus combination therapy were lacking.

Overall completeness and applicability of evidence

Overall this review contains a good body of evidence with a total of 2872 participants, despite there being insufficient agreement across studies to ascertain clear benefit of GORD treatment for people with asthma. All trials assessed participants with diagnoses of both asthma and GORD. Based on the information provided, only two included studies used the current gold standard of objective GORD diagnosis (dual‐lumen pH probe with impedance) (Levin 1998; Stordal 2005), Most studies either used subjective means to determine the presence of GORD or did not provide enough information to determine the type of probe used. Most trials assessed participants with asthma across a range of spirometric severities, mainly from "mild" to moderate. Broad international recruitment was seen across these studies, with participants enrolled predominantly from the United states, Europe, United Kingdom, India, Brazil, Chile, Iran, and China. As a result, the outcomes of this review could be generalised to most people with asthma and GORD. A wide range of medical treatment regimens were included in this review of 23 studies. Most studies investigated the interventional effects of proton pump inhibitors, which are currently the gold standard of GORD management. Some included studies are outdated, and as a result, investigated agents that are no longer used in practice (i.e. cimetidine ‐ Goodall 1981; Larrain 1991 ‐ and ranitidine ‐ Aiguo 1999; Ekstrom 1989; Nagel 1988; Sontag 2003). Additionally, given the GORD diagnostic techniques and approaches used in the included studies, we are likely to have captured only individuals with comorbid acid reflux and asthma.

Although the pool of evidence has grown since the original publication of this review (Gibson 2003), there remains a paucity of evidence to underpin treatment with surgery or to guide practice in children. Further, few studies reported on the primary outcome of this review (acute asthma exacerbations), and none reported on clinically relevant, pre‐specified outcomes related to hospital utilisation.

Certainty of the evidence

Certainty of the evidence overall was moderate to low. This was impacted by the inability to pool many of the included studies into meta‐analyses. Further, there were no data in the included studies by which to understand the impact of intervention on several pre‐specified outcomes. Certainty was downgraded in the domain of inconsistency because substantial heterogeneity was noted based on the value of the I² statistic in the meta‐analyses and the lack of clear agreement across studies synthesised narratively. We further downgraded the certainty of evidence for indirectness because surgical intervention was underrepresented in the analysis. Certainty was also downgraded in the domain of imprecision owing to the small numbers of events and studies that could be pooled together.

Other domains assessed, including risk of bias and publication bias, presented no cause for downgrading in our assessment of certainty.

Potential biases in the review process

Bias may have been introduced in the conduct of the meta‐analyses for this review. We omitted and reported narratively instead all but one of the included cross‐over studies (Levin 1998). The reason for this is that data were not reported in a way that enabled meaningful pooling with parallel studies. Despite rigorous and systematic literature searches, evidence specifically related to surgical intervention is lacking; therefore, it is possible that effects reported in this review are under‐estimated or over‐estimated. Further, Sharma 2007 reported that all 99 participants treated with antireflux therapy experienced improvement and published highly significant benefits over placebo for all outcomes. The review author team in discussion with Dr Chris Cates (data and analysis advisor) believed these results to be implausible and elected to omit these data from the meta‐analyses to prevent drawing misleading conclusions. Likewise, FEV₁ data published in Fallahi 2008 appear implausibly low, no baseline values were reported, and it is not clear which measure of dispersion was used throughout. Clarification has been sought from Sharma 2007 and Fallahi 2008, with no response at the time of publication; hence, results from these studies have been synthesised only narratively in the text of this review.

We identified a number of additional intervention search terms during the course of the review. The search strategy we used contained terms to identify gastro‐oesophageal reflux; this enabled us to identify a range of interventions. The intervention search terms in our strategy were used to broaden rather than limit the gastro‐oesophageal reflux search. We checked if the new search terms added anything to our results and did not find any additional studies; however, we will add the new intervention terms to the search strategy when the review is next updated.

Additionally, although the pool of included studies has grown since publication of the original review (Gibson 2003), we were unable to report on one of our primary outcomes, as none of the included studies reported on hospital and emergency service utilisation or unscheduled doctor visits.

There is potential that inappropriate exclusion of relevant studies may have occurred in addition to data entry error. However, steps were taken to limit the impact of this by having two independent review authors screen, extract, and check data.

Agreements and disagreements with other studies or reviews

Current clinical guidelines suggest that people with asthma, particularly those with nocturnal symptoms, should be evaluated for GORD and treated when appropriate, even in the absence of obvious manifestations (King‐Biggs 2019; Moore 2010). If GORD is detected in people with asthma, the current recommendation is to treat with proton pump inhibitors (National Heart, Lung, and Blood Institute 2007). This recommendation is presently underpinned by single studies.

The original publication of this review was unable to detect clear benefit of treatment for GORD in people with asthma (Gibson 2003). Our updated review includes a greater number of randomised controlled trials, which enabled us to perform pooled analyses for some outcomes, allowing us to draw conclusions with more confidence. Our analyses indicate medical treatment for GORD could benefit people with asthma, specifically with reduced use of rescue medications and improved FEV₁ and morning PEFR. The latter is corroborated by a meta‐analysis of 11 studies comparing proton pump inhibitors to placebo (Chan 2011). From this publication, a subgroup analysis determined that in people with asthma and a diagnosis of GORD, a clinically and statistically significant improvement in morning PEFR was noted (mean difference (MD) 16.90 L/min, 95% confidence interval (CI) 0.85 to 32.95; 1004 participants, 7 studies; P = 0.006), in line with data presented in this review (MD 18.30 L/min, 95% CI ‐0.37 to 36.97; 1262 participants, 5 studies; Analysis 1.3; P = 0.05). Chan 2011 also assessed the effect of proton pump inhibitor therapy on AQLQ(S), noting there is uncertainty about benefit for this outcome (MD 0.20, 95% CI ‐0.078 to 0.472; 1828 participants, 4 studies; P = 0.16), again, supporting the findings of this review (MD 0.21, 95% CI ‐0.02 to 0.44; 1595 participants, 5 studies; P = 0.07; Analysis 1.5). Although it should be noted that for this outcome, Chan 2011 did not perform a subgroup analysis, and some participants included in the analysis did not have a confirmed diagnosis of GORD. Additionally, this study reviewed only studies investigating effects of proton pump inhibitors (Chan 2011), although this review included other classifications of GORD medical therapy. Evidence syntheses related to prokinetic agents and H₂ receptor antagonists are lacking and are likely reflective of the fact that in practice they are routinely administered as adjunct therapy to proton pump inhibitors (Wang 2013).

Available reviews of the existing literature refer to a single study to underpin the conclusion that medical treatment for GORD has uncertain benefit for a number of exacerbations for adults with a diagnosis of asthma (Bardin 2018Harding 2019). Littner 2005 is included for analysis in this review, and hence, our findings strengthen this position. A recently published conference abstract reports the outcomes of a secondary analysis of morbidity data from four large asthma trials (Tang 2019). These results indicate that use of proton pump inhibitor therapy in children with comorbid GORD and asthma may increase the number of respiratory tract infection‐related asthma exacerbations; however there was no relationship between these variables in adults (Tang 2019).

This review indicates there is not a high risk of adverse events with GORD treatment in the short term (average study duration, 15 weeks) for people with asthma. It should be noted that some literature indicates potential for increased risk of conditions including vitamin B12 deficiency, fracture, and small‐intestine bacterial overgrowth, with longer‐term use of proton pump inhibitors for general treatment of GORD (Jaynes 2019; Nehra 2018). However, review authors note that the evidence underpinning these conclusions is of low certainty and should not outweigh consideration of the benefits of treatment for individual patients.

Likewise, evidence related to effects of surgical intervention for GORD in people with asthma is sparse. An available systematic review of 24 randomised and non‐randomised studies corroborates the findings of this review update (Field 1999). This review reported that surgical intervention improved asthma symptoms by 79% (Field 1999), in line with the two studies identified for inclusion in this review (Larrain 1991; Sontag 2003). Further, a more recent, retrospective study of 208 people with respiratory manifestations of GORD reported that 75% of participants experienced short‐term improvement in respiratory symptoms following fundoplication; in the long term, seven of these individuals relapsed, and four participants experienced latent improvement (Adaba 2014). Findings related to effects of surgical intervention on pulmonary function outcomes were similarly matched. Field 1999 reports that pulmonary function did not benefit as much as symptoms from surgical intervention, improving by 27%. Available evidence included in this review indicates that FEV₁ may see a small, initial improvement postoperatively that is not sustained (Larrain 1991). Further, PEFR was reported to improve, although the analysis was underpowered (Sontag 2003). The ability to conclude with certainty the benefits of surgical intervention for asthma control is limited by the lack of relevant, high‐quality studies.

A systematic review including randomised and non‐randomised studies reports that when proton pump inhibitor therapy is provided for children with GORD and asthma, benefits of treatment for asthma‐related outcomes are uncertain (Sopo 2009). The only randomised trial solely concerning children included in this systematic review is likewise the only one eligible for inclusion in this Cochrane Review (Stordal 2005). Despite a lack of evidence underpinning GORD medical treatment in children living with asthma, guidelines recommend treatment but advise clinicians not to promise improvement in asthma control (National Asthma Council Australia 2019). Based on the outcomes of this review, this recommendation is unlikely to be changed.

Chan 2011 performed a meta‐regression analysis to determine any effect of treatment duration on the outcome of morning PEFR. These researchers conclude that there is no evidence of a relationship between the variables, which is consistent with the observations noted in this review.

Overall, it appears that the findings of this review are in agreement with those of other available evidence syntheses, although other sources focus on single interventions and tended to include both randomised and non‐randomised studies in their analyses.

Authors' conclusions

Implications for practice.

Some uncertainty surrounds the effectiveness of GORD treatment for people with asthma, particularly around outcomes of acute exacerbations and change in AQLQ. However, some evidence suggests that medical treatment with proton pump inhibitors, histamine 2 receptor antagonists, or prokinetics for GORD may result in reduced use of rescue medications and improved FEV₁ and morning PEFR, although the certainty of this evidence is currently moderate to low, and it is unlikely that the improvements seen are clinically significant.

Evidence to support surgery for adults with asthma and GORD is currently lacking, as is evidence in the paediatric population.

Implications for research.

Additional research is required to improve our understanding of the benefits of treating GORD in people with asthma. Specifically, there is currently a paucity of evidence to guide practice in children. Researchers interested in this topic should consider appropriately powered randomised controlled trials to capture data on clinical outcomes including acute exacerbations, use of rescue medications, and hospital utilisation. Further, future updates of this review should include a rate ratio analysis for all asthma exacerbations to better describe the benefits of GORD treatment for asthma management and to support its role in current clinical practice.

Across the board, it would be beneficial if researchers used a standardised approach to collect quality of life and symptom data, ideally based on an appropriate validated scale. This will improve our ability to pool results into a meaningful analysis to better guide clinical practice.

Surgical approaches to treatment for GORD in people with asthma are currently under‐studied and represent potential topics for future research, especially in the context of people who experience non‐acid reflux along with changes in asthma symptoms. Another potential area for enquiry is determination of the minimal effective doses of medical therapies.

Further research is necessary to determine which patients would most benefit from GORD treatment to support asthma symptom management. Asthma is a heterogeneous condition; therefore, studies are needed to investigate defined sub‐groups of people with asthma, for example, those with moderate/severe asthma that is uncontrolled by standard treatment, those within whom a correlation exists between severity of asthma and GORD symptoms, and/or those with a temporal relationship between asthma symptoms and reflux episodes.

Finally, little is known about the impact of GORD treatment on people who have asthma and a non‐acid‐type reflux presentation. This may be aided in future trials by consistent use of a dual‐lumen pH probe with impedance to diagnose GORD and to characterise participants' GORD.

What's new

Date	Event	Description
23 June 2020	New search has been performed	Literature search updated and screened. No new studies identified for inclusion prior to publication
30 August 2019	New search has been performed	New literature search run
30 August 2019	New citation required and conclusions have changed	Added ten new studies, added summary of findings table, updated to new risk of bias assessment, updated methods, background, discussion, and results. Review updated to reflect current standards of reporting. Analyses changed

History

Review first published: Issue 2, 1999

Date	Event	Description
30 September 2008	Amended	Converted to new review format
12 September 2002	New citation required and conclusions have changed	Substantive amendments made

Notes

Zoe Kopsaftis and Hooi Shan Yap contributed equally to this review update and are joint first authors.

Appendices

Appendix 1. Database search strategies

Cochrane Airways Trials Register via the Cochrane Register of Studies (CRS)

Search date: 23 June 2020

1	AST:MISC1 AND INREGISTER
2	MeSH DESCRIPTOR Asthma Explode All AND INREGISTER
3	asthma*:ti,ab AND INREGISTER
4	#1 or #2 or #3 AND INREGISTER
5	MeSH DESCRIPTOR Gastroesophageal Reflux Explode All AND INREGISTER
6	Gastro‐oesophageal* or gastro‐esophageal* or gastrooesophageal* OR gastroesophageal* AND INREGISTER
7	reflux* AND INREGISTER
8	GERD or GORD AND INREGISTER
9	GER:TI,AB AND INREGISTER
10	oesophag* or esophag* AND INREGISTER
11	cimetidine OR tagamet OR tratul AND INREGISTER
12	ranitidine AND INREGISTER
13	famotidine AND INREGISTER
14	nizatidine AND INREGISTER
15	omeprazole AND INREGISTER
16	pantoprazole AND INREGISTER
17	lansoprazole AND INREGISTER
18	MeSH DESCRIPTOR Anti‐Ulcer Agents AND INREGISTER
19	MeSH DESCRIPTOR Gastric Acid AND INREGISTER
20	MeSH DESCRIPTOR Fundoplication AND INREGISTER
21	fundo* AND INREGISTER
22	nissen* AND INREGISTER
23	Toupet* AND INREGISTER
24	#5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 AND INREGISTER
25	#4 and #24 AND INREGISTER

CENTRAL, in the Cochrane Library, via the Cochrane Register of Studies (CRS)

Search date: 23 June 2020

1	AST:MISC1 AND CENTRAL:TARGET
2	MeSH DESCRIPTOR Asthma Explode All AND CENTRAL:TARGET
3	asthma*:ti,ab AND CENTRAL:TARGET
4	#1 or #2 or #3 AND CENTRAL:TARGET
5	MeSH DESCRIPTOR Gastroesophageal Reflux Explode All AND CENTRAL:TARGET
6	Gastro‐oesophageal* or gastro‐esophageal* or gastrooesophageal* OR gastroesophageal* AND CENTRAL:TARGET
7	reflux* AND CENTRAL:TARGET
8	GERD or GORD AND CENTRAL:TARGET
9	GER:TI,AB AND CENTRAL:TARGET
10	oesophag* or esophag* AND CENTRAL:TARGET
11	cimetidine OR tagamet OR tratul AND CENTRAL:TARGET
12	ranitidine AND CENTRAL:TARGET
13	famotidine AND CENTRAL:TARGET
14	nizatidine AND CENTRAL:TARGET
15	omeprazole AND CENTRAL:TARGET
16	pantoprazole AND CENTRAL:TARGET
17	lansoprazole AND CENTRAL:TARGET
18	MeSH DESCRIPTOR Anti‐Ulcer Agents AND CENTRAL:TARGET
19	MeSH DESCRIPTOR Gastric Acid AND CENTRAL:TARGET
20	MeSH DESCRIPTOR Fundoplication AND CENTRAL:TARGET
21	fundo* AND CENTRAL:TARGET
22	nissen* AND CENTRAL:TARGET
23	Toupet* AND CENTRAL:TARGET
24	#5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 AND CENTRAL:TARGET
25	#4 and #24 AND CENTRAL:TARGET

Ovid MEDLINE(R) ALL <1946 to 22 June 2020>

1	exp Asthma/
2	asthma$.ti,ab.
3	1 or 2
4	exp Gastroesophageal Reflux/
5	(gastro‐oesophageal$ or gastro‐esophageal$ or gastrooesophageal$ or gastroesophageal$).ti,ab.
6	reflux$.ti,ab.
7	(GERD or GORD).ti,ab.
8	GER.ti,ab.
9	(oesophag$ or esophag$).ti,ab.
10	(cimetidine or tagamet or tratul).ti,ab.
11	ranitidine.ti,ab.
12	famotidine.ti,ab.
13	nizatidine.ti,ab.
14	omeprazole.ti,ab.
15	pantoprazole.ti,ab.
16	lansoprazole.ti,ab.
17	exp Anti‐Ulcer Agents/
18	Gastric Acid/
19	Fundoplication/
20	Gastric Fundus/
21	fundo$.ti,ab.
22	nissen$.ti,ab.
23	Toupet$.ti,ab.
24	or/4‐23
25	3 and 24
26	(controlled clinical trial or randomised controlled trial).pt.
27	(randomised or randomised).ab,ti.
28	placebo.ab,ti.
29	dt.fs.
30	randomly.ab,ti.
31	trial.ab,ti.
32	groups.ab,ti.
33	or/26‐32
34	Animals/
35	Humans/
36	34 not (34 and 35)
37	33 not 36
38	25 and 37

Embase <1974 to 2020 Week 25>

1	exp Asthma/
2	asthma$.ti,ab.
3	1 or 2
4	exp gastroesophageal reflux/
5	(gastro‐oesophageal$ or gastro‐esophageal$ or gastrooesophageal$ or gastroesophageal$).ti,ab.
6	reflux$.ti,ab.
7	(GERD or GORD).ti,ab.
8	GER.ti,ab.
9	(oesophag$ or esophag$).ti,ab.
10	(cimetidine or tagamet or tratul).ti,ab.
11	ranitidine.ti,ab.
12	famotidine.ti,ab.
13	nizatidine.ti,ab.
14	omeprazole.ti,ab.
15	pantoprazole.ti,ab.
16	lansoprazole.ti,ab.
17	exp antiulcer agent/
18	stomach acid/
19	exp antireflux operation/
20	fundo$.ti,ab.
21	nissen$.ti,ab.
22	Toupet$.ti,ab.
23	or/4‐22
24	3 and 23
25	Randomized Controlled Trial/
26	randomization/
27	controlled clinical trial/
28	Double Blind Procedure/
29	Single Blind Procedure/
30	Crossover Procedure/
31	(clinica$ adj3 trial$).tw.
32	((singl$ or doubl$ or trebl$ or tripl$) adj3 (mask$ or blind$ or method$)).tw.
33	exp Placebo/
34	placebo$.ti,ab.
35	random$.ti,ab.
36	((control$ or prospectiv$) adj3 (trial$ or method$ or stud$)).tw.
37	(crossover$ or cross‐over$).ti,ab.
38	or/25‐37
39	exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/
40	human/ or normal human/ or human cell/
41	39 and 40
42	39 not 41
43	38 not 42
44	24 and 43

ClinicalTrials.gov

Search field	Search terms
Study type	interventional
Other terms	asthma AND reflux

WHO ICTRP

Search field	Search terms
Condition
Intervention
Search terms	asthma AND reflux

Appendix 2. Effects of intervention: individual study results (secondary outcomes)

This appendix presents a a detailed description of findings for studies and outcomes that were not suitable for meta‐analysis, as reported per publication.

Forced expiratory volume in one second (FEV₁)

Of the studies that were not suitable for meta‐analysis, four parallel studies ‐ Maev 2002; Kiljander 2006; Dos Santos 2007; Sharma 2007 ‐ and five cross‐over studies ‐ Goodall 1981; Ekstrom 1989; Meier 1994; Teichtahl 1996; Kiljander 1999 ‐ involving adults reported on FEV₁ with conflicting results. Five studies reported that any differences between medical treatment and placebo were not statistically significant for absolute FEV₁ (Dos Santos 2007; Goodall 1981), as well as per cent predicted value (Ekstrom 1989; Kiljander 2006; Teichtahl 1996). Between groups, comparisons were not reported in three studies; therefore the data are not presented in this review (Kiljander 1999; Maev 2002; Sharma 2007).

Two omeprazole studies included paediatric participants (Fallahi 2008; Stordal 2005), with mixed outcomes. Fallahi 2008 reported a significant change in FEV₁ in adolescents with moderate to severe asthma and GORD, with twice‐daily omeprazole treatment (24 ± 3%) compared to placebo (8 ± 1%; P < 0.0001; n = 36 participants). However, there was no evidence of a change in mean FEV₁ with once‐daily omeprazole compared to placebo (‐1.38 ± 1.96% vs ‐2.01 ± 1.96%; P = 0.77; n = 36 participants) in children with mild to moderate asthma (Stordal 2005).

A three‐arm study comparing surgery, medical treatment with cimetidine, and placebo reported improved absolute FEV₁ from baseline with both intervention conditions, although this was not sustained in the surgery group at six‐week follow‐up; trialists report that these improvements were not significant (Larrain 1991). With cimetidine, participants experienced maximum improvement of 12% from baseline in the first week, tapering to 7% at final follow‐up. Participants who underwent surgery also experienced maximum improvement in FEV₁ change from baseline in the first week post treatment (7%); however, this benefit was not evident at final follow‐up, with FEV₁ returning to baseline to match the placebo group.

Morning peak expiratory flow rate (PEFR)

Of the studies not suitable for inclusion in the meta‐analysis, nine reported specifically on morning PEFR (Ekstrom 1989; Ford 1994; Goodall 1981; Kiljander 1999; Kiljander 2006; Nagel 1988; Sharma 2007; Teichtahl 1996), and six reported an unspecified PEFR value (Aiguo 1999; Fallahi 2008; Frison 2002; Jiang 2003; Maev 2002; Sontag 2003). Two RCTs reported statistically significant improvement in morning PEFR (Kiljander 2006; Sharma 2007). Kiljander 2006 showed a statistically significant difference in morning PEFR between esomeprazole treatment and placebo over 16 weeks (5.6 L/min, P = 0.042). The improvement in morning PEFR was especially significant with esomeprazole for participants with GORD and history of nocturnal asthma symptoms (8.7 L/min, P = 0.03). Combination treatment with omeprazole and domperidone was also reported to result in a statistically significant improvement in mean change from baseline in morning PEFR compared to placebo (7.9% vs 0.2%; P = 0.004), although benefits of combining cisapride with lansoprazole were uncertain (333 ± 89 L/min vs 307 ± 85 L/min; P = 0.47; Frison 2002). Of the six cross‐over trials reporting on morning PEFR, all documented uncertainty about the benefit of GORD treatment for morning PEFR. This uncertainty was seen across a variety of omeprazole dosing regimens including 40 mg daily in Teichtahl 1996 and Kiljander 1999 and 20 mg daily in Ford 1994, where morning PEFR was reported as largely unchanged. Treatment with ranitidine produced improvement in morning PEFR of 6 L/min over placebo, although this was reported with uncertainty (P = 0.61; Ekstrom 1989). Likewise, 200 mg daily of cimetidine had uncertain benefit for median morning PEFR both immediately after waking (10 L/min; P > 0.05) and 30 to 60 minutes later (10 L/min; P > 0.05) compared to placebo (Goodall 1981).

Results reported by study authors who did not specify at what time point in the day PEFR measurement was taken were similarly conflicting (Aiguo 1999; Fallahi 2008; Frison 2002; Jiang 2003; Maev 2002; Sontag 2003). Omeprazole monotherapy was reported to significantly improve mean PEFR compared to placebo in adolescents with moderate asthma (150 ± 1.4 L/min vs 45 ± 0.8 L/min, respectively; P < 0.0001; Fallahi 2008). Sontag 2003 reported a sustained, clinically relevant improvement in per cent variation in PEFR with surgical intervention at two‐year follow‐up, from 18% to 11%. In comparison, ranitidine and control groups demonstrated worsening PEFR at two‐year follow‐up, with variation increasing from 18% to 22%. However, study authors report the number of patients remaining with evaluable PEFR data was insufficient to demonstrate statistically significant differences between groups (Sontag 2003). Conversely, mean PEFR was reported to improve with ranitidine and cisapride combination therapy compared to placebo (5.7 ± 1.1 L/s vs 4.9 ± 1.6 L/s; P < 0.01; Aiguo 1999), as well as with omeprazole and domperidone (5.9 ± 1.6 L/s vs 4.8 ± 1.7 L/s; P < 0.05; Jiang 2003). Alternately, combining cisapride with lansoprazole was reported to have only slight benefit for mean PEFR, although there was uncertainty around this (Frison 2002).

Between‐group comparisons were not reported in two studies; therefore the data are not presented in this review (Maev 2002; Nagel 1988).

Use of "rescue" medications and emergency action plans

Studies that could not be pooled reported mixed results on the benefit of GORD treatment for use of rescue medication. Kjellen 1981 reported that significantly more participants reduced their use of asthma medications with conservative treatment for GORD compared to those in the control group (75% vs 42%; P < 0.05). Similarly, Ekstrom 1989 reported clinically modest but statistically significant differences in beta₂‐agonist use (puffs/d) for ranitidine (5.0 ± 0.56 SEM) compared to placebo (5.6 ± 0.60 SEM; P = 0.006).

Treatment with various doses of omeprazole as a single agent resulted in small, non‐significant differences in beta₂‐agonist use (Ford 1994; Kiljander 1999; Kiljander 2010; Teichtahl 1996). One study reported that this was the case both during the day (4.7 ± 2.8 vs 6.0 ± 4) and during the night (0.8 ± 1.2 vs 1.0 ± 1.7), although study authors noted that the analysis was underpowered (Ford 1994). Additionally, there was no difference in the total number of rescue inhalations with esomeprazole treatment compared to placebo whether asthmatic patients had a history of nocturnal symptoms (MD 0.02, 95% CI ‐0.18 to 0.23; P = 0.83) or not (MD ‐0.22, 95% CI ‐0.47 to 0.04; P = 0.097) (Kiljander 2006).

Conversely, combination therapy with omeprazole and domperidone was reported to produce a large and highly statistically significant reduction in beta₂‐agonist use from baseline compared to placebo (23.2% vs 3.08%; P = 0.0001) in adult asthmatic patients (Sharma 2007). However, combination therapy with lansoprazole and cisapride was reported not to affect the median frequency of rescue inhalations compared to placebo either during the day (median 0.71, IQR 0 to 4.1 vs median 0.14, IQR 0 to 2.5; P = 0.08) or at night (median 0.07, IQR 0 to 3.4 vs median 0.0, IQR 0 to 1.8; P = 0.839) (Frison 2002).

Ranitidine treatment was not associated with any difference compared to placebo with regard to the mean doses of asthma medications used by people who experienced a clinically significant dip in morning PEFR (10.8 vs 11.2) or those who experienced no dip in PEFR (7.0 vs 6.4) (Nagel 1988). Similarly, the median number of salbutamol puffs per day did not differ following treatment with cimetidine compared to placebo (median 4.0, IQR: 0 to 12 vs median 3.8, IQR 0 to 12; P > 0.05) in a cross‐over trial of 18 people with asthma and GORD (Goodall 1981).

In children, treatment with omeprazole was not reported to improve the mean use of rescue medication (‐1.9 ± 1.96) compared to placebo (‐1.9 ± 1.96; P = 0.89) (Stordal 2005).

Use of an emergency action plan was not reported as an outcome in any of the studies included in this review.

Change in quality of life

Two studies reporting on quality of life were not suitable for meta‐analysis. Frison 2002 reported on overall quality of life using a validated scale translated into Portuguese, detecting a higher median quality of life score in the placebo group (6.0) compared to the intervention group (5.2). Although this difference did not reach statistical significance (P = 0.10), it is clinically significant. The authors of this study further reported that both intervention and placebo groups improved statistically and clinically from baseline (Frison 2002). Dos Santos 2007 measured quality of life using a questionnaire developed jointly by the Federal University of São Paulo and the Paulista School of Medicine, demonstrating a statistically significant improvement in overall quality of life with pantoprazole compared to placebo (61.8 ± 13 vs 48.7 ± 12; P = 0.001; n = 44 participants).

Asthma symptom scores

A total of 20 studies reported on asthma symptoms (Aiguo 1999; Dos Santos 2007; Ekstrom 1989; Ford 1994; Frison 2002; Goodall 1981; Kiljander 1999; Kiljander 2006; Kiljander 2010; Kjellen 1981; Larrain 1991; Littner 2005; Maev 2002; Meier 1994; Nagel 1988; Sharma 2007; Sontag 2003; Stordal 2005; Susanto 2008; Teichtahl 1996), seven of which were cross‐over studies. Overall, heterogeneity across studies and the small number of studies involving surgery and children led to very low‐certainty evidence for this outcome.

Seven RCTs assessed the potential benefits of monotherapy for GORD in adult asthmatic patients for improvement in asthma symptoms in the treatment group compared to the control group (Dos Santos 2007; Kiljander 2006; Kiljander 2010; Kjellen 1981; Littner 2005; Maev 2002; Susanto 2008). Dos Santos 2007 reported an uncertain outcome when comparing treatment and control at final follow‐up (64.94 ± 4 vs 58.9 ± 23; P = 0.11). Likewise, twice‐daily lansoprazole was reported to have minimal impact on mean asthma symptoms, scored out of four, compared to placebo (1.18 ± 0.59 vs 1.20 ± 0.57), with study authors reporting that comparisons did not reach statistical significance (Littner 2005). However, 40 mg daily of omeprazole in Maev 2002 or esomeprazole in Susanto 2008 was reported to significantly improve asthma symptom scores after eight weeks of therapy compared to placebo. A clinically meaningful mean reduction of 2.29 in mean asthma symptom score was seen from baseline with esomeprazole, study authors report that this was significantly more than the mean reduction of 0.90 noted in the placebo group (P < 0.05; Susanto 2008). Maev 2002 calculated clinical indices of effectiveness, reporting greater improvement with omeprazole (15.7 ± 0.6 vs 4.3 ± 0.02) than with placebo (15.2 ± 1.2 vs 11.3 ± 1.0).

Conservative GORD treatment was reported to improve four key asthma symptoms significantly compared to placebo (Kjellen 1981). More participants in the treatment group compared to the control group experienced improvement in dyspnoea (54% vs 11%; P < 0.01), wheeze (48% vs 16%; P < 0.05), cough (46% vs 4%; P < 0.001), and expectoration (52% vs 4%; P < 0.001) (Kjellen 1981).

Combination treatment with 20 mg of omeprazole twice daily and 10 mg of domperidone three times daily was reported to significantly reduce daytime asthma symptom score compared to placebo after 16 weeks (17.4% vs 8.94%; P = 0.0001; Sharma 2007). Likewise, 150 mg of ranitidine twice daily in combination with cisapride 10 mg three times daily was reported to improve mean asthma symptom score compared to placebo (6.8 ± 1.7 vs 8 ± 1.7; n = 36 participants; P < 0.01; Aiguo 1999). Conversely, combination therapy with daily lansoprazole and cisapride was reported to have no significant effect on median asthma score compared to placebo (placebo 0.78, IQR 0 to 2.2 vs 0.28, IQR 0 to 1.2; P = 0.194; n = 20 participants; Frison 2002).

Treatment with omeprazole once daily in Kiljander 2006 or twice daily in Kiljander 2010 did not result in significant differences in asthma symptom scores between treatment and placebo groups. Kiljander 2006 also did not detect significant improvement when considering subgroups that did (MD ‐0.01, 95% CI ‐0.11 to 0.09; P = 0.86) and did not (MD ‐0.08, 95% CI ‐0.20 to 0.04; P = 0.20) have a history of nocturnal respiratory symptoms. Between‐group comparisons were not reported in Kiljander 1999 therefore the data are not presented in this review.

Six other cross‐over trials reported uncertainty related to the benefit of medical treatment for asthma symptoms among people with co‐morbid GORD (Ekstrom 1989; Ford 1994; Goodall 1981; Meier 1994; Nagel 1988; Teichtahl 1996). Meier 1994 reported that during a 24‐hour oesophageal pH monitoring period, six of 15 participants experienced symptoms of wheeze or hoarseness, one of whom was classified as omeprazole responsive, and five participants were classified as not responsive to omeprazole. Study authors further report that these symptoms represented the most commonly recorded in their study (27 of 77 total symptoms), and 44% of these occurrences occurred simultaneously with an episode of GORD (Meier 1994). Other cross‐over trials investigating potential benefits of omeprazole recorded little change in asthma symptom score compared to placebo (1.0 ± 0.7 vs 0.9 ± 0.7; Ford 1994), with one study reporting non‐significant differences without numerical data to support this statement (Teichtahl 1996). Further, cross‐over trials investigating potential benefits of H₂ receptor antagonist agents also reported uncertain benefits of treatment compared to control regardless of whether ranitidine, as in Ekstrom 1989 and Nagel 1988, or cimetidine, as in Goodall 1981, was used. A modest, non‐significant reduction in median symptom score was reported with cimetidine compared to placebo (median 0.9, IQR 0 to 2.3 vs 1.2, IQR 0 to 2.6; P > 0.05; Goodall 1981). Ranitidine was reported to have a similar, minimal impact on mean asthma symptoms compared to placebo, regardless of whether they were measured in the morning (0.87 ± 0.08 (placebo) vs 0.82 ± 0.09 (ranitidine); P = 0.58; n = 48 participants) or during the day (0.73 ± 0.09 (placebo) vs 0.67 ± 0.09 (ranitidine); P = 0.50; n = 48 participants). Nagel 1988 reported that none of the participants who demonstrated a clinically significant decrease in PEFR in the morning experienced improvement in their asthma symptoms. However, more than half reported no change (four of seven individuals), and the remainder reported a worse asthma symptom score with GORD treatment (three of seven individuals; Nagel 1988). Among participants in the study who did not experience the clinically relevant decrease in morning PEFR, three of seven individuals reported improved asthma symptoms, whilst two of seven individuals recorded a worse symptom score or no change (Nagel 1988). All cross‐over studies measured asthma symptoms on a scale of zero to three; however, Goodall 1981 and Nagel 1988 state that the scale they used related only to the degree of wheeze.

In comparison to 10 out of 28 participants on placebo, 20 of 27 who received cimetidine (300 mg four times a day) and 20 of 26 surgically treated participants reported improvement in wheeze at six‐month follow‐up (Larrain 1991). Study authors reported that this improvement was significantly better than with placebo with both cimetidine (P < 0.03) and surgery (P < 0.01) (Larrain 1991). Sontag 2003 also compared placebo to surgery and ranitidine (150 mg three times a day); study authors accepted a 40% or greater change (improvement or decline) from baseline as clinically significant. Per publication, surgery but not medical treatment or placebo resulted in an immediate reduction in wheeze, cough, and dyspnoea that was sustained until final follow‐up at two years (Sontag 2003). Study authors report that 75% of the surgical group experienced clinically significant improvement in asthma symptoms compared with 20% in the control group and 0% in the ranitidine group (P < 0.05) (Sontag 2003). Further, none of the participants who received surgical intervention experienced worsening of asthma symptoms. Conversely, 18% of individuals treated with medication and 7% of those given control suffered clinically significant worsening of their asthma symptoms (Sontag 2003).

Treatment with omeprazole (‐1.28, 95% CI ‐2.65 to 0.1) compared with placebo (‐1.28, 95% CI ‐3.27 to 0.72; P = 1.0) did not impact mean asthma symptom score in children with comorbid GORD (Stordal 2005).

Nocturnal symptoms

Eleven studies reported nocturnal asthma symptoms (Dos Santos 2007; Ekstrom 1989; Ford 1994; Frison 2002; Goodall 1981; Kiljander 1999; Kiljander 2006; Littner 2005; Sharma 2007; Susanto 2008; Teichtahl 1996).

Nocturnal symptoms, on a scale of zero to three, were measured in two studies testing the effectiveness of histamine receptor agonists. Symptoms were reduced significantly to a mean (SEM) of 0.53 (0.08) with use of ranitidine compared to 0.61 (0.09) with placebo (P = 0.02) in a cross‐over trial involving 48 people with asthma (Ekstrom 1989). Trialists conducted a subgroup analysis demonstrating that participants with a history of reflux‐associated respiratory symptoms experienced a significant decrease in mean nocturnal symptoms (0.71 ± 0.12 vs 0.52 ± 0.11; P < 0.001; 27 participants), and people without this history appeared to experience a non‐significant increase in nocturnal symptom score from 0.49 (0.13) on placebo to 0.53 (0.14) on ranitidine (Ekstrom 1989). This finding was corroborated by Goodall 1981, who compared cimetidine to placebo. This cross‐over study detected a decrease in median nocturnal asthma score (from median 1.1, IQR 0 to 1.7 to 0.7, 0 to ‐1.8; P < 0.05) in 18 people with asthma. Study authors further note that on placebo there was a moderate, statistically significant correlation (0.45; P < 0.05) in the severity of both nocturnal asthma and reflux symptoms (Goodall 1981). This relationship was not evident following cimetidine therapy (r = 0.11).

Treatment with proton pump inhibitor medications produced conflicting results across studies. Sharma 2007 reported a highly statistically significant improvement in mean change in nocturnal symptoms from baseline of 14.2% with omeprazole over placebo (P = 0.0001). This was supported by a cross‐over trial reporting a smaller but still significant (P = 0.04) improvement in nocturnal asthma symptoms (scale 0 to 21) with 40 mg once‐daily omeprazole (median 0.7, IQR 3.3 to 0.0) compared to placebo (median 1.0, IQR 8.0 to.0) (Kiljander 1999). A parallel study by the same authors found that, on a scale of zero to four, 40 mg of omeprazole twice daily did not improve nocturnal asthma symptoms in people with a history of nocturnal symptoms (MD 0.02, 95% CI ‐0.07 to 0.11; P = 0.66) nor in those without (MD ‐0.04, 95% CI ‐0.16 to 0.07; P = 0.44) (Kiljander 2006). A lower dose of 20 mg of omeprazole once daily produced a similar result compared to placebo (1.0 ± 0.6 vs 1.0 ± 0.7), as measured on a scale of zero to three, in a cross‐over trial of 11 people with asthma with GORD (Ford 1994), as did 30 mg of lansoprazole twice daily (mean 1.03, SD 0.62), conferring no benefit from baseline (mean 1.38, SD 0.58) on a 4‐point scale (Littner 2005). Combination therapy with 60 mg of lansoprazole and 30 mg of cisapride daily resulted in no difference in reported median nocturnal asthma symptoms compared to placebo (0.28, IQR 0 to 1.2 vs 0.28, IQR 0 to 1.8; P = 0.969; 21 participants) (Frison 2002). Using an accumulating weekly scale of zero to 105, Dos Santos 2007 reported that although pantoprazole therapy conferred no additional benefit for nocturnal symptoms compared to placebo (57.9 ± 23 vs 63.42 ± 6; P = 0.16; 44 participants), a within‐group analysis of the treatment group demonstrated significant improvement from baseline (66.92 ± 7 vs 57.9 ± 23; P = 0.01; 22 participants).

One study evaluated sleep disturbance as part of its evaluation of asthma symptoms but did not isolate these data from the other components for reporting in this review (Susanto 2008). Likewise, Teichtahl 1996 reported no significant difference in asthma symptoms ‐ a component of which was nocturnal asthma symptoms. However, study authors did not present any numerical data to support this statement.

Treatment preferences

Treatment preference was reported in two studies (Ford 1994; Goodall 1981). Among 18 participants who completed the trial reported in Goodall 1981, 14 preferred medical therapy with cimetidine, and 3 out of 18 participants preferred placebo. Ford 1994 recorded 7 out of 11 participants preferred intervention with omeprazole, and none preferred placebo; this difference was statistically significant (P < 0.01).

Adverse events

Adverse events were not a pre‐specified outcome for this review. However, for safety, we report data available from the included studies related to this. Kiljander 2006 reported that 6% of the intervention (esomeprazole) group and 8% of the placebo group prematurely terminated participation in the study due to adverse events. Only 1% in each group experienced serious adverse events, although study authors reported that these were not attributed to the study medication. Non‐serious events experienced by participants were asthma, nasopharyngitis, headache, nausea, back pain, rhinitis, and influenza. These were reported evenly across esomeprazole and placebo groups, with study authors noting that these events were not clinically relevant and their cause not established (Kiljander 2006). Likewise, the same study authors reported no safety concerns in a later study comparing a once‐ or twice‐daily dose of esomeprazole with placebo (Kiljander 2010). All 20 reported serious adverse events (n = 5 once‐daily dose, n = 7 twice‐daily dose, n = 5 placebo) that were deemed not to be related to involvement in the study, and non‐serious adverse events were evenly spread across the three groups (Kiljander 2010). Participants taking part in a study involving combination therapy with omeprazole and domperidone also reported a similar percentage of adverse events, regardless of allocation to treatment (64%) or placebo (60%; P = 0.7). This was similar for serious adverse events (10% and 8%; P = 0.4); for the combination group, these included myalgia, aggression, thrombocytopenia, urticaria, and Stevens‐Johnson syndrome, as reported by trial authors (Sharma 2007).

Study authors reported similar percentages of adverse events (74% and 69%) and serious adverse events (8% and 6%) with lansoprazole treatment compared to placebo (Littner 2005). However, it was more likely that these were possibly, probably, or definitely treatment related in the intervention group (13% vs 4%; P = 0.02) (Littner 2005). The most commonly reported adverse events in this study were diarrhoea and infection. When comparing ranitidine to placebo, study authors simply reported no adverse clinical effects noted during therapy (Ekstrom 1989).

Finally, one study reported an acute asthma exacerbation as an adverse event with cimetidine treatment, which resulted in the participant's hospitalisation and withdrawal from the trial (Goodall 1981).

Data and analyses

Comparison 1. Medical intervention for gastro‐oesophageal reflux compared to nil intervention, delayed intervention control, or placebo for asthma in adults and children.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Number of participants with any moderate/severe acute exacerbations	2	1168	Odds Ratio (M‐H, Random, 95% CI)	0.53 [0.17, 1.63]
1.2 Change in FEV₁ (L)	7	1333	Mean Difference (IV, Fixed, 95% CI)	0.10 [0.05, 0.15]
1.3 Morning peak expiratory flow (L/min)	5	1262	Mean Difference (IV, Fixed, 95% CI)	6.02 [0.56, 11.47]
1.4 Use of "rescue" medications and emergency action plans: B2 use puffs per day	2	239	Mean Difference (IV, Fixed, 95% CI)	‐0.71 [‐1.20, ‐0.22]
1.5 Change in AQLQ	5	1595	Mean Difference (IV, Random, 95% CI)	0.21 [‐0.02, 0.44]
1.5.1 Adult	4	1559	Mean Difference (IV, Random, 95% CI)	0.24 [‐0.04, 0.51]
1.5.2 Pediatric	1	36	Mean Difference (IV, Random, 95% CI)	0.12 [‐0.24, 0.48]
1.6 AQLQ responder analysis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aiguo 1999.

Study characteristics
Methods	Country: China Design: randomised, placebo‐controlled trial Objective/aim: to investigate the clinical efficacy, lung function, and airway reactivity of Chinese medicine (Jiang Ni Decoction) to patients with asthma and GORD Study site: outpatient Methods of analysis: t‐test, Chi² test
Participants	Eligible for study: 54 Randomisation: intervention a: 18, intervention b: 18, control: 18 Participants completed: intervention a: 18, intervention b: 18, control: 18 Age, mean ± SD: intervention a: 35 ± 15, intervention b: 38 ± 18, control: 36 ± 17 Gender, M/F: intervention a: 7/11, intervention b: 8/10, control; 8/10 Co‐morbidities: not specified Diagnostic criteria for asthma: doctor's diagnosis Diagnostic criteria for GORD: symptoms of heartburn and/or acid reflux; barium oesophagogram; endoscopy Association between asthma and GORD tested? no Major exclusion criteria: not specified Baseline severity of asthma: FEV₁ L, mean ± SD: intervention a: 2.2 ± 0.8, intervention b: 2.3 ± 0.9, control: 2.3 ± 0.8; FEV₁ % predicted, mean ± SD: intervention a: 75.2 ± 15.4, intervention b: 77.2 ± 12.6, control: 77.2 ± 11.9; PEFR L/s, mean ± SD: intervention a: 4.7 ± 1.5, intervention b: 4.6 ± 1.7, control: 4.5 ± 1.6; PEFR % predicted, mean ± SD: intervention a: 75.9 ± 18.6, intervention b: 75.6 ± 20.4, control: 75.1 ± 20.3 Baseline severity of GORD: all had symptoms of GORD Baseline complications of GORD: not specified
Interventions	Duration of intervention: 6 weeks Type of intervention: intervention a: Jiang Ni decoction 1 portion, divided to twice‐daily intake; intervention b: ranitidine 150 mg twice daily and cisapride 10 mg 3 times daily Type of control: placebo
Outcomes	Pre‐specified outcomes: not specified Follow‐up period: not specified Outcomes measured: FEV₁*, PEFR*, asthma symptoms*, airway hyper‐responsiveness*, reflux score*
Notes	*Indicates significant result
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported; however method not mentioned
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals/dropouts
Selective reporting (reporting bias)	Unclear risk	Pre‐specified outcomes not specified
Other bias	Low risk	No other significant bias detected

Dos Santos 2007.

Study characteristics
Methods	Country: Brazil Design: randomised, double‐blind, placebo‐controlled trial Objective/aim: to investigate clinical and functional response in patients with asthma and concomitant GORD submitted for anti‐reflux therapy Study site: outpatient Methods of analysis: Wilcoxon rank sum test; Mann‐Whitney U test; Student's t‐test
Participants	Eligible for study: 49 Randomisation: intervention: 22, control: 22 Participants completed: intervention: 22, control: 22 Age, mean ± SD: intervention: 40 ± 12, control: 45 ± 12 Gender, M/F: intervention: 7/15, control: 2/20 Co‐morbidities: not specified Diagnostic criteria for asthma: FEV₁/FVC < 90% and obstruction reversibility represented by FEV₁ > 200 mL and 7% of predicted; positive methacholine bronchoprovocation test Diagnostic criteria for GORD: oesophageal manometry and 24‐hour oesophageal pH‐metry Association between asthma and GORD tested? Yes; association not required for entry; association tested by history/symptoms: 15/44 had reflux‐associated respiratory symptoms Major exclusion criteria: recent history of smoking (past 8 weeks); abnormalities in sinus/chest X‐rays; history of proton pump inhibitor use within 4 weeks preceding study outset; history of H₂ receptor blocker use within 2 weeks preceding study outset; systemic arterial hypertension that could not be changed when angiotensin‐converting enzyme inhibitors, β‐adrenergic receptor blockers, or calcium channel blockers were used; presence of other severe systemic illness; pregnancy; illiteracy or complete lack of understanding of the forms that had to be completed Baseline severity of asthma: FEV₁ % predicted, mean ± SD): intervention 61.6 ± 19, control 60.4 ± 19; diurnal PEFR, mean ± SD: intervention 317 ± 13, control 264 ± 86; nocturnal PEFR, mean ± SD: intervention 307 ± 12, control 261 ± 83; use of long‐acting beta₂ agonists: intervention: 10/22, control: 14/22; use of oral corticosteroid: intervention: 2/22, control: 4/22 Baseline severity of GORD: all had documented acid reflux: 35/44 had symptomatic reflux Baseline complications of GORD: not specified
Interventions	Duration of intervention: 12 weeks Type of intervention: pantoprazole 40 mg once daily Type of control: placebo
Outcomes	Pre‐specified outcomes: not specified Follow‐up period: 90 days Outcomes measured: FEV₁, mPEFR, ePEFR, asthma symptoms*, nocturnal symptoms*, quality of life*, reflux score
Notes	*Indicates significant result
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details specified
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind reported
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind reported
Incomplete outcome data (attrition bias) All outcomes	High risk	35 patients completed the protocol, but 44 were included in the analysis; Also, 7 patients were excluded from evaluation of effects of reflux‐associated respiratory symptoms; reasons for insufficient data were not mentioned
Selective reporting (reporting bias)	Unclear risk	Pre‐specified outcomes not specified; reasons for incomplete outcome data not explained
Other bias	Low risk	No other significant bias identified

Ekstrom 1989.

Study characteristics
Methods	Country: Sweden Design: randomised, double‐blind, cross‐over study Objective/aim: to determine if treatment with H₂ receptor antagonist ranitidine could improve asthma control or bronchial activity or both in a group of asthmatic patients with a history of gastro‐oesophageal reflux, and whether any factors predicted which patients with asthma would benefit from anti‐reflux treatment Study site: outpatient Methods of analysis: Wilcoxon signed rank test; Mann‐Whitney U test; 3‐way analysis of variance (ANOVA)
Participants	Eligible for study: 50 Randomisation: 50 Participants completed: 48 Age, mean (range): 58.5 (28 to 70) Gender, M/F: 30/18 Co‐morbidities: not specified Diagnostic criteria for asthma: American Thoracic Society Diagnostic criteria for GORD: symptoms of regurgitation and/or heartburn (n = 48); acid perfusion test (abnormal n = 27); 24‐hour pH monitoring (abnormal n = 32) Association between asthma and GORD tested? Yes; association not required for entry; association tested by history/symptoms: 27/48 had 1 or more reflux‐associated respiratory symptoms Major exclusion criteria: not specified Baseline severity of asthma: study author reported "moderate or severe asthma for several years" Baseline severity of GORD: all had symptoms of GORD Baseline complications of GORD: not specified
Interventions	Duration of intervention: 4 weeks Type of intervention: ranitidine 150 mg twice daily Type of control: identical placebo
Outcomes	Pre‐specified outcomes: not specified Follow‐up period: 12 weeks Outcomes measured: FEV₁, mPEFR, ePEFR, use of beta₂‐agonists, asthma symptoms, nocturnal symptoms*, airway hyper‐responsiveness, eosinophils, reflux score*
Notes	*Indicates significant result Financial support provided by the Swedish Medical Research Council and Glaxo Pharmaceutical Company
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised in groups of 10 patients according to “"Principles of Medical Statistics", 9th Edition
Allocation concealment (selection bias)	Low risk	Investigators unaware as to order of treatment group assignment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals reported with explanation
Selective reporting (reporting bias)	Unclear risk	Pre‐specified outcomes not specified
Other bias	Low risk	No other significant bias identified

Fallahi 2008.

Study characteristics
Methods	Country: Iran Design: randomised, double‐blind, placebo‐controlled study Objective/aim: to determine the efficacy of omeprazole for treatment of asthma and improvement of pulmonary function in adolescents with gastro‐oesophageal reflux disease (GORD) Study site: outpatient Methods of analysis: Student t‐test; Chi² test; Mann‐Whitney U test
Participants	Eligible for study: 36 Randomisation: intervention: 18, control: 18 Participants completed: intervention: 18, control: 18 Age, mean (range): intervention: 13 to 20, control: 13 to 20 Gender, M/F: not specified Co‐morbidities: not specified Diagnostic criteria for asthma: National Asthma Education and Prevention programme guidelines Diagnostic criteria for GORD: symptoms Association between asthma and GORD tested? No Major exclusion criteria: not specified Baseline severity of asthma: not specified Baseline severity of GORD: not specified Baseline complications of GORD: not specified
Interventions	Duration of intervention: 6 weeks Type of intervention: omeprazole 20 mg twice daily Type of control: placebo
Outcomes	Pre‐specified outcomes: pulmonary function test Follow‐up period: not specified Outcomes measured: FEV₁*, PEFR*, reflux score*
Notes	*Indicates significant result
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported, but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	No mention of dropouts from the study
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias identified

Ford 1994.

Study characteristics
Methods	Country: United Kingdom Design: randomised, double‐blind, cross‐over study Objective/aim: to study effects of omeprazole for treatment of asthmatic patients with nocturnal symptoms and GORD Study site: outpatient Methods of analysis: intention‐to‐treat analysis
Participants	Eligible for study: 11 Randomisation: 11 Participants completed: 10 Age, mean (range): 63 (50 to 80) Gender, M/F: 6/5 Co‐morbidities: not specified Diagnostic criteria for asthma: doctor's diagnosis; objective lung function; nocturnal attack of asthma Diagnostic criteria for GORD: GORD symptoms with mean duration of 52 (7 to 99) months; endoscopically proven oesophagitis; 24‐hour pH monitoring Association between asthma and GORD tested? No Major exclusion criteria: not specified Baseline severity of asthma: FEV₁ not specified; PEFR, mean ± SD (range): before inhaled terbutaline: 253 ± 83 (100 to 360), after inhaled terbutaline: 308 ± 94 (130 to 414); exacerbation not specified Baseline severity of GORD: all had symptoms and nocturnal coughing/choking Baseline complications of GORD: Barrett's oesophagus n = 2; ulceration grade I n = 1, grade II n = 1, grade III n = 4; oesophageal stricture n = 0; pH score not reported
Interventions	Duration of intervention: 4 weeks Type of intervention: omeprazole 20 mg once daily Type of control: Identical placebo
Outcomes	Pre‐specified outcomes: primary outcome: PEFR with asthma symptoms; secondary outcome: bronchodilator usage Follow‐up period: 10 weeks Outcomes measured: mPEFR, ePEFR, day use of beta₂‐agonists, nocturnal use of beta₂‐agonists, asthma symptoms, nocturnal symptoms, treatment preferences*
Notes	*Indicates significant result Astra Pharmaceuticals provided study drugs
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported; however method not mentioned
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals reported with explanation and data excluded from analysis
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	High risk	Study drugs supplied by phamaceutical company that also provided assistance with statistical analysis

Frison 2002.

Study characteristics
Methods	Country: Brazil Design: randomised, double‐blind, parallel‐controlled study Objective/aim: to determine effects of treatment of GORD on clinical outcome of asthma in severe asthmatic patients Study site: outpatient Methods of analysis: Wilcoxon test; Mann‐Whitney test; Student t‐test
Participants	Eligible for study: 132 Randomisation: intervention: 11, control: 11 Participants completed: intervention: 11, control: 9 Age, median (range): intervention: 47 (23 to 61), control: 44 (41 to 67) Gender, M/F: intervention: 0/11, control: 0/9 Co‐morbidities: not specified Diagnostic criteria for asthma: doctor's diagnosis; pulmonary function test Diagnostic criteria for GORD: doctor's diagnosis; symptoms; endoscopy; oesophageal manometry; 24‐hour pH monitoring Association between asthma and GORD tested? Yes; association required for entry; tested by history and symptoms, 24‐hour pH monitoring Major exclusion criteria: presence of obstruction not reversible with bronchodilators for patient stability, or phlegm for at least 3 months for 2 or more years; previous smoking history for greater than 10 pack‐years or cessation less than a year ago; evidence of respiratory infection characterised by fever and cough with purulent sputum in the last 6 weeks; abnormal chest X‐ray, paranasal sinus, or electrocardiogram; evidence of significant systemic disease or heart disease or liver disease, with special attention given to individuals with arrhythmias in electrocardiogram or taking antiarrhythmics; systemic arterial hypertension in the use of ACEIs, ARBs, or CCBs could not be changed; clinical and radiological evidence of chronic sinusitis within 4 weeks before the start of the study; history of use of proton pump inhibitors up to 4 weeks or H₂ receptor blockers up to 2 weeks before study entry; endoscopic evidence of peptic, gastric, or duodenal ulcer; pregnancy; illiteracy; need for continuous use of oral corticosteroids to control symptoms Baseline severity of asthma: mPEFR, mean: intervention: 328, control: 285; ePEFR, mean: intervention: 315, control: 280; FEV₁, mean % predicted: intervention: 73, control: 66 Baseline severity of GORD: 22/26 had abnormal levels of oesophageal acid exposure Baseline complications of GORD: score for heartburn, median (range): intervention: 2.1 (0.2 to 0.7), control: 3.0 (0.1 to 7.0); score for regurgitation, median (range): intervention: 0.9 (0 to 7.0), control: 0.7 (0 to 7.0); respiratory symptoms associated with reflux, number: intervention: 7, control: 8; reflux oesophagitis, number: intervention: 2, control: 4; hiatal hernia, number: intervention: 1, control: 4
Interventions	Duration of intervention: 8 weeks Type of intervention: lansoprazole 60 mg once daily, cisapride 30 mg once daily, and behavioural treatment Type of control: placebo tablet and behavioural treatment
Outcomes	Pre‐specified outcomes: primary clinical indicators of asthma control (symptom score, use of symptomatic medication, quality of life); secondary clinical indicators of asthma control (spirometry and serial peak expiratory flow) Follow‐up period: 8 weeks Outcomes measured: FEV₁, mPEFR, ePEFR, use of beta₂‐agonists, asthma symptoms, nocturnal symptoms, reflux score
Notes	Behavioural treatment: avoidance of fatty foods, chocolate, citrus juices, tomato‐based products, coffees and teas, soft drinks, alcoholic beverages; avoidance of feeding at least 2 hours before bedtime; all were advised to elevate the head of the bed by about 15 cm
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised according to statistical computer programme
Allocation concealment (selection bias)	Low risk	Received 2 vials containing either lansoprazole or placebo and cisapride or placebo.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals reported with explanation
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias detected

Goodall 1981.

Study characteristics
Methods	Country: United Kingdom Design: randomised, double‐blind, cross‐over study Objective/aim: to demonstrate measurable improvement in symptoms and respiratory function in a group of asthmatic patients who also had well‐documented reflux, by controlling their reflux with cimetidine in a double‐blind, cross‐over trial Study site: outpatient Methods of analysis: Mann‐Whitney U test
Participants	Eligible for study: 20 Randomisation: 20 Participants completed: 18 Age, mean (range): 54 (30 to 65) Gender, M/F: 13/7 Co‐morbidities: not specified Diagnostic criteria for asthma: doctor's diagnosis based on 'clinical grounds' Diagnostic criteria for GORD: any symptoms with abnormal endoscopy, 24‐hour pH monitoring, acid perfusion, or manometry; 19/20 had symptomatic reflux Association between asthma and GORD tested? Yes; association found in 10 participants Major exclusion criteria: not specified Baseline severity of asthma: nocturnal cough or wheezing 20/20 Baseline severity of GORD: heartburn 19/20; regurgitation 12/20 Baseline complications of GORD: oesophagitis: mild n = 7/20, marked n = 4/20, normal n = 9/20; abnormal pH n = 8/20, normal pH n = 12/20; manometry low pressure n = 8/20, normal pressure n = 12/20
Interventions	Duration of intervention: 6 weeks Type of intervention: cimetidine 200 mg 3 times daily plus cimetidine 400 mg at night Type of control: identical placebo
Outcomes	Pre‐specified outcomes: not specified Follow‐up period: 12 weeks Outcomes measured: FEV₁, PEFR*, use of beta₂‐agonists, asthma symptoms, nocturnal symptoms*, reflux score*
Notes	*Indicates significant result Funding support provided by North West Regional Health Authority. Study drugs supplied by Smith, Kline, and French Ltd
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	Allocation reported but method not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals reported with explanation
Selective reporting (reporting bias)	Unclear risk	Pre‐specified outcomes not specified
Other bias	Low risk	No other significant bias detected

Jiang 2003.

Study characteristics
Methods	Country: China Design: randomised controlled study Objective/aim: to determine effects of anti‐reflux treatment on bronchial hyper‐responsiveness and lung function in asthmatic patients with gastro‐oesophageal reflux disease (GORD) Study site: not specified Methods of analysis: t‐test
Participants	Eligible for study: 30 Randomisation: intervention: 15, control: 15 Participants completed: intervention: 15, control: 15 Age, mean ± SD (range): intervention: 35 ± 17.4 (20 to 65), control: 34.9 ± 19.2 (23 to 60) Gender, M/F: intervention: 6/9, control: 7/8 Co‐morbidities: not specified Diagnostic criteria for asthma: global initiative for asthma issued by National Heart, Lung and Blood Institute Diagnostic criteria for GORD: symptoms; barium oesophagogram; endoscopy Association between asthma and GORD tested? No Major exclusion criteria: not specified Baseline severity of asthma: FEV₁ % predicted, mean ± SD: intervention: 75.6 ± 14.5, control: 76.8 ± 11.6; PEFR L/s, mean ± SD: intervention: 4.6 ± 1.2, control: 4.4 ± 1.5 Baseline severity of GORD: not specified Baseline complications of GORD: not specified
Interventions	Duration of intervention: 6 weeks Type of intervention: omeprazole 20 mg once daily and domperidone 10 mg 3 times a day Type of control: nil intervention
Outcomes	Pre‐specified outcomes: pulmonary function test and bronchial hyper‐responsiveness Follow‐up period: not specified Outcomes measured: FEV₁*, PEFR*, airway hyper‐responsiveness*
Notes	*Indicates significant result
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	No mention of blinding of participants, but participants unlikely blinded as there are no placebo medications for the control group
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals/dropouts
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias identified

Kiljander 1999.

Study characteristics
Methods	Country: Finland Design: randomised, double‐blind, placebo‐controlled, cross‐over study Objective/aim: to investigate the prevalence of GORD among patients with asthma and to determine effects of omeprazole on the outcome of asthma in patients with GORD Study site: outpatient Methods of analysis: Mann‐Whitney U test
Participants	Eligible for study: 57 Randomisation: 57 Participants completed: 52 Age, mean (range): 49 (21 to 75) Gender, M/F: 20/37 Co‐morbidities: not specified Diagnostic criteria for asthma: American Thoracic Society Diagnostic criteria for GORD: manometry and 24‐hour pH monitoring Association between asthma and GORD tested? No Major exclusion criteria: not mentioned Baseline severity of asthma: FEV₁ % predicted, mean (range): 81 (31 to 114); PEFR L/min, mean (range): 455 (250 to 700) Baseline severity of GORD: 35% of patients had no symptoms Baseline complications of GORD: not specified
Interventions	Duration of intervention: 8 weeks Type of intervention: omeprazole 40 mg once daily Type of control: placebo
Outcomes	Pre‐specified outcomes: not specified Follow‐up period: 19 weeks Outcomes measured: FEV₁*, PEFR, use of beta₂‐agonists, asthma symptoms, nocturnal symptoms*, reflux score*
Notes	*Indicates significant result Funding support provided by the Finnish Anti‐Tuberculosis Association Foundation, the Väinö and Laina Kivi Foundation, and the Research Foundation of Respiratory Diseases
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind reported
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Most likely part of blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Withdrawal/missing data not fully explained
Selective reporting (reporting bias)	Low risk	All important outcomes reported
Other bias	Low risk	No other significant bias detected

Kiljander 2006.

Study characteristics
Methods	Country: Argentina (10 centres), Brazil (6 centres), Bulgaria (7 centres), Canada (7 centres), Czech Republic (8 centres), Finland (4 centres), Hungary (6 centres), Italy (9 centres), Mexico (5 centres), Romania (8 centres), Sweden (2 centres), and United States of America (50 centres) Design: randomised, double‐blind, placebo‐controlled study Objective/aim: primary objective: to investigate effects of 16 weeks of PPI therapy on pulmonary function using esomeprazole 40 mg twice daily in participants with persistent moderate to severe asthma; to establish the role of GORD in asthma; and to examine the possibility that asymptomatic acid reflux may be linked to respiratory symptoms; secondary objective: to assess the safety and tolerability of this high‐dose esomeprazole regimen in this asthma population Study site: outpatient Methods of analysis: ANCOVA analysis; Kaplan‐Meier plot; post‐hoc analysis
Participants	Eligible for study: 770 Randomisation: intervention: 387, control: 383 Participants completed: intervention: 322, control: 302 Age, mean (range): intervention: 44.7 (18 to 70), control: 44.8 (18 to 70) Gender %, M/F: intervention: 28/72; control: 33/67 Co‐morbidities: not specified Diagnostic criteria for asthma: objective measurement of FEV₁ of 50% to 80% predicted with 12% or greater (and ≥ 0.20 L) reversibility; mPEFR less than 80% predicted Diagnostic criteria for GORD: mean of 2 or more episodes of heartburn per week; 1 episode of acid regurgitation per week in the 3 months before enrolment; documented history of erosive oesophagitis or Barrett's oesophagus (without dysplasia) in the previous 12 months; documented history of abnormal 24‐hour oesophageal pH; correlation of heartburn with subsequent asthma symptoms (within 1 hour) on 2 or more occasions in the previous 3 months Association between asthma and GORD tested? Yes; classification into 3 strata according to the presence of GORD and/or nocturnal respiratory symptoms Major exclusion criteria: current smoking or history ≥ 10 pack‐years; use of oral, rectal, or parenteral glucocorticosteroids ≤ 30 days before enrolment; previous oesophageal or gastric surgery; erosive oesophagitis ≤ 16 weeks before enrolment; PPI use in the 14 days before enrolment; recurrent moderate or severe GORD symptoms in the previous year in participants > 40 years old; during run‐in period: severe heartburn on ≥ 4 days per week; night‐time awakening with associated respiratory symptoms on ≥ 2 consecutive nights; intake of GORD rescue medication with binding capacity > 66 mmol HCl per day (e.g. no more than 4 Rennie tablets, or 6 Gelusil tablets); mean ≥ 5 actuations per day of inhaled short‐acting beta₂ agonists or ≥ 9 per day on any 2 consecutive days Baseline severity of asthma: FEV₁ % predicted, mean: intervention: 66.2, control: 66.5; morning PEFR % predicted, mean: intervention: 69.7, control: 69.8; number of participants with inhaled corticosteroid use: intervention: 380, control: 376; number of participants with inhaled long‐acting beta₂ agonist use: intervention: 145, control: 162 Baseline severity of GORD: 74% had GORD; mean daily antacid use, number of tablets: intervention: 0.92, control: 0.87; number of night‐time heartburn symptoms/d, mean: Intervention: 0.35, control: 0.36; number of daytime heartburn symptoms/d, mean: intervention: 0.54, control: 0.51 Baseline complications of GORD: not specified
Interventions	Duration of intervention: 16 weeks Type of intervention: esomeprazole 40 mg twice daily Type of control: placebo
Outcomes	Pre‐specified outcomes: primary endpoint: change in mPEFR; secondary endpoints: change in ePEFR; daytime and night‐time asthma symptoms score; percentage of nocturnal awakenings due to asthma; percentage of days with ≥ 15% overnight PEFR variability; inhaled short‐acting beta₂‐agonist use; FEV₁; change in ACQ and AQLQ; time to asthma exacerbation Follow‐up period: 16 weeks Outcomes measured: exacerbations, FEV₁, mPEFR*, ePEFR*, use of beta₂‐agonists, asthma symptoms, nocturnal symptoms, quality of life, adverse effects
Notes	*Indicates significant result Research funding provided by AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	High risk	Inconsistent numbers of data reported for each outcome; missing data not addressed
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	High risk	Pharmaceutical company funded the study, provided the study drug, and set the study design

Kiljander 2010.

Study characteristics
Methods	Country: 13 countries (Argentina, Bulgaria, Canada, Czech Republic, France, Germany, Hungary, Italy, Mexico, Poland, Portugal, Slovakia, United States of America) Design: randomised, double‐blind, placebo‐controlled study Objective/aim: to determine the efficacy of esomeprazole, administered at a dose of 40 mg once daily or 40 mg twice daily, or matching placebo for 26 weeks, in terms of improving asthma outcomes in patients with moderate to severe asthma and symptomatic GORD Study site: outpatient Methods of analysis: intention‐to treat; ANCOVA; Cox proportional hazards model; Poisson regression model
Participants	Eligible for study: 961 Randomisation: intervention a: 313, intervention b: 320, control: 328 Participants completed: intervention a: 273, intervention b: 272, control: 283 Age, mean (range): intervention a: 45 (19 to 70), intervention b: 44 (18 to 69), control: 45 (18 to 70) Gender, M/F: intervention a: 73/240, intervention b: 79/240, control: 81/247 Co‐morbidities: not specified Diagnostic criteria for asthma: clinical diagnosis of asthma of 6 months' duration or longer according to ATS criteria; FEV₁ reversibility ≥ 12% and ≥ 0.20 L after inhalation of a beta₂‐agonist (terbutaline or albuterol) Diagnostic criteria for GORD: 3 months or longer history of GORD symptoms; abnormal oesophageal 24‐hour pH monitoring within 3 years Association between asthma and GORD tested? No Major exclusion criteria: any significant disease or disorder that may influence results or a patient's ability to participate in the study; presence of alarm symptoms (unintentional weight loss, hematemesis, jaundice, dysphagia, serious or malignant disease); history of smoking 20 or more cigarettes per day for 10 years (> 10 pack‐years); use of oral, rectal, or parenteral corticosteroids within 30 days before the 2‐week run‐in period; uninvestigated GORD symptoms within the previous year for patients older than 50 years of age; previous oesophageal or gastric surgery; endoscopy‐verified reflux oesophagitis within 16 weeks before run‐in period; presence of Barrett oesophagus with associated dysplasia; use of antacids with acid‐binding capacity greater than 100 mmol HCl per day during the run‐in period; women who were pregnant or breastfeeding, or those of childbearing age who were not using an acceptable form of contraception; known hypersensitivity to PPIs Baseline severity of asthma: FEV₁ % predicted, mean (range): intervention a: 66.0 (24.3 to 137.7), intervention b: 65.8 (24.3 to 97.2), control: 66.5 (24.3 to 113.4); FEV₁ L, mean (range): intervention a: 2.0 (0.7 to 4.3), intervention b: 2.1 (0.6 to 4.4), control: 2.0 (0.6 to 4.8); mPEFR L/min, mean (range): intervention a: 288 (100 to 619), intervention b: 288 (113 to 610), control: 286 (103 to 684) Baseline severity of GORD: all had symptoms of GORD Baseline complications of GORD: not specified
Interventions	Duration of intervention: 26 weeks Type of intervention: intervention a: esomeprazole 40 mg once daily; intervention b: esomeprazole 40 mg twice daily Type of control: placebo
Outcomes	Pre‐specified outcomes: primary endpoint: change from baseline in mPEFR; secondary endpoints: change in ePEFR; change in FEV₁; change in asthma score (total, morning, and evening); use of beta₂‐agonists; percentage of asthma symptom‐free days; time to first asthma exacerbation and number of severe asthma exacerbations; change in AQLQ and RDQ scores; tolerability (adverse events, laboratory tests, and vital signs) Follow‐up period: not specified Outcomes measured: exacerbations, FEV₁₂*, mPEFR, ePEFR, asthma symptoms, quality of life*, reflux score*, adverse effects
Notes	*Indicates significant result Funding provided by AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing data balanced across 3 groups. Reasons for discontinuation explained
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias identified

Kjellen 1981.

Study characteristics
Methods	Country: Sweden Design: randomised, parallel‐controlled study Objective/aim: to evaluate effects of an oesophageal regimen on OD, oesophageal symptoms, respiratory function, and symptoms in patients with exogenous and endogenous bronchial asthma Study site: outpatient Methods of analysis: Fisher's exact test; Wilcoxon rank test; Student's t‐test
Participants	Eligible for study: 62 Randomisation: intervention: 31, control: 31 Participants completed: intervention: 31, control: 31 Age, range: intervention: 36 to 65, control: 36 to 65 Gender, M/F: intervention: 16/15, control: 17/14 Co‐morbidities: not specified Diagnostic criteria for asthma: American Thoracic Society Diagnostic criteria for GORD: manometry and acid perfusion test; symptomatic GORD was not required for entry and was not reported Association between asthma and GORD tested? No Major exclusion criteria: not specified Baseline severity of asthma: FEV₁ L, mean ± SD: before bronchodilating: 2.16 ± 1.0; after bronchodilating: 2.50 ± 1.0 Baseline severity of GORD: not specified Baseline complications of GORD: hiatal hernia 55%; dysmotility 58%; positive acid perfusion test 35%; decreased lower oesophageal sphincter pressure 40%
Interventions	Duration of intervention: 8 weeks Type of intervention: conservative treatment including elevation of head of bed; warm water after meals; avoidance of food 3 hours before bedtime; refraining from aspirin and/or anticholinergic drugs; avoidance of procedures that raise intra‐abdominal pressure Type of control: control group was informed that there was suspicion of oesophageal dysfunction but that results had to be checked in 2 months' time; both groups kept diaries of asthma drugs
Outcomes	Pre‐specified outcomes: effect of an oesophageal regimen on OD, oesophageal symptoms, respiratory function, and respiratory symptoms Follow‐up period: 2 months Outcomes measured: FEV₁, use of beta₂‐agonists*, asthma symptoms* (number that self‐reported improvements in dyspnoea, wheeze, cough, expectoration), reflux score* (number that self‐reported improvement in oesophageal symptoms)
Notes	*Indicates significant result Funding provided by the Swedish Medical Research Council and the Swedish National Association Against Heart and Chest Diseases
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Randomisation by alternation
Allocation concealment (selection bias)	High risk	Unconcealed interviewers
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No mention of dropouts from the study
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias detected

Larrain 1991.

Study characteristics
Methods	Country: Chile Design: randomised study of medical and surgical therapy Objective/aim: to determine the prevalence of oesophageal reflux in group of patients presenting with pulmonary symptoms, and to investigate effects of medical and surgical treatment for reflux on subjective and objective manifestations of pulmonary disease Study site: outpatient Methods of analysis: ANOVA; ANCOVA; Chi² test; Wilcoxon matched‐pairs signed‐rank test; Mann‐Whitney U test
Participants	Eligible for study: 90 Randomisation: intervention a: 30, intervention b: 30, control: 30 Participants completed: intervention a: 27, intervention b: 26, control: 28 Age, mean ± SD: intervention a: 43 ± 11, intervention b: 46 ± 13, control: 42 ± 9 Gender, M/F: intervention a: 2/25, intervention b: 6/20, control: 9/19 Co‐morbidities: not specified Diagnostic criteria for asthma: symptoms: wheezing and shortness of breath Diagnostic criteria for GORD: heartburn symptoms (60 had mild symptoms, 21 had no symptoms), endoscopy (all had either a normal oesophagus n = 60 or erythema n = 20), 30‐minute pH monitoring after loading stomach with 300 mL 0.1 N HCl followed by barium mean if no reflux seen on X‐ray Association between asthma and GORD tested? No Major exclusion criteria: people with family history of asthma, symptoms of chronic bronchitis (productive cough for longer than 3 months per year), or correlation between acute attacks and inhaled allergens; people under 18 years of age; people with positive immediate skin tests to a battery of common allergens; people with elevated immunoglobulin E levels in the serum; people with arterial PO₂ levels less than 60 mmHg or FEV₁ less than 1 L; radiographic evidence of emphysema Baseline severity of asthma: 56/81 had reactive airways; 35/81 used corticosteroids Baseline severity of GORD: heartburn symptoms: 60/81; free reflux shown on radiography: 38/81 Baseline complications of GORD: 20/81 had grade 1 oesophagitis; 60/81 had normal endoscopy
Interventions	Duration of intervention: 26 weeks Type of intervention: intervention a: cimetidine 300 mg 4 times daily; intervention b: surgery: posterior gastropexy with cardiac calibration Type of control: identical placebo
Outcomes	Pre‐specified outcomes: not specified Follow‐up period: average 77 months Outcomes measured: pulmonary symptoms (surgery* and cimetidine*), FEV₁ (cimetidine*), asthma symptoms, steroid use (surgery*)
Notes	*Indicates significant result Funding provided by Smith, Kline, and French Laboratories
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation using randomisation code
Allocation concealment (selection bias)	Low risk	Centralised randomisation conducted by Smith Kline in USA
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Placebo identical to study drug was used. However, it is unlikely that the surgical arm could be blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Evaluated by chest physicians who had not taken part in initial selection or randomisation of people; they made no effort to determine whether patients had been treated by medical or surgical means
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data on patients who refused and withdrew from the study were excluded; The number of withdrawals from each group was similar
Selective reporting (reporting bias)	Unclear risk	Pre‐specified outcomes were not specified
Other bias	Low risk	No other significant bias was detected

Levin 1998.

Study characteristics
Methods	Country: United States of America Design: randomised, double‐blind, placebo‐controlled, cross‐over study Objective/aim: to determine if omeprazole improves pulmonary function and quality of life in asthmatic patients with GORD Study site: outpatient Methods of analysis: 2‐tailed, paired t‐test; Fisher's exact test
Participants	Eligible for study: 11 Randomisation: 11 Participants completed: 9 Age, mean (range): 57 (35 to 72) Gender, M/F: 6/3 Co‐morbidities: not specified Diagnostic criteria for asthma: objective lung function: ≥ 15% reversibility post B2 and daily asthma medication Diagnostic criteria for GORD: symptoms: heartburn or regurgitation Association between asthma and GORD tested? No Major exclusion criteria: COPD, prior gastroesophageal surgery, acute peptic ulcer disease, use of omeprazole within 30 days, upper respiratory infection within previous 30 days, severe medical or surgical illness Baseline severity of asthma: FEV₁ L, mean (range): 1.9 (1.0 to 2.9); mPEFR L/min, mean (range): 376 (283 to 488); ePEFR L/min, mean (range): 381 (286 to 468) Baseline severity of GORD: mean % time pH < 4 in proximal oesophagus: total: 4.5%; upright: 6.5%; supine: 0.6% Baseline complications of GORD: not specified
Interventions	Duration of intervention: 8 weeks Type of intervention: omeprazole 20 mg once daily Type of control: identical placebo
Outcomes	Pre‐specified outcomes: primary outcomes: mean R, FEV₁, AQOLQ scores Follow‐up period: 20 weeks Outcomes measured: FEV₁, mPEFR*, ePEFR, quality of life*
Notes	*Indicates significant result First study author was supported for this work by an American Digestive Health Foundation Outcomes Research Training Award
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random draw from sequentially numbered drug containers of identical appearance
Allocation concealment (selection bias)	Low risk	Sequentially numbered drug containers of identical appearance
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinded until completion of study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded until completion of study
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals recorded with explanation
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Unclear risk	Nil washout periods between 2 treatment periods; possible contamination not reported/tested

Littner 2005.

Study characteristics
Methods	Country: United States of America Design: randomised, double‐blind, placebo‐controlled study Objective/aim: to determine whether a proton pump inhibitor improves asthma control in adult asthmatic patients with acid reflux symptoms Study site: outpatient Methods of analysis: Fisher's exact test; Cochran‐Mantel‐Haenszel test; Wilcoxon 2‐sample test; 2‐way analysis of variance; log‐rank test; Poisson regression
Participants	Eligible for study: 207 Randomisation: intervention: 99, control: 108 Participants completed: intervention: 88, control: 85 Age, mean ± SD: intervention: 47 ± 12, control: 45 ± 13 Gender %, M/F: intervention: 33/67, control: 33/67 Co‐morbidities: not specified Diagnostic criteria for asthma: FEV₁ > 50% predicted and < 85% predicted; ≥ 12% improvement in FEV₁ L after inhalation of 180 μg of albuterol Diagnostic criteria for GORD: doctor's diagnosis based on reflux symptoms Association between asthma and GORD tested? No Major exclusion criteria: people receiving ipratropium bromide or > 10 mg daily prednisone or equivalent; people receiving astemizole; people undergoing immunotherapy for < 6 months or unable to continue receiving current dose; history of upper respiratory tract infection or hospitalisation for asthma within 30 days; hospitalisation more than once within 6 months; any uncontrolled clinically significant medical condition; people who had been treated with a PPI within 14 days of study inclusion, or with an anticoagulant, β‐blocker, tricyclic antidepressant, monoamine oxidase inhibitor, or cholinergic agent before screening Baseline severity of asthma: FEV₁ % predicted, mean ± SD: intervention: 82 ± 12, control: 83 ± 13; FEV₁ L, mean ± SD: intervention: 2.6 ± 0.6, control: 2.7 ± 0.7; mPEFR L/min, mean ± SD: intervention: 366 ± 77, control: 355 ± 88; ePEFR L/min, mean ± SD: intervention: 377 ± 80, control: 369 ± 91 Baseline severity of GORD: reflux symptoms score, mean ± SD: intervention: 1.66 ± 0.69, control: 1.70 ± 0.65 Baseline complications of GORD: not specified
Interventions	Duration of intervention: 24 weeks Type of intervention: lansoprazole 30 mg twice daily Type of control: identical placebo
Outcomes	Pre‐specified outcomes: primary endpoint: asthma symptom score by diary; secondary endpoints: rescue albuterol use; pulmonary function tests (daily mPEFR and ePEFR, FEV₁, FVC); AQLQ; investigator‐assessed symptoms; exacerbations Follow‐up period: 24 weeks Outcomes measured: exacerbations*, FEV₁, mPEFR, ePEFR*, use of beta₂‐agonists, asthma symptoms, nocturnal symptoms, quality of life*, reflux score*
Notes	*Indicates significant result
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details mentioned
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind reported
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Most likely part of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Numbers of withdrawals and reasons were balanced between 2 groups; although 5 patients withdrew from the study due to "therapeutic failure"; incomplete data should not impose significant effects on outcome data
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias detected

Maev 2002.

Study characteristics
Methods	Country: Russia Design: randomised, 2‐arm, placebo‐controlled study Objective/aim: to investigate the prevalence of gastroesophageal reflux disease among patients with bronchial asthma (BA), and to determine effects of omeprazole therapy on the outcome of asthma in patients with GORD Study site: outpatient Methods of analysis: Chi² test; Wilcoxon signed‐rank test; Mann‐Whitney test; Student's t‐test
Participants	Eligible for study: 64 Randomisation: intervention: 32, control: 32 Participants completed: intervention: 32, control: 32 Age, mean (range): 42 (29 to 55) Gender, M/F: 38/26 Co‐morbidities: not specified Diagnostic criteria for asthma: objective confirmation by history, doctor's diagnosis, and evidence of variable expiratory airflow obstruction Diagnostic criteria for GORD: endoscopy and 24‐hour monitoring of pH gastric juice Association between asthma and GORD tested? No Major exclusion criteria: not specified Baseline severity of asthma: inhaled corticosteroid use: 53/64; oral β2‐adrenergic agonist use: 53/64; nocturnal asthma: 17/64 Baseline severity of GORD: not specified Baseline complications of GORD: not specified
Interventions	Duration of intervention: 8 weeks Type of intervention: omeprazole 20 mg twice daily Type of control: placebo twice daily
Outcomes	Pre‐specified outcomes: asthma: signs and symptoms (cough, dyspnoea, PEFR, FEV₁), rate of sympathomimetic use; GORD: eructation, heartburn, dysphagia, pain during food swallowing; Clinical Indices of Effectiveness (CIE 1 and CIE 2) calculated by daily summarising of pulmonary (cough, dyspnoea; CIE 1) and gastric (eructation, heartburn, dysphagia, pain during food swallowing; CIE 2) symptom improvement Follow‐up period: 8 weeks Outcomes measured: FEV₁*, PEFR*, asthma symptoms*, total numbers of reflux episodes, CIE 1*, CIE 2*
Notes	*Indicates significant result
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals/dropouts
Selective reporting (reporting bias)	High risk	All pre‐specified outcomes not reported
Other bias	Low risk	No other significant bias detected

Meier 1994.

Study characteristics
Methods	Country: United States of America Design: randomised, double‐blind, placebo‐controlled, cross‐over study Objective/aim: to determine if more potent suppression of acid reflux with omeprazole would objectively improve respiratory function in asthmatic patients, and to determine if demographic characteristics of asthmatic patients with pyrosis are helpful in predicting improvement in asthma when GORD is treated with omeprazole Study site: outpatient Methods of analysis: Student's t‐test; Mann‐Whitney 2‐sample test
Participants	Eligible for study: 15 Randomisation: 15 Participants completed: 15 Age, mean (range): 49 (34 to 63) Gender, M/F: 9/6 Co‐morbidities: not specified Diagnostic criteria for asthma: American Thoracic Society; objective lung function Diagnostic criteria for GORD: included if abnormal endoscopy or abnormal pH on 24‐hour monitoring; all had symptoms of pyrosis; additional investigations included acid perfusion test (Bernstein), manometry, oesophageal motility Association between asthma and GORD tested? Yes; association required for entry, tested by history, symptoms, and 24‐hour pH monitoring Major exclusion criteria: age ≤ 18 years; unable to give informed consent; pregnancy; female unwilling to comply with birth contraception during entire study period Baseline severity of asthma: FEV₁ > 15% response to bronchodilator; PEFR > 15% response to bronchodilator Baseline severity of GORD: endoscopic oesophagitis and/or distal oesophageal pH score ≥ 22; 15/15 had GORD symptoms Baseline complications of GORD: number per grade of oesophageal erosion: Grade 1 n = 1, Grade 2 n = 4, Grade 3 n = 8, Grade IV n = 2; stricture: 10/15; pH mean for distal probe 60.5; hiatal hernia 10/15
Interventions	Duration of intervention: 6 weeks Type of intervention: omeprazole 20 mg twice daily Type of control: placebo
Outcomes	Pre‐specified outcomes: not specified Follow‐up period: 14 weeks Outcomes measured: FEV₁*, PEFR, use of beta₂‐agonists, asthma symptoms (number of people with wheeze/hoarseness), reflux score
Notes	*Indicates significant result Funding support provided by Merck Sharp and Dohme and Astra/Merck Group through Facilitators of Applied Clinical Research Trials grant
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation scheme designed to provide equal randomisation
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind reported
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Most likely part of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals/dropouts
Selective reporting (reporting bias)	Unclear risk	Pre‐specified outcomes not specified
Other bias	Low risk	No other significant bias detected

Nagel 1988.

Study characteristics
Methods	Country: United Kingdom Design: randomised, double‐blind, cross‐over study Objective/aim: to find out if there was a difference in the degree of GORD between people with asthma with "morning dipping", in which the PEFR falls during the night, and people with asthma in which this does not occur ("non‐dippers"); also, to see if people with asthma with GORD given ranitidine or placebo would benefit from reduction of acidity in the stomach Study site: outpatient Methods of analysis: 2‐sample Wilcoxon test; Chi²; and 2‐samples t‐tests or t‐tests for paired differences
Participants	Eligible for study: 15 Randomisation: 15 Participants completed: 14 Age, mean (range): 42 (20 to 64) Gender, M/F: 11/4 Co‐morbidities: not mentioned Diagnostic criteria for asthma: doctor's diagnosis and objective lung function Diagnostic criteria for GORD: symptoms, 24‐hour pH monitoring: required pH < 4 for > 4.2% of the time or > 3 episodes of reflux lasting longer than 5 minutes; required to have symptomatic GORD at least once every 6 weeks Association between asthma and GORD tested? Yes; association required for entry, tested by history, symptoms, and 24‐hour pH monitoring associated with a dip in PEFR during the night Major exclusion criteria: not specified Baseline severity of asthma: FEV₁ > 25% reversibility after bronchodilators; PEFR > 25% reversibility after bronchodilators Baseline severity of GORD: symptoms occurred at least once every 6 weeks Baseline complications of GORD: not specified
Interventions	Duration of intervention: 7 days plus 3‐day washout period Type of intervention: ranitidine 300 mg at 9 pm and 150 mg at 9 am Type of control: placebo
Outcomes	Pre‐specified outcomes: not specified Follow‐up period: 17 days Outcomes measured: mPEFR, ePEFR, use of beta₂‐agonists, asthma symptoms, reflux symptoms (number of people)
Notes	*Indicates significant result
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals reported with explanation
Selective reporting (reporting bias)	Unclear risk	Pre‐specified outcomes not specified
Other bias	Low risk	No other significant bias detected

Sharma 2007.

Study characteristics
Methods	Country: India Design: randomised, double‐blind, placebo‐controlled study Objective/aim: to study effects of combined omeprazole and domperidone therapy on asthma symptoms and pulmonary function in asthmatic patients with GORD Study site: outpatient Methods of analysis: Fisher's exact test; paired t‐test
Participants	Eligible for study: 204 Randomisation: intervention: 102, control: 102 Participants completed: intervention: 99, control: 99 Age, mean ± SD: intervention: 51.49 ± 9.83, control: 51.48 ± 9.79 Gender %, M/F: intervention: 68.7/31.3, control: 68.7/31.3 Co‐morbidities: not specified Diagnostic criteria for asthma: > 12% improvement in FEV₁ L after inhalation of 180 μg of albuterol Diagnostic criteria for GORD: 24‐hour oesophageal pH monitoring: positive if total time for which pH was < 4 was > 4.5% Association between asthma and GORD tested? No Major exclusion criteria: any unstable chronic medical condition; history of smoking in past or present; history of any other lung disease except asthma; use of anti‐reflux medications including antacids, histamine‐2‐receptor antagonists, PPIs, or prokinetic agents Baseline severity of asthma: FEV₁ % predicted, mean ± SD: intervention: 68.58 ± 3.56, control: 68.89 ± 3.59; FEV₁ L, mean ± SD: intervention: 1.89 ± 0.40, control: 1.85 ± 0.40; mPEFR L/min, mean ± SD: intervention: 283.58 ± 43.27, control: 285.45 ± 44.27; ePEFR L/min, mean ± SD: intervention: 283.69 ± 54.49, control: 288.06 ± 57.38 Baseline severity of GORD: reflux symptoms score, mean ± SD: intervention: 2.48 ± 0.76, control: 2.49 ± 0.73 Baseline complications of GORD: not specified
Interventions	Duration of intervention: 16 weeks Type of intervention: omeprazole 20 mg twice daily plus domperidone 10 mg 3 times a day Type of control: identical placebo
Outcomes	Pre‐specified outcomes: primary endpoints: mean daily daytime and night‐time asthma symptom scores; secondary endpoints: mean daily reflux symptom scores; albuterol use (number of puffs); daytime and night‐time PEFR; postbronchodilator FEV₁; postbronchodilator FVC Follow‐up period: 16 weeks Outcomes measured: FEV₁*, mPEFR*, ePEFR*, use of beta₂‐agonists, asthma symptoms*, nocturnal symptoms*, reflux score*, adverse effects
Notes	*Indicates significant result Funding provided by the University of Delhi, Glaxo Smithkline Pharmaceuticals Limited, and Dr Reddy's Laboratories Ltd
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Six patients dropped out after randomisation, and details of dropouts were not provided; however, the percentage of dropouts was small and was unlikely to affect outcomes
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias detected

Sontag 2003.

Study characteristics
Methods	Country: United States of America Design: randomised controlled study of 3 different GORD therapies Objective/aim: to determine whether prolonged treatment of GORD would improve or eliminate pulmonary symptoms of asthma, reduce or eliminate the need for pulmonary medication, or improve pulmonary function and alter the natural history of asthma Study site: outpatient Methods of analysis: Chi² tests; Mann‐Whitney U test; ANOVA; Wilcoxon t‐test; Kaplan‐Meier survival curve
Participants	Eligible for study: 124 Randomisation: intervention a: 24, intervention b: 25, control: 26 Participants completed: intervention a: 22, intervention b: 16, control: 24 Age, mean (range): intervention a: 52 (26 to 75), intervention b: 48 (21 to 65), control: 52 (27 to 71) Gender %, M/F: intervention a: 95/5, intervention b: 100/0, control: 88/12 Co‐morbidities: not specified Diagnostic criteria for asthma: clinical history of discrete attacks of wheezing, coughing, or dyspnoea and increase in FEV₁ of 20% from baseline with bronchodilator administration or 20% decrease in FEV₁ with up to 205.5 dose units of methacholine Diagnostic criteria for GORD: positive 24‐hour ambulatory oesophageal pH recording and presence of macroscopic (endoscopic) oesophageal mucosal erosions/ulcerations or positive oesophageal mucosal biopsy if oesophageal mucosa was macroscopically normal Association between asthma and GORD tested? No Major exclusion criteria: PaO₂ less than 60 mmHg; PaCO₂ > 44 mmHg; FEV₁ (after bronchodilator therapy) less than 50% predicted or < 1.5 L; illness, age, or habitat precluding anti‐reflux surgery; mild asthma that causes no impairment in activities; asthma that is unequivocally occupational, extrinsic, or seasonal; previous gastroesophageal surgery or current gastric outlet obstruction; age > 80 years Baseline severity of asthma: asthma symptom score, mean ± SD: intervention a: 5.9 ± 2.1, intervention b: 5.1 ± 2.1, control: 5.9 ± 1.4; night wheeze, %: intervention a: 50%, intervention b: 43.8%, control: 58.3%; night cough, %: intervention a: 59.1%, intervention b: 56.2%, control: 45.8%; night gasping, %: intervention a: 41.7%, intervention b: 56.2%, control: 33.3% Baseline severity of GORD: reflux symptom score, mean ± SD: intervention a: 5.3 ± 0.6, intervention b: 4.8 ± 0.5, control: 5.2 ± 0.6; heartburn, %: intervention a: 66.7, intervention b: 87.5%, control: 75%; pharyngeal burning, %: intervention a: 54.2%, intervention b: 37.5%, control: 41.7%; reflux of food, %: intervention a: 33.3%, intervention b: 37.5%, control: 50% Baseline complications of GORD: erosions, %: intervention a: 40.9%, intervention b: 56.2%, control: 45.8%; ulcers, %: intervention a: 18.2%, intervention b: 18.8%, control: 12.5%; hiatal hernia, %: intervention a: 77.3%, intervention b: 68.8%, control: 79.2%
Interventions	Duration of intervention: 2 years Type of intervention: intervention a: ranitidine 150 mg 3 times a day plus conservative treatment; intervention b: surgical: Nissen fundoplication plus conservative treatment Type of control: symptomatic treatment as needed: Mylanta II 30 mL
Outcomes	Pre‐specified outcomes: subjective parameter: asthma symptom score; objective parameters: mean PEFR volumes, mean PEFR percent variation, pulmonary function tests and pulmonary medicine requirements; overall pre‐defined clinical status grade Follow‐up period: 19.1 years Outcomes measured: PEFR, asthma symptoms*, reflux symptoms (number of people with improvement)*
Notes	Conservative treatment: avoid wearing tight garments, eating supper, eating fatty foods, and reclining after meals; eat smaller, more frequent meals; elevate head of bed 6 inches *Indicates significant result Funding provided by a VAMerit Review grant from VA Central Office and from Loyola University Stritch School of Medicine
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not possible given surgical intervention, although study authors attempted to reduce placebo effect by admitting participants from all groups to hospital for 7 days. Not placebo‐controlled
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals with explanation reported
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias detected

Stordal 2005.

Study characteristics
Methods	Country: Norway Design: randomised, double‐blind, placebo‐controlled study Objective/aim: to assess whether acid suppression would lead to reduced asthma symptoms in children with concomitant asthma and GORD Study site: outpatient Methods of analysis: 2‐sided t‐tests; Mann‐Whitney U test
Participants	Eligible for study: 45 Randomisation: intervention: 19, control: 19 Participants completed: intervention: 18, control: 18 Age, mean (median): intervention: 10.2 (9.2), control: 11.3 (11.0) Gender, M/F: intervention: 15/4, control: 14/5 Co‐morbidities: not specified Diagnostic criteria for asthma: doctor's diagnosis Diagnostic criteria for GORD: symptoms; 24‐hours pH monitoring: abnormal if reflux index (RI = percentage of total recording time with ph < 4.00) 5.0 or more Association between asthma and GORD tested? No Major exclusion criteria: previously known or treated GORD Baseline severity of asthma: FEV₁ % predicted, mean ± SD: intervention: 88.6 ± 9.5, control: 86.9 ± 7.8; use of daily ICS, number: intervention: 17, control: 17; use of daily LABA, number: intervention: 10, control: 12; GINA classification of asthma severity (step 1/2/3/4): intervention: 4/8/7/0, control: 3/6/10/0 Baseline severity of GORD: reflux index %, mean ± SD: intervention: 8.8 ± 4.0, control: 9.7 ± 5.1 Baseline complications of GORD: not specified
Interventions	Duration of intervention: 12 weeks Type of intervention: omeprazole 20 mg once daily Type of control: placebo
Outcomes	Pre‐specified outcomes: primary endpoints: asthma symptoms (daytime wheeze; symptoms at night, in the morning, and during exercise), quality of life (PAQLQ); secondary endpoints: changes in lung function; use of beta₂‐agonists Follow‐up period: 12 weeks Outcomes measured: FEV₁, use of beta₂‐agonists, asthma symptoms, quality of life, reflux score, eosinophils
Notes	*Indicates significant result Funding provided by Norwegian Foundation for Health and Rehabilitation and AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Low risk	Treatment allocation performed using sequentially numbered containers from the manufacturer
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinded reported
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	One in each group withdrew due to suspected side effects, leaving 18 in each group for final analysis; The proportion of withdrawal in each group was similar and small
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes reported
Other bias	Low risk	No other significant bias detected

Susanto 2008.

Study characteristics
Methods	Country: Indonesia Design: randomised, single‐blind, placebo‐controlled study Objective/aim: to evaluate effects of esomeprazole on reducing asthma symptoms, use of inhaled bronchodilators, and PEFR in moderate persistent asthma with GORD Study site: outpatient Methods of analysis: parametric test for normally distributed data with multiple repeated measures of analysis of variance (ANVOA) test to evaluate variables by time of treatment and compare between the 2 groups. P < 0.05 considered significant Non‐parametric tests for abnormally distributed data, with Friedmann test for variables by time of treatment analysis and with Mann‐Whitney test or t‐test to evaluate comparative variables between 2 groups at the same time (e.g. cough score, sleep disturbance); Bonnferoni correction was undertaken due to extrapolation of results from 2 different tests; difference between 2 qualitative data proportions was evaluated with the Chi² test. P < 0.003125 considered significant
Participants	Eligible for study: not reported Randomisation: intervention: 18, control: 18 Participants completed: intervention: 16, control: 16 Age, mean (SD): intervention: 42.69 (11.11), control: 37.88 (11.01) Gender %, M/F: intervention: 4/12, control: 5/11 Co‐morbidities: not specified Diagnostic criteria for asthma: moderate persistent asthma patients (GINA 2002), age 15 to 65 years, postbronchodilator reversibility test > 12%, bronchial provocations test must be positive Diagnostic criteria for GORD: 1 or more symptoms of GORD recorded; oesophagitis established by endoscopy and classified according to Los Angeles 1994 standards; histopathology via oesophageal biopsy Association between asthma and GORD tested? No Major exclusion criteria: pre‐specified exclusion criteria not reported Baseline severity of asthma: asthma symptom score, mean ± SD: intervention: 3.36 ± 1.92, control: 3.49 ± 1.22; use of beta₂‐agonists, mean ± SD: intervention: 1.51 ± 1.24, control: 1.82 ± 1.08; mPEFR, mean ± SD: intervention: 252.7 ± 71.3, control: 269.7 ± 81.9; ePEFR, mean ± SD: intervention: 256.9 ± 65.6, control: 272.7 ± 80.7 Baseline severity of GORD: mean ± SD: intervention: 17.34 ± 8.63, control: 16.88 ± 8.34
Interventions	Duration of intervention: 14; 2‐week run in period, 8‐week treatment period, 4‐week washout period Type of intervention: intervention ‐ 40 mg esomeprazole daily plus standard treatment budesonide inhalation 2 × 400 mg/d and salbutamol 100 mg/puff + conservative treatment of GORD was given such as lifestyle modifications and antacid (if necessary) Type of control: no intervention plus standard treatment (budesonide inhalation 2 × 400 mg/d and salbutamol 100 mg/puff + conservative treatment of GORD was given such as lifestyle modifications and antacid (if necessary)
Outcomes	Pre‐specified outcomes: daily evaluation of asthma symptoms; use of beta₂‐agonists, mPEFR, ePEFR, and weekly evaluation for GORD symptoms; scoring for asthma symptoms of cough, night sleep disturbance, activity disturbance, and wheezing; asthma symptom total score is the total value of asthma symptom scores in 1 day; scoring for GORD symptoms is evaluated by diary card through symptoms (e.g. heartburn, atypical chest pain, regurgitation); GORD symptom total score is the total value of GORD symptom scores in 1 week Follow‐up period: end of washout period
Notes	No sources of funding listed for this study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient detail in paper to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient detail in paper to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient detail in paper to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient detail in paper to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	Numbers and reasons for dropouts given in the paper. Declare that dropouts were excluded from analysis after randomisation. Small number of dropouts (n = 4). Unclear why exacerbating patient was excluded; if this was the decision of the patient or related to negative effects from treatment
Selective reporting (reporting bias)	Unclear risk	No pre‐specified protocol available to determine if other bias was present
Other bias	Low risk	No other significant bias detected

Teichtahl 1996.

Study characteristics
Methods	Country: Australia Design: randomised, double‐blind, placebo‐controlled, cross‐over study Objective/aim: to investigate effects of the potent gastric acid inhibitor omeprazole 40 mg orally daily on PEFR, asthma symptoms, and histamine bronchial responsiveness in adult patients with both asthma and GORD Study site: outpatient Methods of analysis: Student's paired t‐test
Participants	Eligible for study: 30 Randomisation: 25 Participants completed: 20 Age, mean ± SD (range): randomised: 43 ± 13 (19 to 60), completed: 46 ± 12 (19 to 60) Gender, M/F: randomised: 14/11, completed: 12/8 Co‐morbidities: not specified Diagnostic criteria for asthma: doctor's diagnosis, objective lung function, positive provocation test Diagnostic criteria for GORD: endoscopy and pH < 4 for > 5% of the 24‐hour period; 19/20 had symptomatic GORD; the other participant had difficult to control nocturnal asthma Association between asthma and GORD tested? No Major exclusion criteria: significant respiratory disease other than asthma; evidence of respiratory tract infection in the 4 weeks before inclusion in the study; evidence of significant systemic, cardiac, or hepatic illness; oesophageal stricture requiring dilatation; oesophageal varices; gastric ulcer, prepyloric ulcer, duodenal ulcer, or pregnancy Baseline severity of asthma: FEV₁ 15% reversibility within 15 to 30 minutes of beta₂‐agonist and diurnal variation in PEFR > 19% documented in the past 6 months Baseline severity of GORD: all had GORD symptoms Baseline complications of GORD: number per grade of oesophagitis: Grade 0 n = 3, Grade I n = 4, Grade II n = 11, Grade III n = 2; pH score: average % of time with pH < 4 = 12.2%
Interventions	Duration of intervention: 12 weeks Type of intervention: omeprazole 40 mg once daily in the morning Type of control: placebo
Outcomes	Pre‐specified outcomes: mPEFR, ePEFR, FEV₁, PC₂₀FEV₁,asthma symptoms Follow‐up period: 12 weeks Outcomes measured: hospitalisations, unscheduled visits to the doctor, FEV₁, mPEFR, ePEFR*, use of beta₂‐agonists, asthma symptoms, nocturnal asthma, airway hyper‐responsiveness
Notes	*Indicates significant result Funding provided by Astra Pharmaceuticals
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation reported but method not described
Allocation concealment (selection bias)	Unclear risk	No details specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind reported but no details specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals reported with explanation
Selective reporting (reporting bias)	High risk	Study did not report all pre‐specified outcomes
Other bias	Low risk	No other significant bias detected

ACEI: angiotensin‐converting enzyme inhibitor; ACQ: Asthma Control Questionnaire; ANCOVA: analysis of covariance; ANOVA: analysis of variance; ARB: angiotensin II receptor blocker; AQLQ: Asthma Quality of Life Questionnaire; CCB: calcium channel blocker; COPD: chronic obstructive pulmonary disease; ePEFR: evening peak expiratory flow rate; F: female; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; GORD: gastro‐oesophageal reflux disease; HCl: hydrochloride; ICS: inhaled corticosteroid; LABA: long‐acting beta₂‐agonist; M: male; MD: mean difference; mPEFR: morning peak expiratory flow rate; OD: oesophageal dysfunction; PaO₂: partial pressure of oxygen; PaCO₂: partial pressure of carbon dioxide; PEFR: peak expiratory flow rate; pH: potential hydrogen; PPI: proton pump inhibitor; SD: standard deviation; RDQ: reflux disease questionnaire.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Adamko 2012	Not all participants had a formal diagnosis of asthma; no response from study authors to request to identify percentage with a diagnosis
Alagaratnam 2009	No GOR diagnosis
Al‐Biltagi 2013	Not using placebo or appropriate control
Anonymous 2005	No GOR diagnosis
Arand 2008	No intervention, commentary article
Bai 2001	Not using placebo or appropriate control
Bai 2002	Not using placebo or appropriate control
Bediwy 2012	Not using placebo or appropriate control
Bediwy 2014	Not using placebo or appropriate control
Berthon 2015	No GOR diagnosis
Bocskei 2005	Not using placebo or appropriate control, not randomised
Boeree 1998	Not all asthma
Bossley 2013	No GOR diagnosis
Bucknall 2009	No control group, not a randomised controlled trial ‐ observational study
Byun 2015	No asthma diagnosis, patients with asthma excluded
Cai 2016	Unable to access full text in Chinese
Centanni 2000	No GOR diagnosis
Chen 2005	Not using placebo or appropriate control
Dal Negro 1998	Unable to confirm eligibility: abstract only, no full paper, unable to determine eligibility; no response from trial authors for clarification
Dias‐Junior 2014	No GOR diagnosis
Ejiofor 2012	Not randomised
EudraCT 2005‐004543‐57	Unable to confirm eligibility: reported in registry as ongoing; no full text available
EudraCT2007‐005550‐23	Unable to confirm eligibility: reported in registry as ongoing; no full text available
Ezratty 2014	No GOR diagnosis
Farcau 2004	Participants were not randomised
Filippov 2007	No control group
Fitzpatrick 2014	Not the intervention of interest
Garrigues 1991	No intervention
Gillies 1993	Unable to confirm eligibility: no abstract or full text available for review
Giubergia 2013	Unable to confirm eligibility: no full text available
Giudice 2019	Unable to confirm eligibility: no full text available
Goldsobel 2012	Participants excluded if they had GOR
Gustafsson 1992	Not all gastro‐oesophageal reflux disease
Harding 2005	Unable to confirm eligibility: abstract only, no full paper
Jain 2005	No intervention: prevalence study, not a randomised controlled trial
Jayasrikrupaa 2014	No GOR diagnosis
Jehan 2014	No GOR diagnosis
JPRN‐UMIN000011811	Unable to confirm eligibility: no full article available; unable to determine based on protocol
Kahrilas 1996	Unable to confirm eligibility: no full text available
Khoshoo 2007	Not using placebo or appropriate control
Kiljander 2000	No asthma diagnosis
Kim 2011	No intervention: narrative review, not a trial
Kobayashi 1985	No control: not a randomised controlled trial
Koch 2012	No asthma diagnosis
Koch 2012a	No asthma diagnosis and not using placebo
Koch 2012b	Not all asthma
Lang 2015	Not the intervention of interest
Lv 2014	No GOR diagnosis
Maev 2003	Unable to confirm eligibility: unable to access full text in Russian
Maglione 2016	No GOR diagnosis
Martinez 2012	No intervention: commentary on the NCT00442013 study
Mastronarde 2009	Less than 70% of participants with gastro‐oesophageal reflux disease
Mutnick 2014	No asthma diagnosis
National 2003	Unable to confirm eligibility: unable to access full text
NCT00069823	Unable to confirm eligibility: no full article
NCT00214552	No GOR diagnosis
NCT00234117	Not randomised
NCT00237068	Participants excluded if they had GOR
NCT00442013	Less than 70% of participants with gastro‐oesophageal reflux disease
NCT00628953	No GOR diagnosis: "believed to have acid reflux"
NCT01536457	No intervention: retrospective study
Nikitin 2010	Not anti‐reflux therapy
Nogrady 1984	Not randomised
Nolan 1990	No intervention: case study
Ohta 2015	No GOR diagnosis
Patel 2013	No GOR diagnosis
Peterson 2009	No GOR diagnosis, not all asthma participants
Pratama 2007	Unable to confirm eligibility: abstract only, no full paper
Ronge 2009	Unable to confirm eligibility: no full text available
Rutkowski 1989	Unable to confirm eligibility: no full text available
She 2003	Not all asthma
Shimizu 2006	Not using placebo or appropriate control
Smith 2006	Unable to confirm eligibility: no full text available
Susanto 2006	Unable to confirm eligibility: abstract only, no full paper
Tagaya 2015	No GOR diagnosis

Differences between protocol and review

When the review was first undertaken, a very crude protocol was used to guide the process. Subsequently, an updated protocol based on the latest recommendations in the Cochrane Handbook for Systematic Reviews of Interventions was used to guide the review process (Higgins 2011). This protocol was agreed upon by the Cochrane Airways Group. In the 2021 update, we adjusted the wording of the outcomes in the methods section to improve clarity. When post‐hoc decisions were made resulting in deviations from the protocol, these are noted below.

Post‐hoc decisions

Airway hyper‐responsiveness was removed as an outcome from this review. Quality of life was added as a secondary outcome. Selection of outcomes for inclusion in the 'Summary of findings table' was made post identification of studies for inclusion in this review and completion of data extraction, but before results were synthesised. Selections were made on the basis of clinical and public policy relevance rather than presence or absence of data for each outcome. A sensitivity analysis was conducted wherein the same study reported discrepant results across multiple sources. This post‐hoc decision was made following different results reported for the Kiljander 2010 study based on the journal publication compared to NCT portal results. We also reported adverse events based on feedback from the Cochrane Airways editorial team.

Contributions of authors

Protocol was conceived and prepared by HY and was reviewed by KVC.

Literature selection was done by ZK, KVC, HY, and KH.

Data entry, data analysis, and first draft writing were completed by ZK, KVC, HY, and KH.

Data extraction and risk of bias assessment were performed by ZK, KVC, HY, and KT.

Data were extracted by ZK, KVC, HY, KH, and KT.

Manuscript was prepared by ZK, KVC, HY, KH, and KT.

Contributions of editorial team

Chris Cates (Co‐ordinating Editor and Contact Editor) checked data entry prior to the full write‐up of the review; edited the review; and advised on methods, interpretation, and content.

Rebecca Fortescue (Co‐ordinating Editor) checked responses to peer review comments and approved the review prior to publication.

Emma Dennett (Managing Editor) co‐ordinated the editorial process; advised on interpretation and content; and edited the review.

Emma Jackson (Assistant Managing Editor) conducted peer review; obtained translations; and edited acknowledgements section, plain language summary, and reference sections of the protocol and the review.

Elizabeth Stovold (Information Specialist) designed the search strategy; ran the searches; and edited the search methods section.

Sources of support

Internal sources

• Department of Respiratory and Sleep Medicine, Flinders Medical Centre, Australia

• Respirator Medicine Unit, The Queen Elizabeth Hospital, Australia

External sources

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

Declarations of interest

ZK: none known.

HY: none known.

KT: none known.

KH: none known.

KVC: none known.

New search for studies and content updated (conclusions changed)