Proton pump inhibitors for the prevention of non‐steroidal anti‐inflammatory drug‐induced ulcers and dyspepsia

Objectives

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

To assess the effects of proton pump inhibitors on the prevention of dyspepsia and ulcers in individuals with chronic consumption of non‐steroidal anti‐inflammatory drugs.

Background

Description of the condition

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are among the most frequently prescribed medicines (Yang 2017), commonly used in a wide variety of clinical conditions, such as musculoskeletal disorders, cardiovascular protection, arthritis, and post‐operative pain, as well as headache and fever (Rostom 2009). The overall use of NSAIDs has continued to grow over the last few years, with reported increases in consumption ranging from 8.7% in Canada to 54% in Spain. In Spain, consumption went from close to 5 million defined daily doses (DDD) per month in 2000 to more than 7.6 million per month in 2005 (Mamdani 2002; Peiró Moreno 2011). NSAID consumption might be considered chronic when taken longer than three weeks (Rostom 2002), which is frequent in adults with persistent pain caused by osteoarthritis and other musculoskeletal disorders (Marcum 2010).

Chronic NSAID use can exacerbate several chronic diseases, including heart failure and hypertension, and interact with some drugs (e.g. warfarin, corticosteroids) (Marcum 2010). In addition, studies show that chronic NSAID consumption increases the risk of acute renal failure, stroke, myocardial infarction, and gastrointestinal (GI) toxicity. NSAIDs inhibit the enzyme cyclooxygenase (COX). COX‐1 is a COX isoform responsible for producing gastric prostaglandins that maintain mucosal integrity and ulcer healing. COX‐2 is responsible for producing inflammatory cytokines. Non‐selective NSAIDs (for example, naproxen, ibuprofen) inhibit both isoforms, whereas selective NSAIDs (e.g. celecoxib, etoricoxib) inhibit COX‐2, with a more favourable profile of gastrointestinal side effects. However, both COX‐1 and COX‐2 isoforms are lines of defence for the gastrointestinal mucosa necessary for maintaining mucosal integrity and ulcer healing (Akarca 2005; Xue 2011).

The severity of gastrointestinal toxicity ranges from mild dyspepsia to serious ulcer complications like bleeding, obstruction, and perforation. Dyspepsia is usually defined as difficult digestion, with a set of symptoms considered to originate from the gastroduodenal region that includes early satiation, postprandial fullness, epigastric pain, and epigastric burning (Oustamanolakis 2012; Wauters 2021). Ulcers are usually acid‐induced lesions found in the stomach and duodenum, characterised by exposed mucosa with the defect extending into the submucosa (Narayanan 2018). It has been shown that dyspepsia and endoscopic‐identified gastroduodenal ulcers may develop in approximately 4% to 9% and 15% to 30% of chronic NSAID users, respectively (Straus 2002; Yang 2017). In the general population, dyspepsia prevalence is approximately 10% to 21% (Aziz 2018; Ford 2015), and duodenal ulcer prevalence is approximately 2% (Sung 2009), varying according to country and diagnostic criteria used.

The relative contribution of NSAIDs is reported to be approximately 40% to 60%, especially in the older population (Musumba 2012). Multiple factors, such as age > 65 years; history of peptic ulcer disease; concomitant use of aspirin, corticosteroids, or anticoagulants; high‐dose NSAID therapy; and Helicobacter pylori infection, are thought to affect the risk of NSAID‐induced ulcers and dyspepsia (Lanza 2009; Yang 2017). The risk of NSAID‐related gastrointestinal injuries is stratified into low (no risk factors), moderate (one or two risk factors), or high risk (more than two risk factors or history of complicated ulcer), with Helicobacter pylori infection being an independent and additive risk factor in people taking NSAIDs, which needs to be addressed separately (Lanza 2009).

Following Helicobacter pylori infection, chronic NSAID consumption is the second most common cause of gastroduodenal ulcers bleeding (Sánchez‐Delgado 2011). Older age, previous gastrointestinal ulcer, Helicobacter pylori infection, history of different NSAID consumption, high‐dose NSAID usage, anticoagulants, and corticoids prescription have been determined as risk factors for gastroduodenal ulcer bleeding caused by NSAIDs (Tielleman 2015). The absence of any of these factors, as well as one to two or more than two factors, leads to a mild, moderate, and high‐risk stratification for gastroduodenal ulcer bleeding, respectively (Sostres 2010).

Description of the intervention

Proton pump inhibitors (PPIs) are alkaline substances derived from benzimidazole. The most commonly used PPIs are omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole, and dexlansoprazole, and they can be administered orally or intravenously. Oral administration is used in outpatient settings, while intravenous is used in hospitalised people. It is recommended to take them while fasting, 30 to 60 minutes before eating the first food of the day, except for dexlansoprazole, which must be taken with the first food of the day (Savarino 2018).

Numerous types of adverse events are associated with PPIs, ranging from increased risk of gastric tumours, kidney disease, bone fractures, impaired absorption of micronutrients, dementia, and liver disease (Fossmark 2019) to an increased risk of infections and mortality (Lanas‐Gimeno 2019). However, many adverse events are relatively rare in contrast to the PPIs widespread worldwide use (Fossmark 2019).

How the intervention might work

PPIs exert their gastroprotective effects from NSAID gastroduodenal injury by reducing gastric acid secretion (Strand 2017). PPIs inhibit the action of hydrogen/potassium ion (H+/K+)‐adenosinetriphosphatase (ATPase) at the gastric parietal cell, the final common pathway of acid secretion. This inhibition reduces the acid level by lowering the acid production from H+/K+‐ATPase, maintaining intragastric pH > 4 for between 15 and 21 hours daily (Strand 2017), which leads to consequent control of NSAID‐induced dyspepsia and ulcers.

Why it is important to do this review

NSAIDs continue to be one of the most commonly prescribed drug classes worldwide. The last Cochrane Review on this topic used a wider scope considering several interventions for the prevention of NSAID‐induced gastrointestinal ulcers besides PPIs (Rostom 2002). Since then, PPI prescription, dispensation, and consumption have widely spread (Peiró Moreno 2011), and new evidence has emerged with conflicting results, raising additional questions from patients and practitioners related to the absolute benefit and harm of the intervention (Corley 2019).

Therefore, there is a need for an up‐to‐date high‐quality review on the effect of PPIs for the prevention of NSAID‐induced gastrointestinal disorders, with a focus on ulcers and dyspepsia. This review will include the latest evidence and follow the best available methods for grading the certainty of the evidence to inform decision‐making.

Objectives

To assess the effects of proton pump inhibitors on the prevention of dyspepsia and ulcers in individuals with chronic consumption of non‐steroidal anti‐inflammatory drugs.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs), including cluster‐RCTs. We will not include cross‐over RCTs since they are not relevant to the review question.

We will include studies reported as full text as well as those published as abstract only. We will include unpublished data where it is possible to establish their eligibility for inclusion when data are limited. We will impose no language or publication restrictions.

Types of participants

We will include adults (> 18 years) and children (< 18 years) with chronic consumption of non‐steroidal anti‐inflammatory drugs (NSAIDs) (for four weeks or longer (Rostom 2009)) who were enrolled for the prophylaxis of NSAID‐induced ulcer or dyspepsia with proton pump inhibitors (Rostom 2002). We will include studies in which only a subset of participants is relevant to this review (i.e. studies with more than 75% of participants that meet our inclusion criteria) if data are available separately for the relevant subset.

We will exclude participants with an established diagnosis of functional dyspepsia or gastric ulcer.

Types of interventions

We will include trials comparing proton pump inhibitors (PPIs) taken orally with placebo, histamine 2‐receptor antagonists, misoprostol, or sucralfate. We will restrict PPIs to omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole (both sodium and magnesium), and rabeprazole. These PPIs are the most commonly used in the clinical setting for managing peptic ulcer disease; they act effectively in a similar fashion, with minor differences only in their pharmacokinetics, metabolism, and approved clinical indications (Strand 2017). We will include any intervention dosing, frequency, and duration as defined by study authors, and reflect this in the 'Characteristics of included studies' table (see Data collection and analysis).

We will include co‐interventions, provided they are not part of the randomised treatment and are consistent across groups.

We will include the following comparisons.

• PPI versus placebo.

• PPI versus histamine 2‐receptor antagonists.

• PPI versus misoprostol.

• PPI versus sucralfate.

Types of outcome measures

Studies reporting the outcomes listed here will not be inclusion criteria for the review.

Primary outcomes

• Global symptoms of dyspepsia measured by a validated score or scale, such as the gastrointestinal symptom score (GIS) (Adam 2005), the severity of dyspepsia assessment scale (SODA) (Rabeneck 2001), the dyspepsia symptom severity index (DSSI) (Leidy 2000), or other validated instruments. This outcome can be measured both as continuous and the number of individuals with worsened or improved symptoms scores. If a study reports several scales for this outcome, we will select the most reported scale across the included studies, following guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Table 9.3.c) (Higgins 2021).

• Incident ulcer: endoscopically confirmed gastric or duodenal ulcer

• Adverse events: defined as any unexpected or harmful occurrence in the participant, reported in absolute numbers or proportions. If there are multiple events reported within one participant, we will report this separately.

Secondary outcomes

• Ulcer complications: bleeding and perforation

• Quality of life measured by validated scales, such as the Nepean Dyspepsia Index (Talley 1999), the Glasgow dyspepsia severity score (GDSS) (el‐Omar 1996), the 36‐item short‐form health survey (SF‐36) (Ware 1992), EuroQol‐5D (EQ‐5D) questionnaire (Herdman 2011), or other validated scales. If a study reports several scales for this outcome, we will select the most reported scale across the included studies, following guidelines in the Handbook (Table 9.3.c) (Higgins 2021).

Timing of outcome measurement

We will consider outcomes measured up to 12 months after randomisation as short term and more than 12 months as long term. When multiple results are reported for each outcome, we will include the longest follow‐up in each category.

For continuous outcomes, we will consider a minimally important difference of 0.5 standard deviations (Khanna 2017). There is no reported threshold for dichotomous outcomes; therefore, we will consider the clinically important difference for these outcomes as relative risk reduction of at least 25% (Guyatt 2011).

Search methods for identification of studies

We will design the search strategies with the help of the Cochrane Gut Information Specialist before performing literature searches. We will place no restrictions on the year of publication, the language of publication, or publication type when searching the electronic databases or reviewing reference lists in identified studies.

Electronic searches

We will search the following sources from the inception of each database to the date of search and will place no restrictions on the language of publication.

We will search the following electronic databases:

• Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (Appendix 1);

• MEDLINE Ovid (Appendix 2); and

• Embase Ovid (Appendix 3).

Searching other resources

We will check the reference lists of all primary studies and review articles for additional references. We will contact the authors of identified trials and ask them to identify other published and unpublished studies. We will also contact manufacturers and experts in the field.

We will search for errata or retractions from eligible trials on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date we did this in the review.

Clinical trials registers and trial result registers

We will also search clinical trial registers/trial result registers:

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

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

Data collection and analysis

Selection of studies

Two review authors (MP and LG) will independently screen titles and abstracts for inclusion. We will code all of the potential studies we identify as a result of the search as either 'retrieve' (eligible, potentially eligible, or unclear) or 'do not retrieve'.

We will retrieve the full text of potentially eligible studies. Two review authors (MP and LG) will independently screen the full text, identify studies for inclusion, and identify and record the reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion, or if required, we will consult a third author (JF).

We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review.

We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Page 2021) and 'Characteristics of excluded studies' tables. We will use Covidence software for study selection (Covidence 2021). We will not impose any language restrictions.

Data extraction and management

We will use a standardised data collection form for study characteristics and outcome data, which we will pilot on at least one study included in the review. Two review authors (MP or LG) will independently extract the following study characteristics from the included studies.

• Methods: study design, total duration of the study and run in, number of study centres and location, study setting, withdrawals, study dates.

• Participants: total randomised, mean age, age range, gender, the severity of the condition, diagnostic criteria, inclusion criteria, exclusion criteria, detail of NSAID consumption (drug, dosing, duration), the baseline risk of ulcer.

• Interventions: intervention, comparison, dosing, frequency and duration of interventions, concomitant medications, excluded medications.

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

• Notes: funding for the trial, notable conflicts of interest of the trial authors.

Two review authors (MP or LG) will independently extract outcome data from the included studies. We will note in the 'Characteristics of included studies' tables if the study authors reported outcome data in an unusable way. We will resolve disagreements by consensus or by involving a third review author (JF). One review author (LG) will copy the data from the data collection form into RevMan Web (RevMan Web 2021). We will double‐check that the data are entered correctly by comparing the study reports with how the data are presented in the systematic review. A second review author (JF) will check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

We will assess the risk of bias using a recently developed revision of the Cochrane risk of bias tool (RoB 2: a revised tool to assess risk of bias in randomised trials) following guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8) (Higgins 2021).

Two review authors (JF, MP, or LG) will independently assess five domains of bias for the main outcomes (i.e. those included in the summary of findings table). These five domains include bias cause by the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results.

Answers to signalling questions and supporting information will collectively lead to a domain‐level judgment in the form of low risk, some concerns, or high risk of bias. These domain‐level judgments will inform an overall risk of bias judgment for the outcome. These judgments will be presented visually next to each analysis. We will resolve discrepancies between the two reviewers by discussion to reach a consensus. If necessary, we will consult a third reviewer (JF) to achieve a decision.

We will provide a quote from the study report and justification for our judgment in the risk of bias table. We will summarise the risk of bias judgments across studies for each of the domains listed. When judging the "bias due to deviations from intended interventions", we will focus on the effect of assignment to intervention (Higgins 2021). Where information on the risk of bias relates to unpublished data or correspondence with a study author, we will note this in the risk of bias table.

We will use the RoB 2 Excel tool to manage the data supporting the answers to the signalling questions and risk of bias judgments (available at www.riskofbias.info). All of these data will be publicly available as supplementary material in the Open Science Framework platform (www.osf.io).

For cluster‐RCTs, we will use the RoB 2 tool and add an additional domain specifically for cluster RCTs from the archived version of the tool (domain 1b ‐ "bias arising from the timing of identification and recruitment of participants"), available at www.riskofbias.info, with its corresponding signalling questions. We will follow the guidance in the Cochrane Handbook (Section 23.1.2 and Table 23.1.a) (Higgins 2021).

When considering treatment effects, as part of the GRADE methodology, we will take into account the risk of bias of the studies that contribute to the outcome.

Assessment of bias in conducting the Cochrane Review

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

Measures of treatment effect

We will enter the outcome data for each study into the data tables in RevMan Web to calculate the treatment effects (RevMan Web 2021).

We will analyse dichotomous data as risk ratios (RR) and 95% confidence intervals (95% CI). We will also report risk differences. We will analyse continuous data as mean difference (MD) or standardised mean difference (SMD) for results across studies with outcomes that are conceptually the same but measured in different ways. If necessary, we will combine final value and change‐from‐baseline scores when we use the MD method. We will ensure that higher scores for continuous outcomes have the same meaning for the particular outcome, explain the direction to the reader, and report where the directions were reversed if this was necessary.

Unit of analysis issues

Where multiple trial arms are reported in a single trial, we will include only the treatment arms relevant to the review topic. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same study, we will follow the guidance in Section 6.2 of the Cochrane Handbook to avoid double counting (Higgins 2021). Our preferred approach will be to combine groups to create a single pair‐wise comparison. For cluster‐RCTs, we will consider the cluster as the unit of analysis, not the individual participants, in order to avoid unit of analysis errors, as stated in Section 23.1.1 of the Cochrane Handbook (Higgins 2021). If the effect measure for the cluster is not determined by appropriate methods in the included studies, we will multiply the standard error of the effect estimate (from an analysis ignoring clustering) by the square root of the design effect, calculated using an intracluster (or intraclass) correlation coefficient (ICC) of 0.02, following guidance in Sections 23.1.4 and 23.1.5 of the Cochrane Handbook (Higgins 2021).

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data as indicated (e.g. when a study is identified as abstract only). If we are unable to obtain the continuous outcome data from the investigators or study sponsors, we will impute the mean from the median (i.e. consider median as the mean) and the standard deviation from the standard error, interquartile range, or P values, according to the Cochrane Handbook (Higgins 2021). We will assess the impact of including such studies in a sensitivity analysis. If we are unable to calculate the standard deviation from the standard error, interquartile range, or P values, we will impute standard deviation as the highest standard deviation in the remaining trials included in the outcome. (We will be fully aware that this method of imputation will decrease the weight of the studies in the meta‐analysis of mean difference and shift the effect towards no effect for the standardised mean difference.) For our primary analyses, we will conduct available case analyses, considering these issues when assessing the risk of bias and the certainty of the evidence.

Assessment of heterogeneity

We will consider all possible sources of clinical, methodological, and statistical heterogeneity. For the latter, we will use the I² statistic to measure heterogeneity among the trials in each analysis (Higgins 2003). For its interpretation, we will use the recommendations of the Cochrane Handbook (Higgins 2021), as expressed below.

• 0% to 40%: may not be important.

• 30% to 60%: may indicate moderate heterogeneity.

• 50% to 90%: may indicate substantial heterogeneity.

• 75% to 100%: considerable heterogeneity.

If we identify substantial heterogeneity, we will explore it by prespecified subgroup analysis (Higgins 2021). We will also assess heterogeneity by visual inspection of forest plots, evaluating the direction and magnitude of effects and the degree of overlap between confidence intervals.

Assessment of reporting biases

We will attempt to obtain study protocols in order to assess the presence of selective outcome reporting.

If we can pool at least 10 trials for the same outcome, we will use funnel plots to investigate small‐study effects. As the presence of asymmetry in funnel plots may have several explanations besides publication bias, we will interpret the results carefully. We will perform Egger's test to corroborate asymmetry statistically (Egger 1997).

Data synthesis

We will perform meta‐analyses using RevMan Web (RevMan Web 2021). We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants, and the underlying clinical question are similar enough for pooling to make sense. If more than one study provides usable data in any single comparison, we will perform a meta‐analysis. We will use a random‐effects model as this is usually a more conservative approach. For dichotomous outcomes, we will use the Mantel‐Haenszel method; for continuous outcomes, we will use the inverse variance method.

We will include all studies in the primary analysis, and we will explore the effect of bias in a sensitivity analysis (see Sensitivity analysis).

If meta‐analysis is not possible due to incompletely reported outcome data or clinical and methodological diversity, we will perform a narrative synthesis of the available quantitative data following the Cochrane Handbook's guidance (McKenzie 2021), as well as the latest guidance on Synthesis Without Meta‐analysis (SWiM) (Campbell 2020). When available, we will report the absolute number of events for each outcome and the corresponding statistics (P values). If sufficient data are available, we will report risk ratios or hazard ratios and their 95% confidence intervals or risk differences when absolute risks in both groups are < 1%. We will summarise the results using vote counting based on the direction of effect, prioritising the findings from larger studies and, when available, studies at low risk of bias. In this scenario, we will assess heterogeneity qualitatively, and we will follow GRADE methods for assessing the overall quality of evidence, presenting results in summary of findings tables.

Subgroup analysis and investigation of heterogeneity

To address all possible reasons for heterogeneity in the research question and to consider known reported risk factors for developing NSAID‐induced ulcers and dyspepsia, we plan to carry out the following subgroup analyses.

• By subtype of NSAID consumption (selective, non‐selective NSAIDs).

• By age (adults (> 18 years old), children).

• By ulcer risk (low risk, moderate risk, high risk) based on the approach to risk stratification proposed by Lanza 2009.

• By individual type of proton pump inhibitor (omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole (both sodium and magnesium), and rabeprazole) (Strand 2017).

The following outcomes will be assessed in subgroup analysis.

• Global symptoms of dyspepsia.

• Incident ulcer.

• Adverse events.

We will use the formal Chi² test for subgroup differences to test for subgroup interactions.

Sensitivity analysis

We will perform sensitivity analysis defined to assess the robustness of our conclusions.

The sensitivity analysis will include the evaluation of the effect on the primary outcomes, excluding only those studies with an overall high risk of bias.

Summary of findings and assessment of the certainty of the evidence

We will create a summary of findings table for each comparison with the following outcomes.

• Global symptoms of dyspepsia (long term).

• Incident ulcer (long term).

• Adverse events (long term).

• Quality of life (long term).

Two reviewers (MP and LG) will use the five GRADE considerations (overall RoB 2 assessment, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence, based on the studies that contributed data to the meta‐analyses for each outcome. They will classify the evidence as high, moderate, low, or very low. We will resolve any disagreements by discussion or by involving another author (JF).

For the risk of bias domain in the GRADE assessment, we will follow the guidance in Table 14.2.a of the Cochrane Handbook (Higgins 2021). We will downgrade the certainty of evidence by one level if most of the evidence comes from individual studies either with a crucial limitation for one item or with some limitations for multiple items. We will downgrade the certainty of the evidence by two levels if the proportion of information from results at high risk of bias is sufficient with a crucial limitation for one or more criteria.

We will consider a partially contextualised approach for rating down due to imprecision (Hultcrantz 2017). We will use the methods and recommendations described in Chapter 14 of the Cochrane Handbook (Higgins 2021) and GRADEpro GDT software (GRADEpro GDT).

We will assess the certainty of the body of evidence according to the GRADE criteria. We will consider RCTs as high‐certainty evidence (studies that contribute data for the prespecified outcomes) if the five factors above are not present to any serious degree but may downgrade the certainty to moderate, low, or very low. We will downgrade evidence once if a GRADE consideration is serious and twice if very serious. We will justify all decisions to downgrade or upgrade the certainty of evidence in the footnotes and where necessary, provide comments to aid the reader's understanding of the review. We will consider whether there is additional outcome information that was not incorporated into the meta‐analyses, note this in the comments, and state if it supports or contradicts the information from the meta‐analyses.

If meta‐analysis is not possible, we will present results in a narrative summary of findings table, providing key information about the best estimate of the magnitude of the effect in relative terms and absolute differences for each relevant comparison, numbers of participants and studies addressing each outcome, and the rating of the overall confidence in effect estimates for each outcome, following guidance in Section 14.1 of the Cochrane Handbook (Higgins 2021).

We will formulate statements for the findings and certainty of the evidence using wording templates that combine the size and certainty of an effect to improve the clarity of communication (Santesso 2020).

Appendices

Appendix 1. CENTRAL (Cochrane Library) search strategy

#1 MeSH descriptor: [Proton Pump Inhibitors] explode all trees 
#2 ((proton near/2 inhibi*) or (PPI or PPIs)):ti,ab,kw 
#3 MeSH descriptor: [Omeprazole] explode all trees 
#4 ((omeprazole* or esomeprazole* or losec* or nexium* or prilosec* or rapinex* or zegerid* or ocid* or Lomac* or Omepral* or Omez*)):ti,ab,kw 
#5 ((pantoprazole* or protium* or protonix* or Pantotab* or Pantopan* or Pantozol* or Pantor* or Pantoloc* or Astropan* or Controloc* or Pantecta* or Inip* or Somac* or Pantodac* or Zurcal*or Zentro*)):ti,ab,kw 
#6 ((Dexlansoprazole* or Kapidex* or Dexilant*)):ti,ab,kw 
#7 ((lansoprazole* or lanzoprazole* or agopton* or bamalite* or Inhibitol* or Levant* or Lupizole* or lanzor* or monolitum* or ogast* or ogastro* or opiren* or prevacid* or prezal* or pro ulco* or promeco* or takepron* or ulpax* or zoton*)):ti,ab,kw 
#8 #1 or #2 or #3 or #4 or #5 or #6 or #7 
#9 MeSH descriptor: [Anti‐Inflammatory Agents, Non‐Steroidal] explode all trees 
#10 ((non?steroid* or non steroid*) and (anti?inflammator* or anti inflammator*)):ti,ab,kw 
#11 MeSH descriptor: [Apazone] explode all trees 
#12 (apazone*):ti,ab,kw 
#13 MeSH descriptor: [Celecoxib] explode all trees 
#14 (celecoxib*):ti,ab,kw 
#15 MeSH descriptor: [Diclofenac] explode all trees 
#16 (diclofenac*):ti,ab,kw 
#17 MeSH descriptor: [Diflunisal] explode all trees 
#18 (diflunisal*):ti,ab,kw 
#19 MeSH descriptor: [Etodolac] explode all trees 
#20 (etodolac*):ti,ab,kw 
#21 MeSH descriptor: [Fenoprofen] explode all trees 
#22 (fenoprofen*):ti,ab,kw 
#23 MeSH descriptor: [Flurbiprofen] explode all trees 
#24 (flurbiprofen*):ti,ab,kw 
#25 MeSH descriptor: [Ibuprofen] explode all trees 
#26 (ibuprofen*):ti,ab,kw 
#27 MeSH descriptor: [Indomethacin] explode all trees 
#28 (indomethacin*):ti,ab,kw 
#29 MeSH descriptor: [Ketoprofen] explode all trees 
#30 (ketoprofen*):ti,ab,kw 
#31 MeSH descriptor: [Ketorolac Tromethamine] explode all trees 
#32 MeSH descriptor: [Ketorolac] explode all trees
#33 (ketorolac*):ti,ab,kw 
#34 MeSH descriptor: [Meclofenamic Acid] explode all trees 
#35 (Meclofenamic* Acid*):ti,ab,kw 
#36 (meclofenamate*):ti,ab,kw 
#37 MeSH descriptor: [Meloxicam] explode all trees 
#38 (meloxicam*):ti,ab,kw 
#39 ((methyl salicylate or methylsalicylate)):ti,ab,kw 
#40 MeSH descriptor: [Nabumetone] explode all trees 
#41 (nabumetone*):ti,ab,kw 
#42 MeSH descriptor: [Naproxen] explode all trees 
#43 (naproxen*):ti,ab,kw 
#44 (nimesulide*):ti,ab,kw 
#45 MeSH descriptor: [Oxaprozin] explode all trees 
#46 (oxaprozin*):ti,ab,kw 
#47 MeSH descriptor: [Phenylbutazone] explode all trees 
#48 (phenylbutazone*):ti,ab,kw 
#49 MeSH descriptor: [Piroxicam] explode all trees 
#50 (piroxicam*):ti,ab,kw 
#51 MeSH descriptor: [Salicylates] explode all trees 
#52 (salicylate*):ti,ab,kw 
#53 MeSH descriptor: [Sulindac] explode all trees 
#54 (sulindac*):ti,ab,kw 
#55 (tenoxicam*):ti,ab,kw 
#56 MeSH descriptor: [Tolmetin] explode all trees 
#57 (tolmetin*):ti,ab,kw 
#58 (tiaprofenic* acid*):ti,ab,kw 
#59 MeSH descriptor: [Niflumic Acid] explode all trees 
#60 (niflumic* acid*):ti,ab,kw 
#61 (Acetylsalicylic* Acid*):ti,ab,kw 
#62 (morniflumate*):ti,ab,kw 
#63 (NSAID*):ti,ab,kw 
#64 MeSH descriptor: [Aspirin] explode all trees 
#65 (aspirin*):ti,ab,kw 
#66 #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 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48  or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61 or #62 or #63 or #64 or #65 
#67 #8 and #66

Appendix 2. MEDLINE Ovid search strategy

Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process, In‐Data‐Review & Other Non‐Indexed Citations, Daily and Versions(R) <1946 to February 14, 2022>

1 exp Proton Pump Inhibitors/ 
2 ((proton adj2 inhibi$) or PPI or PPIs).tw. 
3 Omeprazole/ 
4 (omeprazole* or esomeprazole* or losec* or nexium* or prilosec* or rapinex* or zegerid* or ocid* or Lomac* or Omepral* or Omez*).tw. 
5 (pantoprazole* or protium* or protonix* or Pantotab* or Pantopan* or Pantozol* or Pantor* or Pantoloc* or Astropan* or Controloc* or Pantecta* or Inip* or Somac* or Pantodac* or Zurcal*or Zentro*).tw. 
6 (Dexlansoprazole* or Kapidex* or Dexilant*).tw. 
7 (lansoprazole* or lanzoprazole* or agopton* or bamalite* or Inhibitol* or Levant* or Lupizole* or lanzor* or monolitum* or ogast* or ogastro* or opiren* or prevacid* or prezal* or pro ulco* or promeco* or takepron* or ulpax* or zoton*).tw. 
8 1 or 2 or 3 or 4 or 5 or 6 or 7
9 exp Anti‐Inflammatory Agents, Non‐Steroidal/ 
10 ((non?steroid* or non steroid*) and (anti?inflammator* or anti inflammator*)).tw. 
11 apazone*.tw. or Apazone/ 
12 celecoxib*.tw. or Celecoxib/ 
13 diclofenac*.tw. or Diclofenac/ 
14 diflunisal*.tw. or Diflunisal/ 
15 etodolac*.tw. or Etodolac/ 
16 fenoprofen*.tw. or Fenoprofen/ 
17 flurbiprofen*.tw. or Flurbiprofen/ 
18 ibuprofen*.tw. or Ibuprofen/ 
19 indomethacin*.tw. or Indomethacin/ 
220 ketoprofen*.tw. or Ketoprofen/ 
21 Ketorolac/ or Ketorolac Tromethamine/ or ketorolac*.tw.
22 Meclofenamic Acid.tw. or Meclofenamic Acid/ 
23 meclofenamate*.tw. 
24 meloxicam*.tw. or Meloxicam/ 
25 (methyl salicylate or methylsalicylate).tw. 
26 nabumetone*.tw. or Nabumetone/ 
27 naproxen*.tw. or Naproxen/ 
28 nimesulide*.tw. 
29 oxaprozin*.tw. or Oxaprozin/ 
30 phenylbutazone*.tw. or Phenylbutazone/ 
31 piroxicam*.tw. or Piroxicam/ 
32 salicylate*.tw. or Salicylates/ 
33 sulindac*.tw. or Sulindac/ 
34 tenoxicam*.tw. 
35 tolmetin*.tw. or Tolmetin/ 
36 tiaprofenic acid*.tw. 
37 niflumic* acid*.tw. or Niflumic Acid/ 
38 Acetylsalicylic* Acid*.tw. 
39 morniflumate*.tw. 
40 NSAID*.tw. 
41 aspirin*.tw. or Aspirin/ 
42 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 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41
43 9 and 42
44 randomized controlled trial.pt. 
45 controlled clinical trial.pt. 
46 randomized.ab. 
47 placebo.ab. 
48 clinical trials as topic.sh. 
49 randomly.ab. 
50 trial.ti. 
51 44 or  45 or 46 or 47 or 48 or 49 or 50 
52 exp animals/ not humans.sh. 
53 51 not 52 
55 43 and 53 
 

Appendix 3. Embase Ovid search strategy

1 exp proton pump inhibitor/

2 ((proton adj2 inhibi$) or PPI or PPIs).ab,kw,ti.

3 exp omeprazole/

4 (omeprazole* or esomeprazole* or losec* or nexium* or prilosec* or rapinex* or zegerid* or ocid* or Lomac* or Omepral* or Omez*).ab,kw,ti.

5 (pantoprazole* or protium* or protonix* or Pantotab* or Pantopan* or Pantozol* or Pantor* or Pantoloc* or Astropan* or Controloc* or Pantecta* or Inip* or Somac* or Pantodac* or Zurcal*or Zentro*).ab,kw,ti.

6 (Dexlansoprazole* or Kapidex* or Dexilant*).ab,kw,ti.

7 (lansoprazole* or lanzoprazole* or agopton* or bamalite* or Inhibitol* or Levant* or Lupizole* or lanzor* or monolitum* or ogast* or ogastro* or opiren* or prevacid* or prezal* or pro ulco* or promeco* or takepron* or ulpax* or zoton*).ab,kw,ti.

8 1 or 2 or 3 or 4 or 5 or 6 or 7

9 exp nonsteroid antiinflammatory agent/

10 ((non?steroid* or non steroid*) and (anti?inflammator* or anti inflammator*)).ab,kw,ti.

11 exp azapropazone/

12 "apazone*".ab,kw,ti.

13 exp celecoxib/

14 "celecoxib*".ab,kw,ti.

15 exp diclofenac/

16 "diclofenac*".ab,kw,ti.

17 exp diflunisal/

18 "diflunisal*".ab,kw,ti.

19 exp etodolac/

20 "etodolac*".ab,kw,ti.

21 exp fenoprofen/

22 "fenoprofen*".ab,kw,ti.

23 exp flurbiprofen/

24 "flurbiprofen*".ab,kw,ti.

25 exp ibuprofen/

26 "ibuprofen*".ab,kw,ti.

27 exp indometacin/

28 "indomethacin*".ab,kw,ti.

29 exp ketoprofen/

30 "ketoprofen*".ab,kw,ti.

31 exp ketorolac trometamol/

32 exp ketorolac/

33 "ketorolac*".ab,kw,ti.

34 exp meclofenamic acid/

35 Meclofenamic Acid.ab,kw,ti.

36 "meclofenamate*".ab,kw,ti.

37 exp meloxicam/

38 "meloxicam*".ab,kw,ti.

39 (methyl salicylate or methylsalicylate).ab,kw,ti.

40 exp nabumetone/

41 "nabumetone*".ab,kw,ti.

42 exp naproxen/

43 "naproxen*".ab,kw,ti.

44 "nimesulide*".ab,kw,ti.

45 exp oxaprozin/

46 "oxaprozin*".ab,kw,ti.

47 exp phenylbutazone/

48 "phenylbutazone*".ab,kw,ti.

49 exp piroxicam/

50 "piroxicam*".ab,kw,ti.

51 exp salicylic acid derivative/

52 "salicylate*".ab,kw,ti.

53 exp sulindac/

54 "sulindac*".ab,kw,ti.

55 "tenoxicam*".ab,kw,ti.

56 exp tolmetin/

57 "tolmetin*".ab,kw,ti.

58 "tiaprofenic acid*".ab,kw,ti.

59 exp niflumic acid/

60 "niflumic* acid*".ab,kw,ti.

61 "Acetylsalicylic* Acid*".ab,kw,ti.

62 "morniflumate*".ab,kw,ti.

63 "NSAID*".ab,kw,ti.

64 exp acetylsalicylic acid/

65 "aspirin*".ab,kw,ti.

66 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 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65

67 8 and 66

68 Randomized controlled trial/

69 Controlled clinical study/

70 random$.ti,ab.

71 randomization/

72 intermethod comparison/

73 placebo.ti,ab.

74 (compare or compared or comparison).ti.

75 ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab.

76 (open adj label).ti,ab.

77 ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.

78 double blind procedure/

79 parallel group$1.ti,ab.

80 (crossover or cross over).ti,ab.

81 ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.

82 (assigned or allocated).ti,ab.

83 (controlled adj7 (study or design or trial)).ti,ab.

84 (volunteer or volunteers).ti,ab.

85 human experiment/

86 trial.ti.

87 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 77 or 78 or 79 or 80 or 81 or 82 or 83 or 84 or 85 or 86

88 (random$ adj sampl$ adj7 (“cross section$” or questionnaire$1 or survey$ or database$1)).ti,ab. not (comparative study/ or controlled study/ or randomi?ed controlled.ti,ab. or randomly assigned.ti,ab.)

89 Cross‐sectional study/ not (randomized controlled trial/ or controlled clinical study/ or controlled study/ or randomi?ed controlled.ti,ab. or control group$1.ti,ab.)

90 (((case adj control$) and random$) not randomi?ed controlled).ti,ab.

91 (Systematic review not (trial or study)).ti.

92 (nonrandom$ not random$).ti,ab.

93 “Random field$”.ti,ab.

94 (random cluster adj3 sampl$).ti,ab.

95 (review.ab. and review.pt.) not trial.ti.

96 "we searched".ab. and (review.ti. or review.pt.)

97 (databases adj4 searched).ab.

98 (rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$1).ti. and animal experiment/

99 Animal experiment/ not (human experiment/ or human/)

100 88 or 90 or 91 or 92 or 93 or 94 or 95 or 96 or 97 or 98 or 99

101 87 not 100

102 67 and 101 

Contributions of authors

Conceiving the protocol: JVAF, LG
Designing the protocol: JVAF, LG, MPT
Co‐ordinating the protocol: JVAF, LG
Designing search strategies: CMEL
Writing the protocol: all authors
Providing general advice on the protocol: JVAF
Securing funding for the protocol: not applicable
Performing previous work that was the foundation of the current study: not applicable

Sources of support

Internal sources

• Instituto Universitario Hospital Italiano de Buenos Aires, Argentina

  Provides a salary for LG and CMEL.

• Heinrich Heine University Düsseldorf, Other

  Provides a salary for JVAF.

External sources

• No sources of support provided

Declarations of interest

JVAF: has declared that they have no conflict of interest.
LG: has declared that they have no conflict of interest.
CMEL: has declared that they have no conflict of interest.
MPT: has declared that they have no conflict of interest.

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