Proton Pump Inhibitors: Rational Use and Use-Reduction – The Windsor Workshop

Abstract

Background

Despite deprescribing initiatives to curb overutilization of proton pump inhibitors (PPIs), achieving meaningful reductions in PPI use is proving a challenge.

Summary

An international group of primary care doctors and gastroenterologists examined the literature surrounding PPI use and use-reduction to clarify: (i) what constitutes rational PPI prescribing; (ii) when and in whom PPI use-reduction should be attempted; and (iii) what strategies to use when attempting PPI use-reduction.

Key Messages

Before starting a PPI for reflux-like symptoms, patients should be educated on potential causes and alternative approaches including dietary and lifestyle modification, weight loss, and relaxation strategies. When commencing a PPI, patients should understand the reason for treatment, planned duration, and review date. PPI use at hospital discharge should not be continued without a recognized indication for long-term treatment. Long-term PPI therapy should be reviewed at least annually. PPI use-reduction should be based on the lack of a rational indication for long-term PPI use, not concern for PPI-associated adverse events. PPI use-reduction strategies involving switching to on-demand PPI or dose tapering, with rescue therapy for rebound symptoms, are more likely to succeed than abrupt cessation.

Introduction

Proton pump inhibitors (PPIs) are potent antisecretory agents indicated for the treatment of a number of acid-related gastrointestinal conditions, including gastric and duodenal ulcers, gastro-oesophageal reflux disease (GORD)/erosive oesophagitis, dyspepsia, Helicobacter pylori eradication, and Zollinger-Ellison syndrome [1, 2]. Since the introduction of the first PPI in 1989, their effectiveness and low toxicity have become firmly established and they are currently one of the world’s most widely used classes of drugs [2, 3]. A recent systematic review of PPI use (most evidence from North America, Europe, and Australia) estimated that nearly a quarter of adults (23.4%) were prescription PPI users [3]. Initiation of a PPI occurred most frequently in individuals aged 46–57 years, with PPI use increasing with age and being greater among females. PPIs were more often prescribed at standard versus maintenance doses (63.7 vs. 36.3%, respectively) and for long periods (≥1 year: 25.1%), with most users maintaining their initial prescribed dose without dose adjustments [3]. While the prevalence of PPI use continues to rise in most countries worldwide, some countries, such as Germany and the USA, have shown a recent decline [4, 5]. However, this may reflect increased use of over-the-counter (OTC) PPIs, with data from the USA suggesting that as many as 32% of PPI users for GORD now purchase them OTC [6].

The dramatic expansion in PPI prescribing has increased scrutiny towards their overutilization, including unnecessary exposure to potential PPI-associated adverse effects [7, 8]. An estimated 20–82% of people globally are using a PPI without a clear verifiable indication [9]. Even with the relatively favourable PPI safety profile, this extensive use of PPIs, often without regular reassessment, has raised concerns, leading to broad “deprescription” initiatives [10, 12]. However, achieving a sustained reduction in prescribing rates is proving a challenge [13–15] and, in some cases, PPIs are being discontinued inappropriately [16, 17]. This review, conducted by an international group of primary care doctors and gastroenterologists, aims to simplify the key information surrounding PPI use and use-reduction to clearly establish: (i) what constitutes rational PPI prescribing; (ii) when and in whom PPI should use-reduction be attempted; and (iii) what strategies to use when attempting PPI use-reduction.

Rational PPI Use

The decision to start or continue PPI treatment should be individualized, based on indication, patient preference, and assessment of the risks and benefits [10, 18]. However, confusion around what constitutes rational use of PPI is compounded by published evidence of PPI efficacy for “off-label” indications and a multitude of reports of PPI-associated adverse effects that are largely based on low quality evidence with unproven causality. Thus, clinical decision-making on a case-by-case basis is not always straightforward. The accepted key rational indications for short-term and long-term PPI use are presented in Table 1. The steady increase in PPI use that has taken place over several decades cannot be explained by a parallel rise in morbidity or prevalence of these indicated scenarios, suggesting that PPIs are increasingly being used for indications where their benefits are less certain.

Table 1.

Rational short- and long-term use of PPI

Duration	Reason for treatment [7, 11, 18, 19]
Short-term therapy (4–8 weeks)	Low-grade (LA A, Ba) oesophagitis
	Uncomplicated H. pylori infection treated for 2 weeks (in conjunction with antibiotics)
	Reflux-like symptoms of sufficient magnitude and/or frequency to impair QoL
	Dyspepsiab of sufficient magnitude and/or frequency to impair QoL
	Stress ulcer prophylaxis in an intensive care unit
Long-term therapy (>8 weeks, maintenance)	High-grade (LA C, D) oesophagitis or peptic stricture
	Zollinger-Ellison syndrome
	Barrett’s oesophagus (endoscopic tongue or segment >1 cm with intestinal metaplasia)
	Eosinophilic oesophagitis
	Prior bleeding gastric or duodenal ulcer (H. pylori negative)
	Idiopathic pulmonary fibrosis
	Chronic use of NSAIDs with moderate to high bleeding risk (age >65 years, high-dose NSAIDs, prior ulcer, concomitant corticosteroids, antiplatelet meds, significant renal disease)
	Prior unsuccessful attempt to reduce or discontinue because of recurrent upper gastrointestinal symptoms that impair QoL (despite utilization of a strategy that accounts for potential rebound hypersecretion)
	Co-administration with digestive enzyme replacement for chronic pancreatitis

H. pylori, Helicobacter pylori; LA, The Los Angeles classification of erosive oesophagitis; NSAIDs, nonsteroidal anti-inflammatory drugs; QoL, quality of life.

^aLA grade A is mild; LA grade C and D are severe; healthcare provider discretion is required for LA grade B classification, which covers a range of severity, meaning that some patients may require longer term PPI. The revised Lyon Consensus for the diagnosis of GORD, contrary to the original [20], states that well-characterized LA grade B oesophagitis represents conclusive evidence for GORD and a similar acid exposure time to LA grade C [21].

^bPatients with uninvestigated dyspepsia should be tested for H. pylori infection and treated if positive [29].

Key Drivers of PPI Overutilization

Some factors potentially contributing to PPI use are summarized in Table 2. PPIs represent a low-risk treatment option, especially when doctors are faced with patient pressure for a pharmaceutical treatment, when there is no specified alternative management strategy, and/or when there is limited access to investigational techniques within secondary care [18, 22, 23]. Initiating or continuing PPI treatment is also a highly attractive capacity-saving approach compared with lifestyle changes such as weight loss or smoking cessation, which are notoriously difficult to sustain long term. Similarly, stopping chronic PPI treatment may result in transient gastric acid hypersecretion above pre-treatment levels, leading to a transient increase in symptom severity [24–26]. Such “rebound hypersecretion” is attributable to PPI-induced hypergastrinaemia, which typically resolves after 1–2 weeks [26]. Thus, patients may require counselling or extra support to mitigate rebound and prevent resumption of PPI use.

Table 2.

Major factors driving PPI overuse

Healthcare professionals	Patients
Timesaving (vs. lifestyle counselling)	Desire for simple, easy solution; minimal effort
Over-diagnosis of “GORD” on a clinical basis	Lack of proper and timely review of prescription
Misconceptions regarding “refractory GORD”	Misconception that PPIs are curative
Unnecessary continuation of hospital-initiated prescriptions	Belief that reflux-like symptoms are caused by excessive acid
Limited access to investigations and/or secondary care	Reluctance or failure to modify behaviour
Limited alternative therapies	Ease of access to PPIs in the pharmacy
Belief that all reflux-like symptoms are caused by acid reflux	Poor understanding of alternative therapeutic options
ENT-initiated for suspected reflux syndrome without a long-term plan
Missing information in electronic patient records regarding indication

ENT, ear, nose, and throat department; GORD, gastro-oesophageal reflux disease; PPI, proton pump inhibitor.

Assumption That Upper Gastrointestinal Symptoms Are Related to Acid Reflux

A key contributor to PPI overutilization, especially high-dose and long-term use, is prescription for reflux-like symptoms (e.g., heartburn, regurgitation) or non-specific symptoms, leading to a presumptive diagnosis of “refractory” GORD. Despite growing awareness of “Disorders of Gut-Brain Interaction” and recognition of altered perception as a major determinant of reflux-like symptoms (reflux hypersensitivity and functional heartburn), PPIs remain a pragmatic first-line approach for patients presenting with reflux-like symptoms [27]. Dyspepsia and GORD clinical guidelines recommend 4–8 weeks of PPI treatment for resolution of GORD symptoms, after which PPIs should be discontinued [28, 29]. However, up to 40% of patients with suspected GORD do not respond fully to PPI therapy [30] and acute PPI treatment often leads to chronic, open-ended therapy, at the original or an increased dose. In fact, a study of patients referred to a tertiary centre for endoscopy and ambulatory oesophageal pH metry revealed that 42% of patients continued PPI, even after reflux testing was within normal limits and there was no identified association between symptoms and gastro-oesophageal reflux during the pH-metry study [31]. PPIs are also often initiated for empiric treatment of extra-oesophageal symptoms including cough, throat clearing, globus, voice hoarseness, and asthma, for which their efficacy remains uncertain [7, 18, 32]. When such patients report no concomitant oesophageal symptoms, they are often told that they have “silent” reflux. It is not unusual for treatment with high-dose PPIs to continue in these unresponsive patients, despite a complete lack of evidence that their symptoms are mediated by acid reflux [18, 32].

Inappropriate Prophylaxis Strategies Continued in Primary Care

Although specialists may be involved in the decision to initiate PPI treatment, long-term PPI prescribing and follow-up generally take place within primary care [11]. General practitioners (GPs) may be reluctant to stop prescribing a medication when they were not the initial prescriber, especially if they do not have all the relevant information. A large observational study using annual survey data collected by the Center for Disease Control (CDC) in the USA revealed that nearly two-thirds of PPI-treated patients attending office-based practices were found to have no gastrointestinal complaints or diagnosis warranting PPI use [33]. A major contributor to overutilization in this setting appears to be a high rate of unwarranted PPI prescribing in patients discharged from hospital [34–39]. An audit of 36 primary care practices in Germany revealed that 65% of PPI-treated patients discharged from hospital had no clear evidence-based indication [34] and similarly high rates are reported by other retrospective analyses of data from hospitals worldwide [35, 36, 40–42]. Over-prescription is mainly due to ulcer prophylaxis in non-critically ill (low-risk) patients, especially anticoagulated patients, patients on corticosteroid therapy or antibiotics, or young patients taking aspirin [8, 36, 40, 42]. Unless a patient on corticosteroid therapy has a peptic ulcer or is taking concomitant nonsteroidal anti-inflammatory drug (NSAID) therapy, ulcer prophylaxis using a PPI is not necessary, and there is no need to use PPIs for gastroprotection in patients taking anticoagulants unless they are combined with antiplatelet or NSAID therapy [7, 18]. Other scenarios where PPIs may be used unnecessarily include prevention of bleeding from portal hypertension related gastropathy in cirrhotic patients and in acute pancreatitis [7]. For a GP to determine whether the potential benefit of PPI outweighs the potential harms, knowing why the PPI was initiated and the intended duration of treatment or review date is critical, but not always provided at hospital discharge [34, 43].

Potential Risks of Long-Term PPI Use

As detailed in recent reviews, PPIs are among the safest classes of drugs. However, they are not without any associated risks at all [7, 44–47]. They have potential to modify the gut microbiota and contribute to dysbiosis, which may predispose individuals to certain gastrointestinal disorders [48]. Adverse events with the strongest evidence for a probable causative relationship with PPI include enteric symptoms (diarrhoea, constipation, abdominal pain), increased susceptibility to infectious gastroenteritis and Clostridium difficile, increased incidence of small intestinal bacterial overgrowth, vitamin B₁₂ deficiency, iron deficiency, hypomagnesaemia (rare), acute interstitial nephritis (rare, idiosyncratic), fundic gland polyps, and drug-drug interactions (e.g., with clopidogrel, diazepam, warfarin, phenytoin, and methotrexate) [7, 18]. However, several other adverse events have been associated with PPIs in observational studies (e.g., bone fracture, kidney disease, dementia, various cancers, and acute myocardial infarction), leading to a dramatic increase in the number of news items on the subject of PPI safety and concern among patients [16, 18, 47, 49]. Generally, the associations detected in these observational studies are weak (about 2-fold) and inconsistent, making them easily explained away by residual confounding and bias. A recent umbrella review of 42 meta-analyses on the safety of PPIs in different organ systems highlights the weak associations and low certainty of evidence in GRADE assessments for almost all reported PPI-associated adverse events [47]. Such weak associations should be considered hypothesis-generating at best and represent a potential focus of future prospectively collected data. Given the paucity of controlled data to confirm these associations, the decision for PPI use-reduction should be based on the lack of need or benefit gained from a PPI, not concern for these reported adverse events associated with chronic PPI use.

Candidates for PPI Use-Reduction

Traditionally, clinical practice guidelines and package inserts recommending a short course of PPI treatment (e.g., 4–8 weeks for GORD/dyspepsia) have provided little to no advice on the optimal strategy for discontinuing treatment [29, 50]. However, a growing number of professional societies and government health agencies have released their own guidance to support PPI use-reduction in primary care [10, 11, 51, 52]. In general, candidates for PPI use-reduction are those who have completed a minimum 4-week course and who do not have a recognized indication for long-term use (Table 3). However, decisions about PPI discontinuation should be considered in the context of the individual’s personal and medical circumstances and their personal goals and preferences.

Table 3.

Candidate scenarios for PPI use-reduction

Clinical scenario where PPI use-reduction should be considereda
Symptoms of mild oesophagitis (LA A, B) or NERD, now controlled
Uninvestigated reflux-like symptoms, now controlled
After 4–12 weeks of empirically treated dyspepsia
After eradication therapy for H. pylori-associated gastric or duodenal ulcer (eradication should be confirmed with stool antigen test 1 month after cessation of PPI)
After eradication therapy for uncomplicated H. pylori infection
After hospital/ICU admission wherein PPI therapy was initiated for stress ulcer prophylaxis, anaesthesia, or empirically
Inappropriate prescription for gastroprotection in patients with comorbidities
PPI indication unclear

H. pylori, Helicobacter pylori; ICU, intensive care unit; LA, Los Angeles classification of gastro-oesophageal reflux disease; NERD, non-erosive reflux disease; PPI, proton pump inhibitor.

^aPatients with an approved indication for chronic PPI should not be considered for discontinuation.

Strategies for PPI Use-Reduction

A significant barrier to PPI use-reduction is concern about the return of symptoms that were previously controlled [53]. Symptoms caused by rebound acid hypersecretion may occur when discontinuing a PPI, but they tend to be manageable and transient in nature [53, 54]. Patients who agree to attempt a reduction in their PPI use should be prepared for the potential emergence of rebound symptoms and reassured that this does not necessarily imply a return of, or worsening of, the underlying condition [11, 53]. Several PPI use-reduction strategies have been proposed and/or investigated as alternatives to abrupt cessation to increase the likelihood of sustained reduction. These include tapering the dose (e.g., twice daily to once daily, halving the dose, or taking every second day) before stopping, switching to alternative treatments (H₂RAs, alginates), or using short courses of PPI on-demand. The available RCT evidence is summarized in Table 4. There is limited evidence to directly compare these strategies, so the choice should depend on which approach is most acceptable to the patient. A systematic review of RCT evidence found that lowering the dose of PPI from healing to maintenance dose (e.g., lansoprazole 30 mg daily to 15 mg daily) led to a small increased risk of symptom recurrence compared with continued PPI use, but the difference was not statistically significant [53]. One RCT of abrupt PPI cessation found recurrence of symptoms in around two-thirds of patients [9]. Another RCT of PPI discontinuation in patients without an appropriate indication found that slightly more patients discontinued when the PPI dose was first tapered (week 1, omeprazole 20 mg daily; week 2, 10 mg daily; week 3, 10 mg every other day, then stop) compared to stopping abruptly (20 mg daily for 3 weeks, then stop) [55]. The American Gastroenterology Association deprescribing guidelines suggest that 3 weeks may not be sufficient, and that a longer period of tapering may be required to observe the full benefit of this regimen [11]. Several guidelines recommend switching PPI to alternative treatments or on-demand PPI and non-pharmacological strategies to address lifestyle and behavioural risk factors [10, 11, 29, 52]. In 5 RCTs of PPI-treated patients with mild-to-moderate GORD switching to on-demand PPI, approximately 9 in 10 people had no return of symptoms [9, 53]. In this context, “on-demand” refers to resumption of short courses of daily PPI dosing only when symptoms appear, and stopping when they resolve [53].

Table 4.

Summary of RCT evidence for PPI use-reduction strategies

Strategy for PPI use-reduction	Study description	Outcome	Results
Lowering dose	Systematic review (2017) of patients with mild to moderate GORD [10, 53]	Recurring upper GI symptoms	49% lacked symptom control with maintenance dose versus 43% continuing PPI at healing dose
	• 5 RCTs (n = 1,912)		No statistical difference
	• 12 months		RR 1.16, 95% CI: 0.93 to 1.44
Abrupt stopping	RCT of patients (aged ≥65 years) with healed oesophagitis; abrupt stopping (placebo) versus maintenance dose PPI (n = 105) [9]	Recurring upper GI symptoms	68% lacked symptom control with abrupt cessation versus 22% continuing PPI
	• 6 months		RR 3.02, 95% CI: 1.74 to 5.24
Tapering dose and then stopping	RCT of patients using daily PPI for upper GI symptoms; tapering versus abrupt stopping (n = 97) [55]	Restarting PPI	69% restarted PPIs with tapering versus 78% stopping abruptly
	12 months		Not statistically significant; no relative risk provided
On-demand PPI (stop PPI; if symptoms return, use PPI daily until symptoms controlled, then stop)	Systematic review (2017) of patients with mild to moderate GORD [9]	Recurring upper GI symptoms	16% lacked symptom control with on-demand versus 9% continuing PPI
	• 5 RCTs (n = 1,653)		RR 1.71, 95% CI: 1.31 to 2.21
	• 3–6 months
Switch to H2RA	Systematic review (2017) of patients with reflux oesophagitis and reflux-like symptoms [10, 53]	Recurring upper GI symptoms	39% lacked symptom control when switching to H2RA versus 21% continuing PPI
	• 3 RCTs (n = 468)		RR 1.92, 95% CI: 1.44 to 2.58

Table adapted from Farrell et al. [53] and Boghossian et al. [9].

CI, confidence interval; GI, gastrointestinal; H₂RA, histamine H₂-receptor antagonists; PPI, proton pump inhibitor; RCT, randomized controlled trial; RR, relative risk.

Several GORD and dyspepsia practice guidelines recommend stepping off PPIs and returning to self-care with the use of alginate or antacid for occasional symptoms [11, 29, 51]. Alginate has also been shown to be a useful short-term rescue therapy that can effectively help patients manage rebound symptoms during PPI de-escalation [56, 57]. In a large prospective study, alginate was supplied for use “as-needed” to 6,000 PPI-treated adult dyspeptic patients (with no clear PPI indication), as part of a nurse-led deprescribing programme. After 1 year, 75% of eligible patients had reduced the dose or stopped PPIs (40% stopped [5% reduced dose, then stopped], 35% reduced dose) [57].

Overall, the limited published RCT evidence suggests that tapering strategies or on-demand PPI, with rescue therapy for rebound symptoms, are the use-reduction strategies that are the most likely to succeed. Available studies have not examined the benefit of lifestyle modifications and weight loss in facilitating PPI use-reduction, but these should be encouraged in all patients with reflux-like symptoms. Advice to help control risk factors for reflux-like symptoms should include avoidance of personal dietary triggers, overeating, tight-fitting clothing, and recumbence after meals [58]. For patients with symptoms during the night, a 3-h interval between an evening meal and bedtime, raising the head-of-the-bed, and sleeping in left decubitus position should be advised [58]. Patients with a suspected perceptual component or hypervigilance may benefit from stress management, diaphragmatic breathing, or cognitive behavioural therapy [58].

Monitoring

Follow-up appointments should be arranged between 4 and 12 weeks after implementing the use-reduction strategy to assess symptoms, frequency of on-demand use (if applicable), and the need for further investigation or resumption of PPI therapy [10]. Severe recurrent symptoms lasting more than 2 months after PPI discontinuation may represent a continuing indication for PPI therapy [11].

Implementation of Standardized Processes

A standardized protocol-driven PPI deprescribing toolkit has been developed by “Choosing Wisely Canada,” a national organization for reducing unnecessary tests and treatments [52]. Two key messages of their campaign for reducing PPI use in the primary care setting are as follows: (i) do not maintain long-term PPI therapy for gastrointestinal symptoms without an attempt to stop or reduce PPI at least once per year in most patients and (ii) do not continue a PPI at hospital discharge unless there is a compelling reason to continue therapy. Central to their approach is achieving local clinician consensus regarding appropriate indications for long-term PPI use, then developing a process to capture patients taking PPIs for more than 8 weeks, and engaging allied health providers (e.g., nurses, pharmacists, physician assistants) to advise patients how to reduce the dose, whether to stop it altogether, and how to make lifestyle changes that can prevent heartburn symptoms from returning. A specified duration is agreed with patients before follow-up to provide any further support and/or to troubleshoot rebound symptoms.

Providing appropriate and accurate information to patients is key to successfully reducing long-term PPI use. Patients presenting with reflux-like symptoms should receive educational material on potential mechanisms, including the brain-gut axis relationship, weight management, lifestyle and dietary changes, and relaxation strategies [27, 59]. When commencing PPI treatment, patients should understand why they are taking the medication, how long the course should be, and when their medication will be reviewed. Patients should also be counselled on when to take the PPI (20–30 min before breakfast/meal). When reducing or discontinuing PPI use, patients should be forewarned about the possibility of rebound symptoms and provided with management strategies. Provision of information in advance of an appointment has been shown to help optimize the counselling time available by changing the theme of the doctor-patient dialogue, e.g., to focus on discussion of efficacy and risks [60].

Alternative Anti-Secretory Agents

Potassium-competitive acid blockers are acid suppressants increasingly prescribed as an alternative to PPI, particularly in Asia. These agents block the K⁺H⁺ ATPase potassium channel through a reversible mechanism, are not acid labile, and have a much longer half-life compared with PPIs, resulting in more rapid and sustained inhibition of gastric acid secretion [61]. The safety of potassium-competitive acid blockers in the short term is similar to that of PPIs [62] and long-term adverse event data are assumed to be the same. Regardless, the principles discussed for PPI in terms of rational short-term and long-term prescribing, regular review, and deprescribing where appropriate also apply to these agents.

Role of the Pharmacist

Since the COVID-19 pandemic, the role of community pharmacists has evolved rapidly from a service for dispensing medicines to one that actively participates in the treatment of patients by providing key health services and advice to the public [63]. In several countries, such as Australia [64] and the UK [65], there has been some integration of pharmacists into general practice, which has been shown to help optimize prescribing and health outcomes in patients with polypharmacy, as well as to reduce inappropriate prescribing [66]. With ever-increasing pressure on primary care services, this is a move that is broadly welcomed by GPs, especially with regard to medicine optimization [67]. Being among the most accessible healthcare professionals, the inclusion of pharmacists within an interdisciplinary team can help drive a programme of protocol-based PPI use-reduction, facilitating patient education, lifestyle advice, dose changes, monitoring, alerting the prescriber to ongoing symptoms and inappropriate PPI use, and advising patients when to consult their GP [10, 29]. PPI use in the self-care setting is less likely to be optimally dosed, compared with PPI prescribed by a specialist [6], and community pharmacists also have an important role in helping patients use OTC PPI correctly [29].

In a recent initiative, the Spanish Society of Community Pharmacy (SEFAC) and the Spanish Society of General Practitioners (SEMERGEN) developed a joint algorithm for managing patients with upper GI symptoms in the community pharmacy, which included medical referral, lifestyle education, and recommendation of pharmacological and natural products according to the clinical characteristics of the patient [68]. Most patients with retrosternal symptoms, or overlapping retrosternal/epigastric symptoms, received lifestyle education and a recommendation of OTC alginate or antacid and were found to have a significant improvement in symptoms and quality of life, with an impressive 99.2% of patients reporting satisfaction with the care they received through implementation of the algorithm [69].

Conclusion

The decision to reduce PPI use should be individualized and prioritized primarily on a rational indication for use (e.g., Barrett’s oesophagus, chronic NSAID use with bleeding risk factors, high-grade oesophagitis, bleeding ulcer history, Zollinger-Ellison syndrome), rather than the potential risks associated with long-term use. To achieve sustainable PPI use-reduction for upper GI symptoms, there is a need to re-evaluate the role of PPIs; PPIs should be considered a useful short-term measure to help control symptoms while addressing an individual’s underlying risk factors. PPI use-reduction in these patients is also an opportunity to shift management to a patient-centred, holistic approach.

Some patients will have a clear indication for long-term PPI use and should be reviewed regularly to assess continued benefit and the possibility of dose reduction. Clear protocols and processes should be implemented consistently across pharmacies, primary care, and gastroenterology services so that patients without a rational indication for long-term PPI use can be identified and supported through the development of an agreed plan for PPI use-reduction, rebound hypersecretion management, lifestyle support, and follow-up.

Acknowledgment

We would like to thank Lisa O’Rourke PhD of Lumanity, UK, for editorial assistance.

Conflict of Interest Statement

All authors attended the online workshops funded by Reckitt Benckiser Healthcare Ltd. Peter J. Kahrilas has served as an advisor for Reckitt and a speaker for Phathom Pharmaceuticals. Foteini Anastasiou has served as an advisor for Reckitt and has also been a member of the research team on a university project funded by Gilead. Albert J. Bredenoord has received research funding from Nutricia, Thelial, Sanofi/Regeneron, SST, and Dr. Falk Pharma and has received speaker and/or consulting fees from Laborie, Medtronic, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Reckitt, and AstraZeneca. Hashem B. El Serag has served as an advisor for Reckitt and a consultant for Phathom Pharmaceuticals. Joachim Labenz has served as a speaker and/or consultant for Aboca, AlphaSigma, AstraZeneca, Bayer, BMS, Cinclus, EndoStim, Fachingen, Falk, GSK, Implantica, Luvos, Pfizer, Reckitt Benckiser, Sanofi, Schwabe, and Sofar and has received research grants from EndoStim, Reckitt Benckiser, and Sanofi. Juan M. Mendive has participated in educational activities for GPs funded by Reckitt, Gilead, and Novo-Nordisk, is a contributor to Medscape, and has served as a consultant for Reckitt and Novo Nordisk. Edoardo V. Savarino has served as a speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, Mayoly Biohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, and Unifarco; he has served as a consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, and Unifarco and has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, and Zeta Farmaceutici. Daniel Sifrim has served as a consultant for Reckitt (UK), Jinshan Technology (China), and AlfaSigma (Italy). Mihaela Udrescu has served as a speaker for Gilead, Servier, and AstraZeneca SRL. Rena Yadlapati has served as a consultant for Medtronic, Phathom Pharmaceuticals, StatLinkMD, Braintree Pharmaceuticals, and Reckitt Benckiser Healthcare Ltd., has been a contributor to Medscape, received research support from Ironwood Pharmaceuticals, and has served on an advisory board with stock options for RJS Mediagnostix. A. Pali Hungin has been an advisor to Reckitt, a contributor to Medscape, and is Chair of Primary Care Committee of ROME Foundation.

Funding Sources

This work is based on workshops that were funded by Reckitt Benckiser Healthcare Ltd. Editorial assistance was provided by Lumanity, UK, and funded by Reckitt Benckiser Healthcare Ltd.

Author Contributions

All authors meet the ICMJE authorship criteria and participated actively in the workshops on which the content was based. Peter Kahrilas and A. Pali Hungin drafted the article, Foteini Anastasiou, Albert J. Bredenoord, Hashem B. El Serag, Joachim Labenze, Juan Mendive, Edoardo V. Savarino, Daniel Sifrim, Mihaela Udrescu, and Rena Yadlapati critically reviewed and revised the article content. All authors approved the final version of the article prior to submission, including the authorship list.

Funding Statement

This work is based on workshops that were funded by Reckitt Benckiser Healthcare Ltd. Editorial assistance was provided by Lumanity, UK, and funded by Reckitt Benckiser Healthcare Ltd.