Management of Patients With Refractory Reflux-Like Symptoms Despite Proton Pump Inhibitor Therapy: Evidence-Based Consensus Statements

David Armstrong¹, A Pali Hungin², Peter J Kahrilas³, Daniel Sifrim⁴, Paul Moayyedi¹, Michael F Vaezi⁵, Sameer Al-Awadhi⁶, Sama Anvari¹, Reginald Bell⁷, Brendan Delaney⁸, Fabian Emura^{9

10}, C Prakash Gyawali¹¹, Peter Katelaris¹², Adriana Lazarescu¹³, Yeong Yeh Lee¹⁴, Alessandro Repici¹⁵, Sabine Roman¹⁶, Ceciel T Rooker¹⁷, Edoardo Vincenzo Savarino¹⁸, Paul Sinclair¹⁹, Kentaro Sugano²⁰, Rena Yadlapati²¹, Yuhong Yuan¹, Frank Zerbib²², Prateek Sharma²³; International Working Group for the Classification of Oesophagitis (IWGCO)

Affiliations

¹ Division of Gastroenterology & Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
² Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
³ Division of Gastroenterology, Northwestern University, Chicago, Illinois, USA.
⁴ Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁵ Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁶ Department of Gastroenterology, Rashid Hospital, Dubai Academic Health Corporation, Dubai, UAE.
⁷ Institute of Esophageal and Reflux Surgery, Englewood, Colorado, USA.
⁸ Department of Surgery and Cancer, Imperial College London, Saint Mary's Campus, London, UK.
⁹ Digestive Health and Liver Diseases, Miller School of Medicine, University of Miami, Miami, Florida, USA.
¹⁰ Gastroenterology Division, Universidad de La Sabana, Chia, Cundinamarca, Colombia.
¹¹ Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹² Gastroenterology Department, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia.
¹³ Division of Gastroenterology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
¹⁴ GI Function & Motility Unit, Hospital Universiti Sains Malaysia, Kota Bharu, Malaysia.
¹⁵ Department of Gastroenterology, IRCCS Istituto Clinico Humanitas, Rozzano (Milano), Italy.
¹⁶ Division of Digestive Physiology, Centre Hospitalier Universitaire de Lyon, Lyon, France.
¹⁷ International Foundation for Functional Gastrointestinal Disorders (IFFGD), Mount Pleasant, South Carolina, USA.
¹⁸ Gastroenterology Unit, Azienda Ospedale Università di Padova, Padova, Italy.
¹⁹ INSINC Consulting Inc., Guelph, Ontario, Canada.
²⁰ Division of Gastroenterology, Department of Medicine, Jichi Medical University, Tochigi-ken, Japan.
²¹ Division of Gastroenterology, University of California San Diego, La Jolla, California, USA.
²² CHU de Bordeaux, Centre Médico-Chirurgical Magellan, Hôpital Haut-Levêque, Department of Gastroenterology, Université de Bordeaux, INSERM CIC 1401, Bordeaux, France.
²³ Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, and Kansas City VA Medical Center, Kansas City, Missouri, USA.

PMID: 39740235
PMCID: PMC11754941
DOI: 10.1111/apt.18420

Management of Patients With Refractory Reflux-Like Symptoms Despite Proton Pump Inhibitor Therapy: Evidence-Based Consensus Statements

David Armstrong et al. Aliment Pharmacol Ther. 2025 Feb.

. 2025 Feb;61(4):636-650.

doi: 10.1111/apt.18420. Epub 2024 Dec 30.

Authors

Affiliations

¹ Division of Gastroenterology & Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
² Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
³ Division of Gastroenterology, Northwestern University, Chicago, Illinois, USA.
⁴ Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁵ Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁶ Department of Gastroenterology, Rashid Hospital, Dubai Academic Health Corporation, Dubai, UAE.
⁷ Institute of Esophageal and Reflux Surgery, Englewood, Colorado, USA.
⁸ Department of Surgery and Cancer, Imperial College London, Saint Mary's Campus, London, UK.
⁹ Digestive Health and Liver Diseases, Miller School of Medicine, University of Miami, Miami, Florida, USA.
¹⁰ Gastroenterology Division, Universidad de La Sabana, Chia, Cundinamarca, Colombia.
¹¹ Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹² Gastroenterology Department, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia.
¹³ Division of Gastroenterology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
¹⁴ GI Function & Motility Unit, Hospital Universiti Sains Malaysia, Kota Bharu, Malaysia.
¹⁵ Department of Gastroenterology, IRCCS Istituto Clinico Humanitas, Rozzano (Milano), Italy.
¹⁶ Division of Digestive Physiology, Centre Hospitalier Universitaire de Lyon, Lyon, France.
¹⁷ International Foundation for Functional Gastrointestinal Disorders (IFFGD), Mount Pleasant, South Carolina, USA.
¹⁸ Gastroenterology Unit, Azienda Ospedale Università di Padova, Padova, Italy.
¹⁹ INSINC Consulting Inc., Guelph, Ontario, Canada.
²⁰ Division of Gastroenterology, Department of Medicine, Jichi Medical University, Tochigi-ken, Japan.
²¹ Division of Gastroenterology, University of California San Diego, La Jolla, California, USA.
²² CHU de Bordeaux, Centre Médico-Chirurgical Magellan, Hôpital Haut-Levêque, Department of Gastroenterology, Université de Bordeaux, INSERM CIC 1401, Bordeaux, France.
²³ Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, and Kansas City VA Medical Center, Kansas City, Missouri, USA.

PMID: 39740235
PMCID: PMC11754941
DOI: 10.1111/apt.18420

Abstract

Background: Many patients diagnosed with gastro-oesophageal reflux disease (GERD) have persistent symptoms despite proton pump inhibitor (PPI) therapy.

Aims: The aim of this consensus is to provide evidence-based statements to guide clinicians caring for patients with refractory reflux-like symptoms (rRLS) or refractory GERD.

Methods: This consensus was developed by the International Working Group for the Classification of Oesophagitis. The steering committee developed specific PICO questions pertaining to the management of PPI rRLS. Methodologists conducted systematic reviews of the literature. The quality of evidence and strength of recommendations were rated using the GRADE approach.

Results: Consensus was reached on 13 of 17 statements on diagnosis and management. For rRLS, suggested diagnostic strategies included endoscopy, ambulatory reflux testing and oesophageal manometry. The group did not reach consensus on the role of oesophageal biopsies or the use of reflux-symptom association in patients undergoing reflux testing. The group suggested against increasing the PPI dose in patients who had received 8 weeks of a twice-daily PPI. Adjunctive alginate or antacid therapy was suggested. There was no consensus on the role of adjunctive prokinetics. There was little role for adjunctive transient lower oesophageal sphincter relaxation (TLESR) inhibitors or bile acid sequestrants. Endoscopic or surgical anti-reflux procedures should not be performed in patients with rRLS in the absence of objectively confirmed GERD.

Conclusions: The management of rRLS should be personalised, based on shared decision-making regarding the role of diagnostic testing to confirm or rule out GERD as a basis for treatment optimisation. Anti-reflux procedures should not be performed without objective confirmation of GERD.

Keywords: GRADE; endoscopy; gastro‐oesophageal reflux disease (GERD); manometry; pH‐impedance; refractory.

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Conflict of interest statement

Armstrong: Support from Nestlé Health Sciences and the Weston Family Foundation for research unrelated to the submitted work; honorarium from Sanofi for advisory board participation (non‐voting); unpaid advisory board participation for Cinclus Pharma (non‐voting) and Phathom Pharmaceuticals (non‐voting); honorarium from Fresenius Kabi for speakership unrelated to the submitted work; is the co‐founder of AI VALI Inc., an unpaid position unrelated to the submitted work. Hungin: Honoraria from Reckitt Benckiser for advisory board and speaker's bureau participation; research support from Reckitt Benckiser. Kahrilas: Honoraria from Ironwood Pharmaceuticals and Reckitt Benckiser for consulting work. Sifrim: Research funding from Reckitt Benckiser UK and Alfasigma Italy; an honorarium for speaking from Jinshan Technology China. Vaezi: Honoraria from Phathom Pharmaceuticals, Ironwood Pharmaceuticals and Cinclus Pharma for consulting work; an honorarium from Diversatek Healthcare for an advisory role. Bell: Honoraria from Ethicon Endo‐Surgery, Intuitive Surgical and B‐D Inc. for speaking; a honorarium from Ethicon Endo‐Surgery for advisory board participation. Gyawali: Honoraria from Medtronic, Diversatek Healthcare, Ironwood Pharmaceuticals and IsoThrive for consulting work. Lee: Research funding and honoraria for consulting work from Reckitt Benckiser. Repici: Honoraria for speaking from Medtronic, Boston Scientific and ERBE. Roman: Honoraria from Dr. Falk Pharma, Sanofi, Medtronic and Reckitt Benckiser; research support from Medtronic and Diversatek Healthcare. Savarino: Honoraria from Alfasigma, Dr. Falk Pharma, EG Stada Group, JB Pharmaceuticals, Malesci and Sofar for speaker's bureau participation; honoraria from Johnson & Johnson and Reckitt Benckiser for advisory board participation; honoraria from Alfasigma, Dr. Falk Pharma, JB Pharmaceuticals and Sofar for consulting work; research support from Reckitt Benckiser. Sugano: Honoraria from Fujifilm, Biofermin Pharmaceutical Co. and Takeda for consulting work. Yadlapati: Payment directly to the institution from Medtronic, Ironwood Pharmaceuticals and StatLinkMD for consulting work; honoraria from Phathom Pharmaceuticals and Reckitt Benckiser for consulting work; stock options from RJS Mediagnostix for advisory board participation; research grant from Ironwood Pharmaceuticals. Zerbib: Honoraria from Reckitt Benckiser and Dr. Falk Pharma for consulting work. Sharma: Research grants from Medtronic, Fujifilm, ERBE, US Endoscopy, Ironwood Pharmaceuticals, Docbot Inc., Cosmo Pharmaceuticals and CDx Diagnostics; honoraria from Medtronic, Boston Scientific, Bausch, Olympus, Cipla India, Samsung Bioepis, Fujifilm and Lumendi for consulting work. Moayyedi, Delaney, Emura, Al‐Awadhi, Anvari, Katelaris, Lazarescu, Rooker, Sinclair, Yuan: None.

References

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Independent educational grants to the IWGCO from Cinclus Pharma, Ironwood Pharmaceuticals, and Phathom Pharmaceuticals

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Management of Patients With Refractory Reflux-Like Symptoms Despite Proton Pump Inhibitor Therapy: Evidence-Based Consensus Statements

Affiliations

Management of Patients With Refractory Reflux-Like Symptoms Despite Proton Pump Inhibitor Therapy: Evidence-Based Consensus Statements

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical