Journal of Gastroenterology

, Volume 50, Issue 12, pp 1173–1183 | Cite as

Factors affecting response to proton pump inhibitor therapy in patients with gastroesophageal reflux disease: a multicenter prospective observational study

  • Nobuyuki Matsuhashi
  • Mineo Kudo
  • Norimasa Yoshida
  • Kazunari Murakami
  • Mototsugu Kato
  • Tsuyoshi Sanuki
  • Atsushi Oshio
  • Takashi Joh
  • Kazuhide Higuchi
  • Ken Haruma
  • Koji NakadaEmail author
Original Article—Alimentary Tract



Proton pump inhibitor (PPI) therapy, the first-line treatment for gastroesophageal reflux disease (GERD), is not always effective. This study aimed to examine the effect of pretreatment patient characteristics on response to PPI therapy.


Japanese outpatients with symptomatic GERD scheduled to receive endoscopy and PPI therapy were enrolled in this multicenter prospective observational study. The patients’ characteristics, including GERD and dyspeptic symptoms, anxiety, depression, and quality of life, were assessed using questionnaires before and 2 and 4 weeks after the start of PPI therapy. Factors affecting therapeutic response were examined by simple and multiple regression analyses using three patient-reported outcome measures as objective variables.


Data from 182 patients were analyzed. In multiple regression analysis using the residual symptom rate as an objective variable, lower GERD symptom score (p < 0.05), absence of erosive esophagitis (p < 0.05), higher epigastric pain/burning symptom score (p < 0.05), and higher depression subscale score (p < 0.05) accompanied poorer therapeutic response. In analyses using the patient’s impression of therapy, lower GERD symptom score (p < 0.05) and absence of erosive esophagitis (p < 0.05) accompanied poorer therapeutic response. In analyses using the relative GERD symptom intensity evaluated using a numeric rating scale, lower GERD symptom score (p < 0.05), higher epigastric pain/burning symptom score (p < 0.1), and lower body mass index (p < 0.05) accompanied poorer therapeutic response.


Patients who complained of milder GERD symptoms before treatment were likely to have poorer response to PPI therapy. Association of absence of erosive esophagitis, severer epigastric pain/burning symptoms, lower body mass index, and severer depression with poorer therapeutic response was also suggested.


Gastroesophageal reflux disease Dyspeptic symptoms Depression Anxiety Therapeutic response to proton pump inhibitor therapy 



Body mass index


Erosive reflux disease


Gastroesophageal reflux disease


Gastroesophageal reflux and dyspepsia-therapeutic efficacy and satisfaction test


Hospital anxiety and depression scale


Irritable bowel syndrome


Nonerosive reflux disease


Numeric rating scale


Proton pump inhibitor


Quality of life



We are grateful to the GERD Society for support of publication of this work. Assistance in statistical analyses and writing was funded by AstraZeneca (Osaka, Japan).

Conflict of interest

Kazunari Murakami received research grants and lecture fees from Takeda Pharmaceutical and Eisai. Mototsugu Kato received research grants and lecture fees from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, and Eisai. Takashi Joh received research grants from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, and Eisai. Kazuhide Higuchi received research grants from Daiichi Sankyo, Takeda Pharmaceutical, and Eisai, and lecture fees from AstraZeneca, Daiichi Sankyo., and Eisai. Ken Haruma received research grants and lecture fees from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, and Eisai. The other authors declare that they have no conflict of interest.

Supplementary material

535_2015_1073_MOESM1_ESM.docx (42 kb)
Supplementary material 1 (DOCX 42 kb)
535_2015_1073_MOESM2_ESM.docx (44 kb)
Supplementary material 2 (DOCX 44 kb)


  1. 1.
    Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–20.CrossRefPubMedGoogle Scholar
  2. 2.
    Klauser AG, Schindlbeck NE, Müller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet. 1990;335:205–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108:308–28.CrossRefPubMedGoogle Scholar
  4. 4.
    Mearin F, Ponce J, Ponce M, et al. Frequency and clinical implications of supraesophageal and dyspeptic symptoms in gastroesophageal reflux disease. Eur J Gastroenterol Hepatol. 2012;24:665–74.CrossRefPubMedGoogle Scholar
  5. 5.
    Oh JH, Kim TS, Choi MG, et al. Relationship between psychological factors and quality of life in subtypes of gastroesophageal reflux disease. Gut Liver. 2009;3:259–65.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Bytzer P. Goals of therapy and guidelines for treatment success in symptomatic gastroesophageal reflux disease patients. Am J Gastroenterol. 2003;98:S31–9.CrossRefPubMedGoogle Scholar
  7. 7.
    The Japanese Society of Gastroenterology. GERD management guideline. Tokyo: Nankodo; 2009.Google Scholar
  8. 8.
    Chiba N, De Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology. 1997;112:1798–810.CrossRefPubMedGoogle Scholar
  9. 9.
    Dean BB, Gano AD Jr, Knight K, et al. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol. 2004;2:656–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Zerbib F, Belhocine K, Simon M, et al. Clinical, but not oesophageal pH-impedance, profiles predict response to proton pump inhibitors in gastro-oesophageal reflux disease. Gut. 2012;61:501–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Heading RC, Mönnikes H, Tholen A, et al. Prediction of response to PPI therapy and factors influencing treatment outcome in patients with GORD: a prospective pragmatic trial using pantoprazole. BMC Gastroenterol. 2011;11:52.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Niu XP, Yu BP, Wang YD, et al. Risk factors for proton pump inhibitor refractoriness in Chinese patients with non-erosive reflux disease. World J Gastroenterol. 2013;19:3124–9.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Furuta T, Shimatani T, Sugimoto M, et al. Investigation of pretreatment prediction of proton pump inhibitor (PPI)-resistant patients with gastroesophageal reflux disease and the dose escalation challenge of PPIs-TORNADO study: a multicenter prospective study by the Acid-Related Symptom Research Group in Japan. J Gastroenterol. 2011;46:1273–83.CrossRefPubMedGoogle Scholar
  14. 14.
    Ang D, Talley NJ, Simren M, et al. Review article: endpoints used in functional dyspepsia drug therapy trials. Aliment Pharmacol Ther. 2011;33:634–49.CrossRefPubMedGoogle Scholar
  15. 15.
    US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry. Irritable bowel syndrome—clinical evaluation of drugs for treatment. 2012. Accessed 24 Apr 2014.
  16. 16.
    Hoshihara Y. GERD-gastroesophageal reflux disease. Endoscopic diagnosis and classification. Rinshou Shoukakinaika. 1996;11:1563–8.Google Scholar
  17. 17.
    Hongo M. Minimal changes in reflux esophagitis: red ones and white ones. J Gastroenterol. 2006;41:95–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Nakada K, Joh T, Higuchi K, et al. What factors determine whether a gastroesophageal reflux disease (GERD) patient is responder or not to proton pump inhibitor (PPI) therapy? Gastroenterology. 2013;144(Suppl 1):S-856.CrossRefGoogle Scholar
  19. 19.
    Nakada K, Joh T, Higuchi K, et al. Symptoms of functional dyspepsia rather than those of gastroesophageal reflux disease decrease the health-related quality of life of patients. Gastroenterology. 2013;144(Suppl 1):S-683.CrossRefGoogle Scholar
  20. 20.
    Fukuhara S, Suzukamo Y. Manual of the SF-8 Japanese version. Tokyo: Institute for Health Outcomes and Process Evaluation Research; 2004.Google Scholar
  21. 21.
    Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–70.CrossRefPubMedGoogle Scholar
  22. 22.
    Cohen J. A power primer. Psychol Bull. 1992;112:155–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Whitehead WE, Palsson OS, Levy RL, et al. Reports of “satisfactory relief” by IBS patients receiving usual medical care are confounded by baseline symptom severity and do not accurately reflect symptom improvement. Am J Gastroenterol. 2006;101:1057–65.CrossRefPubMedGoogle Scholar
  24. 24.
    Spiegel B, Camilleri M, Bolus R, et al. Psychometric evaluation of patient-reported outcomes in irritable bowel syndrome randomized controlled trials: a Rome Foundation report. Gastroenterology. 2009;137:1944–53.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Passos MC, Lembo AJ, Conboy LA, et al. Adequate relief in a treatment trial with IBS patients: a prospective assessment. Am J Gastroenterol. 2009;104:912–9.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Miyamoto M, Manabe N, Haruma K. Efficacy of the addition of prokinetics for proton pump inhibitor (PPI) resistant non-erosive reflux disease (NERD) patients: significance of frequency scale for the symptom of GERD (FSSG) on decision of treatment strategy. Intern Med. 2010;49:1469–76.CrossRefPubMedGoogle Scholar
  27. 27.
    Hershcovici T, Fass R. Nonerosive reflux disease (NERD)—an update. J Neurogastroenterol Motil. 2010;16:8–21.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Modlin IM, Hunt RH, Malfertheiner P, et al. Diagnosis and management of non-erosive reflux disease—the Vevey NERD Consensus Group. Digestion. 2009;80:74–88.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Wu JC, Lai LH, Chow DK, et al. Concomitant irritable bowel syndrome is associated with failure of step-down on-demand proton pump inhibitor treatment in patients with gastroesophageal reflux disease. Neurogastroenterol Motil. 2011;23:155–60.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  • Nobuyuki Matsuhashi
    • 1
  • Mineo Kudo
    • 2
  • Norimasa Yoshida
    • 3
  • Kazunari Murakami
    • 4
  • Mototsugu Kato
    • 5
  • Tsuyoshi Sanuki
    • 6
  • Atsushi Oshio
    • 7
  • Takashi Joh
    • 8
    • 9
  • Kazuhide Higuchi
    • 9
    • 10
  • Ken Haruma
    • 9
    • 11
  • Koji Nakada
    • 9
    • 12
    Email author
  1. 1.Department of GastroenterologyNTT Medical Center TokyoTokyoJapan
  2. 2.Department of GastroenterologySapporo Hokuyu HospitalSapporoJapan
  3. 3.Department of GastroenterologyJapanese Red Cross Kyoto Daiichi HospitalKyotoJapan
  4. 4.Department of GastroenterologyOita University HospitalOitaJapan
  5. 5.Division of EndoscopyHokkaido University HospitalSapporoJapan
  6. 6.Department of GastroenterologyKita Harima Medical CenterOnoJapan
  7. 7.Faculty of Letters, Arts and SciencesWaseda UniversityTokyoJapan
  8. 8.Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
  9. 9.GERD Society Study CommitteeOsakaJapan
  10. 10.Second Department of Internal MedicineOsaka Medical CollegeOsakaJapan
  11. 11.Division of Gastroenterology, Department of Internal MedicineKawasaki Medical SchoolOkayamaJapan
  12. 12.Department of SurgeryThe Jikei University School of MedicineTokyoJapan

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