Journal of Gastroenterology

, Volume 46, Issue 5, pp 595–602 | Cite as

A randomized controlled trial of rebamipide plus rabeprazole for the healing of artificial ulcers after endoscopic submucosal dissection

  • Shoko Fujiwara
  • Yoshinori Morita
  • Takashi Toyonaga
  • Fumi Kawakami
  • Tomoo Itoh
  • Masaru Yoshida
  • Hiromu Kutsumi
  • Takeshi Azuma
Original Article—Alimentary Tract



Endoscopic submucosal dissection (ESD) is an increasingly common technique for the resection of early gastric cancers. Although 8 weeks of treatment with a proton pump inhibitor (PPI) reportedly heals most patients with ESD-derived artificial ulcers, it does not heal those with severe atrophic gastritis, for whom there is little data. This study examined whether healing rates of the latter especially were improved by the addition of the non-PPI mucosal healing agent rebamipide after ESD.


Patients were randomly assigned to two treatment groups for 8 weeks following ESD: patients in the PPI group received daily rabeprazole alone (20 mg), whereas those in the combination group received daily rabeprazole (20 mg) and rebamipide (300 mg). At the primary endpoint (56 days after ESD) we determined the proportion of patients in whom ulcers had healed to scar-stage (S-stage, complete healing). A pre-specified subgroup analysis examined ulcer healing in patients with severe atrophic gastritis.


Overall, progression to S-stage occurred in 54.8% in the PPI group, and 86.7% in the combination group (odds ratio 5.3, 95% confidence interval 1.50–19.02, p = 0.006). Among those patients with severe atrophic gastritis, healing to S-stage occurred in 30.0% in the PPI group, and in 92.9% in the combination group (odds ratio 30.3, 95% confidence interval 2.63–348.91, p = 0.0023).


Treatment with a PPI plus rebamipide improved healing rates at 8 weeks for patients with ESD-derived artificial ulcer, and appeared to be particularly effective for patients with severe atrophic gastritis.


ESD Artificial ulcer Atrophic gastritis Rebamipide PPI 


Conflict of interest

Professor Azuma has received honoraria and consulting fees from Astellas Pharmaceutical Inc., Eisai Pharmaceutical Co., Ltd, Otsuka Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Co., Ltd. Drs. Shoko Fujiwara, Yoshinori Morita, Takashi Toyonaga, Fumi Kawakami, Tomoo Itoh, Masaru Yoshida, and Hiromu Kutsumi did not receive funding from any companies.


  1. 1.
    Matsuzaka M, Fukuda S, Takahashi I, Shimaya S, Oyama T, Yaegaki M, et al. The decreasing burden of gastric cancer in Japan. Tohoku J Exp Med. 2007;212:207–19.PubMedCrossRefGoogle Scholar
  2. 2.
    Gotoda T, Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shimoda T, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer. 2000;3:219–25.PubMedCrossRefGoogle Scholar
  3. 3.
    Kakushima N, Yahagi N, Fujishiro M, Iguchi M, Oka M, Kobayashi K, et al. The healing of gastric ulcers after endoscopic submucosal dissection. Dig Endosc. 2004;16:327–31.CrossRefGoogle Scholar
  4. 4.
    Fujiwara S, Morita Y, Toyonaga T, Itoh T, Yoshida M, Kutsumi H. Rebamipide combined with PPI enhances the healing process of post-ESD ulcer; a randomized prospective study. Endoscopy 2009;S1460.Google Scholar
  5. 5.
    Tarpila S, Kekki M, Samloff IM, Sipponen P, Siurala M. Morphology and dynamics of the gastric mucosa in duodenal ulcer patients and their first-degree relatives. Hepatogastroenterology. 1983;30:198–201.PubMedGoogle Scholar
  6. 6.
    Siurala M. Gastritis, its fate and sequelae. Ann Clin Res. 1981;13:111–3.PubMedGoogle Scholar
  7. 7.
    Siurala M, Sipponen P, Kekki M. Chronic gastritis: dynamic and clinical aspects. Scand J Gastroenterol. 1985;109(Suppl):69–76.CrossRefGoogle Scholar
  8. 8.
    Yamasaki K, Kanbe T, Chijiwa T, Ishiyama H, Morita S. Gastric mucosal protection by OPC-12759, a novel antiulcer compound, in the rat. Eur J Pharmacol. 1987;142:23–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Terano A, Arakawa T, Sugiyama T, Suzuki H, Joh T, Yoshikawa T, et al. Rebamipide, a gastro-protective and anti-inflammatory drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori in Japanese population: a randomized, double-blind, placebo-controlled trial. J Gastroenterol. 2007;42:690–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Tarnawski A. Molecular mechanism of ulcer healing. Drug News Perspect. 2000;13:158–68.PubMedCrossRefGoogle Scholar
  11. 11.
    Risau W. Mechanisms of angiogenesis. Nature. 1997;386:761–4.CrossRefGoogle Scholar
  12. 12.
    Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9:653–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Ferrara N, Gerber H-P, LeCourter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.PubMedCrossRefGoogle Scholar
  14. 14.
    Tarnawski A, Arakawa T, Kobayashi K. Rebamipide treatment activates epidermal growth factor and its receptor expression in normal and ulcerated gastric mucosa in rats: one mechanism for its ulcer healing action? Dig Dis Sci. 1998;43:90S–8S.PubMedCrossRefGoogle Scholar
  15. 15.
    Tarnawski A, Chai J, Pai R, Chiou SK. Rebamipide activates genes encoding angiogenic growth factors and Cox2 and stimulates angiogenesis: a key to its ulcer healing action? Dig Dis Sci. 2004;49:202–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Lee SY, Kim JJ, Lee JH, Kim YH, Rhee PL, Paik SW, et al. Healing rate of EMR-induced ulcer in relation to the duration of treatment with omeprazole. Gastrointest Endosc. 2004;60:213–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Sakita T, Fukushima H. Endoscopic diagnosis. In: Yoshitoshi Y, editor. Ulcer of the stomach and duodenum. Tokyo: Nankodo; 1971. p. 198–208 (in Japanese).Google Scholar
  18. 18.
    Kimura K, Takemoto T. An endoscopic recognition of the atrophic border and its significance in chronic gastritis. Endoscopy. 1969;3:87–97.Google Scholar
  19. 19.
    Kato T, Araki H, Onogi F, Ibuka T, Sugiyama A, Tomita E, et al. Clinical trial: rebamipide promotes gastric ulcer healing by proton pump inhibitor after endoscopic submucosal dissection—a randomized controlled study. J Gastroenterol. 2010;45:285–90.PubMedCrossRefGoogle Scholar
  20. 20.
    Uedo N, Takeuchi Y, Yamada T, Ishihara R, Ogiyama H, Yamamoto S, et al. Effect of a proton pump inhibitor or an H2-receptor antagonist on prevention of bleeding from ulcer after endoscopic submucosal dissection of early gastric cancer: a prospective randomized controlled trial. Am J Gastroenterol. 2007;102:1610–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Kakushima N, Fujishiro M, Yahagi N, Kodashima S, Nakamura M, Omata M. Helicobacter pylori status and the extent of gastric atrophy do not affect ulcer healing after endoscopic submucosal dissection. J Gastroenterol Hepatol. 2006;21:1586–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Asakuma Y, Kudo M, Matsui S, Okada M, Kawasaki M, Umehara Y, et al. Comparison of ecabet sodium and proton pump inhibitor (PPI) combination therapy with PPI alone in the treatment of endoscopic submucosal dissection (ESD)-induced ulcers in early gastric cancer: prospective randomized study. Hepatogastroenterology. 2009;56:1270–3.PubMedGoogle Scholar
  23. 23.
    Furuta T, Shirai N, Sugimoto M, Nakamura A, Hishida A, Ishizaki T. Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies. Drug Metab Pharmacokinet. 2005;20:153–67.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  • Shoko Fujiwara
    • 1
  • Yoshinori Morita
    • 1
  • Takashi Toyonaga
    • 2
  • Fumi Kawakami
    • 3
  • Tomoo Itoh
    • 3
  • Masaru Yoshida
    • 1
  • Hiromu Kutsumi
    • 1
  • Takeshi Azuma
    • 1
  1. 1.Department of GastroenterologyKobe University, School of MedicineKobeJapan
  2. 2.Department of EndoscopyKobe University, School of MedicineKobeJapan
  3. 3.Department of HistopathologyKobe University, School of MedicineKobeJapan

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