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Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan

  • Pharmacoepidemiology and Prescription
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Abstract

Objective

Studies in Western populations have shown the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB). The role of Helicobacter pylori infection in NSAIDs-related UGIB remains to be studied. We conducted a case-control study in Japan to investigate these related topics.

Methods

Cases of UGIB due to duodenal or gastric ulcer, or gastritis were identified in 14 study hospitals in various areas of Japan. For each case, two controls were identified from population registries in the same district. Information on drugs and other risk factors was obtained from 175 cases and 347 controls by telephone interviews. Anti-H. pylori antibody in the urine was measured in a single laboratory for all the cases and 225 controls.

Results

The odds ratio (OR) of UGIB was 5.5 for aspirin and 6.1 for other NSAIDs (NANSAIDs) (p<0.01). The OR for regular use was higher than for occasional use both for aspirin (7.7 vs 2.0) and NANSAIDs (7.3 vs 4.1). Loxoprofen (5.9), frequently used in Japan as a safe ‘prodrug’, was significantly associated with UGIB. The odds ratio for H. pylori infection was 4.9 and the relative excess risk due to the interaction between H. pylori and the use of NSAID was 1.2 (95% CI: −5.8–8.1).

Conclusion

NSAIDs including loxoprofen increase the risk of UGIB in Japan as in Western countries, with a similar magnitude of association. There was no evidence of biological interaction between NSAIDs and H. pylori infection.

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Acknowledgements

This study was financially supported by Pfizer and Astellas Pharma Inc. We thank all the persons who participated in the study, all gastroenterologists who ascertained case patients in the participated hospitals, and Emi Sakata for her assistance. We also thank the following investigators who contributed to the acquisition of data: Yasuhiro Yamamoto, Futoshi Ogawa (Nippon Medical School); Kiichi Satoh, Hiroshi Kawata (Jichi Medical School); Yukinori Imai (Saitama Medical School); Takao Wakabayashi (Fujita Health University Banbuntane Hotokukai Hospital); Shuuhei Miura (Tokyo Medical University Kasumigaura Hospital); Akemi Ito, Kenichi Watanabe (Tokai University School of Medicine); Kazuhide Higuchi (Osaka City University Medical School, Osaka, Japan); Morio Takahashi (University Hospital at Koshigaya, Dokkyo University School of Medicine); Satoshi Tanabe (Kitasato University East Hospital); Hiroshi Seno, Hiroshi Nakase (Graduate School of Medicine, Kyoto University); Shuichi Ohara, Hitoshi Sekine, Akira Imatani, Tomoyuki Koike, Katsunori Iijima (Graduate School of Medicine, Tohoku University); Hideyuki Hiraishi, Tetsuya Nakamura, Takako Sasai, Yoichiro Fujii (Dokkyo University School of Medicine).

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Authors and Affiliations

  1. Nippon Medical School, Tokyo, Japan

    Choitsu Sakamoto & Taku Tsukui

  2. Jichi Medical School, Tochigi, Japan

    Kentaro Sugano & Hiroyuki Osawa

  3. Saitama Medical School, Saitama, Japan

    Shinichi Ota

  4. Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan

    Nobuhiro Sakaki

  5. Kyorin University School of Medicine, Tokyo, Japan

    Shin’ichi Takahashi

  6. Jichi Medical School Omiya Medical Center, Saitama, Japan

    Yukio Yoshida

  7. Kanto Medical Center NTT EC, Tokyo, Japan

    Yukihiro Sakurai

  8. Fujita Health University Banbuntane Hotokukai Hospital, Aichi, Japan

    Junji Yoshino

  9. Tokyo Medical University Kasumigaura Hospital, Ibaraki, Japan

    Yuji Mizokami

  10. Tokai University School of Medicine, Kanagawa, Japan

    Tetsuya Mine

  11. Osaka City University Medical School, Osaka, Japan

    Tetsuo Arakawa

  12. University Hospital at Koshigaya, Dokkyo University School of Medicine, Saitama, Japan

    Hajime Kuwayama

  13. Kitasato University East Hospital, Kanagawa, Japan

    Katsunori Saigenji

  14. Teikyo University School of Medicine Ichihara Hospital, Chiba, Japan

    Koji Yakabi

  15. Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Tsutomu Chiba

  16. Graduate School of Medicine, Tohoku University, Miyagi, Japan

    Tooru Shimosegawa

  17. Slone Epidemiology Center, Boston University, Boston, MA, USA

    Jane E. Sheehan & David W. Kaufman

  18. Pfizer Worldwide Development, Barcelona, Spain

    Susana Perez-Gutthann

  19. School of Health Sciences and Nursing, University of Tokyo, Tokyo, Japan

    Takuhiro Yamaguchi

  20. Faculty of Medicine, University of Tokyo, Tokyo, Japan

    Tsugumichi Sato & Kiyoshi Kubota

  21. Drug Safety Research Unit Japan, Tokyo, Japan

    Tsugumichi Sato & Kiyoshi Kubota

  22. Dokkyo University School of Medicine, Tochigi, Japan

    Akira Terano

  23. Department of Pharmacoepidemiology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Kiyoshi Kubota

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  1. Choitsu Sakamoto
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  2. Kentaro Sugano
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Corresponding author

Correspondence to Kiyoshi Kubota.

Appendix

Appendix

The relative excess risk of interaction (RERI) [1, 15, 44]: assume that the incidence of upper gastrointestinal bleeding (UGIB) is 1 in 1,000 subjects with no NSAIDs and no H.pylori infection. If the incidence of UGIB is 5 in 1,000 subjects with NSAIDs but with no H. pylori infection, 1 of the 5 subjects with UGIB may be due to the baseline risk while 4 may be due to the additional risk from the use of NSAIDs. Similarly if the incidence is again 5 in 1,000 subjects with no NSAIDs but with H. pylori infection, 1 and 4 may be due to the baseline risk and additional risk from H. pylori infection, respectively. If there is no biological interaction between the use of NSAIDs and H. pylori infection, it is expected that a total of 9 subjects would develop UGIB in 1,000 patients with both NSAIDs and H. pylori infection (1 due to the baseline risk, 4 due to the use of NSAIDs and 4 due to H. pylori infection). In general, the relation for no biological interaction may be given as: Risk (NSAIDs+, H.pylori+) = Risk (NSAIDs−, H.pylori−) + [Risk (NSAIDs+, H.pylori−) − Risk (NSAIDs−, H.pylori−)] + [Risk (NSAIDs−, H.pylori+) − Risk (NSAIDs−, H.pylori−)] leading to the following when divided by the baseline risk: [Risk (NSAIDs−, H.pylori−)]: RR (NSAIDs+, H.pylori+) = 1+[RR (NSAIDs+, H.pylori−)−1] + [RR (NSAIDs−, H.pylori+)−1] where RR is the relative risk compared to the baseline risk. In the case–control study, RR is obtained as odds ratio (OR) and the relationship would be given as: OR (NSAIDs+, H.pylori+) = 1+[OR (NSAIDs+, H.pylori−)−1] + [OR (NSAIDs−, H.pylori+)−1] [44]. RERI is defined as RERI = OR (NSAIDs+, H.pylori+) − OR (NSAIDs+, H.pylori−) − [OR (NSAIDs−, H.pylori+)+1] which has the expected value of zero when there is no biological interaction between the use of NSAIDs and H.pylori infection. The 95% confidence interval of RERI can be obtained according to the method of Hosmer and Lemeshow [15].

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Sakamoto, C., Sugano, K., Ota, S. et al. Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan. Eur J Clin Pharmacol 62, 765–772 (2006). https://doi.org/10.1007/s00228-006-0171-6

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