Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan
- 742 Downloads
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.
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.
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).
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.
KeywordsAdverse drug effects Anti-inflammatory agents, non-steroidal Case-control studies Gastrointestinal hemorrhage Japan
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).
- 3.Asaki S, Toyota T, Fukao A, Hisamichi S, Sato S, Sato K, Karino A, Kasukawa R, Obara K (1991) A case control study of risk factors associated with serious upper gastrointestinal lesions and bleeding: Relation to NSAID intake. Jpn J Med Pharm Sci 26:865–874Google Scholar
- 4.Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352:1092–1102. DOI:10.1056/NEJMoa050493PubMedCrossRefGoogle Scholar
- 11.Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA (2005) Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 365:475–481. DOI:10.1016/S0140-6736(05)17864-7PubMedGoogle Scholar
- 17.Kato M, Asaka M, Saito M, Sekine H, Ohara S, Toyota T, Akamatsu T, Kaneko T, Kiyosawa K, Nishizawa O, Kumagai T, Katsuyama T, Abe M, Kosaka M, Hariya S, Minami K, Sanai Y, Sawamura M, Tachikawa T (2000) Clinical usefulness of urine-based enzyme-linked immunosorbent assay for detection of antibody to Helicobacter pylori: a collaborative study in nine medical institutions in Japan. Helicobacter 5:109–119. DOI:10.1046/j.1523-5378.2000.00017.xPubMedCrossRefGoogle Scholar
- 18.Katsuragi K, Noda A, Tacikawa T, Azuma A, Mukai F, Murakami K, Fujioka T, Kato M, Asaka M (1998) Highly sensitive urine-based enzyme-linked immunoabsorbent assay for detection of antibody to Helicobacter pylori. Helicobacter 3:289–295. DOI:10.1046/j.1523-5378.1998.08045.xPubMedCrossRefGoogle Scholar
- 19.Kaufman DW, Kelly JP, Levy M, Shapiro S (1991) The drug etiology of agranulocytosis and aplastic anemia: the international agranulocytosis and aplastic anemia study. Oxford University Press, New YorkGoogle Scholar
- 21.Kaufman DW, Kelly JP, Wiholm BE, Laszlo A, Sheehan JE, Koff RS, Shapiro S (1999) The risk of acute major upper gastrointestinal bleeding among users of aspirin and ibuprofen at various levels of alcohol consumption. Am J Gastroenterol 94:3189–3196. DOI:10.1016/S0002-9270(99)00576-6PubMedCrossRefGoogle Scholar
- 27.Lanas A, Bajador E, Serrano P, Fuentes J, Carreño S, Guardia J, Sanz M, Montoro M, Sáinz R (2000) Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med 343:834–839. DOI:10.1056/NEJM200009213431202PubMedCrossRefGoogle Scholar
- 31.Lewis SC, Langman MJS, Laporte J-R, Matthews JNS, Rawlins MD, Wilholm B-E (2002) Dose-response relationship between individual nonaspirin non steroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. Br J Clin Pharmacol 54:320–326. DOI:10.1046/j.1365-2125.2002.01636.xPubMedCrossRefGoogle Scholar
- 44.Rothman KJ (2002) Measuring interaction. In: Epidemiology: an introduction, Oxford university press, Oxford, pp 168–80Google Scholar
- 45.Santolaria S, Lanas A, Benito R, Perez-Aisa MA, Montoro M, Sainz R (1999) Helicobacter pylori infection is a protective factor for bleeding gastric ulcer but not for bleeding duodenal ulcers in NSAID users. Aliment Pharmacol Ther 13:1511–1518. DOI:10.1046/j.1365-2036.1999.00631.xPubMedCrossRefGoogle Scholar
- 46.Sato T, Kubota K, Kaufman DW, Perez-Gutthann S (2003) A population-based case-control study of the association between NSAIDs and upper gastro-intestinal bleeding in Japan: methodological lessons from the pilot phase. Pharmacoepidemiol Drug Safety 12(suppl. 1):101Google Scholar
- 47.Shiokawa Y, Nobunaga T, Saito T, Asaki S, Ogawa N (1991) An epidemiological study of non-steroidal anti-inflammatory drug-induced upper gastro intestinal bleeding. Rheumachi 31:96–111Google Scholar
- 53.Wu CY, Poon SK, Chen GH, Chang CS, Yeh HZ (1999) Interaction between Helicobacter pylori and non-steroidal anti-inflammatory drugs in peptic ulcer bleeding. Scand J Gastroenterol 33:234–237Google Scholar