title: Acute Middle Gastrointestinal Bleeding Risk Associated with NSAIDs, Antithrombotic Drugs, and PPIs: A Multicenter Case-Control Study.
abstract: BACKGROUND
  Middle gastrointestinal bleeding (MGIB) risk has not been fully investigated due to its extremely rare occurrence and the need for multiple endoscopies to exclude upper and lower gastrointestinal bleeding. This study investigated whether MGIB is associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (LDA), thienopyridines, anticoagulants, and proton-pump inhibitors (PPIs), and whether PPI use affects the interactions between MGIB and antithrombotic drugs.
  
  
  METHODS
  In this multicenter, hospital-based, case-control study, 400 patients underwent upper and lower endoscopy, 80 had acute overt MGIB and 320 had no bleeding and were matched for age and sex as controls (1:4). MGIB was additionally evaluated by capsule and/or double-balloon endoscopy, after excluding upper and lower GI bleeding. Adjusted odds ratios (AOR) for MGIB risk were calculated using conditional logistic regression. To estimate the propensity score, we employed a logistic regression model for PPI use.
  
  
  RESULTS
  In patients with MGIB, mean hemoglobin level was 9.4 g/dL, and 28 patients (35%) received blood transfusions. Factors significantly associated with MGIB were chronic kidney disease (p<0.001), liver cirrhosis (p = 0.034), NSAIDs (p<0.001), thienopyridines (p<0.001), anticoagulants (p = 0.002), and PPIs (p<0.001). After adjusting for these factors, NSAIDs (AOR, 2.5; p = 0.018), thienopyridines (AOR, 3.2; p = 0.015), anticoagulants (AOR, 4.3; p = 0.028), and PPIs (AOR; 2.0; p = 0.021) were independently associated with MGIB. After adjusting for propensity score, the use of PPIs remained an independent risk factors for MGIB (AOR, 1.94; p = 0.034). No significant interactions were observed between PPIs and NSAIDs (AOR, 0.7; p = 0.637), LDA (AOR, 0.3; p = 0.112), thienopyridine (AOR, 0.7, p = 0.671), or anticoagulants (AOR, 0.5; p = 0.545).
  
  
  CONCLUSIONS
  One-third of patients with acute small intestinal bleeding required blood transfusion. NSAIDs, thienopyridines, anticoagulants, and PPIs increased the risk of acute small intestinal bleeding. However, there were no significant interactions found between antithrombotic drugs and PPI use for bleeding risk.
authors.affiliation: Departments of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Naoyoshi
authors.initials: N
authors.lastname: Nagata
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Niikura
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Departments of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Ohta Nishinouchi Hospital, Fukushima, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Shimbo
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterology, JR Tokyo General Hospital, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Mitsuno
authors.affiliation: Department of Gastroenterology, Tokyo Metropolitan Police Hospital, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Ogura
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Internal Medicine and Gastrointestinal Endoscopy, Saga Medical School, Saga, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Fujimoto
authors.affiliation: Departments of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Akiyama
authors.affiliation: Department of Gastroenterology, Tokyo Metropolitan Police Hospital, Chiba, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Uemura
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001241:Aspirin / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D054328:Proton Pump Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D001241:Aspirin