Most anti-inflammatory drugs have been associated with gastrointestinal side effects. Gastrointestinal mucosa damage can range from endoscopic lesions with no clinical manifestations to serious upper gastrointestinal complications (UGIC) that, in some instances, may be fatal. Because of their relatively low incidence, severe gastrointestinal events can only be effectively evaluated in large, post-marketing, observational studies. This document presents epidemiological evidence of the magnitude of the risk of upper gastrointestinal tract bleeding or perforation among users of anti-inflammatory drugs: oral steroids, aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs), and acetaminophen (paracetamol in Europe). Two methods will be used to examine the interaction resulting from multiple use of anti-inflammatory drugs on the risk of UGIC: firstly, we shall review epidemiological findings published by other authors [1–10]; and, secondly, we shall summarize results published by our group [11–13]. These cited papers provide a more detailed description of the methodology.
Our data was based on a nested case–control study carried out in the UK General Practice Research Database (GPRD) for the period 1993–1998. The study population consisted of 958,397 persons aged 40–79 years who had been enrolled for at least 2 years, and who were free of cancer, esophageal varices, Mallory–Weiss disease, liver disease, coagulopathies and alcohol-related disorders at the start date. All members of the source population were followed-up until they met a case definition criterion or an exclusion criterion, or until they died. We identified patients with codes for UGIC and manually reviewed the demographic data and clinical information in the computerized patient profiles. We excluded subjects with any of the risk factors already mentioned in the 2 months after the date of case detection, and excluded subjects in whom the sources of the bleeding and perforation were the esophagus or lower gastrointestinal tract. A patient was considered to have UGIC when no exclusion criterion was found, the subject had not been hospitalized in the previous month, and the specific site of the bleeding and perforation was located in the stomach or duodenum. Control subjects were frequency matched by age and gender, with the same exclusion criteria for patients also being applied to the control subjects. The analysis included 2105 patients and 11,500 control subjects. We used unconditional logistic regression to compute estimates of relative risk (RR) and 95% confidence intervals (CI) of UGIC associated with current use of steroids, aspirin, NA-NSAIDs, and acetaminophen. All estimates of RR were adjusted for age, sex, calendar year, smoking, antecedents of upper gastrointestinal disorders, and concomitant medications (including anticoagulants, misoprostol, H2-receptor antagonists, omeprazole and nitrates).