Downloaded from http://journals.lww.com/epidem by BhDMf5ePHKbH4TTImqenVAHxkFJp/XpPk1L/H3vMGwqMxG9jwOd8eJPG+b4DlKuAX44qu/vwzmc= on 07/30/2018 Relative Risk of Upper Gastrointestinal Complications among Users of Acetaminophen and Nonsteroidal Anti-Inflammatory Drugs Luis Alberto García Rodríguez 1 and Sonia Hernández-Díaz 2 Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with an increase in upper gastrointestinal compli- cations. There is no agreement, however, on whether all con- ventional NSAIDs have a similar relative risk (RR), and epidemiologic data are limited on acetaminophen. We studied the association between these medications and the risk of upper gastrointestinal bleed/perforation in a population-based cohort of 958,397 persons in the United Kingdom between 1993 and 1998. Our nested case-control analysis included 2,105 cases and 11,500 controls. RR estimates were adjusted for several factors known to be associated with upper gastro- intestinal bleed/perforation. Compared with non-users, users of acetaminophen at doses less than 2 gm did not have an increased risk of upper gastrointestinal complications. The adjusted RR for acetaminophen at doses greater than 2 gm was 3.6 [95% confidence interval (95% CI) = 2.6 –5.1]. The cor- responding RRs for low/medium and high doses of NSAIDs were 2.4 (95% CI = 1.9 –3.1) and 4.9 (95% CI = 4.1–5.8). The RR was 3.1 (95% CI = 2.5, 3.8) for short plasma half-life, 4.5 (95% CI = 3.5–5.9) for long half-life, and 5.4 (95% CI = 4.0 –7.1) for slow-release formulations of NSAIDs. After ad- justing for daily dose, the differences in RR between individual NSAIDs tended to diminish except for apazone. Users of H 2 receptor antagonists, omeprazole, and misoprostol had RRs of 1.4 (95% CI = 1.2–1.8), 0.6 (95% CI = 0.4 – 0.9), and 0.6 (95% CI = 0.4 –1.0), respectively. Among NSAID users, use of nitrates was associated with an RR of 0.6 (95% CI = 0.4 –1.0). (EPIDEMIOLOGY 2001;12:570 –576) Keywords: nonsteroidal anti-inflammatory drugs, acetaminophen, nitrates, gastrointestinal hemorrhage, gastrointestinal tox- icity, peptic ulcer. Current intake of nonsteroidal anti-inflammatory drugs (NSAIDs), studied as a class, is associated with a three- to fivefold increase in upper gastrointestinal complica- tions (UGICs), bleeding or perforation. 1–3 There are extensive epidemiologic data evaluating the risk of UGICs associated with some individual nonaspirin NSAIDs. 4 There is, however, no published epidemio- logic study reporting estimates of relative risk (RR) of UGICs for the several NSAIDs that were introduced in the market in the 1990s that claim a better gastrointes- tinal safety than traditional NSAIDs. 5 Similarly, few studies have evaluated the role of acetaminophen. Among the various preventive strategies of UGICs, use of acid-suppressing drugs in the general population and misoprostol in NSAID users is well accepted. 6–8 A re- cent study has also found that use of nitrates was asso- ciated with a decreased risk of upper gastrointestinal bleeding. 9 We conducted a population-based nested case-control study in the United Kingdom to estimate the RR of UGICs associated with (1) acetaminophen and specific NSAIDs and (2) H 2 receptor antagonists, omeprazole, misoprostol, and nitrates. Subjects and Methods PATIENTS AND STUDY DESIGN We conducted a nested case-control study using the United Kingdom General Practice Research Database during the period between April 1993 and October 1998. This study was an extension of a previous one in which the data collection ended in February 1993. 10 The General Practice Research Database is a population- based database in the United Kingdom in which general practitioners store, in office computers, clinical informa- tion on their patients including demographics, diagnoses and comments, referral information, and records of all prescriptions issued by them. 11,12 The study population comprised persons 40 –79 years of age who had been enrolled at least 2 years with the general practitioner and who were free of cancer, esophageal varices, Mallory- Weiss disease, liver disease, coagulopathies, and alcohol- From the 1 Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain, and 2 Department of Epidemiology, Harvard School of Public Health, Boston, MA. Address correspondence to: Luis Alberto García Rodríguez, CEIFE, Almirante, 28-2, 28004 Madrid, Spain. This study was supported in part by a research grant from Novartis. Submitted November 6, 2000; final version accepted January 24, 2001. Copyright © 2001 by Lippincott Williams & Wilkins, Inc. 570