Steroids and Risk of Upper Gastrointestinal Complications
Sonia Hernández-Díaz1 and
Luis Alberto García Rodríguez2
1 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
2 Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain.
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ABSTRACT
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Most antiinflammatory drugs have been associated with an increase in upper gastrointestinal complications. However, the literature on steroids is more limited than that on nonsteroidal antiinflammatory drugs (NSAIDs). To estimate the risk of upper gastrointestinal complications associated with use of steroids alone and in combination, a nested case-control analysis was conducted on the General Practice Research Database from the United Kingdom. The authors identified 2,105 cases of upper gastrointestinal complications and 11,500 controls between 1993 and 1998. The adjusted odds ratios associated with current use of oral steroids were 1.8 (95% confidence interval (CI): 1.3, 2.4) for upper gastrointestinal complications overall and 2.4 (95% CI: 1.7, 3.4) for gastric and 1.2 (95% CI: 0.8, 1.9) for duodenal damage. Steroids were similarly associated with bleeding (odds ratio (OR) = 1.8; 95% CI: 1.3, 2.4) and perforations (OR = 1.6; 95% CI: 0.9, 3.1). Simultaneous use of steroids with low-medium and high NSAID doses, respectively, produced odds ratios of 4.0 (95% CI: 1.3, 12.0) and 12.7 (95% CI: 6.2, 26.1), compared with users of none. Whenever possible, antiinflammatory drugs should be given in monotherapy and at the lowest effective dose in order to reduce the risk of upper gastrointestinal complications.
adrenal cortex hormones; anti-inflammatory agents; cohort studies; gastrointestinal hemorrhage; peptic ulcer; pharmacoepidemiology
Abbreviations:
CI, confidence interval; NSAID, nonsteroidal anti-inflammatory drug; OR, odds ratio
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INTRODUCTION
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The association between upper gastrointestinal complications and intake of nonsteroidal antiinflammatory drugs (NSAIDs) has been extensively evaluated and reviewed (1
, 2
). In some studies, the use of corticosteroids has been suggested to reinforce the risk associated with NSAIDs (1
, 3
). However, the literature on corticosteroids as an independent risk factor for upper gastrointestinal complications in the general population is limited (4
), and often we learn about them from secondary analyses included in research on NSAIDs (5







14
).
We used data from an ongoing population-based study to assess the risk of upper gastrointestinal complications related to steroid treatment, as well as the potential interaction between steroids and NSAIDs.
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MATERIALS AND METHODS
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Study population
Since 1990, general practitioners throughout the United Kingdom have been collecting information on their patients in the General Practice Research Database. Currently, around 1,500 practices representative of the UK population participate. The general practitioners systematically store in office computers clinical information on their patients including demographics, diagnoses and comments, referral information, and records of all prescriptions issued by them. Data for research purposes are strictly anonymous. Since prescriptions, including dosage instructions, are generated directly from the computer, the information on all prescriptions written by the general practitioner is complete. Since general practitioners in the United Kingdom are the gatekeeper to all health care delivered, the General Practice Research Database includes all referrals to specialists, hospital admissions, and the results from these visits (15
). The accuracy and completeness of these data have been validated in previous studies (16
).
This study included the period between April 1993 and October 1998, and it was an extension of a previous study in which the data collection ended in February 1993 (9
). From this population we considered persons aged 4079 years 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-related disorders at the start date. A total of 958,397 study members were followed until they met a case definition criterion, one of the above listed exclusion criteria, died, or the end of follow-up, whichever came first. The study protocol was approved by the Scientific and Ethical Advisory Board of the General Practice Research Database.
Cases
Cases consisted of patients referred to a specialist or admitted to a hospital with a diagnosis of bleed/perforation located in the stomach or duodenum or a clinical diagnosis of bleeding peptic ulcer. Subjects with any of the exclusion criteria previously mentioned in the 2 months after the date of case detection (index date), subjects with the source of the bleed/perforation in the esophagus or lower gastrointestinal tract, and subjects discharged from a hospital in the previous 2 weeks were excluded.
We identified patients with codes for upper gastrointestinal complications and manually reviewed the information in their computerized patient profiles. To validate the cases we sent the general practitioners a questionnaire for a random sample of 100 patients. We received information on 99 patients with only one patient not confirmed as a case of upper gastrointestinal complications.
Controls
Controls were frequency matched to cases by age (interval of 1 year) and gender, and a date was randomly selected from the eligible person-time so that the likelihood of being selected as a control was proportional to the person-time at risk. Specifically, a random date within the study period was generated for each of the members of the study cohort. All persons with a random date included in their person-time period of observation (from study entry to end of follow-up) were eligible as controls. The same computer-based inclusion criteria as those for the cases were applied to all eligible controls, using each control's random date as his or her index date.
We included 2,105 cases and chose a fixed size of 11,500 for the control series (slightly more than five times the number of cases).
Exposure assessment
The general practitioners record in the computer the name, dose, frequency, and number of pills prescribed by them. We considered that a subject was exposed while the supply of the prescription lasted. Exposure to steroids was categorized as "current," when the supply of the most recent prescription lasted until the index date or ended in the 30 days before the index date; "recent," when it ended 3190 days before the index date; "past," when it ended 91180 days before the index date; and "nonuse," when there was no recorded use in the 6 months before the index date. Exposure to NSAIDs in the last month was further divided into "current," when the supply of the most recent prescription lasted until the index date or ended in the week before; and "intermediate," when it ended 730 days before the index date. Among current NSAID users, we distinguished three mutually exclusive categories: "single users," who received only one NSAID during the month prior to the index date; "multiple users," who received simultaneous prescriptions for different NSAIDs with their respective supply ending within the month prior to the index date; and "switchers," who received consecutive prescriptions for different NSAIDs with their respective supply ending within the month prior to the index date. Current users of NSAIDs and steroids were subsequently divided into "low-medium doses" and "high doses" (table 1). Combined therapy was defined as current exposure to steroids and NSAIDs.
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TABLE 1. Cutoff values of daily dose for individual antiinflammatory drugs, United Kingdom General Practice Research Database, 19931998
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Data analysis
Within our source population we performed a nested case-control analysis. Odds ratios of upper gastrointestinal complications and 95 percent confidence intervals were estimated for patients exposed versus not exposed to an anti-inflammatory drug, using unconditional logistic regression. The odds ratios for concurrent exposure to more than one drug were examined by using a common reference group (those exposed to neither drug). The associations presented below were adjusted, using multivariate models, for age, sex, calendar year, smoking, antecedents of upper gastrointestinal disorders, aspirin, and anticoagulant use.
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RESULTS
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This study included 2,105 cases and 11,500 controls. Five percent of cases and 2 percent of controls were current steroid users. The risk of upper gastrointestinal complications was 1.8 (95 percent confidence interval (CI): 1.3, 2.4) times higher for users of oral steroids than for nonusers (table 2). The risk of upper gastrointestinal complications was elevated during the first (odds ratio (OR) = 1.5; 95 percent CI: 1.0, 2.4), second and third (OR = 2.3; 95 percent CI: 1.2, 4.4), and after the third (OR = 1.7; 95 percent CI: 1.1, 2.5) month of use and dropped 1 month after treatment was stopped. Prednisolone was the most frequently used steroid, accounting for more than 85 percent of systemic steroid use (OR = 1.9; 95 percent CI: 1.4, 2.5). Among steroid users, the most common indications were arthritis (23 percent of controls and 26 percent of cases), bronchitis (23 percent of controls and 17 percent of cases), and asthma (13 percent of controls and 14 percent of cases).
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TABLE 2. Odds ratio and 95% confidence interval of upper gastrointestinal complications associated with use of steroids and NSAIDs,* United Kingdom General Practice Research Database, 19931998
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The risk associated with the use of oral steroids tended to be greater for high doses than for low doses, although the difference was not statistically significant (table 3). The risk for steroid doses equivalent to 1030 mg of prednisone was equal to that for doses below 10 mg. The use of oral steroids increased about twofold the risk of upper gastrointestinal complications across all age groups; such increased risk was greater for women (OR = 2.4; 95 percent CI: 1.6, 3.5) than for men (OR = 1.3; 95 percent CI: 0.8, 2.0). Users of inhaled and intramuscular steroids had odds ratios of 1.0 (95 percent CI: 0.8, 1.2) and 0.9 (95 percent CI: 0.3, 2.8), respectively. However, the latter odds ratio was based only on four exposed cases.
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TABLE 3. Odds ratio and 95% confidence interval of upper gastrointestinal complications associated with current use of antiinflammatory drugs at high and low-medium doses, both alone or combined, United Kingdom General Practice Research Database, 19931998
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Among the 2,105 cases identified, 800 had lesions located in the stomach, 1,047 in the duodenum, and 258 at an unspecified site. Oral steroids were more strongly associated with gastric damage (OR = 2.4; 95 percent CI: 1.7, 3.4) than with duodenal damage (OR = 1.2; 95 percent CI: 0.8, 1.9). For gastric lesions, the risk was greater for high doses (OR = 5.4; 95 percent CI: 1.9, 15.5) than for low doses (OR = 2.1; 95 percent CI: 1.4, 3.1) of oral steroids. For duodenal lesions, the odds ratios associated with high and low doses were 1.7 (95 percent CI: 0.4, 7.7) and 1.1 (95 percent CI: 0.7, 1.8), respectively. Notice that, when we stratified by site, the sample size for the analysis of steroids at high doses was small, yielding to broad confidence intervals.
Regarding the type of lesion, 1,833 cases had suffered bleeding and 272 had perforations. The odds ratio associated with current use of oral steroids was 1.8 for bleeding (95 percent CI: 1.3, 2.4) and 1.6 for perforated (95 percent CI: 0.9, 3.1) lesions. Most perforations occurred in the duodenum (n = 237), while bleeding originated in the stomach (n = 764), duodenum (n = 811), or unspecified site (n = 258).
About 21 percent of the cases of upper gastrointestinal complications and 7 percent of the controls were current NSAID users, yielding an overall adjusted odds ratio of 4.3 (95 percent CI: 3.8, 5.0). Patients taking multiple NSAIDs and switchers had odds ratios greater than did patients taking a single NSAID. The risk of upper gastrointestinal complications dropped 1 month after treatment was stopped. Among users of a single NSAID, the risk was greater for high NSAID doses than for low-medium doses (tables 2 and 3).
Compared with nonusers of either drug, the odds ratios were 4.0 (95 percent CI: 3.4, 4.6) for current users of NSAIDs alone, 1.8 (95 percent CI: 1.3, 2.5) for current users of oral steroids alone, and 8.9 (95 percent CI: 5.0, 15.8) for users of both NSAIDs and oral steroids. We further analyzed the association between steroids and upper gastrointestinal complications when subjects were concomitantly exposed to either low or high NSAID doses. Concomitant use of steroids and a low-medium dose NSAIDs gave an odds ratio of 4.0 (95 percent CI: 1.3, 12.0), while concomitant use of steroids and a high dose NSAIDs gave an odds ratio of 12.7 (95 percent CI: 6.2, 26.1). Only two cases and one control were taking high doses of steroids while using NSAIDs. Thus, we were not able to study the effect of using high steroid doses and NSAIDs simultaneously (table 3).
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DISCUSSION
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Current intake of systemic steroids increased 1.8 times the risk of having a new episode of upper gastrointestinal bleeding or perforation. Concomitant use of systemic steroids with high doses of NSAIDs was associated with a 12-fold increased risk of upper gastrointestinal complications. This pattern of use represented 2 percent of the total number of NSAID users in our population.
Meta-analyses of early clinical trials showed conflicting results between them (17
). One suggested a small but significant dose-dependent increased risk of peptic ulcers in the groups treated with steroids (18
), and another failed to find a difference between the steroid and placebo groups (19
). Regarding observational data, we found 11 previously published epidemiologic studies that included odds ratio estimates of serious upper gastrointestinal events associated with the use of steroids (4








14
). Results from individual studies were heterogeneous and often based on small numbers. The pooled odds ratio estimate was 1.9 (95 percent CI: 1.5, 2.4).
The risk of upper gastrointestinal complications has been shown to be higher when steroids are administered concomitantly with NSAIDs: Piper et al. (4
) found odds ratios of 1.1 (95 percent CI: 0.5, 2.1) among patients taking steroids only and of 14.6 (95 percent CI: 6.7, 32.0) among patients taking steroids and NSAIDs concurrently, compared with users of none. Pérez-Gutthann et al. (12
) found effects of 2.2 (95 percent CI: 0.9, 5.4) and 12.5 (95 percent CI: 7.1, 22.1) for users of steroids only and for concomitant users of both steroids and NSAIDs, respectively, compared with nonusers of either drug. It has been suggested that steroids may delay the healing of underlying erosive lesions caused by other factors such as NSAIDs, rather than causing ulcer de novo (4
, 12
). That could explain in part the interaction found between NSAIDs and steroids.
Potential limitations of all studies using computerized prescription data are the underascertainment of drugs obtained from other sources (e.g., over-the-counter) and the overestimation of exposure when compliance with the drug supplied is incomplete. However, it is probable that such misclassification (expected to be small, because steroids are rarely purchased over-the-counter) would be nondifferential, thus resulting in conservative odds ratio estimates.
Because steroids are often indicated for patients with certain diseases, illness itself, and not the drugs, might be elevating the risk of upper gastrointestinal complications. The drop in risk after treatment is stopped and the dose-response found suggest a drug effect. More directly, we reviewed the patient profiles and found little difference between the steroid indications for cases and controls. An elevated risk among steroid users might also be due to a preferential prescription of steroids, instead of other antiinflammatory drugs, to patients at higher risk of upper gastrointestinal complications. To control for this potential confounding, all estimates of risk were adjusted for antecedents of upper gastrointestinal disorders (including dyspepsia), NSAIDs, aspirin, and several other risk factors for upper gastrointestinal complications. However, unmeasured or inaccurately measured factors may lead to residual confounding.
In conclusion, use of oral steroids and NSAIDs was associated with about twofold and fourfold increased risk of upper gastrointestinal complications, respectively. Patients using steroids concomitantly with high-dose NSAIDs had the highest risk of upper gastrointestinal complications. Whenever possible, antiinflammatory drugs should be given in monotherapy and at the lowest effective dose in order to reduce the risk of upper gastrointestinal complications.
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ACKNOWLEDGMENTS
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The study was supported in part by a research grant from Novartis.
The authors are indebted to the Boston Collaborative Drug Surveillance Program for providing access to the data. They thank the general practitioners for their excellent collaboration.
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NOTES
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Reprint requests to Dr. Sonia Hernández-Díaz, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115 (e-mail: shernan{at}hsph.harvard.edu).
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Received for publication March 29, 2000.
Accepted for publication October 5, 2000.