1 Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain.
2 Slone Epidemiology Center, Boston University, Boston, MA.
Received for publication March 27, 2003; accepted for publication June 26, 2003.
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ABSTRACT |
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anti-inflammatory agents, non-steroidal; aspirin; drug toxicity; peptic ulcer
Abbreviations: Abbreviations: CI, confidence interval; GPRD, General Practice Research Database; ICD, International Classification of Diseases, Eighth Revision; NSAID, nonsteroidal antiinflammatory drug; RR, relative risk.
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INTRODUCTION |
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We used a population-based cohort in the United Kingdom to estimate the incidence of uncomplicated but symptomatic peptic ulcer and performed a nested case-control analysis to study the association between the risk of these ulcers and the use of aspirin and nonaspirin NSAIDs. We examined the role of dose and duration of aspirin and nonaspirin NSAIDs in the risk of peptic ulcer and estimated this risk for gastric and duodenal ulcers.
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MATERIALS AND METHODS |
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Source population and cohort definition
The study population included persons aged 4079 years between January 1995 and September 1999 who had been enrolled at least 2 years with the general practitioner, had at least 1 year elapsed since their first computerized prescription, and were free from cancer (International Classification of Diseases, Eighth Revision (ICD), codes 14002090), uncomplicated and complicated peptic ulcer, esophageal varices (ICD code 4560), Mallory-Weiss disease (Oxmis classification code 5309MW), chronic liver disease (ICD codes 57105739), coagulopathies (ICD codes 28602879), and alcoholism at the start date. We excluded persons who were aged 65 years or older at the beginning date with a follow-up greater than 1 year and who had no recording of any data during their follow-up time. The latter was to avoid the inclusion of subjects with incomplete data, since we believe it is unlikely that a person older than 65 years had no medical visit over a time period greater than 1 year.
Two cohorts were identified within the population in the GPRD that met inclusion criteria: an exposed cohort (at least one prescription of aspirin and/or nonaspirin NSAIDs during follow-up) of 258,840 subjects and a nonexposed cohort (no prescription of aspirin and/or nonaspirin NSAID during follow-up) of 463,296 subjects. All members in the exposed cohort and an approximate 50 percent random sample (n = 200,000) of the nonexposed cohort (these two cohorts comprised our studys nested cohort) were followed until they met a case definition criterion for uncomplicated peptic ulcer, one of the exclusion criteria, their 80th birthday, death, or October 1999, whichever came first. This nested cohort included 458,840 subjects who contributed a total of 1,167,469 person-years, calculated by adding the years of follow-up contributed by each subject in the cohort.
Case ascertainment and validation
From our study cohort, nested in the GPRD, we identified 1,967 patients with codes for peptic ulcer and manually reviewed the demographic data and clinical information in their computerized patient profiles. Patient profiles do not have any personal identifiers. Patients had codes for peptic ulcer when the general practitioner or a consultant considered the ulcer clinically relevant; we followed their criteria for defining an ulcer and applied further study-specific inclusion criteria. We considered a patient to be a case of uncomplicated peptic ulcer when no exclusion criterion was found (see cohort definition above), the subject had not been discharged from a hospital in the previous month for reasons other than peptic ulcer, the clinical diagnosis of peptic ulcer was made during a visit to a specialist or during hospitalization (most likely by endoscopic examination, the standard diagnostic technique in the United Kingdom), and the specific site of the ulcer was located in the stomach or duodenum. Patients with complicated peptic ulcer (either bleeding or perforation) or with any of the exclusion criteria in the 2 months after the date of case detection (index date) were excluded. We classified cases according to the site of the ulcer into gastric, duodenal, or multiple site. For all 677 potential cases with no specific site mentioned in the computer profiles, we sent the general practitioners a questionnaire and a request to provide us with all paper-based information related to the episode of peptic ulcer. We received information for 615 patients, with 397 patients confirmed as a case of peptic ulcer. After the review of the computerized files and the manual records received, we ended up with 1,197 cases of symptomatic peptic ulcer, 419 of which had gastric ulcers, 705 had duodenal ulcers, 42 had multiple-site ulcers, and 31 had ulcers at an unknown site. These 31 cases remained with an unknown site because information on the specific site of the lesion was not mentioned in the correspondence of the consultant sent to the general practitioner. For 728 cases, Helicobacter pylori status was also mentioned and had been usually determined through urease and breath tests methods.
Controls
A total of 10,000 controls were randomly sampled from the entire nested study cohort that gave rise to the cases, so that the likelihood of being selected as a control was proportional to the person-time at risk. Specifically, a date during the study period was generated at random for each of the members of the source population. If the random date of a study member was included in his or her eligible person-time, we used his or her random date as the index date and marked that person as an eligible control. The same exclusion criteria were applied to controls as to cases. Ten thousand controls, frequency matched to cases by age (within 1 year), gender, and calendar year, were randomly selected from the pool of eligible controls.
Exposure definition
Exposure to aspirin and nonaspirin NSAIDs, assessment based on prescriptions written by the general practitioners and considered independently, was categorized as one of the following: "current," when the supply of the most recent prescription lasted until the index date or ended in the 30 days before the index date based on the length of drug therapy as prescribed by the general practitioner; "recent," when it ended 31180 days before the index date; "past," when it ended 181365 days before the index date; and "nonuse," when there was no recorded use during the 365 days prior to the index date.
Among current users, we studied the effect of duration, dose, and formulation. We evaluated duration of use adding the periods of "consecutive" prescriptions, defined as an interval of less than 2 months between two prescriptions. Current nonaspirin NSAID users were divided into "current single users" and "current multiple users." The latter category included patients who received prescriptions for different nonaspirin NSAIDs with their respective supply ending within the month before the index date. We also considered individual nonaspirin NSAIDs among current single users. Finally, we took into account simultaneous use of aspirin and nonaspirin NSAIDs.
Exposure to other drugs, such as acetaminophen, corticosteroids, H2 receptor antagonists (cimetidine, famotidine, nizatidine, and ranitidine), proton pump inhibitors (omeprazole, lanzoprazole, and pantoprazole), and prostaglandin analog (misoprostol), was also evaluated and categorized as current, recent, or past, as defined above.
Analyses
We computed incidence rates of symptomatic peptic ulcer both overall and in age and sex strata. These analyses were based on 1,167,469 person-years and 1,197 incident cases. The case-control analysis included 1,197 cases and 10,000 controls. We computed odds ratio estimates, assumed to provide a valid estimate of the relative risk (17), and the 95 percent confidence interval of symptomatic peptic ulcer associated with current use of aspirin and nonaspirin NSAIDs compared with nonuse with unconditional logistic regression.
All estimates of relative risk were adjusted for age (4059, 6069, or 7079 years), sex (male or female), study calendar year (19951999), study cohort (exposed or unexposed), past history of gastrointestinal symptoms (none, dyspepsia, or heartburn), smoking (current, past, or never), and use of corticosteroids, gastroprotective drugs, NSAIDs, and acetaminophen (current, recent, past, or no use, as defined above). Further adjustment for body mass index, alcohol intake, anticoagulants, cardiovascular disease, and indication (i.e., rheumatoid arthritis and osteoarthritis) did not change the results presented above and, therefore, these factors were not included in the final models. Statistical analyses were performed using StatView software (SAS Institute, Inc., Cary, North Carolina).
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RESULTS |
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Aspirin
Overall, use of aspirin was associated with an elevated risk of symptomatic peptic ulcer (RR = 2.9, 95 percent CI: 2.3, 3.6) (table 1). The risk was similarly elevated for both regular and enteric coated preparations. The risk of symptomatic peptic ulcer was elevated throughout treatment independently of its duration, was elevated with doses as low as 75 mg per day, and was no different from the one with doses of 150 and 300 mg daily. There was very little use at doses greater than 300 mg daily.
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Nonaspirin nonsteroidal antiinflammatory drugs
Current intake of nonaspirin NSAIDs increased the risk of symptomatic peptic ulcer four times (95 percent CI: 3.2, 5.1) (table 2). We found a slightly greater relative risk among those already on therapy for more than 6 months (RR = 4.6, 95 percent CI: 3.5, 6.0) than among newer users (RR = 2.8, 95 percent CI: 2.1, 3.7). In users of a medium daily dose or lower, the relative risk was 2.6 (95 percent CI: 2.0, 3.5), while in users of a high daily dose, the relative risk was 4.9 (95 percent CI: 3.8, 6.5). Nonaspirin NSAIDs with and without a slow-release formulation presented relative risks of 4.6 (95 percent CI: 3.1, 6.7) and 3.3 (95 percent CI: 2.6, 4.3), respectively. There was a dose effect within each formulation. Users of both nonaspirin NSAIDs and aspirin in the last month had a relative risk of 6.8 (95 percent CI: 4.5, 10.3) compared with users of neither. This risk is slightly greater than the sum of the independent effects of aspirin and nonaspirin NSAIDs.
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Topical nonaspirin NSAIDs were not associated with an increased risk of symptomatic peptic ulcer (RR = 1.0, 95 percent CI: 0.6, 1.7).
Acetaminophen
Current intake of acetaminophen was associated with a relative risk of 1.9 (95 percent CI: 1.5, 2.3) (table 4). The risk of symptomatic peptic ulcer was elevated months after continuous acetaminophen use but was slightly lower among long-term users. We did not find a dose response; the relative risk was 1.9 (95 percent CI: 1.5, 2.4) for doses up to 2 g and 1.8 (95 percent CI: 1.4, 2.4) for higher doses. The increase in risk did not vary much with either the primary site of the lesion or the H. pylori status.
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Misoprostol was the only gastroprotective agent associated with a reduced risk of symptomatic peptic ulcer regardless of the duration of therapy; the relative risk was 0.4 (95 percent CI: 0.2, 0.9) for patients who started taking misoprostol during the previous month and 0.5 (95 percent CI: 0.2, 1.5) for patients taking misoprostol for more than 1 month. The relative risks for treatments started during the last month were 2.9 (95 percent CI: 2.1, 4.2) for proton pump inhibitors, 8.3 (95 percent CI: 6.2, 11.2) for H2 receptor antagonists, and 3.7 (95 percent CI: 2.8, 5) for antacids. The relative risks for treatments started more than 1 month ago were 0.6 (95 percent CI: 0.4, 1.0) for proton pump inhibitors, 1.7 (95 percent CI: 1.2, 2.4) for H2 receptor antagonists, and 1.0 (95 percent CI: 0.6, 1.4) for antiacids. These results were similar for gastric and duodenal ulcers.
Other analyses
The risk of symptomatic peptic ulcer among current users of the antiinflammatory drugs studied above was elevated across all age categories and in both sexes, and it was similar for subjects with and without osteoarthritis. We did not find an association between the use of nitrates and the risk of symptomatic peptic ulcer.
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DISCUSSION |
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These findings are consistent with those of previous studies. In clinical trials, from 1 percent to 2 percent of the patients treated during 1 year with NSAIDs developed a symptomatic ulcer (18, 19). However, clinical trials often include a very selective group of patients, and the trials have limited power to study the risk of more relatively uncommon events, such as clinically relevant ulcers. Observational studies have estimated an incidence rate of hospitalizations for noncomplicated gastrointestinal events from 0.5 to 10 per 1,000 person-years (2, 2025); the incidence was increased from two to six times with NSAID use (2, 23, 24, 2628). The magnitude of these incidence rates and relative risks is similar to that estimated for complicated ulcers, for which the incidence has been estimated to be in the order of one case per 1,000 person-years among nonusers (14) and around two and four times higher for users of aspirin and nonaspirin NSAIDs, respectively (57).
In our population, the increased risk of symptomatic peptic ulcer remained elevated, or even intensified, with chronic treatment beyond 6 months of NSAID use. A higher relative risk among long-term users might be due in part to a lag of time between mucosal damage and clinical symptoms/diagnosis in some patients. Persistent gastrotoxic effects throughout therapy translate into an ever-increasing cumulative risk for chronic NSAID users. For aspirin, we did not find a dose effect over the range of cardioprotective doses nor a lower risk among users of enteric coated preparations. For nonaspirin NSAIDs, we found an increased risk associated with higher doses and for slow-release formulations. The relative risk was relatively similar among individual nonaspirin NSAIDs except for piroxicam that presented a greater risk. Nonaspirin NSAIDs presented a greater association with gastric than with duodenal ulcers.
We also considered H. pylori infection among cases and found that the relative risk for nonaspirin NSAID use was higher for noninfected than for infected lesions. This finding would be consistent with a protective effect of H. pylori infection against the ulcerogenic effect of nonaspirin NSAIDs (29). These data are intriguing, especially in light of the ongoing debate on the potential interaction between H. pylori and NSAIDs. However, because of incomplete data on H. pylori status (we did not have data on H. pylori for noncases, and the H. pylori diagnosis for cases was incomplete and not validated), our study cannot adequately contribute to our understanding of the role of H. pylori.
The current study has several strengths and limitations. Both cases and controls were identified from a well-defined population, which minimizes the probability of biased selection of controls. Furthermore, the population-based design expands the generalizability of the results. Drug use was ascertained prior to the diagnosis of the outcome, which minimizes the probability of information bias. The computer profiles of patients with possible peptic ulcer were manually reviewed, and cases were included in this study only when the clinical diagnosis of peptic ulcer was made during a visit to a specialist or hospitalization. In addition, we reviewed copies of original medical records of patients with an unclear ulcer site. These procedures minimize the probability of false positive cases. However, even after our effort to confirm and validate cases and our conservative exclusion of potential cases, there might still be a certain level of misclassification, which would tend to bias the results toward the null. On the other hand, due to our conservative approach and to undiagnosed ulcers among patients who do not seek medical advice, the reported incidence might be an underestimate.
Unlike most clinical trials, the current study had no information on compliance and, therefore, our observational data can only resemble an intention to treat analysis. Although the GPRD contains detailed information on prescribed medications, we did not have information on over-the-counter medications. However, nondifferential misclassification of drug use due to noncompliance or over-the-counter use would underestimate the association between NSAIDs and peptic ulcer. A preferential use of over-the-counter NSAIDs among ulcer patients, as suggested by the small amounts of NSAIDs often found in their serum despite denying the use of these drugs, would yield to an underestimation of the NSAID effect. Although differential misclassification of exposure is unlikely, a differential outcome misclassification might be plausible. That is, physicians might preferentially search for ulcers when their patients are on NSAIDs, which would reduce the probability of false negatives among NSAID users more than among nonusers. The latter would tend to overestimate the association between NSAIDs and peptic ulcer.
A plausible alternative explanation to a causal relation between NSAIDs and peptic ulcer is confounding by the indication for which the drug was prescribed. However, when we controlled for the main indications (i.e., rheumatoid arthritis and osteoarthritis) in the analysis, the association remained practically unchanged. Nonetheless, since we did not validate data on concomitant illnesses or other potential confounders such as alcohol consumption or smoking, residual confounding remains of some concern. More worrisome is the role of confounding in the association between gastroprotective drugs and peptic ulcer. Ulcers occurred more often in users of gastroprotective medications, which does not imply that these drugs are ineffective but rather that they are prescribed to high-risk patients. Patients using gastroprotective drugs were older, had a history of gastrointestinal symptoms, and were using antiinflammatory medications more often than were nonusers. Although we controlled for these well-known risk factors, residual channeling bias might explain at least partially the remaining elevated ulcer risk. Nonetheless, there was a clear trend toward protection with long-term use of proton pump inhibitors. In addition, use of misoprostol was associated with a reduced risk of developing symptomatic peptic ulcer among NSAID users. Clinical trials, which are unaffected by channeling bias, have shown the efficacy of acid-suppressing drugs in the general population and of misoprostol in NSAID users for the prevention of peptic ulcers (30).
An additional challenge encountered in the study of outcomes of the nature of uncomplicated peptic ulcers is the uncertainty around the incidence date, that is, the moment when the ulcer began. Unlike studies on severe complications or in series of screening endoscopies, the date of clinical diagnosis might occur months after the appearance of the first symptoms of peptic ulcer. Such misclassification would have several implications. The relevant drug exposure might have happened months before the date of diagnosis, which could explain the increased risk associated with NSAID use that terminated more than 1 month before the diagnosis. For the same reason, the relative risk assigned to "current" NSAID use would be under- or overestimated because of the inclusion of NSAID use that actually occurred after ulcer development. An additional potential implication of mixing incident cases with at least some prevalent cases is that part of the association found between NSAID exposure and peptic ulcer might be due to an effect on the duration of the ulcer (e.g., NSAIDs delay ulcer healing) rather than to a causal effect on the occurrence of the ulcer. Nonetheless, analyses of the data as if the actual incidence date occurred several months before the diagnosis weakened the associations (data not shown).
In summary, findings from a population-based study in the United Kingdom suggest that the incidence rate of symptomatic uncomplicated peptic ulcer is about one case per 1,000 person-years and that aspirin and nonaspirin NSAIDs multiply this risk by a factor of three and four, respectively, which is consistent with the incidences and relative risks reported in other observational studies. These findings, together with prior endoscopic evidence, suggest that NSAIDs might not only complicate preexisting peptic ulcers but also cause clinically relevant ones de novo.
ACKNOWLEDGMENTS
The authors are indebted to the Boston Collaborative Drug Surveillance Program for providing access to the General Practice Research Database. They thank Dr. Consuelo Huerta for helping in the review of the questionnaires and the general practitioners for their excellent collaboration.
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NOTES |
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REFERENCES |
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