Risk of Upper Gastrointestinal Complications Associated with Cyclooxygenase-2 Selective and Nonselective Nonsteroidal Antiinflammatory Drugs

Jordi Castellsague, M.D., M.P.H.; Crystal N. Holick, Sc.D., M.P.H.; Clorinda C. Hoffman, M.P.H.; Victoria Gimeno, M.D., M.P.H.; Mary-Rose Stang, Ph.D.; Susana Perez-Gutthann, M.D., M.P.H., Ph.D., FISHE, FRCP


Pharmacotherapy. 2009;29(12):1397-1407. 

In This Article

Abstract and Introduction


Study Objective. To estimate the risk of upper gastrointestinal complications associated with use of cyclooxygenase-2 (COX-2) selective (celecoxib and rofecoxib) and individual nonselective nonsteroidal antiinflammatory drugs (NSAIDs) compared with nonuse of these drugs.
Design. Nested case-control study.
Data Source. Administrative health care databases of Saskatchewan, Canada.
Patients. Among a population of men and women aged 20–89 years who were covered by public health insurance with prescription drug benefits between November 15, 1999, and December 31, 2001, 726 case patients with first hospitalization for upper gastrointestinal complications (with validation of cases through review of hospital medical records) were confirmed from 1,054,532 person-years of follow-up, and 20,002 control patients were randomly selected from all eligible controls, frequency matched to cases on their index date (±3 mo).
Measurements and Main Results. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between upper gastrointestinal complications and use of NSAIDs. Current rofecoxib and naproxen users had the highest risk for upper gastrointestinal complications with adjusted ORs of 3.6 (95% CI 2.2–5.7) and 3.4 (95% CI 1.8–6.7), respectively. No association was found between the risk of upper gastrointestinal complications and use of celecoxib (OR 1.1, 95% CI 0.7–1.8) or the use of diclofenac plus misoprostol (OR 0.7, 95% CI 0.3–1.8). A dose-response relationship was observed for rofecoxib and naproxen with ORs for high dose of 5.2 (95% CI 2.5–10.6) and 5.1 (95% CI 2.1–12.3), respectively. Short-term users of celecoxib and naproxen had a higher risk than long-term users, whereas among users of rofecoxib the risk was higher among long-term than short-term users.
Conclusion. These findings support the variability of individual NSAIDs in the elevated risk of upper gastrointestinal complications. Our results suggest that the risk for rofecoxib is similar to that for naproxen. Celecoxib users appear to have a similar risk for upper gastrointestinal complications as nonusers; however, the risk may be increased at the start of treatment with celecoxib.


Cyclooxygenase 2 (COX-2) selective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with a lower risk of gastrointestinal complications compared with nonselective NSAIDs. Randomized clinical trials have shown a reduction by half in the risk of peptic ulcer complications in patients randomly assigned to receive celecoxib and rofecoxib compared with nonselective NSAIDs;[1,2] however, only a few studies have examined the effect of COX-2 selective NSAIDs as used in general practice. A cohort study of an elderly population in Ontario, Canada, found that the risk of upper gastrointestinal bleeding among users of celecoxib and rofecoxib was lower than the risk among users of nonselective NSAIDs and diclofenac plus misoprostol.[3] Results from other population-based studies suggest that the risk of upper gastrointestinal complications associated with rofecoxib use might be similar to that of some individual nonselective NSAIDs.[4–6] Furthermore, both celecoxib and rofecoxib have been associated with a higher risk of cardiovascular events, leading to the withdrawal of rofecoxib from the market and to a restricted use of celecoxib.[7,8] A higher risk of cardiovascular events has been reported for some individual NSAIDs, although naproxen has been associated with a protective cardiovascular effect.[9,10] Overall, the risks versus benefits of these drugs remain uncertain and warrant further investigation to obtain valid population-based risk estimates. We conducted a nested case-control study to estimate the risk of upper gastrointestinal complications associated with the use of individual COX-2 selective and nonselective NSAIDs compared with nonuse of these drugs in the general population of Saskatchewan, Canada.


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