Nonsteroidal anti-inflammatory drugs (NSAIDs) are heavily prescribed by physicians and are increasingly available on an over-the-counter basis in reduced dosages. Although effective for a variety of conditions, NSAIDs have potential toxicity, usually involving the gastrointestinal tract. Ulcer formation and bleeding ultimately result from the inhibition of protective prostaglandins that are mediated by cyclooxygenase-1. Standard NSAIDs inhibit the effect of this enzyme and its counterpart, cyclooxygenase-2 (COX-2). New anti-inflammatory agents have been developed that selectively inhibit COX-2, which, in theory, should limit their gastrointestinal toxicity. Bombardier and colleagues recently completed a prospective, randomized, double-blind study that compared one of the newer selective NSAIDs with a traditional anti-inflammatory agent.
Patients enrolled in this study were at least 50 years of age, with a history of rheumatoid arthritis, who were expected to require NS AID therapy for at least one year. Excluded were patients with significant renal or cardiovascular disease or a positive test for fecal occult blood, patients taking anticoagulants or platelet-inhibiting agents, proton pump inhibitors or prescription dosages of hista-mine H2-receptor antagonists.
Eligible patients were assigned to receive 50 mg of rofecoxib daily or 500 mg of naproxen twice daily, along with a matching placebo for each medication. Patients were allowed to continue taking glucocorticoids, acetaminophen or disease-modifying agents to control their rheumatoid arthritis. Follow-up was at six weeks and four months after randomization, then every four months until the end of the study. Frequent telephone contact was also maintained. The primary end point of the study was any clinical upper gastrointestinal event, including perforation, obstruction, bleeding or symptomatic ulcer formation. Efficacy of the two NSAIDs was assessed by the Global Assessment of Disease Activity questionnaire at baseline and at six weeks, four months, 12 months and the end of the study, or when treatment was discontinued.
The trial enrolled more than 4,000 patients in each of the study groups. The majority of patients (80 percent) were women, and the mean age was 58 years. Median follow-up was nine months, and 71 percent of patients were still taking an NSAID at the completion of the trial. Approximately 16 percent of patients in each group discontinued the drug because of adverse events, and 6 percent of patients discontinued use because of lack of efficacy. The Global Disease Activity scores were similar in the naproxen and rofecoxib groups.
There were 177 confirmed upper gastrointestinal events, including gastric ulcers, duodenal ulcers and bleeding. A total of 121 of these occurred in patients receiving naproxen, and 56 occurred in patients receiving rofecoxib. Fifty-three of the events were classified as complicated, as confirmed by upper endos-copy, and 37 of these occurred in the patients receiving naproxen. Overall, there was a complication rate of 0.6 and 1.4 per 100 patient-years in patients receiving rofecoxib and patients receiving naproxen, respectively.
The authors conclude that in patients with rheumatoid arthritis, rofecoxib taken at a dosage of 50 mg daily (which is actually twice the maximal dosage approved by the U.S. Food and Drug Administration for chronic use) produces significantly fewer clinical gastrointestinal adverse events compared with 1,000 mg of naproxen per day. Based on analysis of this data, they note that 41 patients would have to be treated with rofecoxib instead of naproxen to prevent one clinically important upper gastrointestinal event in one year.
editor's note: This large study validates other studies that have reached similar conclusions. However, with clinical efficacy being the same, it comes down to economics because of the substantially greater price of the new selective COX-2 anti-inflammatory agents. The question remains as to whether the costs saved by fewer severe episodes of upper gastrointestinal bleeding are offset by the much greater expense of these medications.—j.t.k.