Fewer GI Events With Supertherapeutic Doses of Rofecoxib

Family Pratice News,  August 1, 2000  by Betsy Bates

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SAN DIEGO -- Rheumatoid arthritis patients who took supertherapeutic doses of rofecoxib for pain relief experienced fewer than half as many significant upper GI events as patients who took standard doses of naproxen.

The results of the large prospective study, which was funded by Merck, makers of rofecoxib (Vioxx), were released at the annual Digestive Disease Week.

Merck plans to submit the study results to the Food and Drug Administration to seek an indication for rofecoxib for the treatment of rheumatoid arthritis. It is already approved for osteoarthritis, acute pain, and menstrual pain.

Symptomatic ulcers, perforation, obstruction, and bleeding were 54% less common in the patients who were assigned to take a supertherapeutic dose of rofecoxib than in the patients who took standard doses of naproxen.

Upper GI events that were considered to be "complicated"--a category that included perforation, obstruction, or major bleeding episodes--were 57% less common in the patients who took rofecoxib in the trial.

The relative risk of any upper GI event was 62% lower in patients on the COX-2 inhibitor, said Dr. Loren Laine, cochair of the study, which was conducted at the University of Southern California in Los Angeles; University of Toronto; and University of Nottingham (United Kingdom).

More than 8,000 patients were enrolled in the randomized trial. A total of 4,047 patients received 50 mg of rofecoxib once a day, a dosage that is two to four times higher than the dosage for chronic use in osteoarthritis patients. The remaining 4,029 patients took 500 mg of naproxen twice daily.

All of the patients were followed up between 6 and 13 months, with a 9-month mean duration of study participation.

Of 190 upper GI events, 177 were confirmed and 53 were judged by an independent panel of physicians to be complicated.

GI-related events were more common among patients taking naproxen beginning in and persisting beyond the third week of the study.

Because the length of participation varied, the risk of a GI-related event was calculated per 100 patient-years of exposure, explained Dr. Laine, professor of medicine at USC.

The risk of a complicated GI event was 1.4 per 100 patient-years for naproxen and 0.6 for rofecoxib. The risks of less serious events were 4.5 and 2.1, respectively, he said.

Upper GI events were more common in patients with a prior upper GI event, patients over age 65, those on steroids, and men.

Patients who had been using NSAIDs at baseline were significantly less likely than other patients to have an upper GI event. Dr. Laine speculated that these patients had already demonstrated their ability to tolerate NSAIDs.

Interestingly, the 42% of patients who had positive tests for Helicobacter pylori at baseline were not statistically more likely than other patients to have an upper GI event.

Efficacy was equivalent among the two groups. Fewer than 7% of patients in each arm of the study withdrew because the medication was ineffective for pain.

This finding should be kept in perspective, Dr. Laine noted, since patients were taking supertherapeutic dosages of rofecoxib and standard dosages of naproxen.

Adverse events led to withdrawal from the trial by 5.3% of patients taking naproxen and 3.7% of patients taking rofecoxib. All of the top five adverse events leading to withdrawal were GI-related symptoms, including dyspepsia, abdominal pain, upper abdominal pain, nausea, and heartburn.

Patients in the study represented an older population, with an average age of 58. Nearly half of those enrolled had a history of cardiovascular disease and 4% had symptoms that were significant enough to meet criteria for secondary cardiovascular prophylaxis.

Total deaths and deaths from cardiovascular disease were comparable in both groups, but there were fewer myocardial infarctions among patients taking naproxen, Dr. Laine reported.

"This seems likely to be due. to naproxen's potent antiplatelet effect, similar to aspirin. Even in superpotent doses, rofecoxib has no antiplatelet activity due to its COX-2 selectivity," he said.

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