Major Finding: In patients with rheumatoid arthritis or osteoarthritis on long-term NSAID treatment, daily celecoxib produced a 0.9% rate of lower gastrointestinal bleeding events, significantly less than the 3.6% rate in patients treated with diclofenac plus omeprazole.
Data Source: Multicenter, randomized trial with 4,484 patients.
Disclosures: The study was sponsored by Pfizer. Dr. Goldstein said that he has received grant support and honoraria from Pfizer. He also disclosed financial relationships with AstraZeneca, TAP, Takeda, Novartis, Pozen, Logical Therapeutics, Procter & Gamble, PLX, Wyeth, Astellas, Amgen, Given, GlaxoSmithKline, and Merck.
ROME — Daily treatment with a selective cyclo-oxygenase-2 inhibitor triggered significantly fewer lower gastrointestinal adverse events than did a nonsteroidal anti-inflammatory drug plus a proton pump inhibitor, in a randomized trial with more than 4,000 patients.
Results from many studies have already shown that small bowel ulcers, obstruction, perforations, and bleeding can all occur during treatment with a non-steroidal anti-inflammatory drug, although at a lower rate than in the upper gastrointestinal tract. The new findings “give us an idea of what is the relative risk up and down the gastrointestinal tract,” Dr. Jay L. Goldstein said while presenting a poster at the meeting.
“Upper GI tract [adverse events] are still more common, but injury in the small bowel is a real phenomenon. This is the first study to systematically address the issue of these events in a prospective, randomized control trial,” said Dr. Goldstein of the University of Illinois at Chicago.
He acknowledged that upper GI bleeds usually have a more acute and dramatic onset, often causing vomiting and even shock, whereas the anemias resulting from the lower GI bleeds in this study had a more insidious course. The lower GI events “are not immediately life threatening, but when you see a drop in hemoglobin, it's a call to action,” Dr. Goldstein said in an interview.
CONDOR (Study of Celecoxib or Diclofenac and Omeprazole for Gastrointestinal Safety in High GI Risk Patients With Arthritis) ran at 196 centers in 32 countries during 2005-2009. The study randomized patients expected to need regular NSAID treatment for at least 6 months to either the cyclo-oxygenase-2 inhibitor (coxib) celecoxib at 200 mg b.i.d, or to a slow-release formulation of the nonselective NSAID diclofenac at 75 mg b.i.d. plus the proton pump inhibitor omeprazole at 20 mg once daily. The study was sponsored by Pfizer, which markets celecoxib (Celebrex).
“It makes sense that a proton pump inhibitor will only protect the upper GI tract. The concept was that we wanted to be sure that the patients [in the control arm] had upper GI protection to find out what goes on beyond the upper GI tract,” Dr. Goldstein said.
The study's primary end point was the composite incidence of clinically significant events occurring throughout the gastrointestinal tract during the first 6 months of treatment. The investigators confirmed 20 primary end points among 2,238 patients on celecoxib (0.9%), and 81 events among 2,246 patients on diclofenac plus omeprazole (3.6%). The difference in event rates between the two treatment arms was statistically significant. The main driver behind this difference was a higher incidence of patients with a hemoglobin decrease of at least 20 g/L: 15 patients in the celecoxib arm and 77 in the control arm.
These primary results from the trial appeared in an article published simultaneously with Dr. Goldstein's poster report at the meeting (Lancet 2010;376:173-9).
A new analysis that he presented in his poster identified risk factors linked with the increased risk for GI events in CONDOR, including age of 65 or older, which boosted the risk by 40% compared with younger patients; a history of gastritis, which boosted the risk by 50% compared with patients without this history; having rheumatoid arthritis, which raised the risk by 90% compared with osteoarthritis; and a C-reactive protein level at baseline of more than 1 mg/dL, which raised the risk by 50% compared with patients with lower C-reactive protein levels.
“We know that age is a risk factor for upper GI events; now we're suggesting that it's also a risk factor for lower events. And patients with prior GI problems may also be at risk,” Dr. Goldstein said. The increased risks linked with RA and elevated C-reactive protein “may be very similar things,” reflecting the effect of a chronic, underlying inflammatory disease. “The evidence is split on a role [for RA] in upper GI events. Here we have a clear signal of lower GI sensitivity that warrants further study.”
The findings suggest that an otherwise healthy 55-year-old patient with no history of gastritis who needs long-term NSAID treatment would face a relatively low risk for GI bleeds on a nonselective NSAID, Dr. Goldstein said. But in a similar, 65-year-old patient, “I—d use a coxib or add a proton pump inhibitor,” he said.