National Harbor, Md.—A large randomized, “real-world” study demonstrated that celecoxib (Celebrex, Pfizer) is associated with a lower risk for upper and lower gastrointestinal (GI) events compared with nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs).

The study “demonstrates the improved GI safety profile of celecoxib throughout the GI tract,” said senior investigator, Byron Cryer, MD, professor of medicine in the Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, in Dallas. The results of the trial, called GI-REASONS (GI Randomized Event and Safety Open-label NSAID Study), were presented at the 2011 annual meeting of the American College of Gastroenterology.

Data from GI-REASONS confirm the conclusions of two earlier landmark studies in the field. More than 10 years ago, CLASS (Celecoxib Long-term Arthritis Safety Study) demonstrated that celecoxib was associated with a lower risk for upper GI events compared with ibuprofen or diclofenac in adult patients with osteoarthritis or rheumatoid arthritis (JAMA 2000;284:1247-1255). CLASS was one study among a series of large randomized trials that demonstrated that selective inhibitors of cyclooxygenase (COX)-2, like celecoxib, are associated with a reduced risk for GI events compared with classical nsNSAIDs, like ibuprofen. More recently, the CONDOR (Celecoxib versus Omeprazole and Diclofenac in patients with Osteoarthritis and Rheumatoid arthritis) trial examined GI risk in adult patients with osteoarthritis or rheumatoid arthritis who were taking celecoxib or diclofenac slow release in combination with the proton pump inhibitor (PPI) omeprazole (Lancet 2010;376:173-179). Patients included in the CONDOR trial (aged 60 years and older, or 18 years and older with previous gastroduodenal ulceration) had an increased risk for GI events. The CONDOR trial demonstrated that risk for clinical outcomes throughout the GI tract was lower in patients treated with celecoxib compared with those receiving an nsNSAID plus a PPI.

Angel Lanas, MD, Gastroenterology Service, University Hospital, Zaragoza, Spain, a co-author of the CONDOR study, said that the current study, GI-REASONS, “provides confirmatory evidence of data obtained from CONDOR.”

The initial focus of COX-2 inhibitor research was on relative protection from gastric ulcers, said Dr. Lanas. But a newer emphasis on events in the lower GI tract as well in studies of COX-2 inhibitors may be meaningful for patients at risk for GI bleeding, he added.

In GI-REASONS, like the CONDOR trial, investigators examined NSAID use and the risk for events throughout the GI tract, including lower GI bleeding, as detected by changes in hemoglobin or hematocrit. The study employed a prospective, randomized, open-label, blinded, end point design, with exclusion and inclusion designed to reflect “real-world” practice, Dr. Cryer said.

A total of 8,067 patients with osteoarthritis and moderate risk for GI events were enrolled in GI-REASONS; 4,035 were randomized to receive celecoxib and 4,032 received an nsNSAID (meloxicam, 42%; naproxen, 21%; diclofenac, 20%; and nabumetone, 14%). Aspirin use was not permitted in either group; patients in whom aspirin was indicated because of cardiovascular risk factors were excluded from the study. The use of gastroprotective agents (GPAs), including PPIs, was permitted, regardless of treatment assignment. GPAs were used by approximately 25% of patients in each treatment group. Testing for Helicobacter pylori was conducted, and the presence of H. pylori was used as a stratification factor in the analysis of the results.

At six months of treatment, a GI event occurred in almost twice the proportion of patients receiving an nsNSAID as in those who received celecoxib (2.4% vs. 1.3%; odds ratio [OR], 1.82; 95% confidence interval [CI], 1.31-2.55; P=0.0003). When stratified by the presence or absence of H. pylori, the relative advantage of celecoxib was greater for those who were H. pylori-negative (2.4% vs. 1.1%) than for those who were H. pylori-positive (2.5% vs. 1.8%). Moderate to severe abdominal symptoms occurred in 2.3% of patients who received celecoxib compared with 3.4% of those randomized to an nsNSAID (P=0.0035).

According to Dr. Cryer, the difference in the rates of GI events could be attributed largely to GI bleeding, as revealed by changes in hemoglobin (defined as a >2 g/dL reduction) or hematocrit.

Dr. Cryer noted that there was a numerically, but not statistically, greater number of cardiovascular (CV) events among patients who received celecoxib than with the nsNSAIDs. CV events, which included unstable angina, revascularization and transient ischemic attacks, were recorded in 17 patients in the celecoxib group versus 13 patients in the nsNSAID group, which Dr. Cryer described as “a slight imbalance.” Serious adverse events were uncommon in both groups.

The results of the study suggest that for patients with moderate GI risk and relatively low CV risk (i.e., <10% estimated likelihood for having a CV event in the next 10 years), treatment with celecoxib is safer than treatment with an nsNSAID. The study did not require that patients taking nsNSAIDs take a concomitant GPA; it was designed to reflect “real-world” risks. The results indicated that much of the risk protection offered by the COX-2 inhibitor takes place in the lower GI tract, where a GPA would not be expected to provide much benefit.

“When considering the entire GI tract, celecoxib is superior to the other accepted alternative of a traditional NSAID plus a PPI in patients with increased GI risk,” concluded Dr. Lanas, professor of medicine, University of Zaragoza, Spain, who was not an investigator in GI-REASONS. “The difference is particularly relevant for hemoglobin or hematocrit drops of either confirmed or presumed GI origin,” he said.

Dr. Cryer has served as a consultant to AstraZeneca, Cogentus Pharmaceuticals, Inc., Horizon Pharma, NicOx, Pfizer Inc., PLx Pharma, Pozen and TAP Pharmaceuticals. Dr. Lanas is an adviser for and has received research funds from AstraZeneca, Bayer, NicOx and Pfizer.