Atlanta, GA - Experts disagree over whether celecoxib (Celebrex, Pfizer) increases the risk of cardiovascular events, and the results of meta-analyses on the subject have been ping-ponging back and forth, with some suggesting an increased risk and others arguing the threat is minimal. This latest finding, looking at 41 000 patients and presented at the recent American College of Cardiology 2006 Scientific Sessions, suggests that the risk associated with the popular coxib is comparable to traditional nonsteroidal anti-inflammatory drugs (NSAIDs) [1].

Dr William White

"We did not see an increase in events with this particular COX-2 inhibitor," lead author Dr William White (University of Connecticut School of Medicine, Farmington, CT) told heartwire. "We also performed an assessment of dose and looked at 200, 400, and 800 mg. We found no dose-related increases in cardiovascular events," the cardiologist reported.

But this finding contradicts that of previous groups, such as New Zealand researchers who reported that celecoxib is associated with an increased risk of myocardial infarction consistent with a class effect of COX-2 inhibitors. The group suggests that the preferential risk/benefit assessment afforded celecoxib over other COX-2 inhibitors by the US Food and Drug Administration may not be supported by the currently available evidence [2].

Spokespeople from Pfizer criticized this finding and accused the authors of selectively choosing studies to include in the analysis.

Dr Richard Beasley

But senior author Dr Richard Beasley (Medical Research Institute of New Zealand, Wellington) dismissed the allegations. "Pfizer's criticism that the meta-analysis selectively chose six studies is simply incorrect," he said. "To be included in the systematic review, studies had to be randomized, double-blind, controlled trials of at least six weeks' duration and report serious cardiovascular thromboembolic events. To include studies that did not meet these criteria would be flawed—this is the problem with Pfizer's own meta-analysis, which included a greater number of studies, the majority of which did not report serious cardiovascular thromboembolic events."

Beasley criticizes this latest Pfizer-promoted meta-analysis for not including studies on bowel adenomas in high-risk subjects, such as the Solomon study published in the New England Journal of Medicine [3]—the major study in which cardiovascular risks with celecoxib were observed.

White responds that Beasley's own study was "small" and says his group did not include data on adenomas because they were using a cutoff date of 2004. "Unfortunately, that study was not finished early enough, but I don't think it would have changed much," White said during an interview.

In White's analysis, the researchers studied the incidence of cardiovascular events for celecoxib, placebo, and NSAIDs in a clinical-trial database for celecoxib using the defined end points of nonfatal myocardial infarction, stroke, and cardiovascular death.

They derived patient data from studies in arthritis, back pain, and Alzheimer's disease. A three-member cardiovascular-end-point committee blinded to treatment group and study evaluated events.

Cardiovascular events in celecoxib trials

Events	Celecoxib CV events, events/n (and per 100 patient-y)	Comparator CV events, events/n (and per 100 patient-y)	Relative risk (95% CI)	p
Nonadjudicated
Placebo-controlled	23/7462 (1.81)	8/4057 (1.37)	1.26 (0.57, 2.80)	0.57
NSAID comparator	57/19 773 (1.01)	54/13 990 (1.23)	0.86 (0.59, 1.26)	0.44
Adjudicated
Placebo-controlled	18/7462 (1.42)	7/4057 (1.20)	1.11 (0.47, 2.67)	0.81
NSAID comparator	54/19 773 (0.96)	49/13 990 (1.12)	0.90 (0.60, 1.33)	0.59

"This meta-analysis is the largest on the cardiovascular safety of a coxib to date," Professor Jürgen Frölich, former head of the department of clinical pharmacology at the Hannover Medical School in Germany, said in a news release. "It shows that there is no greater risk of cardiovascular events with celecoxib compared with traditional NSAIDs."

The researchers emphasize that event rates were similar for adjudicated and nonadjudicated data. Dose of celecoxib, use of aspirin, presence of CV risk factors, and treatment indication—osteoarthritis vs rheumatoid arthritis vs other—did not alter these results.

"This sets the stage nicely for a larger prospective trial," White told heartwire. Pfizer's 20 000-patient Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) study is projected to be complete in three years.