COX-2 inhibitor not inferior to naproxen, ibuprofen for CV risk


Concern about the cardiovascular risks of cyclooxygenase-2 (COX-2) inhibitors may be overblown. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial showed that the COX-2 inhibitor celecoxib is not inferior to ibuprofen or naproxen in cardiovascular safety.

While the PRECISION trial was a comparison of the three drug regimens rather than a comparison of the three drugs, it is clear that celecoxib is at least as safe as the two nonsteroidal anti-inflammatory drugs (NSAIDs) in terms of cardiovascular risk, according to trial results presented Nov. 13 during the AHA Scientific Sessions.

“The highest event rates occurred in the ibuprofen arm and the lowest rates in the celecoxib group,” said lead author Steven E.  Nissen, MD, chairman of cardiovascular medicine at Cleveland Clinic in Ohio. “The time to major cardiovascular events was highest with ibuprofen and lowest with celecoxib, although the differences were not statistically significant. The time to death from cardiovascular causes was shortest with naproxen and longest with celecoxib. And the time to all-cause mortality was shortest with naproxen and longest with celecoxib, although these differences were not statistically significant.”

NSAIDs are among the most commonly prescribed drugs in the world, with more than 100 million prescriptions in the U.S. in 2013, Nissen said. The class gained a significant boost when rofecoxib, a selective COX-2 inhibitor was withdrawn from the market over concerns about its cardiovascular safety. Those same cardiovascular concerns led to the launch of PRECISION in 2006.

The trial compared three regimens for pain in osteoarthritis and rheumatoid arthritis: celecoxib 100 mg b.i.d., ibuprofen 600 mg t.i.d., and naproxen 375 mg b.i.d. (with matching placebo). All of the participants were given esomeprazole to minimize GI toxicity.

In PRECISION, all of the regimens could be increased as needed for analgesia up to the maximum dose allowable under local conditions at 926 global sites. A total of 24,081 patients were randomized starting in October 2006.

The primary outcome was a non-inferiority assessment of the cardiovascular safety of celecoxib versus ibuprofen and naproxen. The primary analysis used the Antiplatelet Trialists Collaboration (APTC) criteria of cardiovascular death, including hemorrhagic death, nonfatal myocardial infarction or nonfatal stroke.

Other outcomes included the comparative safety of the three agents for all-cause mortality as well as adverse gastrointestinal and renal events. Comparisons included major cardiovascular events, defined as APTC plus revascularization or hospitalization for unstable angina or transient ischemic attack, major GI events, major renal events and hospitalization for hypertension or congestive heart failure. The trial included both an intent-to-treat analysis and an on-treatment analysis.

Celecoxib was not inferior to either ibuprofen or naproxen in terms of cardiovascular safety, Nissen said, and was superior to the comparators in some on-treatment analyses. It was significantly safer than the two NSAIDs in terms of serious gastrointestinal and renal events, he added. A post-hoc analysis showed celecoxib was safer than either ibuprofen or naproxen for any adjudicated cardiovascular, GI or renal event. It also had significantly fewer investigator adverse events including anemia, increased blood pressure, hypertension and increased creatinine.

Celecoxib had a hazard ratio of 0.60 for adjudicated hospitalization for hypertension compared to ibuprofen and there was no clinical difference in analgesia between the three regimens.

“After the withdrawal of rofecoxib, there ensued a rush to judgment about the cardiovascular safety of COX-2 inhibitors,” Nissen concluded. “Fueled by the controversy, investigators and some expert commentary used observational data, small RCTs [randomized controlled trials] and theoretical concerns to ‘confirm’ what they expected. The PRECISION trial demonstrates the hazards inherent in prejudgment about the risks and benefits of therapies based upon expectations and indirect methods. These findings serve as an important warning to the medical community that we may arrive at erroneous conclusions when we fail to follow a systematic and unbiased approach to scientific and public health questions.”