PRECISION Substudy: Celecoxib’s Safety Edge Remains Intact but Attenuated with Aspirin Use

A new substudy of the large PRECISION trial shows that adding aspirin attenuates celecoxib’s safety advantage over the nonselective NSAIDs naproxen and ibuprofen but that celecoxib, a selective COX-2 inhibitor, still retains an equal or better safety profile relative to both agents even with aspirin coadministration.

“Concomitant use of NSAIDs and aspirin is widespread,” says Steven Nissen, MD, Chairman of Cardiovascular Medicine at Cleveland Clinic and corresponding author of the substudy, published by the Journal of the American College of Cardiology on April 16.

He notes that all NSAIDs increase cardiovascular, gastrointestinal (GI) and renal risk but that individual NSAIDs’ risk profiles differ and are modified by concomitant aspirin use. “These modifications are not well understood,” he says, “which makes advising patients about the safety of combined NSAID and aspirin use challenging. So the PRECISION trial protocol prespecified an analysis stratified by aspirin use to address this question.”

PRECISION recap

The multicenter randomized PRECISION trial, directed by the Cleveland Clinic Coordinating Center for Clinical Research (C5 Research), involved 24,000 patients with osteoarthritis or rheumatoid arthritis on long-term NSAID therapy who were at elevated cardiovascular risk.

As reported by Dr. Nissen and colleagues in the New England Journal of Medicine in late 2016, the study’s primary analysis demonstrated the noninferiority of moderate-dose celecoxib to naproxen and ibuprofen with regard to cardiovascular safety. Celecoxib was also associated with lower rates of GI and renal adverse events — and perhaps with reduced all-cause mortality.

PRECISION enrollees were randomized by their primary diagnosis (osteoarthritis or rheumatoid arthritis) and stratified by use of low-dose aspirin (≤ 325 mg) at baseline to ensure equal distribution among the NSAIDs groups. Aspirin doses greater than 325 mg/d were not permitted.

Substudy findings

The present prespecified substudy evaluated the trial’s on-treatment population, which consisted of 11,018 patients taking concomitant aspirin and 12,935 patients not on aspirin. Propensity score weighting was used to adjust for baseline characteristics, thereby increasing the validity of comparisons.

Among the patients not taking aspirin, celecoxib demonstrated a more favorable overall safety profile than both naproxen and ibuprofen, including significantly lower rates of the primary composite end point of major adverse cardiovascular events (MACE), noncardiovascular death, GI events or renal events. Compared with celecoxib, ibuprofen was associated with significantly more MACE, and both ibuprofen and naproxen were associated with significantly more GI and renal events.

With the addition of aspirin, celecoxib was still associated with lower rates of the primary composite end point relative to ibuprofen but not relative to naproxen (to which it still remained noninferior). In addition, rates of MACE were statistically comparable among all three NSAIDs. However, celecoxib remained associated with fewer GI events than either ibuprofen or naproxen and with fewer renal events than ibuprofen.

Continued support for the PRECISION hypothesis

“This substudy shows that the relative cardiovascular and overall safety of NSAID treatment is modified by concurrent aspirin use,” says the paper’s first author, Grant Reed, MD, MSc, an interventional cardiology fellow at Cleveland Clinic. “Celecoxib had a more favorable overall safety profile than ibuprofen or naproxen among NSAID users not taking aspirin, whereas the addition of aspirin attenuated this advantage. While celecoxib no longer showed advantages in MACE with concomitant aspirin use, it still was associated with advantages over ibuprofen in overall, GI and renal safety and with an advantage over naproxen in GI safety.”

Dr. Nissen adds that these findings support the hypothesis and primary findings of the PRECISION trial that the elevated cardiovascular risk observed with an earlier selective COX-2 inhibitor, rofecoxib, is not a COX-2 inhibitor class effect, even in the setting of aspirin coadministration.

Takeaways for practice

“These results suggest that, in many cases, celecoxib may be preferred to naproxen or ibuprofen for long-term NSAID therapy, particularly if the patient does not need to also use aspirin,” says Dr. Reed.

Dr. Nissen notes that, despite the prespecified nature of this substudy, its results should be considered hypothesis-generating since PRECISION was not designed to detect an interaction between NSAIDs and aspirin. Nevertheless, it represents one of the most robust investigations of the safety of combined long-term NSAID and aspirin use to date.

“Physicians prescribing any NSAID should consider the potential GI, renal and cardiovascular risks of combined NSAID and aspirin therapy,” Dr. Nissen advises, “since aspirin modifies the relative safety of various NSAIDs. Our findings underscore how important patient counseling on the relative safety of NSAIDs can be when starting therapy.”