Celecoxib Remains Safer With Aspirin Than Other NSAIDs

Steve Nissen, MD

A new sub-study of the decade-long, PRECISION noninferiority trial has revealed that while taking celecoxib (Celebrex, Pfizer) in combination with aspirin can lessen the cardiovascular safety profile of the therapy, there is still a lower risk for gastrointestinal issues compared with naproxen (Naprosyn, Atnahs) and ibuprofen (Motrin, Johnson & Johnson), and less kidney problems than with ibuprofen.

Principle investigator Steve Nissen, MD, the chairman of Cardiovascular Medicine at Cleveland Clinic, and colleagues examined 23,953 patients with osteoarthritis or rheumatoid arthritis that were at an increased risk for cardiovascular events that were randomized to celecoxib, naproxen, or ibuprofen for at least 18 months. In total, 11,018 of the patients were also taking aspirin, while the remaining 12,935 were not.

The primary outcomes of the trial were composite major adverse cardiovascular events (MACE), non-cardiovascular death, gastrointestinal or renal events, and components of the composite with the 3 nonsteroidal anti-inflammatory drugs (NSAIDs).

“NSAIDs are some of the most widely used drugs in the world with more than 100 million prescriptions issued annually in the United States,” Nissen said in a statement. “Past studies have reported conflicting results regarding using NSAIDs together with aspirin, but we know that many patients do combine the medications, so it was vital to understand the risks and differences among the drugs.”

"Opposed to the overall PRECISION trial, an intent-to-treat analysis, we looked at on-treatment analysis, which is, I think, the more important analysis for cardiovascular and overall safety," Grant Reed, MD, an interventional cardiology fellow at Cleveland Clinic, and the study’s first author told MD Magazine. "We only count the patients actually taking the medications. Patients in pain often switch between medications consistently because they feel bad and they want to achieve an analgesic effect."

Ultimately, Reed said, these data add more to the understanding of the interplay between COX-1 and COX-2 inhibition and overall safety, "and really suggest that there is a difference between NSAIDs when it comes to safety."

Naproxen (hazard ratio [HR], 1.52; 95% CI, 1.22 to 1.90; P <.001) or ibuprofen (HR, 1.81; 95% CI, 1.46 to 2.26; P <.001) use without aspirin was associated with a greater risk of the composite than celecoxib. Ibuprofen was associated with more MACE (P <.05) than celecoxib and both ibuprofen and naproxen were linked to more gastrointestinal (P <.001) and renal (P <.05) events.

In conjunction with aspirin, ibuprofen was revealed to have a greater risk of the composite (HR, 1.27; 95% CI, 1.06 to 1.51; P < 0.01) than celecoxib. Naproxen, however, did not have a significantly higher risk (HR, 1.18; 95% CI, 0.98 to 1.41; P= 0.08). When comparing events while taken with aspirin, MACE was similar among the 3 NSAIDs, however, when compared with celecoxib, ibuprofen-related gastrointestinal (0.9% vs. 1.4%, respectively) and renal (0.6% vs. 1.2%) events were worse (P <.05), and gastrointestinal events were worse with naproxen (1.6%; P <.05).

When the findings were examined utilizing an adjusted Kaplan-Meier analysis, the results were similar, and according to Reed, "should be enough to inform patient care. I think that with this information, a physician can use this to better inform patients about the relative pros and cons and make an informed decision about use."

Nissen said that overall, patients can take aspirin safely with these drugs. "There are still advantages to taking celecoxib rather than ibuprofen or naproxen but if anything, you know, the drugs are overall reasonable to take with aspirin,” he said.

“The outcomes of this study could lead to changes in clinical practice. If a patient is not on aspirin, these results suggest that in many cases, celecoxib may be the NSAID of choice,” Reed said in a statement. “Our findings underscore how important it is that physicians counsel their patients when starting them on an NSAID and consider the potential effects of use together with aspirin.”

The study, “Effect of Aspirin Coadministration on the Safety of Celecoxib, Naproxen, or Ibuprofen,” was published in the Journal of the American College of Cardiology.