FDA Advisors Take Fresh Look at Celecoxib Safety as PRECISION Aspirin Analysis Unveiled

The addition of aspirin appears to the modify the cardiovascular and overall safety of nonsteroidal anti-inflammatory drug (NSAID) therapy, specifically the beneficial safety profile of celecoxib over ibuprofen and naproxen, according to new data from the PRECISION trial.

The analysis was published just as US Food and Drug Administration (FDA) advisors were gearing up to review the relative cardiovascular safety of popular NSAIDs.

In the overall PRECISION trial, the use of celecoxib, a COX-2 inhibitor, was associated with a better overall safety profile than naproxen or ibuprofen in patients with osteoarthritis or rheumatoid arthritis at increased cardiovascular risk who were not taking aspirin. In the new analysis, adding aspirin attenuated the celecoxib’s safety advantage, such that there was no significant difference in the risk of major adverse cardiovascular events between the three NSAIDs, although celecoxib was still associated with fewer gastrointestinal events than ibuprofen or naproxen and fewer renal events than ibuprofen.

“We had the ability to look at whether or not there was any evidence naproxen or ibuprofen interferes with aspirin,” senior investigator Steven Nissen, MD (Cleveland Clinic, OH), told TCTMD. “The conclusions were that it didn’t. There was just no evidence of anything. The data trend in the opposite direction. It’s yet another demonstration of what we have seen over a very long period of time—biomarkers don’t predict what happens in people. It’s a lesson about why you don’t take effects seen in rats or mice or a petri dish and apply it to medicine without evidence. When you do, you often make mistakes.”

It’s a lesson about why you don’t take effects seen in rats or mice or a petri dish and apply it to medicine without evidence. When you do, you often make mistakes. Steven Nissen

The theoretical concern is that NSAIDs, particularly naproxen or ibuprofen which are nonselective COX inhibitors, might interfere with aspirin’s antiplatelet effect and increase the risk of atherothrombotic events. There was concern naproxen or ibuprofen might prevent the acetylation of COX-1, which is part of aspirin’s mechanism of action, if the NSAIDs access critical channels in COX-1 before aspirin. Nissen added that there is no evidence to date suggesting celecoxib interferes with aspirin, and that the interaction concerns with ibuprofen and naproxen date back many years but have never been proven to adversely affect outcomes.

Despite this, numerous agencies, including the FDA and the American Heart Association, have previously warned of the potential interaction. Such advisories, said Nissen, were “inappropriate.”

The FDA is set to tackle the question again, however, with a 2-day joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee that kicks off today. The committees will discuss and debate the main results from PRECISION, namely whether the study supports the cardiovascular safety of celecoxib and how it compares with naproxen and ibuprofen.

The FDA advisory committees are also tackling the aspirin question and whether or not there are clinically significant interactions between the antiplatelet agent and celecoxib, ibuprofen, and naproxen. In 2005, the FDA warned that taking NSAIDs increases the risk of MI and stroke, and the agency further strengthened that warning in 2015.

PRECISION: 10 Years in the Making 

In the PRECISION trial, which was published in 2016, investigators tested the cardiovascular safety of moderate-dose celecoxib against the nonselective NSAIDs ibuprofen and naproxen. The trial’s origins date back to 2004 when the blockbuster rofecoxib (Vioxx; Merck) was withdrawn from the market due to an excess of MI and stroke among patients taking the drug. Celecoxib, approved in 2001, remained available but only on the condition that a cardiovascular safety trial—PRECISION—be conducted. As reported by TCTMD, the study showed that celecoxib was as safe as from a cardiovascular standpoint as naproxen and ibuprofen.

In the new analysis of PRECISION, which included 23,953 patients, aspirin was used 11,018 individuals at the time of randomization. Among those not taking aspirin, naproxen was associated with a 52% increased risk in the occurrence of the primary safety endpoint, a composite that included major adverse cardiovascular events plus noncardiovascular death, clinically significant gastrointestinal events, iron-deficiency anemia, or a serious renal event, when compared with celecoxib-treated patients. Similarly, naproxen was associated with an 81% increased risk of the primary safety endpoint compared with celecoxib.

The increased risk for the occurrence of the primary safety endpoint with naproxen and ibuprofen was driven largely by an increased risk of gastrointestinal events. Compared with celecoxib, however, ibuprofen was associated with a greater risk of a major adverse cardiovascular events (adjusted HR 1.35; 95% CI 1.02-1.78).

In the 46% of individuals taking aspirin in addition to the NSAIDs, those taking ibuprofen had an increased risk in the primary composite safety endpoint compared with celecoxib (adjusted HR 1.27; 95% CI 1.06-1.51). However, there was no difference in the risk of major adverse cardiovascular events between the three NSAID groups with the addition of aspirin. Ibuprofen plus aspirin, as well as naproxen plus aspirin, was linked to an increased risk of gastrointestinal events compared with the celecoxib/aspirin combination, while ibuprofen plus aspirin was also associated with an increased risk of renal events.

“This is a classic example of where there is some effect observed in platelet function in the laboratory,” said Nissen. “If you expose the platelet to ibuprofen or naproxen, it prevents aspirin from inhibiting platelet function. The theoretical argument has existed for a very long time, that ibuprofen or naproxen would interfere with the benefits of aspirin. I must add that this has never been tested in a clinical trial.”

No Clarity From PRECISION Analysis

In an editorial, Elliott Antman, MD (Brigham and Women’s Hospital, Boston, MA), states that the aspirin analysis of the PRECISION trial is one that clinicians were waiting for given previous analyses suggesting an interaction of aspirin with naproxen and ibuprofen.

However, he said, little can be gleaned to guide clinical practice from the present study given that it’s a subgroup analysis with multiple limitations, including the fact that aspirin use at enrollment reflects the patient’s prior history. In addition, Antman noted the large number of drug discontinuations (69% of participants in PRECISION discontinued the study drug during the trial), crossovers to a nonstudy NSAID, and patients lost to follow-up.

There is also a lack of more detailed information about aspirin use, such as the dose used and timing of aspirin versus NSAID therapy, as well as a lack of data to inform physicians about the potential risks when patients are taking higher doses of celecoxib, such as the 400 and 800 mg/day doses that raised concerns about safety.  

For Antman, “there is no substitute for a well-designed prospective collection of exposure-outcomes data when a drug-drug interaction is investigated in a clinical trial.”

Given the limitations of PRECISION, “if [NSAIDs] must be used, the drug with the safest profile in the lowest dose for the shortest period of time remains the best advice for practice,” he added, pointing to a meta-analysis of NSAID trials suggesting that naproxen 1000 mg/day was associated with fewer vascular and gastrointestinal events than celecoxib ≥ 400 mg/day.

But Nissen disagreed that naproxen is the safest NSAID, stating that “old ideas die hard.” More data supporting the safety of celecoxib will be presented this week to the FDA advisory committees, he said. “If you want to be cautious, you can keep the [celecoxib] warning, and the FDA likes to act in a way that’s cautious,” said Nissen. “But the more important question is, ‘Did we demonstrate noninferiority for celecoxib?’ We think we did.”