Signal of Aortic Stenosis Risk With Celecoxib

Despite recent reassurances that celecoxib (Celebrex; Pfizer) does not increase the risk of cardiovascular events compared with other nonsteroidal anti-inflammatory drugs (NSAIDs), new data suggest the COX-2 inhibitor may be associated with the development of calcific aortic valve disease.

The findings, stemming from basic science research and a retrospective analysis, are particularly concerning given changes to the drug’s label clearing low-dose celecoxib against charges of an increased risk of cardiovascular events compared with other agents.

“It’s a 35% increase [with celecoxib] over ibuprofen and naproxen in our cohort,” senior investigator W. David Merryman, PhD (Vanderbilt University, Nashville, TN), told TCTMD. “We think that’s a pretty significant increase.” He pointed out that while this is a retrospective study of medical records derived from a single center, he believes they conducted a tightly controlled analysis, even adjusting for blood pressure. “Even when we adjust for all the risk factors for valve disease, the [association] remains statistically significant,” said Merryman.

The 2016 PRECISION study in arthritis patients showed celecoxib did not pose any greater cardiovascular risks than naproxen or ibuprofen and this led to the US Food and Drug Administration’s labeling change. This change effectively removed the black-box warning on celecoxib, one that was in place since 2005 following an FDA review of NSAIDs after the rofecoxib (Vioxx; Merck) controversy.

However, the primary endpoint of PRECISION was a composite that included death from cardiovascular causes, nonfatal MI, and nonfatal stroke. Additionally, the mean duration of follow-up was less than 3 years. Merryman said while they also saw no increased risk of MI or stroke with celecoxib, their analysis included much longer followed (mean 10.16 years).

“It takes a while to develop valve disease,” he said. “It’s a degenerative process and takes a while to really become clinically significant.”

Celecoxib Inhibits Cadherin-11 Activity 

Their paper, led by Meghan Bowler, PhD (Vanderbilt University), and published February 22, 2019, in JACC: Basic to Translational Science, includes in vitro experiments with porcine aortic valve cells and the retrospective analysis. Merryman explained they were looking to identify FDA-approved drugs that might block caderin-11 activity for calcific aortic valve disease after Roche shut down research into their cadherin-11 antibody following disappointing phase 2 trials for rheumatoid arthritis. While the antibody effectively blocked cadherin-11 activity, it appeared to be clinically ineffective in rheumatoid arthritis. 

But recent studies in mice, however, have suggested that blocking cadherin-11 could prevent the progression of calcific aortic valve disease, Merryman explained.

“In the cancer literature, someone had been looking at cadherin-11 for the prevention of cancer metastasis,” said Merryman. “They showed that celecoxib and dimethyl celecoxib were binding partners to cadherin-11. We thought: this is an FDA-approved drug that might work against valve disease.”

If you have a family history of valve disease, and you take celecoxib for rheumatoid arthritis or another type of arthritis, it’s something you and your cardiologist may want to be looking at. W. David Merryman

In the present study, the researchers treated porcine aortic valve cells with celecoxib, but unexpectedly, celecoxib contributed to calcification instead of protecting against it. In contrast, dimethyl celecoxib, which doesn’t interfere with COX-2 signaling, did not did not have an effect on the calcification processes.   

To assess the clinical implications of these findings, the researchers turned to approximately 8,300 medical records from Vanderbilt University Medical Center to look for a possible association between aortic stenosis and celecoxib, naproxen, and ibuprofen use, limiting their search to the years 1999 to 2005.  

Over an average follow-up of more than 10 years, 10.3% of celecoxib users developed aortic stenosis compared with 7.6% of naproxen/ibuprofen users. Use of celecoxib was associated with a 24% increased risk of aortic stenosis when compared with matched controls not using celecoxib (OR 1.24; 95% CI 1.00-1.53). There was no increased risk with naproxen or ibuprofen.

Putting the results in perspective, Merryman pointed out there are approximately 9 million celecoxib prescriptions written annually. Based on their data showing a higher rate of aortic stenosis among celecoxib users, roughly 300,000 more individuals would develop aortic stenosis each year by taking celecoxib instead of taking naproxen or ibuprofen. 

Merryman would like to see the results replicated from other medical centers and has reached out to other groups with extensive databases of patients with aortic stenosis. In the meantime, he believes the public should be aware of their findings.

“If you have a family history of valve disease, and you take celecoxib for rheumatoid arthritis or another type of arthritis, it’s something you and your cardiologist may want to be looking at,” he said. According to the researchers, when choosing a pain-control treatment, physicians should balance the risks of COX-1 inhibition (aspirin, ibuprofen, and naproxen) in the stomach with potential risks to the aortic valve with the COX-2 inhibitor celecoxib.