heart attack stroke risk celebrex nsaids

Celecoxib: Not So Hard on the Heart?

The recent findings of a huge study may erase some concerns about a pain reliever that has long been saddled with a worrisome reputation: celecoxib (Celebrex). While all nonsteroidal anti-inflammatory drugs (NSAIDs) carry a warning that users have an increased risk for heart attacks and strokes, celecoxib is closely linked to two similar drugs that were taken off the market due to concerns about their cardiovascular safety. However, the new research suggests that celecoxib may not be more dangerous than other NSAIDs, and might even be safer in some important ways.

COX-2 Inhibitors and the Heart

All NSAIDs relieve pain by blocking a naturally occurring enzyme called COX-2, which plays a critical role in producing inflammation. However, NSAIDs such as ibuprofen and naproxen also interfere with a closely related enzyme, COX-1, which plays a role in protecting the lining of the gastrointestinal (GI) tract. Taking these NSAIDs increases the risk for GI complications; up to one quarter of chronic users develop stomach ulcers, which can bleed and turn life-threatening.

To address this problem, pharmaceutical companies developed NSAIDs called selective COX-2 inhibitors, which don’t block COX-1. Celecoxib was the first to reach the market, gaining approval from the Food and Drug Administration (FDA) Dec. 31, 1998. A second COX-2 inhibitor, rofecoxib (Vioxx) became available the following May. However, a study published after rofecoxib was approved and in wide use revealed that people who took the drug had a significantly increased risk for heart attacks, strokes and other cardiovascular problems. In 2004, the maker of rofecoxib, Merck, voluntarily withdrew it from the U.S. market. In 2005, the FDA called for the removal of another COX-2 inhibitor, valdecoxib (Bextra), from the market, too.

That same year, the FDA determined that the benefits of celecoxib outweighed its risks for some patients. However, the agency was sufficiently concerned about the drug’s potential to cause heart attacks and strokes that it required its manufacturer, Pfizer, to conduct a large study to evaluate the medication’s cardiovascular safety. The result is the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial; its findings were published in November in the New England Journal of Medicine.

The Dose Matters

PRECISION was conducted by doctors at 923 medical clinics around the world. It involved 24,081 arthritis patients, about 90 percent of whom had osteoarthritis (OA), while the remaining participants had rheumatoid arthritis (RA). Patients were split into three equal-sized groups and received one of the following treatment regimens:

  • 100 to 200 milligrams (mg) of celecoxib twice a day
  • 600 to 800 mg of ibuprofen three times a day
  • 375 to 500 mg of naproxen twice a day

This 10-year study found that people who took celecoxib were no more likely to have experienced heart attacks or strokes than patients treated with ibuprofen or naproxen. Meanwhile, celecoxib was associated with significantly fewer GI complications than the other two drugs, and the drug appeared to be safer for the kidneys than ibuprofen. Pain relief was similar among the three drugs.

Concerns that celecoxib may increase the risk for heart attacks and strokes arose from studies that used very high doses of the drug – between 400 and 800 mg, notes Daniel H. Solomon, MD, a rheumatologist at Brigham and Women’s Hospital in Boston and co-leader of the PRECISION trial. But 9 out of 10 people in the United States who are prescribed celecoxib take the lower dose used in this trial, which carries the same cardiovascular risk as the other NSAIDs studied, says Dr. Solomon, “and that’s a very important statement that I can now make to my patients.”

Earlier analyses indicated that celecoxib works in a way that may make it less toxic to the heart than those COX-2 inhibitors that were taken off the market. COX-2 inhibitors block production of certain prostaglandins (hormone-like substances) whose job is to prevent blood clots that cause heart attacks and strokes. But celecoxib doesn’t remain active in the body as long as rofecoxib does, explains Donald Miller, PharmD, a professor of pharmacy practice at North Dakota State University and member of the FDA Arthritis Advisory Committee. Nor does celecoxib inhibit prostaglandins as aggressively as rofecoxib, adds Miller.

Still, cardiologists emphasize that PRECISION didn’t exonerate celecoxib – it merely found the drug to pose no greater cardiovascular threat than other NSAIDs do. “I take these results with a grain of salt,” says Rachel Bond, MD, a cardiologist and associate director of women’s heart health at Lenox Hill Hospital in New York City. Dr. Bond says she may now be more inclined to recommend celecoxib to a patient, especially one prone to GI side effects. But she adds, “I remain cautious when considering NSAID therapy in patients with known, or who are at risk for, cardiovascular disease.”

Surprising Finding

To the surprise of many, PRECISION raised new questions about naproxen, which some earlier research suggested is the most heart-friendly NSAID. Not only did PRECISION fail to back up that theory, but data showed that RA patients (but not OA patients) who used naproxen doubled their risk for dying of any cause during the study period, though no one is sure why. “We need to drill down and make sense of this,” says Dr. Solomon.

Author: Timothy Gower for the Arthritis Foundation

 

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