Cardiovascular Safety of Celecoxib

Nonsteroidal antiinflammatory drugs (NSAIDs) were introduced in the 1960s and became the most widely prescribed class of drugs in the world, with more than 100 million prescriptions issued annually in the United States alone.1

NSAIDs inhibit cyclooxygenase (COX), which reduces pain and inflammation through the inhibition of prostaglandins. However, the COX enzyme is also present in gastric mucosa, where it stimulates gastroprotective prostaglandins.

The identification of two isoforms, COX-1 and COX-2, and the recognition that anti inflammatory and analgesic effects are mediated through COX-2 inhibition whereas the gastrointestinal toxic effects are linked to COX-1 inhibition resulted in the development of selective COX-2 inhibitors that offered the potential to retain efficacy while reducing gastrointestinal adverse effects.2

Evidence of adverse cardiovascular outcomes in a placebo-controlled trial resulted in the withdrawal of the selective COX-2 inhibitor rofecoxib in 2004.3 On the basis of a small number of events, the results of another trial suggested that cardiovascular harm may result from the use of higher-than-approved doses of celecoxib.4 Subsequently, the Food and Drug Administration (FDA) allowed continued marketing of celecoxib, the sole remaining selective COX-2 inhibitor, but mandated a cardiovascular safety trial.

In the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial, we sought to assess cardiovascular, gastrointestinal, renal, and other outcomes with celecoxib as compared with two nonselective NSAIDs.

The PRECISION trial was designed in the aftermath of the withdrawal of rofecoxib during a period of considerable scientific and public controversy about the cardiovascular safety of selective COX-2 inhibitors. Previous knowledge about the relative safety of selective or nonselective COX inhibitors was limited, because NSAIDs received initial approval on the basis of relatively small, short-term studies that typically had been designed to assess pain relief and general safety.

The primary clinical concern was that celecoxib might be associated with adverse cardiovascular effects similar to those associated with rofecoxib.

The PRECISION trial provides statistically strong evidence that the cardiovascular risk associated with moderate doses of celecoxib is not greater than that associated with nonselective NSAIDs.

As compared with two widely used nonselective NSAIDs — naproxen and ibuprofen — celecoxib was associated with numerically fewer cardiovascular events, which resulted in noninferiority P values of less than 0.001.

The trial results do not support the widely advocated belief that naproxen treatment, as compared with treatment with other NSAIDs, results in better cardiovascular outcomes.

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