The New England Journal of Medicine has a paper in its current issue (Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis) that examines the safety of the COX-2 inhibitor celecoxib, best known under its brand name Celebrex, though now available in a generic formulation. This drug is the only COX-2 inhibitor available in the US. All the other nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective, ie they inhibit both COX-1 and 2 enzymes. Examples of nonspecific NSAIDs are naproxen (Aleve) and ibuprofen (Advil).
“Selective COX-2 inhibitors are a type of non-steroidal anti-inflammatory drug that directly targets cyclooxygenase-2, COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class. After several COX-2 inhibiting drugs were approved for marketing, data from clinical trials revealed that COX-2 inhibitors caused a significant increase in heart attacks and strokes, with some drugs in the class having worse risks than others. Rofecoxib (commonly known as Vioxx) was taken off the market in 2004 because of these concerns and celecoxib and traditional NSAIDs received boxed warnings on their labels.”
As the above quotation indicates these drugs were thought to cause heart attacks and strokes. Vioxx was taken off the market and presented a bonanza to trial lawyers. The issue also brought out the worst in many American doctors alleged to be experts on this issue. The following Powerpoint presentation is a Grand Rounds I gave in 2005 summarizing the use of Vioxx – The Vioxx Debacle.
Here’s the background you need to understand the proper use of these drugs. Non-selective NSAIDs relieve pain, but increase the incidence of bleeding both in the GI tract and in the head. COX-2 inhibitors are much less likely to cause bleeding. There was the possibility that they could cause clots leading to heart attacks and strokes. This was what sent my colleagues off the rails. One of them even said: “Any drug that causes heart attacks shouldn’t be on the market.” Well suppose a drug cured 10 patients with cancer, but caused a heart attack in the 11th? Should it be taken off the market? Of course not. The right response to any drug that has both significant therapeutic and serious side effects is a risk benefit analysis. If the benefit outweighs the harm, the drug stays. In the reverse, it goes.
After analyzing all the data available 12 years ago, I concluded that there was not a valid reason to withdraw Vioxx from the market. But it has not yet returned. Celecoxib has an identical pharmacological effect as does rofecoxib. It was allowed to remain on the market because withdrawing it would leave no COX-2 inhibitor available in the US. A decision that caused the FDA’s decision to resemble a drawing by Escher.
Back to the NEJM study. It showed that “The risk of gastrointestinal events
was significantly lower with celecoxib than with naproxen (P = 0.01) or ibuprofen (P = 0.002).” No surprise here. It also showed that “At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety.” When you unravel the twisted syntax, the authors are saying that celecoxib was no more likely to cause CV Disease than the two non-selective NSAIDs studied. Thus, celecoxib is likely safer for long term use than its nonselective counterpoints as it is less likely to cause bleeding. The same is likely true for Vioxx which was assassinated before it could be pardoned.