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Tuesday, 19th October 2004


The class of drugs known as Cox-2 inhibitors is under scrutiny for increasing the risk of heart disease and stroke.


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A few weeks after the withdrawal of the popular pain killer, Vioxx from the market, Bextra is also found to increase the risk of heart disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a large group of drugs that include aspirin, ibuprofen, Vioxx, Bextra and Celebrex. However, Vioxx, Bextra and Celebrex belong to a class of NSAIDs known as Cox-2 inhibitors, aslo known as second generation NSAIDs. All these drugs are effective in relieving arthritis pain.

They work by reducing substances that cause inflammation, pain, and fever in the body and is used to treat arthritis, acute pain in adults, and pain that accompanies menstrual cycles.

Vioxx and the risk of heart disease

Recently Merck, the company that manufactures Vioxx, voluntarily withdrew Vioxx from the market after a clinical trial confirmed that Vioxx increased patients' risk of heart attack and stroke. Merck made this decision independent of input from the FDA.

Merck's decision to withdraw Vioxx from the market is based on new data from a trial called the APPROVe trial. In the APPROVe trial, Vioxx was compared with placebo. The purpose of the trial was to see if Vioxx at 25mg was effective in preventing the recurrence of colon polyps. But the trial was also designed to look at the drug's long-term safety. This trial was stopped early because after 18 months on Vioxx, patients' heart attack and stroke risks doubled from 7.5 out of 1,000 for patients on placebo to 15 out of 1,000 for patients on Vioxx. The threat posed by this finding is very serious when one considers that when patients get into their 60s and 70s, arthritis and heart disease run together.

The safety of other Cox-2 inhibitors

Since then, there has been increased attention on Vioxx's sister drugs, Bextra and Celebrex. Because they have the same mechanism of action, it was feared that these drugs might also increase heart risk.

Now Pfizer, which produces the other two drugs, Celebrex and Bextra, has issued a warning that Bextra may cause rare skin and heart side effects. To date, there is no evidence that Bextra increases heart risk in arthritis patients without heart disease. But studies of Bextra alone or in combination with parecoxib, together with a study published in 2003, show an increase in "cardiovascular events" in patients undergoing heart bypass surgery. Pfizer also warns that Bextra may cause rare but serious skin reactions more often than other Cox-2 inhibitors. The risk of these skin reactions, Pfizer says, is greatest during the first two weeks of Bextra treatment.

So far, there is no hard evidence that Celebrex increases heart risk. On the contrary with Celebrex there is some evidence that it is more heart-friendly than Vioxx or Bextra. Celebrex doesn't raise blood pressure at high doses and there seems to be no increase in heart disease events from the many studies conducted.

European regulators said they were launching a safety investigation into the entire class of Cox-2 inhibitors. Also, an editorial in the New England Journal of Medicine raised questions about the safety of these drugs.

Pfizer is currently considering initiating clinical trials to test the safety of these drugs when used in the long term. In the mean time,  patients currently taking these drugs should consult their physicians about whether to switch to a different drug and what the risks of taking these drugs have on them. If the only thing that works for a particular patient is a Cox-2 drug, it is probably a good idea for that patient to keep other risk factors for stroke or heart disease low.

UPDATE: In December, 2004 the NIH suspended the APC colon cancer prevention trial when findings suggested Celebrex more than doubled heart deaths, heart attacks, and strokes in people enrolled in the study (Full Story).


Topol EJ. Failing the public health -- Rofecoxib, Merck, and the FDA. N Engl J Med 2004 Oct 21; 351:1707-9.
FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004 Oct 21; 351:1709-11.

Article reviewed by:

Dr. Tamer Fouad, M.D.

Edited by:

Dr. Russell Musthafa

Reviewed by:

Dr. Yasser Mokhtar, M.D.

Theresa Jones (Registered Nurse).

Carolyn Merritt (Licensed Practical Nurse).

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