Important New Cardiovascular Safety Warning for Rofecoxib (VIOXX)

Rofecoxib (VIOXX), the heavily promoted and overpriced nonsteroidal anti-inflammatory drug (NSAID), now carries a warning in its professional product labeling, or “package insert,” about its use by people with a history of heart disease.

Rofecoxib is produced by Merck & Company of West Point, Pennsylvania and is approved by the Food and Drug Administration (FDA) for management of osteo- and rheumatoid arthritis, acute pain, and painful menstrual periods in women. It is one member of a crowded family of drugs that includes ibuprofen (MOTRIN).

Rofecoxib is touted as easier on the gastrointestinal (GI) tract because it works in a new way by selectively inhibiting the enzyme COX-2. GI adverse effects are among the most serious adverse reactions seen with the NSAIDs. All NSAIDs, including rofecoxib, work by inhibiting the enzyme cyclooxygenase, or COX for short. Two forms of COX are known to exist, COX-1 and COX-2. In theory, blocking both of these enzymes reduces the symptoms of arthritis but also leads to the adverse GI effects associated with NSAIDs. It is thought, in theory, that if COX-2 is selectively blocked, arthritis pain would be relieved without the serious GI adverse effects seen with other NSAIDs.

Drugs that work in new ways also raise the possibility of new adverse reactions. The new heart disease warning is based on a study that goes by the acronym VIGOR (short for “Vioxx GI Clinical Outcomes Research”). This study was submitted to the FDA by Merck in a request to change rofecoxib’s professional product labeling, or “package insert,” to say that it is a safer NSAID in regard to GI toxicity compared to the numerous other drugs in its family. This is important for drug companies because they cannot legally make superiority claims for either safety or effectiveness for their products unless they first submit proof for such claims to the FDA.

The VIGOR study was discussed at an FDA Arthritis Advisory Committee meeting on February 8, 2001. Here it was revealed that patients taking rofecoxib who should have been taking aspirin but were not had a statistically significant five-fold increase in heart attacks compared to patients taking naproxen (NAPROSYN), another NSAID. This amounted to 20 heart attacks with rofecoxib (out of 4,047 patients) compared to four with naproxen (out of 4,029 patients). The increase in heart attacks was also accompanied by an increase in other thrombotic (blood-clotting) adverse effects such as strokes and clots in the legs as well as problems with high blood pressure in the rofecoxib group compared to those taking naproxen.

Rofecoxib was found to cause fewer serious adverse GI reactions compared to naproxen in the VIGOR study in those patients who were not taking rofecoxib and aspirin together. There was no difference in GI safety between those patients taking rofecoxib plus aspirin compared to naproxen alone. Rofecoxib can be promoted as safer than naproxen on the GI tract, but not as the safest NSAID for two reasons. First, to claim it as the safest NSAID, the VIGOR study would need to be repeated comparing rofecoxib directly to ibuprofen. Second, adding rofecoxib’s GI toxicity to its cardiovascular toxicity especially means it is not the safest NSAID.

The FDA did not allow Merck to remove the GI toxicity warning from the drug’s labeling, which is currently the same for all NSAIDs on the market.

Aspirin and naproxen inhibit the clumping together of elements in the blood called platelets, while rofecoxib does not. Platelets are one of the body’s first defenses against bleeding, but they are also involved early in the development of heart attack and stroke. This is why aspirin is prescribed to prevent heart attack and stroke in those at high risk of developing these serious cardiovascular events.

The text of the new warning contains the information we discussed above in dense technical jargon:

Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis. Therefore, in patients taking VIOXX, antiplatelet therapies should not be discontinued and should be considered in patients with an indication for cardiovascular prophylaxis. Prospective, long term studies on concomitant administration of VIOXX and aspirin evaluating cardiovascular outcomes have not been conducted.

Merck argued at the February 8, 2001 Arthritis Advisory Committee meeting that the increased number of serious cardiovascular events seen in the VIGOR study was solely due to the “protective” effect of naproxen on platelets. The FDA medical officer who reviewed the VIGOR study agreed that Merck’s explanation could not be totally discarded. However, he found several lines of evidence against the effect of naproxen on platelets as being the only explanation for the VIGOR results. There is suggestive evidence that it directly causes heart damage in addition to lacking an antiplatelet effect.

There are no studies with naproxen to support the assumption that it is effective in decreasing the risk of cardiovascular events. The effect of naproxen on platelets is short lived, while that of aspirin is irreversible. The effect of naproxen in reducing cardiovascular events relative to rofecoxib in the VIGOR study was 58 percent. This effect exceeds that of aspirin compared to placebo in reducing cardiovascular risks in other trials, which is 25 to 30 percent. The medical officer also commented that the absence of cardiovascular problems in the original review of rofecoxib may be explained by the short duration and low doses of rofecoxib used in the majority of the studies submitted to the FDA by Merck.

The most likely explanation, in our view, is that the VIGOR results are a combination of naproxen’s ability to inhibit platelets and rofecoxib’s new way of working through selective inhibition of the COX-2 enzyme to increase the risk of cardiovascular adverse events.

What You Can Do

If you require treatment with an NSAID you should not be taking rofecoxib. More effective, safer, and less expensive drugs are on the market, such as ibuprofen.