Anyone who has read a newspaper or watched television in the past few months has heard of celecoxib (Celebrex®) and rofecoxib (Vioxx®), two popular drugs in a class known as Cox-2 inhibitors . When Cox-2 inhibitors were introduced in 1999, they promised the pain relief of traditional NSAIDs, such as ibuprofen (Advil, Motrin) or naproxen (Aleve), but with a decreased risk of stomach ulcers and bleeding.

But in September 2004, Merck Pharmaceuticals voluntarily withdrew Vioxx® from the market after a study showed that it was associated with an increased risk of heart attacks and strokes . Since then, studies have found another Cox-2 inhibitor, valdecoxib (Bextra®), to be associated with an increased risk of cardiovascular events.

Now, in a study released early by the New England Journal of Medicine , scientists report that patients taking Celebrex® were more likely to die of cardiovascular causes, heart attack, stroke, or heart failure than patients taking a placebo. In addition, patients taking a higher dose of Celebrex® had a higher risk of cardiovascular death than patients taking a lower dose.

About the Study

The study participants were enrolled in a trial designed to compare two doses of Celebrex® against a placebo for the prevention of colorectal tumors.

The participants were 32 to 88 years old, and were at high risk for colorectal tumors. At the beginning of the study, a detailed medical history was collected for the 2035 patients, including cardiovascular disease status and risk factors for cardiovascular disease.

The patients were randomly assigned to take a placebo, 200 milligrams (mg) Celebrex®, or 400 mg Celebrex® twice a day. Neither the patients nor the researchers knew whether the patients were taking Celebrex or placebo.

A cardiovascular safety committee (independent from the researchers conducting the colorectal tumor prevention trial) followed the patients for about three years to document deaths from cardiovascular causes, heart attack, stroke, and heart failure.

The Findings

The following deaths from cardiovascular disease, heart attack, stroke, and heart failure occurred:

  • 7 of 679 patients in the placebo group
  • 16 of 685 patients in the group taking 200 mg Celebrex® twice a day
  • 23 of 671 patients in the group taking 400 mg Celebrex® twice a day

Patients taking 200 mg Celebrex® twice daily were 2.3 times as likely, and patients taking 400 mg Celebrex® twice daily were 3.4 times as likely as patients taking placebo to die of cardiovascular disease, heart attack, stroke, or heart failure.

Based on these findings, as well as recent studies about other Cox-2 inhibitors, the cardiovascular safety committee concluded that continued treatment with Celebrex® placed the study subjects at increased risk for cardiovascular events. They recommended that this study be stopped early.

Although these study results link Celebrex® to increased risk of death from cardiovascular disease, it is worth remembering that this study was not designed to study cardiovascular risk. As a result, the statistical analysis of the study findings is based on a relatively small number of cardiovascular deaths.

How Does This Affect You?

This study showed that Celebrex® increases the risk of cardiovascular death compared to placebo.Additionally, a larger dose of Celebrex® was associated with a higher risk of cardiovascular death. Another study, also released early this week by the New England Journal of Medicine , found that the Cox-2 inhibitor Vioxx® increases the risk of cardiovascular disease in patients with a history of colorectal tumors, compared to placebo.

Many patients suffer from chronic, acute pain, such as that of arthritis. Unfortunately for them, this often means long-term use of pain medications, including Cox-2 inhibitors. Many earlier studies did not show an association between Cox-2 inhibitors and cardiovascular risk. But these studies were generally short-term studies, designed to look at pain relief and gastrointestinal side effects. Drugs that are designed to be used on a long-term basis must be assessed by long-term studies to determine their safety.

The evidence against Cox-2 inhibitors appears to be mounting, and in an accompanying New England Journal of Medicine editorial Dr. Jeffrey Drazen commented that “it is reasonable to ask whether the use of these drugs can now be justified.” As Dr. Drazen clearly points out, it has proven very difficult to identify relatively small increases in risk for unexpected serious adverse drug events. Hopefully drug developers, scientists, and regulators will all learn from this process as they work to bring safe new treatments to the public.

Much or all of the protection promised by Cox-2 inhibitors can be achieved by combining traditional NSAIDs with certain other drugs, which protect the stomach from injury. For patients who cannot tolerate traditional NSAIDs or aspirin, the options are narrowing. If you must use a Cox-2 inhibitor, work with you doctor to ensure that you are using the lowest effective dose for the shortest possible time.