Originally published in The Ottawa Citizen August 24, 2005

What have we learned about the cardiovascular risk of Vioxx, with so much media attention lately? Health Canada set up a 13-member expert panel to review and critique the scientific evidence for the Cox-2 painkillers Vioxx, Celebrex and Bextra. The panel recommended in its July report that Merck could resubmit Vioxx for approval.

What were the reasons for this turnaround?

The non-steroidal anti inflammatory drugs (NSAIDs) have provided great relief for people suffering from arthritic and other painful conditions. Prior to the release of Cox-2 inhibitors, long-term NSAID use, especially in the aged, increased the risk of gastrointestinal bleeding and cardiovascular and kidney problems in susceptible individuals.

The Cox-2 inhibitors were promoted as a solution to the gastrointestinal bleeding complications. This was good news for people who required long-term symptom control.

The report released by the panel reviewed the scientific literature collected by the University of Oxford. The data included 138 clinical trials representing more than 144,000 patients. The panel concluded that most NSAIDs, including the Cox-2 inhibitors, share the same risk profile for the development of cardiovascular disease, high blood pressure and kidney disorders.

In a recent Sunday House Call interview on 580 CFRA, Dr. Arthur Bookman, associate professor of medicine at the University of Toronto, who is also president of the Canadian Rheumatology Association and a panelist on Health Canada’s expert advisory panel, said they reviewed every study of greater than one month duration that looked at a Cox-2 inhibitor versus a traditional anti-inflammatory drug such as diclofenac (Voltaren), naproxen (Naprosyn), ibuprofen (Advil, Motrin) or sugar pill (placebo).

They found that when the other Cox-2 inhibitors were compared to other NSAIDs such as diclofenac or ibuprofen, the heart attack risk rate was similar.

Yet studies indicated that Vioxx posed a greater risk of heart attack in older patients who had heart disease or a pre-existing risk of cardiovascular disease. Why was this result different from the other studies of Cox-2 inhibitors versus traditional NSAIDs?

In the analysis of the data, the panel discovered that ibuprofen (Advil, Motrin) had similar health risks. Indeed, ibuprofen was similar to Vioxx with respect to the increased risk of cardiovascular disease. However, Vioxx was pulled from the market because of claims that it was responsible for thousands of deaths.

“The reason Vioxx looked so bad,” explains Dr. Bookman, “is that it was compared with a traditional anti-inflammatory agent called naproxen. Naproxen has a protective effect and it seems to protect against heart attacks, not quite as good as Aspirin but it does protect against heart attacks.”

Dr. Bookman said that clinical trials comparing the Cox-2 inhibitors to sugar pills or placebo seemed to indicate the Cox-2 inhibitors were solely responsible for the increased heart attack rates. However, once the panel analysed the medical literature, both the Cox-2 inhibitor and the traditional anti-inflammatory drugs like ibuprofen and diclofenac were all increasing heart attack rates to similar degrees. “Naproxen was the only exception and it did not seem to increase heart attack rates,” said Dr. Bookman.

“The older you are, the more caution you have to exercise taking any type of anti-inflammatory,” says Dr. Bookman. “But if you have a risk of heart attack and that risk is high, then that risk is going to be increased with the traditional anti-inflammatory agents and with the Cox-2 inhibitors.

“So if you are a person who has had a previous heart attack, who smokes, who has a strong family history of heart attack, and who has a blood clotting problem, then you probably should not take an anti-inflammatory agent without careful consultation with your doctor.”

Almost all medications have side-effect risks. The benefits of the Vioxx and Celebrex as pain relievers outweigh the risks, according to the panel. It recommends that patients be provided more information on the labels and in the package insert.

Healthy people have an extremely low risk for adverse cardiovascular effects from all NSAIDs and Cox-2 inhibitors. The risk does increase with long-term use and in patients who are at risk of heart disease.

“Health Canada should consider that ibuprofen only be sold after discussion with a pharmacist, and must ensure that the risks of cardiovascular events are prominently displayed in materials that individuals receive at the time they purchase the drug,” says the panel report.

Great damage to the public trust occurs when the perception is that the review process fails to protect them from harm. Indeed, many health professionals depend on the review process to include all adverse reactions, benefits and risks.

The panel concurs and states that all information from all randomized trials should be available. Independent groups must have the opportunity to go through that same information and come to their own conclusions about the benefits and harms of these drugs.

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© Dr. Barry Dworkin 2005