Arthritis Drug Rofecoxib (VIOXX) Linked to Increased Risk of Coronary Heart Disease

Investigators from Vanderbilt University in Nashville TN, in a study published in the October 5, 2002 issue of The Lancet, found that patients taking 50 milligrams per day of the arthritis and painkilling drug rofecoxib (VIOXX) for longer than five days are 70 percent more likely to develop coronary heart disease (CHD) than nonusers of the drug.

This research was sponsored in part by the Agency for Healthcare Research and Quality through the Center for Education and Research on Therapeutics or CERT. The CERT program was established by Congress to provide financial support for research that would not be funded by drug companies. In general, the pharmaceutical industry avoids sponsoring comparative studies such as this one because the less that is known about the safety and effectiveness of a drug the easier it is to sell to physicians and patients.

We listed rofecoxib as a DO NOT USE FOR FIVE YEARS (until July 2004) drug at the time it was cleared for marketing by the Food and Drug Administration (FDA) in April 1999 because there was no evidence that it was safer or more effective than drugs such as ibuprofen (MOTRIN, NUPRIN) or naproxen (NAPROSYN, ALEVE) that are also members of the non-steroidal anti-inflammatory drugs (NSAIDs) family of drugs (see Worst Pills, Best Pills News July 1999). Rofecoxib is also substantially more expensive than these older NSAIDs.

The Five Year Rule has been extended to seven years because of research we published in the Journal of the American Medical Association (see Worst Pills, Best Pills News June 2002).

Rofecoxib is a so called selective cyclooxygenase-2, or COX-2, inhibiting NSAID. The first COX-2 drug on the market was celecoxib (CELEBREX). The image that has been heavily promoted for COX-2 drugs, including rofecoxib, is that they are safer NSAIDs on the gastrointestinal (GI) tract. We have been concerned since the approval of the COX-2 drugs that because they work in a slightly different way than the older NSAIDs they may cause additional adverse effects not associated with the older NSAIDs including heart problems.

A study published in the New England Journal of Medicine in 2000 with the acronym VIGOR (Vioxx Gastrointestinal Outcomes Research Study) first suggested a link between high dose rofecoxib use and CHD. However, the control group received naproxen, not a placebo in this trial. Therefore, it was unclear if rofecoxib increased the risk of CHD or if naproxen had a protective effect on the heart. Merck and Company, the producers of rofecoxib, of course maintained that the VIGOR results were due to a protective effect of naproxen and not to an adverse effect of rofecoxib. The question the Vanderbilt investigators sought to answer was: Did rofecoxib cause harm or did naproxen protect against CHD?

The Vanderbilt investigators analyzed data on more than 375,000 people who were registered in the Tennessee Medicaid program. The study included 202,916 people who did not use NSAIDs, 24,132 who used rofecoxib, and 151,728 who had taken ibuprofen, naproxen, or celecoxib. All of these individuals were between 50 and 84 years of age, lived in a community setting, and did not have any life-threatening non-cardiovascular diseases. The investigators were looking for cases of serious CHD, defined as hospital admission for heart attack, or death from CHD associated with the use of NSAIDs.

The Vanderbilt researchers found 190 cases of serious CHD in patients taking ibuprofen, 245 in those on naproxen, and there were 74 cases in celecoxib users. In the group taking rofecoxib 25 milligrams or less per day there were 55 cases and when the dose of rofecoxib was greater than 25 milligrams per day there were 13 cases of serious CHD identified.

By knowing the number of cases of serious CHD and how long each patient was taking one of the NSAIDs, the researchers were able to calculate the rate at which cases of serious CHD occurred. The rate at which an adverse reaction occurs is the best estimate of risk for that adverse reaction. For each 1,000 persons taking ibuprofen for one year, 11.6 would experience serious CHD. The rate was the same for naproxen users and increased slightly to 13.1 cases per 1,000 in patients taking celecoxib for one year. The rate was 13.6 in those taking rofecoxib at a dose of 25 milligrams or less per day.

In the group taking 25 milligrams of rofecoxib or more per day the rate jumped to 21.0 cases of serious CHD per 1,000 using the drug for one year. Compared to non-users of NSAIDs this is a 70 percent increase in the risk of developing serious CHD in those taking more than 25 milligrams of rofecoxib per day. This is referred to as the relative risk. The estimate of the absolute increase in risk is about two percent greater in high dose rofecoxib users compared to non-users of NSAIDs.

The type of research used in the Vanderbilt study is known as observational, or epidemiological research. This type of research cannot conclusively show a cause and effect relationship between rofecoxib and CHD. Proof of cause and effect requires the use of the scientific “gold standard” study design, a randomized clinical trial. However, the weight of the evidence strongly supports that rofecoxib causes harm. In addition to the Vanderbilt study, there is research that shows that rofecoxib increases blood pressure, edema (water retention), and alters kidney function. The results of the VIGOR study mentioned above and studies that have failed to show that naproxen has a protective effect against CHD strengthen the conclusion that rofecoxib causes harm.

What You Can Do

If you are now taking rofecoxib, discuss with your doctor changing to a safer NSAID. There is no medical reason that you should be taking rofecoxib rather than one of the older and safer NSAIDs such as ibuprofen for the treatment of pain, dysmenorrhea, or arthritis.