Rofecoxib withdrawal from market shakes the pharmaceutical industry

Patients should reconsider basic NSAIDs as alternatives, pharmacist says

The recent withdrawal of the popular arthritis drug rofecoxib (Vioxx) from the market has left patients scrambling for alternatives and providers looking at long-term consequences.

"I was not dramatically surprised [about the withdrawal], but it has shaken the industry," says Gordon J. Vanscoy, PharmD, CACP, MBA, assistant dean for managed care and associate professor of pharmaceutical sciences at the University of Pittsburgh School of Pharmacy. He also is chairman and chief executive officer of University Pharmacotherapy Associates in Monroeville, PA. "There has been concern about the COX-2 inhibitors, even since the original FDA submission."

The facts behind the withdrawal

Merck & Co. announced the voluntary withdrawal of its drug Sept. 30 after viewing three-year data from a prospective, randomized, placebo-controlled clinical trial — APPROVe (Adenomatous Polyp Prevention on VIOXX).

Merck is stopping the trial, which was designed to evaluate the efficacy of rofecoxib 25 mg in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas. In this study, there were nearly twice as many cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking rofecoxib compared to those taking placebo. The trial’s enrollment began in 2000 and included 2,600 patients.

"Although we believe it would have been possible to continue to market VIOXX with labeling that would incorporate these new data, given the availability of alternative therapies and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take," says Raymond V. Gilmartin, chairman, president, and chief executive officer of Merck, in a statement.

Merck already had changed the drug’s labeling following the results of the safety study VIGOR (Vioxx Gastrointestinal Outcomes Research). The trial had found an increased risk of serious cardiovascular events, including heart attacks and strokes, in patients taking rofecoxib compared to patients taking naproxen. After reviewing the results of the VIGOR study and other available data from controlled clinical trials, the FDA had consulted with its Arthritis Advisory Committee in February 2001 and implemented labeling changes in April 2002. Those changes included information about the increase in risk of cardiovascular events, including heart attack and stroke.

After the announcement, the bad news continued for Merck. In early October, The Wall Street Journal reported that a study led by a FDA safety official projects that the widespread use of rofecoxib may have led to more than 27,000 heart attacks and sudden cardiac deaths before the drug’s withdrawal.

The number compares how many similar incidents would have occurred had the same patients been taking celecoxib (Celebrex) from the time of rofecoxib’s approval in 1999 through 2003. The figures are projections based on findings from an analysis of a database of patients of the HMO Kaiser Permanente.

Reaction is varied

One Atlanta rheumatologist saw the withdrawal as inevitable. "As [Merck] said in its press release, there is probably a place for Vioxx in a certain [patient population]," says Hayes Wilson, MD, a rheumatologist at Piedmont Hospital in Atlanta and a medical adviser for the Arthritis Foundation.

"The problem in the global overall picture is that they marketed it as a safer drug and they, and everyone else, lost confidence that it was a safer drug. I think it is kind of a shame because Vioxx sure helped a bunch of my patients."

The risk, at least in the trials, was not one in which Merck could just restrict its labeling, Vanscoy says. "The findings that they had were broad enough where there weren’t any predictors of specific individuals who were going to experience some of these adverse effects. You couldn’t [say], We’re going to take these 1.2 million people who are using the product, and we are going to isolate it to the 300,000 where we think it’s going to be safest.’ I don’t think they could do that.

"When we end up with broad and long-term use of these agents — sometimes that is the only way we discover these adverse events," he continues.

A cardiologist from The Cleveland Clinic called the rofecoxib withdrawal an "enormous public health issue." "Even a fraction of a percent excess in the rate of serious cardiovascular events would translate into thousands of affected people," says Eric J. Topol, MD, chairman and professor of the department of cardiology at The Cleveland Clinic. His comments were made in an editorial in the Oct. 21 issue of the New England Journal of Medicine (which also was published Oct. 6 on the web site).

Officials have not heeded previous warning signs about rofecoxib, Topol says. "The senior executives at Merck and the leadership at the FDA share responsibility for not having taken appropriate action and not recognizing that they are accountable for the public health." He goes on to call for a full congressional review of the case.

What to do next?

The immediate question now is how to treat patients who have been taking rofecoxib. The decision obviously should be based on the individual, Wilson says. "If they have risk factors for gastrointestinal bleeding and they are not sulfonamide allergic, I think the (COX-2) cousins Celebrex or Bextra are good choices."

Patients who are put on other COX-2 inhibitors should work with their pharmacists and physicians to ensure that they are being monitored appropriately for analogous side effects that were seen with rofecoxib, Vanscoy says.

Patients who need to be on a nonsteroidal should have patience in terms of their clinical response for the other products, he says. "The other products do provide reasonable alternatives. However, sometimes you get into the mentality that, What I was on was working so well, and nothing else will work.’"

Patients also should consider alternatives that may not have been given an appropriate chance, he adds, such as some of the basic nonsteroidal anti-inflammatory drugs that are known to have a broad margin of safety.