Merck recalls rofecoxib due to increased cardiovascular risk

Recall was based on early results of APPROVe, which was testing the agent in patients with colorectal adenomas.

Issue: November 2004

In 2001, Steve Nissen, MD, and Eric Topol, MD, both cardiologists at the Cleveland Clinic, co-authored a paper suggesting that COX-2 inhibitors may have increased cardiovascular risk.

“Dr. Topol and I took a certain amount of criticism over this from the Merck side and their consultants,” Nissen, a cardiologist, told Orthopedics Today. “We weren’t saying that we had the definitive answer; we said we thought it deserved scrutiny and it needed research.”

Topol and Nissen’s research was one of the first papers to question the safety of COX-2 inhibitors. Merck & Co. recently announced its voluntary worldwide withdrawal of rofecoxib (Vioxx), based on data that showed increased risk for cardiovascular events.

Nissen and Topol had performed a Medline search in 2001 that yielded two randomized trials: VIGOR (Vioxx Gastrointestinal Outcome Research Study) and CLASS (Celecoxib Long-term Arthritis Safety Study). The trials had 8076 and 8059 patients, respectively. Two smaller trials had approximately 1000 patients each.

Nissen and Topol noted that the results from the VIGOR trial showed the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event with rofecoxib treatment compared to naproxen was 2.38 (95% C.I. 1.39-4). There was no significant difference in cardiovascular events between celecoxib (Celebrex, Pfizer) and other NSAIDs in CLASS.

They further reported that the annualized MI rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than in placebo groups. In a meta-analysis of 23,407 patients, placebo patients had a 0.52% rate of MI, compared to 0.74% with rofecoxib and 0.80% with celecoxib.

They concluded that the data raised a “cautionary flag” about the risk of cardiovascular events with COX-2 inhibitors and that a further prospective trial evaluation was needed.

APPROVe trial

According to publicly released company materials, Merck based its recall decision on early data from the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial, which enrolled 2600 patients and randomized them to either 25 mg of rofecoxib or placebo to evaluate the agent’s effect on prevention of recurrent colorectal polyps in patients with a history of colorectal adenomas.

After 18 months of treatment, researchers noted an increased risk of confirmed MI and stroke compared to placebo, although Merck said the increase was not noted in the first 18 months. Attempts to contact Merck for a comment about specific relative risk were unsuccessful.

Topol and Nissen said the risk was 3.5% among patients taking rofecoxib compared to 1.9% among patients taking placebo. “This was in a trial that was among patients who would be at low risk for these types of events, so it was a signal that could not be ignored,” Nissen said.

FDA action

Valdecoxib could pose risk to CABG patients

Pfizer has issued new information about its COX-2 inhibitor valdecoxib (Bextra). Available clinical information for valdecoxib suggests there is no increased risk of cardiovascular thromboembolic events in people treated for osteoarthritis and rheumatoid arthritis, according to the company.

In studies in general surgery, valdecoxib in combination with the investigational drug parecoxib (an IV formulation) showed no increased risk of cardiovascular thromboembolic events. However, in two trials in coronary artery bypass graft patients, there was an increase in cardiovascular events in patients receiving valdecoxib alone or in combination with parecoxib.

Pfizer emphasized that valdecoxib is not approved for use in any surgical setting in the United States. The pharmaceutical company will be conducting further studies to confirm the long-term cardiovascular safety profile of valdecoxib.

Also, the company has announced that it is sponsoring a clinical study to further assess its COX-2 medication celecoxib (Celebrex) in osteoarthritis patients at high risk for cardiovascular disease. Expected to start in early 2005, the study will enroll more than 4000 patients worldwide who have had a recent myocardial infarction and who also have a history of OA. The multicenter, randomized, placebo-controlled trial will be conducted over two years.

According to FDA materials, Merck contacted the agency on Sept. 27, 2004, to advise that APPROVe had been halted and advised the agency of the withdrawal the next day.

“We are taking this action because we believe it best serves the interest of 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,” Raymond V. Gilmartin, chairman, president and CEO of Merck & Co., said in a written statement.

“Merck did the right thing by promptly reporting these findings to the FDA and voluntarily withdrawing the product from the market,” acting FDA commissioner Lester M. Crawford said in a written statement.

Crawford said that the FDA would closely monitor other drugs in this class for similar effects. The FDA approved rofecoxib in 1999 for the reduction of pain and inflammation caused by osteoarthritis, as well as for acute pain in adults and for the treatment of menstrual pain. The agent was later approved to treat the signs and symptoms of rheumatoid arthritis in adults and children. It was the second COX-2 selective inhibitor approved by the FDA.

“All of the NSAID drugs have risks when taken chronically, especially of gastrointestinal bleeding, but also liver and kidney toxicity. They should only be used continuously under the supervision of a physician,” Crawford said.

According to the FDA, at the time rofecoxib and other COX-2 selective inhibitors were approved it was hoped they would have a lower risk of gastrointestinal ulcers and bleeding than other NSAIDs such as ibuprofen and naproxen. Rofecoxib is the only NSAID demonstrated to have lower rates of these side effects, according to the FDA.

“Although the FDA has stated that they will be looking at other COX-2 inhibitors, there have been no data to support that similar complications are to be expected,” said James P. Tasto, MD, of the Orthopedics Today editorial board. “These cardiovascular events are not a ‘class’ drug reaction but are specific to Vioxx. Direct-to-consumer ads have already reached the airways suggesting reverting to over-the-counter NSAIDs. We must remember why we were attracted to these COX-2s in the first place. The incidence of gastrointestinal bleeds as well as deaths are real issues and cannot be ignored.”

No safety study in heart patients

“I think the criticism of [Merck] will be that they didn’t do their research, they didn’t do a safety study in cardiovascular patients, and they waited until this came up spontaneously in another trial,” Nissen said.

In an opinion article published in the New York Times, Topol criticized the FDA’s role: “The Food and Drug Administration could have forced Merck to do the appropriate research studies, but instead it was a bystander,” Topol wrote. “As the Vioxx debacle shows, we have a long way to go in this country to get on track with prescription medications. Most important, we need a stronger regulatory agency to compel pharmaceutical companies to do the proper studies and force these companies to stop direct-to-consumer advertising unless a drug has major benefits for patients and negligible increased risk of heart attacks and strokes.”

Patient ramifications

Rofecoxib had approximately $2.5 billion in sales in 2003. In publicly-released materials, Merck said it expected its share earnings to fall by between $0.50 and $0.60 from the current 2004 estimated earnings of between $3.11 to $3.17. The company expects foregone fourth quarter sales to total $700 to $750 million, and approximately one month of worldwide inventory will be returned.

“The current withdrawal raises the question in my mind and in the mind of my patients whether the other COX-2 inhibitors have a potential problem that just has not been detected at this point.”
— Douglas W. Jackson

Nissen said the ramifications for patients would be minimal. “I don’t think there are any patient ramifications. I think there are very few patients who are not going to be able to get relief from pain from their arthritis because there are alternative agents out there,” Nissen said.

Douglas W. Jackson, MD, chief medical editor of Orthopedics Today, said he had many patients taking rofecoxib at the time of the recall. “Most of them contacted our office and many brought in their remaining unused prescriptions and obtained other prescriptions. We had discussed with many of our patients prior to the recall the reported concerns about blood pressure elevation and the possibility of increasing heart attacks with the use of Vioxx … and cardiologists in the past year had recommended that some patients with elevated blood pressure stop taking Vioxx,” he said.

Vioxx representatives “continually brought us articles over the past two years dealing with efficacy and orally dispelling the potential for cardiac complications,” Jackson said. “The current withdrawal raises the question in my mind and in the mind of my patients whether the other COX-2 inhibitors have a potential problem that just has not been detected at this point. Some of my patients have decided to try another COX-2 inhibitor; others have gone back to the older NSAIDs,” Jackson said.

In his New York Times piece, Topol recommended that patients stick with naproxen, commonly sold as Aleve, and ibuprofen, commonly sold as Advil. “These agents work extremely well, are much cheaper than the COX-2 agents, and are not known to have any risk of heart attacks.