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Vioxx Withdrawal Prompts Reevaluation of COX-2 Inhibitor Safety Laurie Barclay, MD - Medscape Medical News Oct. 8, 2004 — In the wake of Merck's voluntary, worldwide withdrawal of rofecoxib (Vioxx) on Sept. 30, concerns are surfacing over whether the adverse cardiovascular risk documented with rofecoxib may be a class effect extending to the other cyclooxygenase-2 (COX-2) inhibitors. The U.S. Food and Drug Administration (FDA) issued a public health advisory to inform patients about the withdrawal of rofecoxib, and Acting Commissioner Lester M. Crawford announced the FDA's intention to closely monitor other COX-2 inhibitors for similar adverse events. "Although the risk that an individual patient would have a heart attack or stroke related to Vioxx is very small, the study that was halted suggests that, overall, patients taking the drug chronically face twice the risk of a heart attack compared to patients receiving a placebo," Dr. Crawford said in a news release. "All of the [nonsteroidal anti-inflammatory drugs (NSAIDs)] 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." Mounting Data Three-year data from the Adenomatous Polyp Prevention on VIOXX (APPROVe) study, a multicenter, prospective, randomized, double-blind trial, documented an increased relative risk for confirmed cardiovascular events, including myocardial infarction and stroke, for rofecoxib compared with placebo. In APPROVe, which was designed to evaluate the efficacy of rofecoxib, 25 mg, in preventing recurrence of colorectal polyps in 2,600 patients with a history of colorectal adenomas, the increased cardiovascular risk began after 18 months of treatment with rofecoxib and persisted. At three years, cumulative incidence of cardiovascular events was 7.5 per 1,000 patients receiving placebo compared with 15 per 1,000 patients receiving rofecoxib. "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," said Raymond V. Gilmartin, chairman, president, and chief executive officer of Merck. The FDA approved rofecoxib in 1999 for pain and inflammation caused by osteoarthritis, for acute pain in adults, and for menstrual pain, and later approved it for symptoms of rheumatoid arthritis in adults and children. Compared with nonselective NSAIDs that block both COX-1 and COX-2, the purported advantage of rofecoxib and other COX-2 selective inhibitors was lower risk of gastrointestinal ulcers and bleeding, because the COX-1 enzyme helps protect the stomach lining from acid. In June 2000, the Vioxx Gastrointestinal Outcomes Research (VIGOR) safety study showed an increased risk of serious cardiovascular events. Myocardial infarction was five times higher with rofecoxib (0.5%) than with naproxen (0.1%), and risks of stroke, venous thrombosis, and hypertension were also significantly increased. Although Merck argued that this difference might reflect a cardioprotective effect of naproxen, epidemiologic studies to test that hypothesis have proved inconclusive. Based on VIGOR and other controlled trials, the FDA changed rofecoxib labeling in April 2002 to include information about increased cardiovascular risk. Safety labels notwithstanding, rofecoxib became one of the most widely used drugs ever to be withdrawn from the market. Two million people worldwide were taking rofecoxib at the time of the withdrawal, resulting in $2.5 billion in rofecoxib sales last year, and about 80 million people have taken the drug since it was first marketed. But now that rofecoxib is withdrawn, will use of other COX-2 inhibitors increase, given combined sales of rofecoxib, celecoxib (Celebrex), and valdecoxib (Bextra) — the two other approved COX-2 inhibitors, both Pfizer products — exceeding $6 billion worldwide last year? Or will storms brewing over rofecoxib cast doubt on the whole class, including drugs still in the pipeline, such as Merck's etoricoxib (Arcoxia) and lumiracoxib (Prexige) from Novartis? "There is really a trend that all COX-2 inhibitors may have increased risk of cardiovascular diseases following long-term use in chronic arthritis patients, based on some meta-analyses," Li-Chia Chen, PhD, from the School of Pharmacy and Pharmaceutical Sciences at the University of Manchester, U.K., told Medscape. "However, the long-term use evidence hasn't been finalized." She added that the U.K.'s National Institute for Clinical Excellence will review the evidence next week, and that the guidelines for using COX-2 inhibitors in chronic arthritis will soon be updated. Potential Mechanisms for Cardiovascular Risk Mechanistically speaking, there are reasons why inhibiting COX-1 and COX-2 might affect cardiovascular risk. Because COX-1 helps promote thrombosis and COX-2 helps inhibit it, blocking COX-2 but not COX-1 could theoretically increase the risk of myocardial infarction and other thrombotic events. On the other hand, inflammation has also been implicated in cardiovascular events, so controlling inflammation via COX-2 inhibition could conceivably be protective. In a perspective released early by the New England Journal of Medicine, Garret A. FitzGerald, MD, a professor and chair of pharmacology at the University of Pennsylvania School of Medicine in Philadelphia, suggests that depression of prostaglandin I2 formation by coxibs might be expected to elevate blood pressure, accelerate atherogenesis, and increase the thrombotic response to rupture of an atherosclerotic plaque. In patients at higher cardiovascular risk, coxibs would be more likely to predispose to a clinical event early in the course of treatment. "The evidence for hazard from Vioxx is much stronger than for other members of the class, [but] there is a clear mechanistic explanation for what we saw in APPROVe and it would apply across the class," Dr. FitzGerald told Medscape. "Although the studies to date have been designed in a way that minimizes the likelihood of detecting a cardivascular signal, there have been suggestions consistent with that possibllity with all members of the class. The outcome of APPROVe shifts the burden of responsibility to those who claim that the results with Vioxx were due to some off target COX-2 independent effect." In a rabbit model (Proc Nat Acad Sci., Aug. 29, 2000), damage after temporary coronary artery ligation was increased by treatment with celecoxib, which completely blocked the cardioprotective effects of the COX-2 enzyme. The authors concluded that the COX-2 enzyme is a "cardioprotective protein," suggesting that COX-2 inhibitors may neutralize these protective effects. Safety of Celecoxib Although the Celecoxib Long Term Arthritis Safety Study (CLASS) trial did not show a significantly increased rate of myocardial infarction with celecoxib compared with the nonspecific NSAIDs ibuprofen or diclofenac, the incidence of adverse events related to cardiac ischemia was higher with celecoxib, especially in patients not taking aspirin. In that group, the rate of myocardial infarction was 0.2% with celecoxib and 0.1% with the other two drugs. For all patients, there was a higher incidence of atrial fibrillation in the celecoxib group than in patients taking ibuprofen or diclofenac, which was more pronounced in the group not taking aspirin. "There was some increase in cardiovascular events sufficient to trigger some worried comments by the FDA physician who reviewed the [CLASS] data," Sidney M. Wolfe, MD, director of Public Citizen's Health Research Group, told Medscape. Dr. FitzGerald pointed out that the original report of the CLASS trial suggested a more favorable gastrointestinal adverse effect profile for celecoxib than for the other NSAIDs with no increase in cardiovascular risk. However, this report contained only six months of data from a one-year study, and the full data showed no difference between celecoxib and the traditional NSAIDs on predefined gastrointestinal end points. Part 2 to follow... Editor's Note: Dr. FitzGerald reports having received consulting fees from NiCox and Merck and research support from Merck. N Engl J Med. Published online Oct. 6, 2004. Reviewed by Gary D. Vogin, MD Laurie Barclay, MD Freelance writer for Medscape Medical News Medscape Medical News is edited by Deborah Flapan, assistant managing editor of news at Medscape. 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