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A correction has been published: N Engl J Med 2005;352(11):1163.
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Merck learned the preliminary VIGOR results in March 2000, with more cardiovascular events over a period of one year in patients receiving Vioxx than in those receiving naproxen, and promptly disclosed this finding to the FDA, other regulators, and the media, beginning that month. Two months later, the VIGOR manuscript was submitted to the Journal, and it was published in November 2000. An application to include the results in the prescribing information was submitted to the FDA in June 2000, followed by a public Advisory Committee meeting in February 2001. In April 2002, the FDA approved the revised Vioxx prescribing information, reflecting the cardiovascular data from VIGOR (which lacked a placebo group) and interim data from long-term, placebo-controlled studies in elderly patients with Alzheimer's disease, which did not show an increased cardiovascular risk.3
Second, Dr. Topol neglects to mention that beginning in 2000, Merck undertook three prospective, randomized, placebo-controlled trials of Vioxx in more than 24,000 patients with or without known cardiovascular disease. After deliberations with numerous consultants, Merck finalized a protocol in 2002, which prespecified the analysis of adjudicated cardiovascular-event data from these studies as a hypothesis-testing end point. Two of these studies, Adenomatous Polyp Prevention on Vioxx (APPROVe), with approximately 2600 patients, and Vioxx in Colorectal Therapy, Definition of Optimal Regimen (VICTOR), a study of 7000 patients with a history of colon cancer, had already begun, and the third, a study of 15,000 patients at risk for prostate cancer, was initiated after consultation with regulatory agencies.
Third, before the results of the APPROVe study were available, completed and ongoing randomized trials involving more than 28,000 patients with more than 14,000 patient-years of exposure showed an incidence of cardiovascular events among patients taking Vioxx that was similar to the incidence among those taking placebo and those taking nonsteroidal antiinflammatory drugs (NSAIDs) other than naproxen.2,4 Because naproxen inhibits platelet aggregation in similar fashion to low-dose aspirin, we concluded that the VIGOR results were most likely due to the effects of naproxen.5 Even Topol and colleagues stated that "aspirin and naproxen . . . have a cardioprotective effect."6
Fourth, Dr. Topol argues that observational studies "confirmed" cardiovascular risks with rofecoxib. However, one observational study reported in the peer-reviewed literature and another such study reported in abstract form, neither funded by Merck, did not.7,8
The APPROVe study began nine months after the FDA approved Vioxx and one month before the results of the VIGOR study were known. Analysis of cardiovascular events was prespecified for the reason cited above. Because the study was designed to examine the effects of long-term use of rofecoxib on gastric polyps, we were able to detect an increase in cardiovascular risk that began after 18 months of continuous Vioxx therapy. At that time, September 2004, Merck moved promptly and voluntarily to remove Vioxx from the market. The record, in short, is one of careful analysis at every stage, a continued commitment to research, and prompt and decisive action in response to clinical-study results.
Peter S. Kim, Ph.D.
Alise S. Reicin, M.D.
Merck Research Laboratories
West Point, PA 19486
References
The FDA convened an advisory committee (on February 8, 2001) to review the data from VIGOR in order to ensure a full public airing and assessment by additional scientific experts. The study showed a 50 percent decreased risk of gastroduodenal perforations, symptomatic ulcers, and bleeding with Vioxx (50 mg daily) but twice the risk of cardiovascular thrombotic events (mostly myocardial infarctions, with no differences in strokes or cardiovascular deaths), as compared with naproxen. The study had several limitations that hampered the generalization of these findings. After careful review, the expert panel (which included cardiologists) recommended that the label for Vioxx should include the unquestionable gastrointestinal advantage as well as the negative cardiovascular safety information in order to provide doctors and patients with the available data on the potential risks and benefits of Vioxx as compared with naproxen.1 Subsequently, the FDA approved changes in the labeling to reflect the risk of cardiovascular thrombotic events as reported in the VIGOR study. Specifically, the new labeling advised doctors to use caution in prescribing Vioxx for patients with ischemic heart disease and stated that Vioxx at 50 mg per day is not recommended for long-term use.
The finding of an increased risk of myocardial infarctions and strokes in Merck's study of colon-polyp prevention (APPROVe) with the 25-mg dose was unexpected but not an accident. The extensive safety monitoring in this and other studies was intended in part to address the fact that, as noted in the precautions section of the Vioxx label, "Prospective studies specifically designed to compare the incidence of serious cardiovascular events in patients taking Vioxx as compared with those taking NSAIDs or placebo have not been performed."
The FDA worked vigorously with Merck to inform the public of the potential cardiovascular risks associated with Vioxx and to ensure adequate ascertainment and analyses of these cardiovascular events in Merck's prevention trials. The FDA will continue to work within its regulatory authority to protect the public health while balancing the available evidence in a rapidly changing scientific and clinical landscape.
(The views presented in this article do not necessarily reflect those of the Food and Drug Administration.)
Lourdes Villalba, M.D.
James Witter, M.D., Ph.D.
Food and Drug Administration
Rockville, MD 20850
References
Although the reasons for these differences cannot be ascertained without a direct prospective comparison, the study design may have contributed. Because aspirin use was not permitted in VIGOR, despite the inclusion of patients with prior myocardial infarction, the thrombogenic potential of rofecoxib may have been not only unmasked but actually potentiated. The possibility that naproxen might be protective was discussed but dismissed because no studies had examined this specific question. Nevertheless, three subsequent retrospective analyses suggested that naproxen may indeed be cardioprotective.
In contrast, 21 percent of the participants took aspirin in CLASS, which, as suggested by FitzGerald, may have concealed the deleterious properties of celecoxib. My one voiced criticism of the FDA was its role in these two studies, which although seemingly similar, included at least three major differences that precluded any meaningful direct comparison — most important, the use of aspirin. Thus, I fully agree with Topol and FitzGerald that on the basis of pharmacologic principles, all precautions should be extended to the use of every coxib. Moreover, FitzGerald's group has reported that nonselective NSAIDs that inhibit thromboxane A2 to a lesser extent than aspirin may not effectively inhibit platelet aggregation.5 In theory, the effective inhibition of prostaglandin I2 by NSAIDs, without sufficient suppression of thromboxane, may promote thrombosis. Thus, in addition to coxibs, I would recommend, that all NSAIDs be reexamined to determine their thrombogenic potential.
Finally, it must be emphasized that the VIGOR study and, to some extent, CLASS did show a decrease in serious gastrointestinal adverse events. The obvious lesson learned from the development of coxibs is that the potential for serious adverse events appears to have outweighed any conferred benefit. As additional information is accrued, pharmaceutical companies, the FDA, and the National Institutes of Health need to work together to prevent future debacles by mandating a thorough investigation of all new and old drugs for which there is even the theoretical possibility of serious effects.
M. Michael Wolfe, M.D.
Boston University School of Medicine
Boston, MA 02118
References
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We indeed acknowledged that naproxen may have a cardioprotective effect,5 but the magnitude of the effect would be unlikely to exceed that of aspirin, at a 25 percent reduction of heart attacks. Instead, in the VIGOR trial, there was a 500 percent increase in heart attacks. This makes any "naproxen hypothesis" of cardioprotection mathematically indefensible.
Drs. Villalba and Witter are incorrect in suggesting that the FDA cannot influence post-marketing clinical trials that a sponsor performs. Their claim that the "50 percent decreased risk of gastroduodenal perforations" outweighed the cardiovascular risk in the VIGOR trial is not substantiated by the data. There were no differences in the rate of perforation (0.1 percent in both the rofecoxib and naproxen groups).2 It is hard to imagine that the small protection from gastric or duodenal ulcers in the VIGOR trial is an acceptable trade-off as compared with twice the incidence of death, heart attacks, and strokes. Indeed, Dr. Targum, the FDA reviewer of the VIGOR, wrote in her report, in reference to the cardiovascular findings, "This analysis could lead one to conclude that naproxen, with a 51 percent reduction compared to rofecoxib, would be the preferred drug."3 It took 14 months after the expert FDA panel convened, from February 2001 to April 2002, to change minimally the cardiovascular safety information for rofecoxib in the package insert. After their cumulative meta-analysis, Juni et al. correctly stated, "Our findings indicate that rofecoxib should have been withdrawn several years earlier."6
Eric J. Topol, M.D.
Cleveland Clinic Foundation
Cleveland, OH 44195
Dr. Topol reports having served as a paid advisor to Great Point Partners, an investment fund that has traded in Merck stock. He reports that he did not invest in the fund, was not compensated on the basis of the fund's performance, and was not aware of its investment in Merck.
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