ICES Report: The Changing Landscape for COX-2 Inhibitors: A Summary of Recent Events
The publication of a large randomized controlled trial in November 2000 convincingly demonstrated a favourable gastrointestinal adverse event profile associated with Vioxx® compared to a commonly used traditional NSAID, Naprosyn® (naproxen). A 50% relative risk reduction in serious gastrointestinal outcomes was observed among Vioxx® users relative to Naprosyn (Bombardier et al. 2000). However, in a secondary analysis of general safety, the same clinical trial also suggested a five fold increased risk of heart attack associated with Vioxx® relative to Naprosyn. Consequently, this prompted numerous systematic reviews and observational studies, the results of which further supported a possible adverse cardiovascular effect of Vioxx®, and were published long before Vioxx's® withdrawal from the market.
Despite this mounting evidence, Vioxx® was not withdrawn until the interim results of a second large randomized controlled trial demonstrated an associated increased cardiovascular risk with the drug; this withdrawal of Vioxx® occurred about four years after the first clinical trial suggested cardiovascular risk. Allegations that the cardiovascular risks associated with Vioxx® were suspected by Merck scientists well before the launch of Vioxx® - as early as 1996 (Lenzer 2004) - have cast serious doubts on the ethical conduct of the pharmaceutical industry and its relationship with the Food and Drug Administration (FDA) of the United States, the federal drug regulatory body.
The Vioxx® withdrawal created a common state of confusion about alternative treatments for frustrated patients and prescribing physicians. At this point, the evidence supporting the use of alternative treatments to Vioxx® varies significantly. Alternatives to Vioxx® include treatment with other drugs marketed as COX-2 inhibitors in Canada, such as Celebrex® (celecoxib), Bextra™ (valdecoxib) and Mobic® (meloxicam); traditional NSAIDs, such as Naprosyn® and Advil® (ibuprofen); topical NSAIDs, such as Pennsaid® (topical diclofenac) for limited joint pain; alternative
therapies, such as Lakota®; and non-drug therapies, such as weight-bearing exercise, knee taping and acupuncture. A first choice for many physicians was to switch patients to Celebrex®, as the overwhelming majority of evidence from large comparative studies suggested no excess cardiovascular risk with exposure to commonly used doses.
In December 2004, however, three large randomized clinical trials examining Celebrex® were halted due to concerns from interim analyses that indicated cardiovascular risks associated not only with Celebrex®, but also with traditional NSAIDs. Two large clinical trials compared Celebrex® at varying doses to placebo for the prevention of pre-malignant colon tumours in more than 3,000 patients. The first of these trials was the Adenoma Prevention with Celebrex® (APC) trial, funded by the US National Institutes of Health (NIH). Among users of Celebrex® at doses of 400 mg daily, the trial found a greater than two-fold risk of cardiovascular events (though not statistically significant). Among those using 800 mg daily of Celebrex®, the trial found a statistically significant three-fold higher risk of such events (Topol 2005). The second of these clinical trials, the Prevention of Spontaneous Adenomatous Polyps (PreSAP), funded by the pharmaceutical company Pfizer, did not find any excess cardiovascular risk associated with Celebrex® at doses of 400 mg daily relative to placebo.
The third trial, the Alzheimer Disease Anti inflammatory Prevention Trial (ADAPT), funded by the NIH, compared Naprosyn® at doses of 220 mg twice daily to Celebrex® at doses of 200 mg twice daily in roughly 2,400 patients. An approximately 50% greater risk of cardiovascular events among users of Naprosyn®, but not Celebrex®, was demonstrated. With all this confusing and conflicting information, in February 2005, the FDA convened an expert group to review available data and provide recommendations.
The recent events have cast considerable suspicion over the cardiovascular safety of not just COX-2 inhibitors as a drug class, but also the entire NSAID category. Further evaluation will determine the future role of COX-2 inhibitors in managing patients with pain and inflammation. Time will tell whether public confidence in the pharmaceutical industry and government regulatory bodies will be restored.
About the Author(s)
Muhammad Mamdani, PharmD, MA, MPH, is Senior Scientist, Institute for Clinical Evaluative Sciences and Associate Professor, University of Toronto Faculty of Pharmacy and Faculty of Medicine (Department of Health Policy, Management, and Evaluation), Toronto, Ontario.
Contact: Address: 2075 Bayview Avenue - G215, Toronto, Ontario, Tel. 416 480-4055 X3887, Fax: 416 480-6048, E-mail: firstname.lastname@example.org.
Bombardier, C., L. Laine, A. Reicin et al. 2000. "Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis." N Engl J Med 343: 1520-28.
Horton, R. 2004. "Vioxx, the Implosion of Merck, and the Aftershocks at the FDA." Lancet 364: 1995-96.
Lenzer, J. 2004. "FDA Is Incapable of Protecting US Against Another Vioxx." BMJ 329: 1253.
Topol, E. 2005. "Arthritis Medications and Cardiovascular Events - 'House of Coxibs.'" JAMA 293: 366-69.
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