Arthritis Medicines and Cardiovascular Events—“House of Coxibs”

Abstract

PHYSICIANS, PATIENTS, AND THE GENERAL PUBLIC ARE confronted with an acute confusional state regarding the cardiovascular safety of medicines for arthritis. Since September 30, 2004, the day that rofecoxib was precipitously withdrawn, there has hardly been a day without significant news on the general topic of cyclooxygenase 2 (COX-2) inhibitors. On December 9, 2004, the US Food and Drug Administration (FDA) issued a black box warning for valdecoxib for life-threatening skin reactions and cardiovascular risk. Just over a week later, on December 17, 2004, the National Cancer Institute announced the premature cessation of a trial of celecoxib known as Adenoma Prevention with Celecoxib (APC) due to a significant excess of cardiovascular death, myocardial infarction (MI), and stroke. The principal cardiovascular event data for APC are summarized in the FIGURE. This was a trial of 2026 patients, with randomization to 1 of 3 groups: placebo; celecoxib, 200 mg twice daily; or celecoxib, 400 mg twice daily. The patients, each of whom had an adenomatous polyp removed before enrollment, were followed up for a mean of 33 months (of a planned 60 months) while taking the study drug, with the primary objective of limiting the development of colorectal cancer. A significant excess of major cardiovascular events was demonstrated, with a dose-response effect (odds ratio, 2.5 for celecoxib 400-mg dose, and 3.4 at the 800-mg dose, vs placebo) (Figure). The absolute excess of major cardiovascular events of 13/1000 patients at the 400-mg dose and 21/1000 patients at the 800-mg dose is similar in magnitude to the results of trials with rofecoxib and valdecoxib. However, it is not possible to meaningfully interpret interdrug differences because the patient populations in the various trials were different; the drug doses, strength, and duration of therapy were different; and each of the drugs in the coxib class are distinct molecules with specific biological properties. While celecoxib is the least COX-2 selective in the class of 5 agents that have gone through pivotal trials, lumiracoxib is the most selective. A trial of 18325 patients, the largest in the field, demonstrated only modest (not statistically significant) excess of cardiovascular risk when lumiracoxib was compared with naproxen, but not when compared with ibuprofen. Importantly, there have not been any direct comparative (head-to-head) trials of one of the agents vs another, which is the only way to definitively establish likeness or difference between the drugs. Notwithstanding these concerns, several epidemiologic studies have considered large populations of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors. In general, these studies found an increased cardiovascular hazard for rofecoxib, especially at higher doses, but not for celecoxib. Some studies therefore concluded that celecoxib did not carry any risk for MI or stroke. But in randomized trials, a signal for potential cardiovascular risk with celecoxib was present. As my colleagues and I described in a 2001 review of the Celecoxib Long-term Arthritis Safety Study (CLASS), the MI rate was 1.6% in the celecoxib group (at a dosage of 400 mg twice per day) and 1.2% in the diclofenac or ibuprofen group for the 1739 patients taking low-dose aspirin. This numerical excess, albeit not statistically significant, was also found in the 6229 Figure. Event Rates of Cardiovascular Death, Myocardial Infarction, and Stroke in the Adenoma Prevention With Celecoxib (APC) Trial