Accumulating evidence on the cardiovascular (CV) risks of selective COX-2 inhibitors points to a class effect, according to researchers from Merck & Co, Inc, speaking Wednesday at a 3-day federal Food and Drug Administration (FDA) advisory panel meeting in Gaithersburg, Maryland.1 The panel is slated to make a recommendation Friday that could range from a mandate for restricted use and stricter warnings on the labels of coxibs to complete withdrawal of the remaining drugs in the class. The FDA has stated its intention to act rapidly based on the panel's recommendations.

In reaction to the sharp criticism the FDA has faced for not acting sooner on concerns about the safety of rofecoxib (VioxxR), Health and Human Services Secretary Michael Leavitt announced Tuesday the creation of a Drug Safety Oversight Board to advise the FDA on approval of new drugs and to help convey new information about risks to patients and healthcare providers.

Class effect?

"We believe the data on celecoxib and valdecoxib and parecoxib together with APPROVe [Adenomatous Polyp Prevention on Vioxx trial] strongly suggest an effect of COX-2 inhibition on risk," Ned S. Braunstein, MD, senior director of Merck Research Labs in Whitehouse Station, New Jersey, told the panel. Merck voluntarily withdrew rofecoxib from the market on September 30, 2004, after the APPROVe study showed the drug doubled the risk of myocardial infarction (MI) and stroke in patients who took it for at least 18 months. Since that time, new information and questions about celecoxib and valdecoxib, as well as over-the-counter nonsteroidal antiflammatory drugs (NSAIDs) such as naproxen, have arisen in a whirlwind of concern about their safety.

Earlier this week, The New England Journal of Medicine published online new studies of all three approved coxibs. New data from the Adenoma Prevention with Celecoxib (APC) trial showed an increased risk of MI, stroke, and heart failure in patients using celecoxib compared with placebo.2 Three events not included in preliminary analysis were included in the online publication, but did not change the overall conclusion of the study, which was halted as a result of the CV safety signal. Other trials, such as Prevention of Spontaneous Adenomatous Polyps (PRESAP), however, showed no such risk.

Kenneth M. Verburg, PhD, vice president of inflammation and immunology of clinical research development at Pfizer Global Research and Development, La Jolla, California, opined that celecoxib has a comparable CV safety profile to nonselective NSAIDs. He pointed out that an analysis of 41 studies found that celecoxib did not appear to increase the chances of MI or other CV problems.

"Patients who discontinue Celebrex will likely turn to [traditional] NSAIDs and, in our view, Celebrex is safe and effective for the arthritis patient [and provides] improved gastrointestinal safety," Dr. Verburg told the panel. "All lines of evidence show that the cardiovascular safety of Celebrex is similar to NSAIDs for up to 1 year and not much is known after that," he continued, noting that "rofecoxib appears to be distinct from Celebrex with regard to cardiovascular effect."

Improved GI safety

Dr. Verburg presented new data from a meta-analysis of randomized control trials (RCTs) scheduled for publication later this month in Arthritis Research & Therapy. In the pooled analysis of 39,605 osteoarthritis (OA) and rheumatoid arthritis (RA) patients with a mean exposure of 7 months, celecoxib was associated with a lower risk of hospitalization due to GI bleeding than were traditional NSAIDS.

"The RCTs show a favorable GI safety profile – supporting the fundamental hypothesis put forth in 1992 [when coxibs were first developed]," adding that, "The medical need for improved GI safety was fulfilled with celecoxib." Only rofecoxib has been shown to cause fewer serious GI problems.

New data from APPROVe

Researchers from Merck presented new data that resulted from an exploratory post-hoc analysis of the APPROVe trial. Dr. Braunstein observed that patients taking Vioxx showed an increased risk of congestive heart failure and pulmonary edema early in the course of treatment, whereas risk for MI and stroke took 18 months to appear.

APPROVe also detected a 4 mm Hg rise in systolic blood pressure and a 2 mm Hg rise in diastolic pressure. "These changes are typical of what is published for traditional NSAIDs," Dr. Braunstein noted. "The changes in systolic and diastolic pressure would not appear to account for the magnitude of the cardiovascular effect."

However, one panel member, citing a pooled analysis published earlier this week in the Archives of Internal Medicine,3 remarked that "it sure looks like rofecoxib is an outlier." In this analysis, rofecoxib conferred a greater risk of developing hypertension and clinically important elevations in both systolic and diastolic pressure compared with celecoxib.

Other panel members cited the lack of intent-to-treat analyses, suggesting that signals could have been stronger if patients who dropped out were followed for extended periods of time. Dr. Braunstein noted that, at this time, data is only available for these patients until 2 weeks after leaving the trial.

Merck scientists indicate that they will to continue to analyze collected data and follow APPROVe patients off-drug. They are also hoping the Multi-national Etoricoxib Diclofenac Arthritis Long- term (MEDAL) trial, which will compare the CV safety of the not-yet-approved etoricoxib (ArcoxiaR) to diclofenac in 23,000 arthritis patients, will shed light on this issue. Data from this study should be available in 2006.

Personalized medicine and postmarketing surveillance

Going forward, Garret A. Fitzgerald, MD, professor of medicine and pharmacology and chair of the department of pharmacology at the University of Pennsylvania School of Medicine, in Philadelphia, suggests the exclusion of patients with intrinsic risk of thrombotic events.

"If they have value, and I believe that they have value as a class, we have to actively move toward an example of personalized medicine," Dr. Fitzgerald tells CIAOMed. Coxibs should be "restricted in some way to patients who really need these drugs for GI reasons, and who are intolerant of traditional NSAIDs and proton pump inhibitors," he suggests.

"We are likely to subject new drugs that might be approved in this class to significant hurdles before they are approved and subject approved drugs to the same hurdles to retain approval, particularly for extended use," he concludes.

References:

1. The Food and Drug Administration (FDA) joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee; February 16, 17, and 18, 2005; Gaithersburg, Md.

2. Solomon SD, McMurray JV, Pfefer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. EPub ahead of print date: February 15, 2005.

3. Aw T-J, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005;165:1-7