Regulatory authorities should request long-term cardiovascular safety studies for any new drug that may be used in high-risk patients in light of the COX-2 safety signals, authors of a Celebrex study state.

The results of the Adenoma Prevention with Celecoxib trial will be published in the Feb. 17 New England Journal of Medicine. The article, titled "Cardiovascular Risk Associated with Celecoxib in a Clinical Trial For Colorectal Adenoma Prevention," is authored by cardiologist Scott Solomon, Brigham & Women's Hospital, et al.

The study, along with four other articles and editorials, are being released early, on Feb. 15, ahead of the Feb. 16-18 COX-2 advisory committee meeting. [Editors' note: To ¹ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

"Given the experience with COX-2 inhibitors, we support the call for regulatory agencies to consider requesting a formal evaluation of long-term cardiovascular outcomes of any new drug with a mechanism of action that could augment the risk of cardiac and vascular events, especially if many patients who are likely to use the new agent are prone to cardiovascular disease," the authors state.

"This experience underscores both the need for long-term, placebo-controlled trials to assess safety as well as efficacy and the need to improve methods for assessing potential adverse cardiovascular outcomes in studies with non-cardiovascular primary endpoints."

The results of the APC trial showed a 2.5-fold risk of cardiovascular events, non-fatal myocardial infarction and stroke at the 200 mg twice daily dose of Celebrex and a 3.4-fold risk at the 400 mg twice daily dose (² Also see "Pfizer Celebrex Polyp Trial Shows Increase In Cardiovascular Events" - Pink Sheet, 17 December, 2004.).

The authors propose one hypothesis for why Celebrex may have been associated with increased cardiovascular risk in their study, but not in previous studies.

Twice daily dosing, which results in prolonged inhibition of COX-2 dependent prostacyclin, may explain why the cardiovascular signal was apparent in the APC trial, but not other Celebrex trials, the authors suggest.

In addition, the authors state that previous COX-2 trials were not powered to detect cardiovascular events because high-risk patients were excluded, the studies were short-term and they were not placebo-controlled.

"Consequently, the studies lacked adequate statistical power to confirm or refute a cardiovascular safety hazard related to the use of COX-2 inhibitors," the authors state.

The advisory committee will discuss whether the potential association of COX-2 inhibitors and cardiovascular risk is a class effect or limited to specific drugs.

[Editor's note: FDA Drug Safety Advisory Committee member Curt Furberg and Chairman Peter Gross will discuss the outcome of the COX-2 committee meeting at a Feb. 23 Drug & Device Dialogue audio conference. To register, visit ³ www.drugdevicedialogue.com or call 800-332-2181. ]

Another article appearing in the Feb. 17 NEJM is "Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after Cardac Surgery," by cardiologist Nancy Nussmeier, the Texas Heart Institute at St. Luke's Episcopal Hospital, et al. The results of that study contributed to Pfizer's modification of Bextra (valdecoxib) labeling to include a contraindication following coronary artery bypass graft surgery (⁴ Also see "Bextra Contraindicated In CABG Surgery Patients" - Pink Sheet, 3 December, 2004.).

The results of the Adenomatous Polyp Prevention on Vioxx study will be published in the Feb. 17 NEJM in an article titled "Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial" by Robert Bresalier, M.D. Anderson Cancer Center, et al. Preliminary results of APPROVe prompted Merck to withdraw Vioxx (⁵ Also see "FDA Has One Month To Mull Approval Of Merck's Arcoxia Following Vioxx Withdrawal" - Pink Sheet, 30 September, 2004.).

In addition, there will be two editorials published, one titled "COX-2 Inhibitors - A Lesson In Unexpected Problems" by NEJM editor Jeffrey Drazen and a second, "COX-2 Inhibitors - Lessons in Drug Safety," by FDA Drug Safety & Risk Management Advisory Committee member Curt Furberg (see ⁶ Also see "COX-2 Use Should Be Limited, FDA Advisory Cmte. Member Furberg Says In NEJM" - Pink Sheet, 15 February, 2005.) .

- Lee Kalowski

Need For Long-Term CV Studies Goes Beyond COX-2s – Celebrex Study Authors

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