Pfizer Inc, the manufacturer of the cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex ÂR ), announced on December 17 that a National Cancer Institute (NCI)-sponsored cancer-prevention trial showed at least a 2.5-fold increased risk of fatal and nonfatal cardiovascular (CV) events compared with placebo.

The findings emerged from an analysis of the long-term Adenoma Prevention with Celecoxib (APC) trial, in which patients received 400 mg to 800 mg of celecoxib daily, a 2- to 4-fold higher dose than that recommended for the management of arthritis. A second, similar trial, the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial, comparing celecoxib 400 mg/day with placebo with the same outcomes did not show a significant difference. (See Table 1)

Table 1. Celecoxib Studies in Patients with Adenomatous Polyps:
Antiplatelet Trialist Collaboration CV Events* (N (%)
Adenoma Prevention With Celecoxib (ACP) Prevention of Adenomatous Polyps (PreSAP)

*Antiplatelet Trialist Collaboration endpoint: myocardial infarction, stroke, CV death, and hemorrhagic death during 33- and 32-month periods, respectively, for the APC and PreSAP trials
1 Given as 200 mg BID in the APC trial and 400 mg QD in the PreSAP trial
2 Given as 400 mg BID in the APC trial
Placebo 6/679 (0.9%) 11/628 (1.8%)
Celecoxib 400 mg TDD1  15/685 (2.2%) 16/933 (1.7%)
Celecoxib 800 mg TDD2 20/671 (3.0%) ----------

This announcement follows the release on December 10 of a comparative study, published in the Annals of Internal Medicine, of rofecoxib (VioxxÂR, Merck) and celecoxib, which concluded that rofecoxib had little or no impact on the risk for myocardial infarction (MI), and that celecoxib had a substantial cardioprotective effect.1

"As reported by the [company's independent] Data Safety and Monitoring Board, one of the studies (APC) demonstrated an increased cardiovascular risk over placebo, while the other trial (PreSAP) revealed no greater cardiovascular risk than placebo," according to a statement issued by Pfizer on December 17. Based on the findings, the NCI has suspended the use of celecoxib in the APC study.

Celecoxib is approved for the treatment of osteoarthritis, rheumatoid arthritis, acute pain in adults, and primary dysmenorrhea, and for reduction of adenomatous colorectal polyps in patients with familial adenomatous polyposis, at recommended doses between 100 mg and 400 mg daily. The APC and PreSAP trials were initiated in an effort to assess the agent for supplemental indications, according to Pfizer.

"These clinical trial results are new. The cardiovascular findings in one of the studies (APC) are unexpected and not consistent with the reported findings in the second study (PreSAP). Pfizer is taking immediate steps to fully understand the results and rapidly communicate new information to regulators, physicians, and patients around the world," said Hank McKinnell, Pfizer chairman and chief executive.

The 2 studies had been following approximately 3600 patients over a 5-year period, about 2400 of whom were analyzed for CV risk after 2 years of treatment.

Pfizer said on December 19 that the company would suspend television, radio, newspaper, and magazine advertising, as well as other promotions to consumers, according to Mariann Caprino, a company spokesperson.

The US Food and Drug Administration issued a warning to physicians on December 9 that the COX-2 inhibitor valdecoxib (BextraÂR, Pfizer), has been linked to elevated CV risk in patients who have undergone coronary artery bypass graft surgery,2 strengthening the existing advisory concerning the risk of life-threatening skin reactions associated with the pain reliever.

Pfizer said doctors should factor in the new information, along with other risks, when considering prescribing celecoxib, but it did not say the drug would be withdrawn. In its December 17 statement, the company said there was a "large body of data that we and others have accumulated over time" that indicated no increased heart risk, even at higher-than-recommended doses. Furthermore, 4 pharmaco-epidemiological studies have indicated in a large number of patients that celecoxib had no risk, whereas a Kaiser Permanente/FDA collaboration showed that patients treated with naproxen and indomethacin also had a risk of MI and sudden cardiac death.

References:

  1. Kimmel SE, Berlin JA, Reilly M, et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med. 2005;142(3).
  2. Dooley K. Pfizer will add heart warning for Bextra, FDA says (Update 2). Bloomberg.com. December 9, 2004. Available at: http://www.bloomberg.com/apps/news?pid=71000001&refer=home&sid=av6QKMB.qz4o . Accessed December 13, 2004.