Pfizer warns of Bextra risk in CABG patients, plans new study of Celebrex as cardioprotectant in OA patients

Janis Kelly

October 18, 2004

Oct 18, 2004

New York, NY - On Friday Pfizer Inc warned doctors that valdecoxib (Bextra) increases the risk of death in heart patients who use the drug to manage postoperative pain following coronary artery bypass graft (CABG) surgery. Today, the company will announce plans for a new study of its other oral COX-2 inhibitor, celecoxib (Celebrex), in osteoarthritis (OA) patients who have preexisting serious heart disease. The 2 announcements will further roil the arguments over heart effects of the coxibs as a class but are likely to cause more confusion for financial analysts than for clinicians.

The valdecoxib announcement, based on 2 studies in the CABG postoperative setting, carries the clear message that valdecoxib is a poor choice for immediate postbypass pain relief. The drug is not approved for this indication. Pfizer stresses that there is no evidence that it poses any cardiovascular risk when used as recommended for treating rheumatoid arthritis (RA) or osteoarthritis.

The planned new celecoxib study is likely meant to answer basic questions about that coxib's cardiovascular effects, to further distance celecoxib from the heart problems that led to Merck's withdrawal of rofecoxib (Vioxx) and (if successful) to position Pfizer for a new indication for celecoxib.


Increased MI, infections seen with postoperative parecoxib/valdecoxib after CABG surgery

According to Pfizer, the warning about use of valdecoxib for post-CABG pain relief was based on data from 2 randomized clinical trials. The first study, reported in 2003 by Drs Elisabeth Ott, Dennis T Mangano, and colleagues (Ischemia Research and Education Foundation, San Francisco, CA), was an extension of work on parecoxib (Dynastat, Rayzon, Xapit) (the first injectable COX-2 inhibitor) for relief of postoperative pain in a variety of settings [ 1 ]. (A single dose of parecoxib is approved for this use in Europe.)

In the Ott trial, patients received intravenous parecoxib within 30 minutes of extubation after CABG but before initiation of patient-controlled analgesia (PCA) with morphine. Parecoxib was then given every 12 hours for 72 hours, at which point patients were switched either to 40 mg of oral valdecoxib or to placebo. Supplementary pain relief with combination codeine/acetaminophen was available throughout. The main objective was to determine whether the coxib regimen would permit use of less morphine and therefore decrease the risk of adverse effects such as confusion, excessive sedation, and respiratory depression in patients undergoing CABG.

The investigators found that to be the case but also found that the coxib regimen "was associated with an increased incidence of serious adverse events overall and sternal wound infections in particular." Myocardial infarctions occurred in 1.6% of parecoxib/valdecoxib patients vs 0.7% of controls (p=NS), and tachycardia was significantly more common in the experimental group (14.6% vs 7.1%, p=0.017).

The investigators suggested that the platelet-sparing coxibs might be tipping the balance toward thrombosis in these patients, nearly all of whom had undergone surgery with cardiopulmonary bypass and hypothermia. They point out that 4 of the 5 MIs in the experimental group occurred in the early postoperative period, soon after initiation of the parecoxib/valdecoxib regimen.

Ott et al called for a large-scale safety trial before use of parecoxib/valdecoxib in CABG surgery, and the as-yet unpublished results of that trial apparently confirmed the problems identified in the earlier study, triggering Pfizer's warning letter.

These concerns do not apply to the use of valdecoxib to treat arthritis. According to Pfizer, "analyses of a comprehensive clinical trial database of nearly 8000 patients treated with Bextra for durations ranging from 6 to 52 weeks" show "no increased risk of cardiovascular thromboembolic events in people treated for osteoarthritis and rheumatoid arthritis."


New Celebrex study will try to prevent MI, stroke in patients with OA and serious heart disease

The new celecoxib study, which today's Wall Street Journal reports is expected to begin accrual in the next few months, will enroll patients with OA and a history of cardiovascular problems such as previous MI or severe angina [ 2 ].

"The point will be to show that Celebrex is actually beneficial in people with known coronary disease," Dr Jeffrey Borer (Weill Medical College, Cornell University, New York, NY) told the Wall Street Journal. Borer is a member of the executive committee for the study, which is being coordinated by Dr Frank Ruschitzka and colleagues at the University of Zurich.

The 2-year, placebo-controlled trial will enroll OA patients with recent acute coronary syndrome. Borer notes that even with aggressive treatment, such patients would be expected to have a 6% or greater annual risk of serious cardiovascular events or stroke. The main study end point will be the rate of such events in celecoxib vs placebo patients. Other medications, including antihypertensives, statins, and aspirin, will be allowed.

The mechanisms behind the apparent cardiovascular differences with rofecoxib vs celecoxib are under investigation but are thought to involve differences in how the 2 coxibs affect vascular function.

Valdecoxib is approved in the US for relief of signs and symptoms of osteoarthritis and adult rheumatoid arthritis and for the treatment of primary dysmenorrhea but not for use in any surgical setting.


Sources

  1. Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003:125:1481-1492.

  2. Hensley S. Celebrex as heart aid. All-or-nothing bet could pave way for broader use of popular arthritis drug. The Wall Street Journal October 18, 2004; A3. Available at: http://www.wsj.com/

 

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