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

[Guest guest]

Rheumawire

October 18, 2004

Pfizer warns of Bextra risk in CABG patients, plans new study of

Celebrex as cardioprotectant in OA patients

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.

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 beth 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. "

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 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 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/

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org