Analysis offers insights into celecoxib's cardiovascular risk.

CHICAGO -- The cardiovascular risk of celecoxib is a function of both dose and dosing schedule, as well as a patient's baseline cardiovascular risk, according to a new National Cancer Institute-sponsored pooled analysis of six randomized trials.

Individuals at higher baseline cardiovascular risk, ac- cording to the Framingham risk score, had substantially higher relative as well as absolute risk of cele-coxib-related cardiovascular events than did those at low baseline risk, Dr. Scott D. Solomon explained at the annual meeting of the American College of Cardiology.

"These data should help guide rational clinical decisions regarding celecoxib use," observed Dr. Solomon of Brigham and Women's Hospital, Boston. "The data may provide a measure of confidence in prescribing celecoxib in patients with very low baseline cardiovascular risk, but would argue for caution in prescribing celecoxib in patients with high baseline cardiovascular risk."

Of the dosing regimens evaluated in the pooled analysis, 400 mg once daily was associated with a significantly lower event rate than was 200 mg b.i.d., which in turn was safer than 400 mg b.i.d., the cardiologist added.

Dr. Solomon presented the results of the Cross Trial Safety Analysis, involving 7,950 patients with 16,070 patient-years of follow-up in six placebo-controlled trials. All of the trials investigated celecoxib for conditions other than arthritis. Three studies evaluated the cyclooxygenase-2 (COX-2)-selective NSAID for secondary prevention of colonic polyps; the others involved degenerative eye disease, secondary prevention of breast cancer, and prevention of Alzheimer's disease. All but one study was sponsored by the NIH.

The rate of the primary study end point--the combination of cardiovascular death, MI, stroke, heart failure, or a thromboembolic event--was 1.1-fold greater in patients on 400 mg of celecoxib once daily than in those on placebo, 1.8-fold greater in patients on 200 mg b.i.d., and 3.1-fold greater in those on 400 mg b.i.d.

The cardiovascular risk associated with the COX-2 inhibitor was unaffected by concomitant use of low-dose aspirin.

The event rate associated with 400 mg of celecoxib once daily wasn't significantly different than with placebo. However, there were relatively few cardiovascular events in patients on this regimen, making for wide confidence intervals. Thus, it was theoretically possible that 400 mg once daily was associated with anything from a 40% reduction in cardiovascular events to a twofold increase, Dr. Solomon noted.

Why did celecoxib at 200 mg b.i.d. carry a significantly higher event rate than did 400 mg once daily? The leading hypothesis involves the fact that the drug suppresses prostacyclin for about 12 hours. Once-daily dosing thus provides the arteries with a respite from the drug's effects, he said.

All doses studied in the analysis are substantially higher than the 200-mg, once daily dosage for which 80%-90% of all celecoxib prescriptions are written. That's the standard dosage in osteoarthritis. But the higher doses are routinely used for patients with rheumatoid arthritis, familial adenomatous polyposis, and acute pain and dysmenorrhea.

The study findings raise the question of whether celecoxib should ever be given to patients with coronary heart disease, or diabetes (considered a CHD risk factor), or rheumatoid arthritis (which is drawing increasing attention as a possible new CHD risk factor).

The trouble with issuing a blanket prohibition in these circumstances, Dr. Solomon said, is that patients who require pain relief have to take something--and it's unclear whether conventional NSAIDs are safer. Indeed, celecoxib's black box warning states, "All NSAIDs may have a similar risk."

The answer to that key question is expected to come from the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen) trial. PRECISION is an ongoing Pfizer Inc.-sponsored randomized trial involving 21,000 patients with osteoarthritis or rheumatoid arthritis with, or at increased risk for, cardiovascular disease. The end points are symptom relief and cardiovascular, renal, and GI safety. The celecoxib dosage is 200 mg once daily, with some patients being titrated to b.i.d. therapy.

"I am a little bit reassured by the data [in the pooled analysis] with the 400-mg once-a-day dose," commented PRECISION principal investigator Dr. Stephen Nissen, chairman of cardiovascular medicine at the Cleve land Clinic Foundation.

BY BRUCE JANCIN

Denver Bureau