Findings confirm risks with rofecoxib use
Last Updated: 2006-09-12 16:00:11 -0400 (Reuters Health)
NEW YORK (Reuters Health) - Use of rofecoxib (Vioxx), the drug at the center of many high-profile lawsuits, does, in fact, increase the risk of cardiovascular events and may adversely affect renal function, according to the results of two studies appearing in the October 4 issue of the Journal of the American Medical Association, released online September 12th.
Both reports suggest that only rofecoxib, not other selective COX-2 inhibitors, markedly raises the risk of these events.
Dr. Jingjing Zhang, from Harvard Medical School in Boston, and colleagues conducted a meta-analysis of trial data to compare the renal and arrhythmia risks of COX-2 inhibitors, including rofecoxib, celecoxib, and valdecoxib, among others. A search of EMBASE and MEDLINE yielded 114 relevant trials with 116,094 participants.
A total of 6394 renal events, including peripheral edema, hypertension, and renal dysfunction, and 286 arrhythmia events occurred in the study group. Statistical analysis suggested no evidence of a class effect for these events.
Compared with placebo, rofecoxib use was associated with a nearly threefold increased risk of arrhythmia. In addition, use of the drug was tied to elevated risks of all three renal events.
By contrast, celecoxib use appeared to cut the risk of renal dysfunction and hypertension by 39% and 17%, respectively, compared with placebo. The other COX-2 inhibitors had no significant effect on the risk of arrhythmia or renal events, the authors note.
In the second report, Dr. Patricia McGettigan and Dr. David Henry, from The University of Newcastle in New South Wales, Australia, conducted a systematic review of observational studies to assess the cardiovascular risk with COX-2 inhibitors and with the older non-selective NSAIDs. Their database search yielded 7086 potential studies, of which 17 case-control and 6 cohort studies were deemed eligible for analysis.
At doses greater than 25 mg/day, rofecoxib more than doubled the risk of cardiovascular events. At lower doses, the drug was associated with a 33% increased risk. These risks were apparent within the first month of treatment.
By contrast, at commonly used doses, celecoxib did not raise the risk of cardiovascular events, the investigators point out.
The older NSAIDs generally had little effect on cardiovascular risk, the exception being diclofenac, which was associated with a 40% increased risk. Contrary to some reports, naproxen use did not seem to confer a cardioprotective effect.
In a related editorial, Dr. David J. Graham, from the US Food and Drug Administration in Silver Spring, Maryland, comments that the two reports "provide clarity on a topic that has been dominated more by disinformation than reason."
Dr. Graham goes on to mention that Vioxx-maker Merck is now seeking US approval of etoricoxib, a COX-2 inhibitor already approved for use in Europe and elsewhere. The concern is that the major study (MEDAL), which showed etoricoxib to be safe, compared the drug against diclofenac, an agent that has now been tied to elevated cardiovascular risks in two meta-analyses.
"From the perspective of patient safety and rational therapeutics, naproxen, not diclofenac, should have been the reference drug in MEDAL," Dr. Graham notes. "Had that been so, it is highly likely that etoricoxib would have been shown to be no different than its first-cousin rofecoxib with respect to cardiovascular risks."
JAMA 2006.
