Die hard fans of COX-2 inhibitors who were left wondering
where to turn for relief of arthritis pain when rofecoxib
(Vioxx) and valdecoxib (Bextra) were pulled off the market
can breathe a sigh of relief — recent research shows
that not all of these drugs deserve to be tarred with
the same brush. "COX-2 inhibitors have a role in treating
patients with OA and RA pain, albeit a much smaller one
than [they have] occupied in the recent past," says University
of Virginia's Dr Stephen Christopher Jones, lead author
of a study on COX-2 inhibitors.
Dr Jones' conclusions are based
on his meta-analysis of eight large Phase 3 and 4 clinical
trials, six retrospective cohort and three case-control
studies of COX-2 inhibitors, published from 1996 to
March of this year. "Each COX-2 inhibitor has a unique
cardiovascular risk profile ... The strongest evidence
suggesting an association with drug and event lies with
rofecoxib followed by valdecoxib," he reports in the
July issue of the Annals of Pharmacotherapy.
Interestingly, "celecoxib appears to be the safest COX-2
inhibitor...[posing] less risk than other COX-2 inhibitors
when used at the lowest effective dose for the shortest
period of time," he says. Results of a study on 2,200
patients with congestive heart failure published in
the June 11 issue of the British Medical Journal
reached the same conclusion, stating that the agent
is also safer than other NSAIDS.
MODUS
OPERANDI
Researchers are just beginning to understand how COX-2
inhibitors induce thromboembolic events, with most currently
favouring the 'prostacyclin to thromboxane' hypothesis,
in which hypercoagulation is attributed to the degree
of imbalance between prostacyclin and thromboxane. Prostacyclin
is produced by the endothelial cells of the vessel under
the control of COX-2, while thromboxane is produced
by platelets under the control of COX-1. The theory
goes that selective inhibition of prostacyclin synthesis
allows the thrombogenic effects of thromboxane to predominate,
promoting platelet adhesion and vasoconstriction.
"More selective COX-2 inhibition
may not afford additional gastrointestinal protection,
but may increase cardiovascular risks," concurs Dr Jones.
But the relative COX-2 selectivity of the agent may
be only part of the picture. As Dr Jones' study shows,
the dose, duration of therapy and patient-specific cardiovascular
risk factors may also contribute to thromboembolic events.
Although regulatory action tempering
the use of COX-2 inhibitors need not leave physicians
feeling powerless, a more cautious approach to treatment
is definitely in order. "Therapy must be designed specifically
for the individual patient, a 'one size fits all' approach
is probably not ideal," he concludes.
Ann Pharmacother July 2005;39(7):1249-59
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