| New data will help guide prescribing of celecoxib | ||||||||||||||||||||||||||
| Fonte: theheart.org - Lisa Nainggolan March 31, 2008 | ||||||||||||||||||||||||||
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Chicago, IL - A new meta-analysis of six randomized trials involving the COX-2 inhibitor celecoxib (Celebrex, Pfizer) should help direct physicians who still want to prescribe this drug [1]. Dr Scott D Solomon (Brigham and Women's Hospital, Boston, MA) presented the findings of the cross-trial safety analysis at a late-breaking trials session here today, and they were published simultaneously in Circulation.
Solomon et al found differences in the risk of adverse cardiovascular events based on the dose regimen of celecoxib and showed that those with the highest baseline cardiovascular risk had the greatest risk of celecoxib-related adverse events. "These data should provide comfort in prescribing celecoxib to patients with very low cardiovascular risk. It helps us to chose which patients we can feel safe about giving celecoxib to," said Solomon. "Similarly, we should be cautious in prescribing celecoxib to patients who have elevated baseline cardiovascular risk. Our data support the recent AHA scientific position statement suggesting that physicians should prescribe the lowest doses of celecoxib possible, especially in higher-risk patients." Dr Raymond Gibbons (Mayo Clinic, Rochester, MN) commented to heartwire: "This is an important study showing that the risk of the drug depends on the cardiovascular baseline risk of a patient as well as on the dose of the drug." Another interesting aspect of the study was that the interaction term was significant, Gibbons noted, something that was not presented by Solomon. "This means that not only was the dose important and the baseline risk important, but the interaction between the two was important—the effect of one depends on the other. For example, in those at lowest baseline risk, the dose of the drug doesn't really matter." Asked by heartwire why this was not explained in the presentation, Gibbons said: "They know even in a sophisticated audience that most people won't get it!" In practice, says Gibbons, most cardiologists will be seeing patients who are at high baseline cardiovascular risk, and "so they should avoid using celecoxib. These data reinforce the AHA guidelines on this," he says. Exceptions could be made in circumstances where, for example, a patient has terrible joint pain despite trying all other recommended medications and where the patient and doctor have fully discussed the potential risk of the coxib, he said. "Some patients might have such discomfort, they say, 'I'll take that risk.' " Attempt
to more fully understand CV risk profile with celecoxib
Solomon said the cross-trial safety analysis—which was commissioned and funded by the National Cancer Institute—was undertaken to try to understand more fully the cardiovascular risk profile associated with the long-term use of celecoxib. It remains the most commonly used COX-2 inhibitor in the world and the only one on the market in the US, he noted. Two other drugs from the class—etoricoxib (Arcoxia, Merck) and lumiracoxib (Prexige, Novartis)—are available elsewhere All of the six trials included were comparing celecoxib with placebo for conditions other than arthritis, with a planned follow-up of three or more years, and all had been stopped in the aftermath of the worldwide withdrawal of rofecoxib (Vioxx, Merck) in the fall of 2004: the Adenoma Prevention with Celecoxib (APC) study; the Prevention of Sporadic Adenomatous Polyps (PreSAP); the ADAPT trial in Alzheimer's disease; the MA-27 breast-cancer recurrence study; a diabetic retinopathy study, CDME; and the celecoxib/selenium trial. In total, 7950 patients were administered celecoxib in one of three dose regimens (400 mg once daily, 200 mg twice daily, or 400 mg twice daily). With 16 070 patient-years of follow-up, Solomon and colleagues calculated a hazard ratio for all dose regimens combined and individual hazard ratios (HRs) for each dose regimen. They also looked at whether celecoxib-related risk was associated with baseline cardiovascular risk, as assessed by a modified Framingham risk score assigned to each patient as low (28% of patients), moderate (27%), or high (45%). All cardiovascular end points were blindly adjudicated from source documents, and the primary end point was the combination of cardiovascular death, MI, stroke, heart failure, or thromboembolic event. Unfortunately, the study did not examine the 200-mg once-daily dose of celecoxib—estimated to be the dose used by 80% to 90% of patients—because the studies included in the meta-analysis did not include this dose. New
data relate to doses for acute pain, rheumatoid arthritis, period pain,
and familial adenomatous polyps
The
hazard ratio for the composite end point combining all the tested doses
was 1.6. The risk was lowest for the 400-mg daily dose; intermediate for
the 200-mg twice-daily dose, with nearly a twofold risk of adverse cardiovascular
events; and highest for the 400-mg twice-daily dose, with an approximately
threefold risk of adverse cardiovascular events. Celecoxib was associated
with increased risk regardless of baseline aspirin use, and there was
no differential effect based on any prespecified subgroups. Pooled
HRs for the principal composite endpoint for each dose regimen and for
all the trials combined (adjusted for baseline cardiovascular risk)
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"By adding the results of four additional trials to the previously reported APC and PreSAP trials, this analysis had the power to address dose and regimen differences and the interaction between baseline cardiovascular risk and risk associated with celecoxib," said Solomon. He noted, however, that there were a number of caveats to his study, including the fact that the doses tested were higher than the 200-mg once-daily dose generally used in osteoarthritis. But he said that the new data "do directly relate to doses recommended in the celecoxib label for rheumatoid arthritis, acute pain, dysmenorrhea, and familial adenomatous polyps." Another limitation was that none of the trials were specifically designed to assess cardiovascular risk, he said. A
measure of comfort in low-risk patients
"Once-daily dosing appears to be safer than twice-daily dosing—although the confidence intervals are quite wide," Solomon commented. He hypothesized that this may be due to the pharmacokinetics of celecoxib and specifically its effect in suppressing prostacyclin, which lasts around 12 hours. "We can speculate that once-daily dosing had a different biologic effect than twice-daily dosing, but this is only conjecture.
"We also found strong evidence of a dose-related risk, although we cannot address whether doses lower than those used in these six trials are safer, and we need to be cautious about this." And he acknowledged that the upper confidence interval for even the lowest dose didn't exclude the possibility that that dose might have had a twofold higher risk [than it did]. "We also found a doubling of risk between low- and moderate-risk groups and a further doubling of risk between moderate- and high-risk groups," Solomon continued. "The data may provide a measure of comfort in prescribing celecoxib to those with a low baseline cardiovascular risk, but caution [should be taken in prescribing] in those at high risk." In a press conference discussing the results, Dr Steve Nissen (Cleveland Clinic Foundation) said: "It's reassuring to see these results, these data on the 400-mg once-daily dose." Nissen is the lead investigator of the PRECISION trial, which is enrolling 20 000 patients with osteoarthritis or rheumatoid arthritis and a high risk for major adverse cardiovascular events who are being randomized to ibuprofen, naproxen, or celecoxib 200 mg once daily, with results expected in 2011. Nissen said he was "glad we chose the 200-mg once-daily dose for PRECISION, as 80% to 90% of patients taking celecoxib take this dose." Solomon said: "PRECISION should help guide us as to which one of these treatment options is best." Source
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