A new meta-analysis of six randomized trials involving the cyclooxygenase-2 (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 at the American College of Cardiology 57th Annual Scientific Session, 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 American Health Association (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, myocardial infarction (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)
Dose Median
follow-up
time (mo) Events/
participants,
placebo Events/
participants,
celecoxib HR (95% CI)
Pooled 400 mg daily 35 20/1038 30/1347 1.1 (0.6-2.0)
Pooled 200 mg twice daily 36 29/1809 38/1450 1.8 (1.1-3.1)
Pooled 400 mg twice daily 11 11/1496 33/1489 3.1 (1.5-6.1)
Pooled all doses 31 52/3664 101/4286 1.6 (1.1-2.3)
“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 Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (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
Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in six randomized placebo-controlled trials: the cross trial safety analysis. Circulation 2008; DOI: 10.1161/CIRCULATIONAHA.108.764530. Available at: http://circ.ahajournals.org.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Study Highlights
A patient-level pooled meta-analysis of 6 randomized clinical trials involving celecoxib vs placebo in 7950 patients was conducted, comparing the dose regimens of 400 mg daily, 200 mg twice daily, and 400 mg twice daily, used for indications other than arthritis.
Planned follow-up was at least 3 years, but all the trials were terminated in 2004 in the aftermath of the withdrawal of rofecoxib by the FDA in the United States.
The 200 mg once-daily dose, the most common dose in use, was not examined in any of the 6 trials.
The primary endpoint for this meta-analysis was the composite of cardiovascular death, MI, stroke, heart failure, or thromboembolic event.
However, none of the trials had a primary endpoint of adverse cardiovascular events.
Patients were stratified by baseline cardiovascular risk by Framingham risk score as low (28% of patients), moderate (27% of patients), or high (45% of patients).
Mean age ranged from 59 to 75 years with 50% to 68% across the 6 trials.
Proportion of white patients was 67% to 97%; black patients, 1.3% to 5.5%; and Asian patients, 0.4% to 6.1%. Of these patients, 6.1% to 10% had diabetes.
34% to 62% had baseline hypertension, 17% to 55% had hyperlipidemia, 3% to 24% were current smokers, and 2 trials did not report smoking status.
14% to 50% of patients were taking low-dose aspirin at baseline, and 1.3% to 14% had a previous cardiovascular event.
More than 16,070 patient-years of follow-up, the combined HR for the composite endpoint for all dose regimens (median follow-up, 31 months) was 1.6 (95% confidence interval [CI], 1.1 – 2.3).
The HR for the 400-mg once-daily regimen (median follow-up, 35 months) was 1.1 (95% CI, 0.6 – 2.0).
The HR for the 200-mg twice-daily regimen (median follow-up, 36 months) was 1.8 (95% CI 1.1 – 3.1).
The HR for the 400-mg twice-daily dose regimen (median follow-up, 11 months) was 3.1 (95% CI, 1.5 – 6.1).
Cardiovascular risk was greater for those with higher Framingham risk score with a disproportionately greater risk for celecoxib-related events for higher risk scores (P for interaction = .034).
The once-daily oral dosing had a lower risk than twice-daily dosing for the same total daily dose of 400 mg.
There was a doubling of cardiovascular risk between low- and moderate-dose groups and a further doubling of risk between moderate- and high-risk groups.
No conclusions can be drawn about the cardiovascular risk associated with the 200-mg once-daily dose.
The authors recommended caution in the use of celecoxib in patients with moderate to high baseline cardiovascular risk and suggest use of the lowest dose of celecoxib.
Pearls for Practice
Cardiovascular risk associated with use of celecoxib in the dose range of 400 to 800 mg/day is greater with higher baseline cardiovascular risk.
The risk for cardiovascular events with the use of celecoxib in the dose range of 400 to 800 mg daily is dose-dependent, and a once-daily dose has a lower risk than a twice-daily dose.
Review by Dr. Ramaz Mitaishvili
