New Data Will Help Guide Prescribing of Celecoxib
Factors Affecting Pharmacists' Pediatric Asthma Counseling
New Data Will Help Guide Prescribing of Celecoxib
Author: Lisa Nainggolan
From American College of Cardiology (ACC) 57th Annual Scientific Session
April 2, 2008 (Chicago) — 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 . 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.
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.
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.
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%).
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
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
Pooled HRs for the principal composite
endpoint for each dose regimen and for all the trials combined
(adjusted for baseline cardiovascular risk)
|HR (95% CI)
|Pooled 400 mg daily
|Pooled 200 mg twice daily
|Pooled 400 mg twice daily
|Pooled all doses
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.
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
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
"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."
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
- 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.
- 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
- 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
- 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.
Factors Affecting Pharmacists' Pediatric Asthma Counseling
Francoise G. Pradel; Nour A. Obeidat; Mona G. Tsoukleris
J Am Pharm Assoc. 2007;47(6):737-746. ©2007 American Pharmacists Association
Objective: To explore various factors that may influence community pharmacists' pediatric asthma counseling.
Setting: Maryland from September 2002 through March 2003.
Participants: Random sample of 400 community pharmacists.
Intervention: Mail survey.
Main outcome measures: Pharmacists' attitude, subjective norm, perceived behavioral control,
intention to provide pediatric asthma counseling, and reported
counseling using the theory of planned behavior as a framework;
demographic and pharmacy characteristics.
Results: 98 of 389
(25%) eligible pharmacists responded. Most acknowledged the importance
of providing asthma counseling to children (54%) or caregivers (68%).
However, only a small number reported demonstrating to children or
caregivers or asking them to demonstrate how to use antiasthmatic
medications. Multivariate logistic regressions revealed that intention
to counsel was a significant predictor of providing counseling for
children or caregivers (odds ratio [OR], 3.95 and 3.09, respectively).
Intention to counsel children was significantly associated with
subjective norm (OR, 1.88) and perceived ease of counseling (OR, 1.48);
intention to counsel caregivers was significantly associated with
perceived ease (OR, 1.45). Pharmacists also reported the following
barriers that made counseling difficult: lack of time, lack of parent's
interest, and lack of placebo devices useful for demonstration of
Conclusion: Despite a positive
attitude toward providing asthma counseling, the majority of
pharmacists reported not fully engaging in counseling. A number of
barriers to counseling were reported that, if targeted, could improve
the management of pediatric asthma through pharmacist-initiated
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