The 2001 JAMA statistical analysis did not reliably link Celebrex to an increase in adverse events:
The 2001 JAMA analysis1 purported to show that data that regarding Celebrex in the CLASS2 trial suggested an increase in the occurrence of heart attacks. This particular portion of the analysis was not reliable.
The CLASS trial2 which studied Celebrex (celecoxib) was analyzed by the JAMA authors1 in a fashion that was unreliable because the treatment arm of a randomized clinical trial was compared to the placebo arm of completely different trials. What the JAMA article1 did was compare the frequency of heart attack with Celebrex use in the CLASS trial with the frequency of heart attack in a combined placebo group from three totally different studies. This type of analysis is quite problematic. A comparison of a treatment group in a randomized study with a placebo group from a different study in regards to side effect incidence does not give reliable information.
The frequency of adverse events varies greatly with what patient group is studied.
To demonstrate how dependent the frequency of adverse cardiac events is on the type of patients being studied, a closer look within the CLASS trial is all that is needed. (The CLASS trial was a randomized trial comparing Celebrex (celecoxib) to ibuprofen or diclofenac.) Aspirin use was not randomized, but rather used if clinical situation was thought to make that advisable. Patients in the CLASS trial, who were identified by their physicians as being at higher risk and warranting the simultaneous administration of aspirin, had a myocardial infarction (heart attack) rate seven times higher than other patients in the trial (14/1645 vs.7/6323)2. This was not because aspirin use was adverse in these patients, but rather that these patients truly were at higher preexisting risk.
The preexisting risk of the patients for developing a heart attack overwhelms other factors. Even when close attention is paid to statistically trying to adjust for those differences in risk, it is extremely difficult to do so reliably.
Randomized trials create groups of equal preexisting risk:
One of the reasons that a comparison within a randomized trial is the gold standard is because the preexisting risk of the patient groups can be made equivalent through randomization. A comparison with a large placebo group from a completely different trial does not increase the precision of determining the expected cardiovascular event rate for the particular randomized group of patients studied within the CLASS trial.
Celebrex was later found to be associated with an increased risk of MI at higher doses. However, the reason for concern in regard to Celebrex in 2001 was not this unreliable cross trial analysis, but rather that Celebrex and Vioxx were in the same class of medications.
How the initial article that admirably and beneficially raised public awareness
of the potential risks of Vioxx and Celebrex was right about Celebrex for the
A Perspective on Celebrex, Vioxx, and Naprosyn: download pdf
Celebrex use in the dose of 400 to 800mg has been shown in a recent study to be associated with an increased risk of heart attack.
The 2001 JAMA article1 which raised the concern of an increased risk with Vioxx and Celebrex was greatly beneficial to the medical community.
The strongest link of Celebrex to an increased risk of cardiovascular events at that time (2001) was that Celebrex was in the same class of medications as Vioxx, not the statistical analysis which was performed.
Celebrex (celecoxib) is one of the newer medications for arthritis. Vioxx (rofecoxib) and Celebrex are both in the same class of medications, COX-2 inhibitors. In 2001, an article1 was published in JAMA which was quite beneficial because concerns were raised about COX-2 inhibitors possibly raising the risk of a cardiovascular event.
This JAMA article did a service to patients and the medical community by raising the issue of the potential for increased cardiovascular events with the use of COX-2 inhibitors. And currently, Celebrex use does appear in some patients to be associated with a higher risk of cardiovascular events, at least, in higher doses.
However, this website will analyze only the portion of the JAMA 2001 article1 that relates to the reliability of cross trial analyses used to analyze the Celebrex trial2.
JAMA 2001 paper gives an example of a cross trial analysis which is not
reliable (i.e., the comparison of a placebo group from one trial to a treatment group from a completely different randomized trial to assess the frequency of
side effects). See right column for details.
The initial JAMA article that suggested an increase in cardiovascular events with Vioxx and Celebrex, analyzed two previously published trials, the Vioxx VIGOR3 trial and the Celebrex CLASS trial2. (details of VIGOR and CLASS trials)
Both rofecoxib (Vioxx) and celecoxib (Celebrex) are selective COX-2 inhibitors. Given an increase in the cardiovascular event rate with rofecoxib (Vioxx) in the Vigor trial, it was of concern in 2001 that there was an increased risk with celecoxib (Celebrex) since these drugs are in the same class of medications.
1. Risk of cardiovascular events associated with selective COX-2 inhibitors. Mukherjee D, Nissen S, Topol E. JAMA 2001; 286:954-959
2. Silverstein F, Faich G Goldstein J, et al. Gastrointestinal Toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis, the CLASS Study: a randomized controlled trial. JAMA. 2000; 284:1247-1255.
3. Bombardier C, Laine L, Reicin A et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343:1520-1528
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