Wednesday, May 30, 2012

Controversy Over Financially-Conflicted Chantix Safety Conclusions Gains Attention

The controversy over the conclusions of a Pfizer-funded researcher who believes that the existing research is enough to state that Chantix poses no cardiovascular risks gained prominent attention recently, as it was highlighted by Ed Silverman over at

In an article titled "Researchers Duel Over Chantix and Heart Risks," Silverman writes: "A spat has broken out among researchers over the extent to which the controversial Chantix quit-smoking pill is linked to cardiovascular risks. A meta-analysis that was published last week in BMJ found the drug, which is sold by Pfizer, does not increase the risk of heart attacks and strokes. The results contrast with a meta-analysis published last year that maintained Chantix does increase heart risks, a conclusion the authors of the latest study labeled “misleading.” ... “There is a simple explanation why this study could not detect a difference in cardiovascular risk. Because of a weak design it was unable to detect any effect on anything,” Thomas Moore, a senior scientist with the Institute for Safe Medication Practices and who serves as a consulting expert in the civil litigation regarding Chantix, writes us in an e-mail. “It would be a serious scientific error to make a safety claim based on a study that did not disprove the null hypothesis.”

The Rest of the Story

Thomas Moore points out the most critical point: that the existing research base consists of studies that were not powered to detect a small adverse cardiovascular effect of Chantix use. They were powered to determine whether Chantix is effective in smoking cessation. Because of the low power of these studies, even the meta-analysis - which combines the results of all of them - has wide confidence intervals around the estimate of risk and leaves open the possibility of a small, but clinically quite significant adverse cardiovascular effect of Chantix.

However, the conflicted researcher, who is funded by Pfizer - the manufacturer of Chantix - was willing to draw a definitive safety conclusion based on the inadequate existing data. The FDA recognizes the problem of the low sample sizes in these studies, and it is for this reason that the agency is requiring a study of 8000 patients (the individual studies generally have just a few hundred patients) to assess the cardiovascular risks of Chantix.

Another major issue with the conflicted researcher's work is that she excluded adverse events occurring more than 30 days after discontinuation of the drug. However, as pointed out by Dr. Sonal Singh from the Johns Hopkins Bloomberg School of Public Health in the Pharmalot article, the cardiovascular risk is not simply due to the presence of the drug in the bloodstream and researchers must look beyond simply 30 days after drug discontinuation: "Singh noted that his meta-analysis examined patients through the duration of the Chantix trials because what remains unknown is the the length of time that a heart risk may appear after treatment ends. “We were learning from the Vioxx issues. With Vioxx, heart risks didn’t climb until long after people were taken off the drug. She assumes the potential CV risk is due to direct effect of the drug being in the body, so when the drug is out the risk should go away. I’m making a very different assumption. I don’t know how the drug is increasing heart risk, so I’ll count data through the end of a study and some lasted up to a year,” he says. “Which world do you live in? She’s assuming she knows how the drug causes CV risks and I’m assuming I don’t know. And those are the kinds of studies that are needed.”"

Dr. Singh makes a critical point. Since we don't know how Chantix increases heart attack risk, if it does increase that risk, then it is imperative not to assume that the effects must occur within 30 days of drug use. The assumption that the conflicted researcher makes is a perfect example of the kind of bias that can easily be introduced into research by a financial conflict of interest.

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