Monday, November 07, 2011

New Study Confirms Suicide Risk from Chantix and Argues It Should Not Be Used as First-Line Therapy for Smoking Cessation

Story Demonstrates Why Conflicts of Interest Are Unacceptable on NIH Expert Smoking Cessation Panel

A new study published this week in the journal PLoS Medicine confirms that Chantix (varenicline) is associated with a substantial increase in suicide, suicidal behavior, and depression, and to a much greater degree than nicotine replacement therapy even though Chantix was available during only four of the 13 study years.

Of the total of 3,249 reported cases of suicidal/self-injurious behavior or depression during the study period, only 3% of cases occurred among NRT users, compared to 90% for varenicline. The authors adjusted the observed increased risk of these adverse outcomes among varenicline users for a number of potential confounders. However, they found that "varenicline has markedly higher reported risk than any of the comparators, a risk that was not reduced regardless of the form of adjustment used."

The study concludes: "Varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. Bupropion for smoking cessation had smaller increased risks. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation."

The study also recommends that:

1. "varenicline should not be prescribed for sensitive occupations such as airline pilots, air controllers, active duty military, police officers, truck and bus drivers, and emergency medical workers."; and

2. "the FDA should consider revising the suicidal behavior and depression language in the Boxed Warning and Highlights of Prescribing Information to state clearly that the risks of suicidal behavior and depression are higher with varenicline than with other smoking cessation treatments."

These results conflict with those of an earlier FDA study which found no increased risk of hospitalization for depression or suicidal ideation among users of Chantix.

According to an article at "The FDA is standing by its Oct. 24 review of two FDA-sponsored studies that examined hospitalizations for psychiatric reasons in users of Chantix and nicotine-replacement therapy."

According to the article, Pfizer also denounced the new study's conclusions: "In a written statement, Pfizer spokesman MacKay Jimeson was highly critical of the reliance of Moore and colleagues on reports that came out after the drug went to market. 'Post-marketing reports can come from any source ranging from patients to health care providers, and from phone calls to Internet postings and lawyers,' he tells WebMD. 'Because of the many limitations of post-marketing reports, the conclusions made by the authors are not supported by the data.'"

The Rest of the Story

There is a good reason why the results of this new study conflict with those of the FDA-sponsored studies. In those studies, the outcome variable was hospitalization for suicidal ideation or depression. But hospitalization for these symptoms are quite uncommon (it takes a lot these days to get yourself admitted acutely for depressive symptoms). Moreover, the study would miss any suicides because persons are not admitted to the hospital for suicide. Furthermore, most of the serious adverse effects of Chantix are sudden and acute and would not necessarily be expected to lead to hospitalization.

For this reason, I find the FDA's defense of its study and its apparent dismissal of these new results to be quite worrisome.

It is also discouraging to see Pfizer criticizing this study on the grounds that it relies on post-marketing reports. It is precisely those reports which resulted in revelations about the adverse effects of drugs like Vioxx and which led to their removal from the market. Does Pfizer really want to be on record as arguing that post-marketing surveillance is not a valid source of information about possible unforeseen drug adverse effects?

But the real rest of the story here is what it says about the participation of conflicted researchers (namely, those with financial relationships with Pfizer) on the FDA expert panel which recommended that drugs be used for every smoking patient and which listed Chantix as a legitimate first-line therapy.

Clearly, that expert panel's recommendation is now in direct conflict with that of the Institute for Safe Medical Practices along with expert researchers from Harvard Medical School, Wake Forest University School of Medicine, and the Johns Hopkins University School of Medicine.

The shame, however, is that as I reported in May 2008, the panel chair and eight members had financial conflicts of interest with Big Pharma. In particular, the panel chair received funding from Pfizer, the manufacturer of Chantix, at about the same time as his panel crafted the recommendation that this drug should be considered as first-line therapy for smoking cessation.

Note that as of the writing of the report, the FDA had already issued a black box warning noting that agitation, depression, suicidal ideation, and suicide had been associated with the use of varenicline. The panel apparently downplayed this risk in its recommendations. Differences in clinical judgment are acceptable when they are genuine, but to have a disagreement like this which has the appearance of potentially being associated with a financial conflict of interest is, in my view, unacceptable.

Moreover, from what I can tell, the 2008 guideline has not been updated to note the subsequent reports of Chantix's adverse effects, including to quantify the number of suicides reported with the use of this drug. No mention is made of the results from the new study above. Thus, physicians relying on the 2008 update do not have the information they need regarding the potential risks of varenicline. At very least, I think they deserve to know that the Institute for Safe Medical Practices along with expert researchers from Harvard Medical School, Wake Forest University School of Medicine, and the Johns Hopkins University School of Medicine do not believe that Chantix should be considered as first-line therapy for smoking cessation.

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