FDA Says Chantix Benefits Outweigh The Risks or were you expeting another end ?

Ed Silverman in Pharmalot

cigarette-smoke-flickrAfter reviewing the results of two epidemiological studies that compared the controversial Chantix smoking-cessation pill with NicoDerm patches, the FDA has decided that the benefits of the Pfizer pill continue to outweigh the risks. The decision comes three years after the drugmaker added warnings its anti-smoking drug is connected to suicidal thoughts and behavior (back story).
Due to the myriad reports linking Chantix to psychiatric side effects, the FDA had sponsored two observational studies of neuropsychiatric adverse events with Chantix. One was conducted by the Department of Veterans Affairs’ Center for Medication Safety and the other by the Department of Defense’s US Army Medical Command’s Pharmacovigilance Center.
The VA study population included 14,131 Chantix users and an equal number of NRT users. The DoD study was also a retrospective cohort study comparing 30-day rates of hospitalizations for neuropsychiatric adverse events among 19,933 new Chantix users and 15,867 NRT patch users who started therapy from August 1, 2006 to August 31, 2007 in the Military Health System. Patients were drawn from active duty military personnel, military retirees and their dependents.
“Neither study found a difference in risk of neuropsychiatric hospitalizations between Chantix and nicotine replacement therapy,” the FDA says in a statement. “However, both studies had a number of study design limitations, including only assessing neuropsychiatric events that resulted in hospitalization, and not having a large enough sample size to detect rare adverse events.
“Although these two studies did not suggest an increased risk of neuropsychiatric events that result in hospitalization, they do not rule out an increased risk of other neuropsychiatric events with Chantix…(But) based on FDA’s assessment of currently available data, the agency continues to believe that the drug’s benefits outweigh the risks and the current warnings in the Chantix drug label are appropriate.”
The verdict is a big win for Pfizer, which has struggled to promote Chantix against a rising mound of studies that its pill is more trouble than it’s worth. In addition to concerns about suicide, studies have suggested Chantix can be responsible for violent behavior and cause serious cardiovascular risks (see herehere and here). The European Medicines Agency, however, recently ruled that Chantix benefits outweigh any heart risks (see this).

Smoked Pfizers Chantix heart problems

Logo of Pfizer Incorporated.Image via Wikipedia

Source: Pharmalot


Yet another red flag is being raised about the Chantix smoking-cessation drug and the likelihood of cardiovascular problems. A new meta-analysis found that the Pfizer pill was associated with a 72 percent increased risk of serious adverse cardiovascular risks in smokers without a history of heart disease, and two authors suggest the FDA should consider having the drug removed from the market.
Just three weeks ago, the FDA added a warning on the product labeling about an association with a small, but increased risk of cardiovascular adverse events in patients with cardiovascular disease. The agency had reviewed a study in which 700 such patients received either Chantix or placebo, although results showed the pill was effective in helping them quit smoking and remain abstinent for up to year (back story).
In the latest analysis, which was published today in the Canadian Medical Association Journal, the researchers analyzed 14 double-blind, randomized controlled trials that involved 8,216 patients and ranged in duration from 7 to 52 weeks. They found a significantly increased risk of serious cardviovascular adverse events – 1.06 percent in Chantix versus 0.82 percent in placebo – including myocardial infarction, stroke and cardiovascular-related death. Only five trials, though, reported death (read the study here).
The findings are likely to add to the controversy over the drug, which has been associated with suicidal behavior and vivid dreams (see here and here). The government later banned Chantix for pilots and licenses wouldn’t be issued to truck drivers taking the med (see this and this). The FDA subsequently imposed a risk management program and Pfizer added warnings. Last year, a study in The Annals of Pharmacotherapy finds Chantix is not only associated with violent and agressive thoughts and acts (read here). Another in PLoS One found an association with serious acts of violence, such as physical abuse, physical assault and homicide (lookhere).
“Ours is the first study to show that Chantix increases cardiac risk substantially among smokers free of cardiac disease at baseline (13 out of 14 trials did not have heart disease at baseline) – important information that is missing from the Chantix label, despite the recent FDA warning on a small increased risk of cardiac events with Chantix among smokers with heart disease based on a single study of 700 patients (we included this study),” Sonal Singh, one of the authors and an assistant professor at the Johns Hopkins University School of Medicine, writes us.
“Since information that Chantix increases cardiac risks was available and noted by FDA safety reviewers at the time of speedy approval in May 2006 priority review, but never made it to the label, there should be no further delay in disseminating these findings to clinicians and patients. Given that there are other substantial risks with Chantix (neuropsychiatric effects) with only modest benefits compared to other therapies (such as Nicotine replacement therapy), this study shifts the risk-benefit profile of Chantix in an unfavorable direction,” he continues. “The FDA should deliberate, but also act with deliberate speed and consider all regulatory options, including removal from the market or further boxed warnings among smokers without heart disease.”
The lead author on the study, Curt Furberg, a professor of medicine at Wake Forest University, wrote us that the FDA should “clearly add the CV risk to the boxed warning (that already appears in the Chantix labeling) and seriously consider removing the drug from the maket due to the sum of serious adverse effects.”
In a statement, Pfizer says it “disagrees with the interpretation of the data” in the meta-analysis, which the drugmakers notes contains several limitations – notably, a small number of events, “which raises concerns about the reliability of the authors’ conclusions. The authors acknowledge that their risk ‘estimates are imprecise owing to the low event rates.’ The actual difference in cardiovascular event rates seen in the Singh analysis was less than one quarter of one percent – 1.06 percent with varenicline versus 0.82 percent with placebo.
“Pfizer works with regulators, like the FDA, on a continual basis to review and monitor data for Chantix. In particular, we are working with FDA to conduct a combined analysis of clinical trial data (meta-analysis), which will help further evaluate the cardiovascular safety of Chantix.” The drugmaker adds that it believes Chantix remains an important treatment option.
The meta-analysis did note that Chantix increases the chances of successfully quitting smoking by twofold compared with unassisted efforts. And there were limitations: the trials analyzed had enrolled different populations, evaluated different doses and had different lengths of follow-up and proportions lost to follow-up. “Our estimates are imprecise owing to the low event rates. None of the trials was adequately powered to detect individual differences in cardiovascular events,” the authors wrote. Furberg, by the way, is a paid expert for plaintiffs who are suing Pfizer over its Cox-2 painkillers.
“Despite the limitations of our analysis,” the authors wrote, “our findings have potential regulatory and clinical implications. Drugs that receive priority review have limited safety data at the time of approval. The initial safety signal regarding cardiovascular events in people using varenicline was not followed up by an adequately powered safety trial. Until such trials are conducted, clinicians should carefully balance the risk of serious cardiovascular events and serious neuropsychiatric adverse events asociated with varenicline use against the known benefits of the drug on smoking cessation.”
One noted cardiologist had this to say: “I continue to be perplexed by the resistance of companies to putting their subject-level data, published and unpublished, in the public domain and allowing independent investigators to evaluate the safety and efficacy of their products,” Harlan Krunholz, a professor of medicine and epidemiology and public health at Yale University School of Medicine, wrote us. “This article raises concerns but the authors are limited by the summary data that are in the public domain. We need companies to take these concerns seriously enough to support inquires by independent investigators who have unfettered access to all the data.”
In an accompanying editorial, J. Taylor Hays of the Department of Medicine at the Mayo Clinic, who has received grant funding from Pfizer to conduct a Chantix trial, wrote that the adverse events were rare; the rate of participants lost to follow-up was greater in the placebo arm than in the treatment arm in most of the studies included in the analysis, which “introduces bias in determining serious adverse events;” cardiac events were adjudicated in only one study and no significant differences were seen in the number of cardiovascular events or in deaths between those taking Chantix or a placebo.
Finally, he added that the “degree of uncertainty for the number needed to treat for harm is considerably greater than it is for the number needed to treat.” The meta-analysis found that the number needed to treat with Chantix for one additional person to successfully quit smoking was estimated to be 10, while the number needed to cause one additional serious cardiovascular event was estimated to be 28.
“These results represent a significant degree of uncertainty about the relative good or harm from Chantix, leaving the issue unsettled,” writes Hays, who acknowledges the pill is not free of risks. “The best outcome from this analysis would be more rigorous and adequately powered studies evaluating the safety of using (Chantix) among smokers who have known cardiovascular disease. The worst outcome would be for health care providers to abandon (Chantix), which has proven to be among the most efficacious pharmacotherapies used for the treatment of tobacco dependence.”
One of the researchers who explored the association between Chantix and violent behavior responded with this: “The more we learn about the safety profile of Chantix, the more unsuitable it looks as an alternative to low-risk nicotine replacement products. Chantix is linked to acts of serious violence, suicidal behavior, depression, psychosis and now increased cardiovascular risks. Canadian health authorities are examining a link to diabetes, a biologically plausible because of dopamine involvement, but not yet proven. Its effects on vision and motor control have led to it being banned for pilots, air controllers and military missile crews. Chantix is emerging as one of the biggest regulatory breakdowns in recent memory,” says 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.