Level 2: Mid-level evidence

The FDA recently announced a labeling change for the smoking-cessation aid varenicline (Chantix) concerning cardiovascular risks.

The concern arose largely from a trial in which 714 patients with stable cardiovascular disease were randomized to varenicline vs. placebo for 12 weeks. Cardiovascular events were reported in 7% of the varenicline group vs. 5.6% of controls, but this difference was not statistically significant (Circulation. 2010;121:221-229). The FDA has asked the manufacturer to provide a meta-analysis of its safety data for varenicline.

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In the meantime, independent investigators reported a systematic review of 14 randomized trials (including the trial cited above) evaluating the cardiovascular risks of varenicline. The other 13 trials (7,502 patients) had much lower incidence of cardiovascular events (pooled rates 0.593% vs. 0.237%), although the definition of cardiovascular outcomes varied across studies.

In a meta-analysis of these 13 trials, varenicline was associated with significantly increased risk (odds ratio 2.54, 95% CI 1.26-5.12), but the NNH was very high, ranging from 103 to 1,627 (CMAJ. 2011; 10.1503/cmaj.110218).

The risk for psychiatric adverse events may be more concerning than these cardiovascular events. The FDA previously required a Boxed Warning to indicate increased risk of serious neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide.

Evidence for the risk of neuropsychiatric events has largely come from case reports, and there have been hundreds of cases reported to the FDA, including 272 cases of completed suicide (Institute for Save Medication Practices. Quarter Watch: 2010 Quarter 3. 2011:1-24). However, quantifying this risk is uncertain, and the specific association with varenicline is unclear.

A cohort study in 2009 with 80,660 patients found similar rates of self-harm among users of varenicline, bupropion and nicotine-replacement products (Level 2: Mid-level evidence) (BMJ. 2009;339:b3805).

The risks of these potential adverse events must be weighed against the mortality benefit associated with smoking cessation and the demonstrated efficacy of varenicline as a cessation aid (JAMA. 2008;299:2037-2047). In the trial cited by the FDA for cardiovascular risk, the varenicline group had significantly higher rates of confirmed continuous abstinence than did the placebo group from nine weeks to one year (19.2% vs. 7.2%; P <0.0001, NNT 9). Also, in a Cochrane review, varenicline was associated with higher rates of continuous abstinence compared with placebo (NNT=6-9 at 24 weeks in analysis of 10 trials with 4,443 patients).

The most common adverse events were nausea, headache, and insomnia (Cochrane Database Syst Rev. 2011;2:CD006103).