Risk of Serious Adverse Cardiovascular Events Associated With Varenicline: A Systematic Review and Meta-Analysis

Study Questions:

Are there serious adverse cardiovascular (CV) effects of varenicline among tobacco users?


The authors conducted a review of adverse CV effects of varenicline in published data, websites of regulatory authorities, and registries of clinical trials, with no date or language restrictions, through September 2010 (updated March 2011) for published and unpublished studies. Study eligibility included double-blind randomized controlled trials of at least 1-week duration involving smokers or people who used smokeless tobacco that reported on CV events (ischemia, arrhythmia, congestive heart failure, sudden death, or CV-related death) as serious adverse events associated with the use of varenicline.


A total of 14 double-blind randomized controlled trials were selected, involving 8,216 subjects. The trials ranged in duration from 7-52 weeks. Varenicline was associated with a significantly increased risk of serious adverse CV events compared with placebo (1.06% [52/4,908] in the varenicline group vs. 0.82% [27/3,308] in the placebo group; Peto odds ratio 1.72, 95% confidence interval 1.09-2.71,I2 = 0%). The results of various sensitivity analyses were consistent with those of the main analysis, and a funnel plot showed no publication bias. The number needed to treat with varenicline for one additional person to successfully quit smoking is estimated to be 10. Assuming a baseline risk of serious adverse CV events of 5.57% per year (among smokers with stable CV disease), the number needed to harm (the number needed to cause one additional serious CV event) with varenicline is estimated to be 28 per year. The number of deaths was inadequate to assess effect of varenicline on mortality.


The meta-analysis raises safety concerns about the potential for an increased risk of serious adverse CV events associated with the use of varenicline among tobacco users.


The Food and Drug Administration has placed a 'black box' warning for varenicline that includes increase in risk for CV events in relatively short-term studies. Other potential serious adverse events include neuropsychiatric symptoms such as depressed mood, agitation, and suicidal thoughts. Possible mechanisms by which varenicline may be associated with CV disease might include the action of varenicline at a brainstem receptor that enhances parasympathetic tone, or, similar to nicotine, a prothrombotic effect. Long-term adverse effects of varenicline need to be assessed prior to advocating chronic use.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Smoking

Keywords: Nicotine, Tobacco, United States Food and Drug Administration, Heart Failure, Death, Sudden, Quinoxalines, Tobacco Use Disorder, Benzazepines, Smoking, United States

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