Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors

Abstract

Background and aims: Analysed using classical frequentist hypothesis testing with alpha set to 0.05, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) did not find enough evidence to reject the hypothesis of no difference in neuropsychiatric adverse events (NPSAEs) attributable to varenicline, bupropion, or nicotine patch compared with placebo. This might be because the null hypothesis was true or because the data were insensitive. The present study aimed to test the hypothesis more directly using Bayes factors.

Design: EAGLES was a randomised, double-blind, triple-dummy, controlled trial.

Setting: Global (16 countries across five continents), between November 2011 and January 2015.

Participants: Participants were smokers with (n = 4116) and without (n = 4028) psychiatric disorders.

Interventions: Varenicline (1 mg twice daily), bupropion (150 mg twice daily), nicotine patch (21 mg once daily with taper) and matched placebos.

Measurements: The outcomes included: (i) a composite measure of moderate/severe NPSAEs; and (ii) a composite measure of severe NPSAEs. The relative evidence for there being no difference in NPSAEs versus data insensitivity for the medications was calculated in the full and sub-samples using Bayes factors and corresponding robustness regions.

Findings: For all but two comparisons, Bayes factors were <1/3, indicating moderate to strong evidence for no difference in risk of NPSAEs between active medications and placebo (Bayes factor = 0.02-0.23). In the psychiatric cohort versus placebo, the data were suggestive, but not conclusive of no increase in NPSAEs with varenicline (Bayes factor = 0.52) and bupropion (Bayes factor = 0.71). Here, the robustness regions ruled out a ≥7% and ≥8% risk increase with varenicline and bupropion, respectively.

Conclusions: Secondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study trial using Bayes factors provides moderate to strong evidence that use of varenicline, bupropion or nicotine patches for smoking cessation does not increase the risk of neuropsychiatric adverse events relative to use of placebo in smokers without a history of psychiatric disorder. For smokers with a history of psychiatric disorder the evidence also points to no increased risk but with less confidence.

Trial registration: ClinicalTrials.gov NCT01456936.

Keywords: Bayes factor; EAGLES; bupropion; neuropsychiatric adverse event; nicotine patch; smoking cessation; varenicline.