Dataset Information

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.

SUBMITTER: Beard E

PROVIDER: S-EPMC8612131 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceQuitting smoking is enhanced by the use of pharmacotherapies, but concerns have been raised regarding the cardiovascular safety of such medications.ObjectiveTo compare the relative cardiovascular safety risk of smoking cessation treatments.Design, setting, and participantsA double-blind, randomized, triple-dummy, placebo- and active-controlled trial (Evaluating Adverse Events in a Global Smoking Cessation Study [EAGLES]) and its nontreatment extension trial was conducted at 140 multinational centers. Smokers, with or without established psychiatric diagnoses, who received at least 1 dose of study medication (n = 8058), as well as a subset of those who completed 12 weeks of treatment plus 12 weeks of follow up and agreed to be followed up for an additional 28 weeks (n = 4595), were included.InterventionsVarenicline, 1 mg twice daily; bupropion hydrochloride, 150 mg twice daily; and nicotine replacement therapy, 21-mg/d patch with tapering.Main outcomes and measuresThe primary end point was the time to development of a major adverse cardiovascular event (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) during treatment; secondary end points were the occurrence of MACE and other pertinent cardiovascular events (MACE+: MACE or new-onset or worsening peripheral vascular disease requiring intervention, coronary revascularization, or hospitalization for unstable angina).ResultsOf the 8058 participants, 3553 (44.1%) were male (mean [SD] age, 46.5 [12.3] years). The incidence of cardiovascular events during treatment and follow-up was low (<0.5% for MACE; <0.8% for MACE+) and did not differ significantly by treatment. No significant treatment differences were observed in time to cardiovascular events, blood pressure, or heart rate. There was no significant difference in time to onset of MACE for either varenicline or bupropion treatment vs placebo (varenicline: hazard ratio, 0.29; 95% CI, 0.05-1.68 and bupropion: hazard ratio, 0.50; 95% CI, 0.10-2.50).Conclusions and relevanceNo evidence that the use of smoking cessation pharmacotherapies increased the risk of serious cardiovascular adverse events during or after treatment was observed. The findings of EAGLES and its extension trial provide further evidence that smoking cessation medications do not increase the risk of serious cardiovascular events in the general population of smokers.Trial registrationclinicaltrials.gov Identifier: NCT01574703.

Project description:Cigarette smoking continues to be the leading cause of preventable death and is the main risk factor of major diseases such as chronic obstructive pulmonary disease (COPD). The best treatment to help smokers quit is a combination of behavioural support with pharmacotherapy. Varenicline is the newest drug on the market and has been shown to be effective in the general smoking population and in smokers with COPD. The safety profile of varenicline was initially established using standard approaches to pharmacovigilance, but postmarketing reports have raised concerns about a possible association between the use of varenicline and cardiovascular and neuropsychiatric events. Although recent studies have not confirmed such an association, further research is needed given the large number of smokers who are being prescribed varenicline, including important subgroups such as smokers with COPD who may be particularly vulnerable to side effects of drugs. The aim of this study is to assess the cardiovascular and neuropsychiatric safety of varenicline using data from the QResearch general practice (GP) database.We will conduct a retrospective cohort study in the QResearch GP database. Patients will be categorised into three exposure groups: prescription of (1) varenicline, (2) bupropion or (3) nicotine replacement therapy (NRT Rx; =reference group). We will separately consider major incident neuropsychiatric and cardiovascular outcomes that occur during 6?months of follow-up using Cox proportional hazards models, adjusted for confounders. Furthermore, propensity score analysis will be used as an analytical approach to account for potential confounding by indication.This work involves analysis of anonymised, routinely collected data. The protocol has been independently peer-reviewed by the QResearch Scientific Board and meets the requirements of the Trent research ethics committee. We plan to disseminate the results from this study via articles in international peer-reviewed journals and presentations at relevant national and international health conferences.

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Project description:BackgroundPre-treatment factors that increase smokers' risk of experiencing neuropsychiatric adverse events (NPSAEs) when quitting smoking are unknown.ObjectiveTo identify baseline smoker characteristics beyond the history of mental illness that predict which participants were more likely to experience moderate to severe NPSAEs in EAGLES.DesignA prospective correlational cohort study in the context of a multinational, multicenter, double-blind, randomized trial.ParticipantsSmokers without (N = 3984; NPC)/with (N = 4050; PC) histories of, or current clinically stable, psychiatric disorders including mood (N = 2882; 71%), anxiety (N = 782; 19%), and psychotic (N = 386; 10%) disorders.InterventionsBupropion, 150 mg twice daily, or varenicline, 1 mg twice daily, versus active control (nicotine patch, 21 mg/day with taper) and placebo for 12 weeks with 12-week non-treatment follow-up.Main measuresPrimary safety outcome was the incidence of a composite measure of moderate/severe NPSAEs. Associations among baseline demographic/clinical characteristics and the primary safety endpoint were analyzed post hoc via generalized linear regression.Key resultsThe incidence of moderate to severe NPSAEs was higher among smokers in the PC (238/4050; 5.9%) than in the NPC (84/3984; 2.1%). Three baseline characteristics predicted increased risk for experiencing clinically significant NPSAEs when quitting regardless of carrying a psychiatric diagnosis: current symptoms of anxiety (for every ~ 4-unit increase in HADS anxiety score, the absolute risk of occurrence of the NPSAE endpoint increased by 1% in both PC and NPC); prior history of suicidal ideation and/or behavior (PC, 4.4% increase; P = 0.001; NPC, 4.1% increase; P = 0.02), and being of White race (versus Black: PC, 2.9% ± 0.9 [SE] increase; P = 0.002; and NPC, 3.4% ± 0.8 [SE] increase; P = 0.001). Among smokers with psychiatric disorders, younger age, female sex, history of substance use disorders, and proxy measures of nicotine dependence or psychiatric illness severity also predicted greater risk. There were no significant interactions between these characteristics and treatment. Smokers with unstable psychiatric disorders or with current, active substance abuse were excluded from the study.ConclusionsIrrespective of cessation pharmacotherapy use, smokers attempting to quit were more likely to experience moderate to severe NPSAEs if they reported current anxiety or prior suicidal ideation at baseline and were White. In smokers with a psychiatric history, female sex, younger age, and greater severity of nicotine dependence were also predictive.Trial registrationClinicalTrials.gov Identifier: NCT01456936.

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