Dataset Information

Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial.

ABSTRACT: BACKGROUND:Neuropsychiatric safety and relative efficacy of varenicline, bupropion, and transdermal nicotine patch (NRT) in those with psychiatric disorders are of interest. METHODS:We performed secondary analyses of safety and efficacy outcomes by psychiatric diagnosis in EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study), a 12-week, randomized, double-blind, triple-dummy, placebo- and active (NRT)-controlled trial of varenicline and bupropion with 12-week follow-up, in a subset population, n = 4092, with a primary psychotic (n = 390), anxiety (n = 792), or mood (n = 2910) disorder. Primary end-point parameters were incidence of prespecified moderate and severe neuropsychiatric adverse events (NPSAEs) and weeks 9 to 12 continuous abstinence rates (9-12CAR). RESULTS:The observed NPSAE incidence across treatments was 5.1% to 6.3% in those with a psychotic disorder, 4.6% to 8.0% in those with an anxiety disorder, and 4.6% to 6.8% in those with a mood disorder. Neither varenicline nor bupropion was associated with significantly increased NPSAEs relative to NRT or placebo in the psychiatric cohort or any psychiatric diagnostic subcohort. There was a significant effect of treatment on 9-12CAR (P < 0.0001) and no significant treatment-by-diagnostic subcohort interaction (P = 0.24). Abstinence rates with varenicline were superior to bupropion, NRT, and placebo, and abstinence with bupropion and NRT was superior to placebo. Within-diagnostic subcohort comparisons of treatment efficacy yielded estimated odds ratios for 9-12CAR versus placebo of greater than 3.00 for varenicline, greater than 1.90 for bupropion, and greater than 1.80 for NRT for all diagnostic groups. CONCLUSIONS:Varenicline, bupropion, and nicotine patch are well tolerated and effective in adults with psychotic, anxiety, and mood disorders. The relative effectiveness of varenicline, bupropion, and NRT versus placebo did not vary across psychiatric diagnoses.

SUBMITTER: Evins AE

PROVIDER: S-EPMC6488024 | biostudies-literature | 2019 Mar/Apr

REPOSITORIES: biostudies-literature

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Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial.

Evins A Eden AE Benowitz Neal L NL West Robert R Russ Cristina C McRae Thomas T Lawrence David D Krishen Alok A St Aubin Lisa L Maravic Melissa Culhane MC Anthenelli Robert M RM

Journal of clinical psychopharmacology 20190301 2

<h4>Background</h4>Neuropsychiatric safety and relative efficacy of varenicline, bupropion, and transdermal nicotine patch (NRT) in those with psychiatric disorders are of interest.<h4>Methods</h4>We performed secondary analyses of safety and efficacy outcomes by psychiatric diagnosis in EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study), a 12-week, randomized, double-blind, triple-dummy, placebo- and active (NRT)-controlled trial of varenicline and bupropion with 12-week fol ...[more]

PMID: 30811371

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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:Background and aimsAnalysed 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.DesignEAGLES was a randomised, double-blind, triple-dummy, controlled trial.SettingGlobal (16 countries across five continents), between November 2011 and January 2015.ParticipantsParticipants were smokers with (n = 4116) and without (n = 4028) psychiatric disorders.InterventionsVarenicline (1 mg twice daily), bupropion (150 mg twice daily), nicotine patch (21 mg once daily with taper) and matched placebos.MeasurementsThe 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.FindingsFor 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.ConclusionsSecondary 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.

Project description:INTRODUCTION:Varenicline (VAR) is an effective smoking-cessation therapy compared to the commonly used nicotine-replacement therapy patch (NRT-P). However, comparative real-world evidence on smoking-cessation therapies is limited, especially for economic outcomes. METHODS:Using national claims databases (2012-2016) in the United States (US), adults initiating VAR or NRT-P without use of any other smoking-cessation products were followed for up to 1 year on a quarterly basis. Outcomes included smoking-attributable (SA) (cardiovascular, diabetes, pulmonary diseases, and smoking cessation) and all-cause costs (2017 US dollars). Adjusted mean costs were estimated from multivariable regressions, with baseline characteristics and propensity scores as covariates. Annual adjusted costs were calculated from quarterly averages. RESULTS:The VAR cohort (n = 209,284) was younger (mean age 46.7 vs. 49.0 years) and had fewer comorbidities [mean Charlson Comorbidity Index (CCI): 0.8 vs. 1.6] than the NRT-P cohort (n = 34,593). After adjustment, VAR cohort had lower SA and all-cause medical costs than NRT-P cohort in Quarters 1-4 (Q1-Q4) of follow-up, and had lower SA and all-cause total costs in Q2-Q4. Annually, VAR cohort had higher SA total costs ($307) and lower all-cause costs (- $2089) than NRT-P cohort. Annual medical costs were lower in VAR cohort (- $640 for SA and - $2876 for all-cause), and pharmacy costs were higher ($762 for SA and $777 for all-cause). In adherent patients (VAR: n = 38,744; NRT-P: n = 2702), VAR patients had lower annual medical costs (- $794 for SA and - $1636 for all-cause) and higher pharmacy costs ($1175 for SA and $1269 for all-cause); differences in SA and all-cause total costs were not statistically significant between treatment groups. CONCLUSIONS:Lower SA and all-cause medical costs associated with the use of VAR versus NRT-P resulted in savings in all-cause total costs and, among adherent patients, potentially offset the high pharmacy costs of VAR. FUNDING:Pfizer, Inc.

Project description:This study replicated and extended results of a previous trial, which found that combination varenicline/bupropion treatment increased smoking abstinence in smokers who were male, highly dependent, and who did not respond to prequit nicotine patch treatment with a >50% reduction in expired-air carbon monoxide in the first week.One hundred and twenty-two male nicotine patch nonresponders and 52 responders were identified. Smokers in each group were randomized to receive 12 weeks of varenicline plus bupropion treatment versus varenicline plus placebo. The primary outcome was continuous smoking abstinence at weeks 8-11 after the target quit date.For smokers with a high level of dependence, judged by having a baseline Fagerstrom Test for Nicotine Dependence (FTND) score ? 6 and cigarette consumption ? 20/d, combination varenicline/bupropion treatment increased the abstinence rate relative to varenicline alone: 71.0% versus 43.8% (odds ratio = 3.14; 95% confidence interval = 1.11-8.92, p [one tailed] = .016). In contrast, less dependent smokers did not show a benefit of combination treatment relative to varenicline (abstinence rates of 32.1% vs. 45.6%, respectively); there was a significant interaction of treatment and dependence level. Patch nonresponders tended to benefit the most from combination treatment, which was well tolerated overall.Combination varenicline/bupropion treatment proved significantly more efficacious than varenicline alone among highly dependent male smokers. These results, together with prior studies, support an adaptive treatment paradigm that assigns smoking cessation treatment according to baseline smoker characteristics and initial response to nicotine patch treatment.This study replicated, in a prospective manner, an important and surprising retrospective finding from a previous clinical trial, which showed that a specific subpopulation of smokers benefited substantially from receiving a combination treatment of varenicline plus bupropion, relative to varenicline plus placebo. Specifically, male smokers having high baseline nicotine dependence (FTND score ? 6 and cigarette consumption ? 20/d), showed a marked increase in smoking abstinence rate on combination pharmacotherapy. The present study likewise found an enhancement in end-of-treatment abstinence rate in this subgroup, from 43.8% to 71.0%. The adaptive treatment paradigm, which classifies smokers based on initial dependence level and response to prequit nicotine patch treatment, may be used to identify target populations of smokers whose success can be enhanced by intervening with combination pharmacotherapy before the quit-smoking date.ClinicalTrials.gov identifier: NCT01806779.

Project description:ImportanceCombining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence.ObjectiveTo determine efficacy and safety of varenicline and bupropion sustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarette smokers.Design, setting, and participantsRandomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites. Five hundred six adult (≥18 years) cigarette smokers were randomly assigned and 315 (62%) completed the study.InterventionsTwelve weeks of varenicline and bupropion SR or varenicline and placebo.Main outcomes and measuresPrimary outcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after the target quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence. Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomes were biochemically confirmed.ResultsAt 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12; P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 and OR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40; 95% CI, 0.96-2.05; P = .08, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03).Conclusions and relevanceAmong cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks. Neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination therapy in smoking cessation.Trial registrationclinicaltrials.gov Identifier: http://clinicaltrials.gov/show/NCT00935818.

Dataset Information

Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial.

Publications

Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial.

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