Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial

Neuropsychiatric safety and relative efficacy of varenicline, bupropion, and transdermal nicotine patch (NRT) in those with psychiatric disorders are of interest. 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). 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. 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.

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.

Objective To determine the efficacy of 16 hour nicotine patches among pregnant smokers, with the dose individually adjusted according to saliva cotinine levels (potential range 10-30 mg/day). Design Randomised, double...

Use of nicotine-replacement therapies and the antidepressant bupropion helps people stop smoking. We conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8. The abstinence rates at 12 months were 15.6 percent in the placebo group, as compared with 16.4 percent in the nicotine-patch group, 30.3 percent in the bupropion group (P<0.001), and 35.5 percent in the group given bupropion and the nicotine patch (P<0.001). By week 7, subjects in the placebo group had gained an average of 2.1 kg, as compared with a gain of 1.6 kg in the nicotine-patch group, a gain of 1.7 kg in the bupropion group, and a gain of 1.1 kg in the combined-treatment group (P<0.05). Weight gain at seven weeks was significantly less in the combined-treatment group than in the bupropion group and the placebo group (P<0.05 for both comparisons). A total of 311 subjects (34.8 percent) discontinued one or both medications. Seventy-nine subjects stopped treatment because of adverse events: 6 in the placebo group (3.8 percent), 16 in the nicotine-patch group (6.6 percent), 29 in the bupropion group (11.9 percent), and 28 in the combined-treatment group (11.4 percent). The most common adverse events were insomnia and headache. Treatment with sustained-release bupropion alone or in combination with a nicotine patch resulted in significantly higher long-term rates of smoking cessation than use of either the nicotine patch alone or placebo. Abstinence rates were higher with combination therapy than with bupropion alone, but the difference was not statistically significant.

It has been suggested that anti-smoking therapy gives encouraging results, but this has not been verified by well-randomized study protocols. The present study was a randomized controlled trial of varenicline vs nicotine patch in adult smokers for comparison of efficacy, safety and withdrawal symptoms. The 32 adult smokers were randomly divided into a varenicline group (VG, n=16) and a nicotine patch group (NG, n=16). The primary endpoints were the 12- and 24-week smoking-abstinence rates, safety and withdrawal symptoms including stress. No significant difference in abstinence rates was observed between the 2 groups over weeks 9-12 (71.4% vs 78.6% in the VG and NG, respectively), and weeks 9-24 (64.3% vs 71.4%, respectively). The frequencies of inability to concentrate at 2, 4, and 8 weeks, and wakeful nights at 2 weeks were higher in the VG than in the NG. Adverse side-effects associated with a gastrointestinal disorder occurred in 14 cases and 1 case in the VG and NG, respectively, and skin allergy was seen in 0 and 9 cases, respectively. The selection of treatment depends on the balance of desired acuteness of cessation of smoking and side-effects, such as psychiatric and gastrointestinal problems or skin allergy.

The aim of this study was to compare the safety and efficacy of the leading smoking cessation medications among individuals with current versus past major depressive disorder (MDD). This was a secondary analysis of a randomized, double-blind trial over 12 weeks with varenicline or bupropion, followed by a 12-week assessment, in participants ages 18-75 with past (N=2,174) or current (N=451) MDD or without psychiatric disorders (N=4,028). Interventions included 12 weeks of pharmacotherapy with placebo, nicotine replacement therapy (NRT; nicotine patch), bupropion, or varenicline, and brief counseling. The primary safety outcome was occurrence of one or more moderate to severe neuropsychiatric adverse events. Efficacy was assessed as biochemically verified continuous abstinence during weeks 9-12. Among all 6,653 participants, the risk of neuropsychiatric adverse events did not differ by medication within the past-MDD, current-MDD, or nonpsychiatric cohorts. The MDD cohorts had higher risk difference (p<0.001) for neuropsychiatric adverse events compared with the nonpsychiatric cohort (past-MDD cohort, risk difference=-0.03, 95% CI=-0.05, -0.02; current-MDD cohort, risk difference=-0.02, 95% CI=-0.05, 0.00). Within the past-MDD cohort, the odds ratios compared with placebo were 3.0 (95% CI=2.0, 4.5) for varenicline, 2.1 (95% CI=1.6, 2.7) for bupropion, and 2.1 (95% CI=1.4, 3.2) for NRT. Within the current-MDD cohort, varenicline differed from placebo (odds ratio=2.67, 95% CI=1.2, 6.15) and NRT (odds ratio=2.93, 95% CI=1.2, 7.2). All medications were generally safe in both MDD cohorts. NRT and bupropion were not more effective than placebo for those with current MDD. Varenicline plus counseling may be the best treatment for individuals with past or current MDD, given its greater efficacy, similar risk of adverse events, and, for those with current depression, reductions in anxiety and depression while trying to quit smoking.

The effects of varenicline, bupropion, nicotine patch, and placebo on smoking cessation among smokers with major depression: A randomized clinical trial.

The Food and Drug Administration and varenicline: should risk communication be improved?

Pharmacotherapy of Tobacco Use Disorder

Reassessing the Safety of Varenicline

Pre-treatment factors that increase smokers' risk of experiencing neuropsychiatric adverse events (NPSAEs) when quitting smoking are unknown. To 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. A prospective correlational cohort study in the context of a multinational, multicenter, double-blind, randomized trial. Smokers 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. Bupropion, 150mg twice daily, or varenicline, 1mg twice daily, versus active control (nicotine patch, 21mg/day with taper) and placebo for 12weeks with 12-week non-treatment follow-up. Primary 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. The 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. Irrespective 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. ClinicalTrials.gov Identifier: NCT01456936.

The concurrent use of both tobacco and alcohol causes substantial disease and early mortality, and smokers who drink heavily tend to be less successful in smoking cessation than smokers who do not. Although varenicline combined with nicotine replacement therapy for smoking cessation has been examined among smokers who do not drink heavily, this combination treatment has not yet been examined among smokers who drink heavily. To determine whether combined treatment with varenicline tartrate and nicotine patch improves continuous abstinence from cigarette smoking among smokers who drink heavily. This double-blind, placebo-controlled, superiority randomized clinical trial evaluated combined treatment with varenicline and nicotine patch compared with placebo and nicotine patch for smoking cessation (primary outcome) and drinking behavior (secondary outcome) among smokers who drink heavily. The clinical trial was conducted at 2 outpatient sites in Chicago, Illinois, with enrollment from March 26, 2018, to February 14, 2020. The 122 participants were recruited from the community via social media and public transit advertisements and equally randomized to the 2 treatment groups, which were stratified by sex and smoking behavior. Eligible participants smoked between 5 and 30 cigarettes per day and drank heavily (>14 drinks per week for men or >7 drinks per week for women and ≥1 heavy drinking day [defined as >5 drinks per occasion for men or >4 drinks per occasion for women] per month for the past year) and had a desire to quit smoking. Varenicline tartrate, 1.0 mg, twice daily or matching placebo pills twice daily for 12 weeks. Nicotine patch at manufacturer-recommended doses for 10 weeks and brief individual smoking cessation counseling the week before the quit date and on the quit date. The primary outcome was self-reported continuous cigarette abstinence through weeks 9 to 12; abstinence was biochemically confirmed at the week 12 study visit. Secondary outcomes were the frequency of weekly drinking and weekly heavy drinking during the study period. Among 122 participants (mean [SD] age, 44.0 [12.4] years; 67 men [54.9%]), 61 were randomly assigned to receive combined treatment with varenicline and nicotine patch (varenicline group), and 61 were randomly assigned to receive placebo and nicotine patch (placebo group). A total of 54 participants (44.3%) self-identified as Black, 56 (45.9%) as White, and 12 (9.8%) as other races (including American Indian or Alaska Native, Asian, >1 race, and unspecified race). A total of 8 participants (6.6%) self-identified as Hispanic and 114 (93.4%) as non-Hispanic ethnicity. Study retention to 12 weeks was 89%. The intention-to-treat analyses showed higher smoking cessation rates during weeks 9 to 12 in the varenicline group vs the placebo group (27 participants [44.3%] vs 17 participants [27.9%]; odds ratio, 2.20; 95% CI, 1.01-4.80; P = .047) and lower likelihood of relapse throughout treatment in the varenicline group relative to the placebo group (hazard ratio, 0.62; 95% CI, 0.40-0.96; P = .03). Both treatments were well tolerated; however, compared with participants in the placebo group, those in the varenicline group experienced more adverse effects, with 5 participants in the varenicline group discontinuing medication due to adverse effects. In this study, combined treatment with varenicline and nicotine patch was more effective than placebo and nicotine patch for smoking cessation among smokers who drink heavily. The combination treatment had no effect on alcohol consumption, with both groups showing significant reductions. Combination treatment with varenicline and nicotine patch may be a viable option for smokers who drink heavily. ClinicalTrials.gov Identifier: NCT02859142.

Reduction in Central Venous Catheter Occlusions: Impact of a Pressure Activated Anti-reflux Connector With a Vascular Access Nurse Algorithm in Assessing Occluded Catheters

High-dose and low-dose varenicline for smoking cessation in adolescents: a randomised, placebo-controlled trial

Background and AimsDue to concerns about increased exposure to nicotine, pregnant women using nicotine replacement therapy (NRT) to stop smoking are usually advised to stop using NRT if they relapse to smoking. This study investigated whether this is justified. We compared changes in saliva cotinine from baseline to 2 weeks post‐target quit date pregnant smokers who relapsed to smoking and continued to use their patches having been assigned to use nicotine patches or placebo.Design and SettingControlled pre–post design stratified by intervention condition from the ‘Study of Nicotine Patch in Pregnancy’, a randomized, placebo‐controlled trial.ParticipantsA sample of 268 pregnant women, assigned placebo (n = 122) or nicotine (n = 146) patches, who returned for further supplies of patches and who reported any smoking in the week prior to a visit at 2 weeks after their target quit date.MeasurementsSaliva cotinine concentrations were measured at baseline and 2 weeks after participants’ target quit dates. Any smoking in the previous week was assessed by self‐report, validated by expired air carbon monoxide (CO).FindingsThere was no change in saliva cotinine concentrations between baseline and 2 weeks post‐target quit date in saliva cotinine concentration in the nicotine patch group [ratio of geometric means = 0.94, 95% confidence interval (CI) = 0.83 to 1.07; P = 0.37, Bayes factor = 0.15]. However, there was a reduction in reported number of cigarettes smoked/day (mean difference −6, 95% CIs −7 to −5, P < 0.001) and in CO concentrations (mean difference −3.0 parts per million, 95% CIs −4.2 to −1.9, P < 0.001). These changes were not significantly different from changes in the placebo group except for cigarette consumption, which reduced more in the nicotine group (P = 0.046).ConclusionsIn women trying to stop smoking with the aid of a nicotine patch but having smoked at 2 weeks post‐target quit, their nicotine concentration did not change from baseline, but they reported smoking fewer cigarettes and had lower carbon monoxide concentrations.