Varenicline and Bupropion and Suicidal Behaviour

Summary

A 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 4 of varenicline and bupropion with 12-week follow-up, in a subset population with a psychiatric disorder (n = 4092). Primary end-point parameters were incidence of prespecified moderate and severe neuropsychiatric adverse events (NPSAEs) and weeks 9 to 12 continuous abstinence rates. The observed NPSAE incidence across treatments was 5.1% to 6.3% in those with a psychotic disorder (n=390), 4.6% to 8.0% in those with an anxiety disorder (n = 792), and 4.6% to 6.8% in those with a mood disorder (n = 2910). 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 continuos abstinence (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 9-12 abstinence rates 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.

A randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) multicentre trial 2of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up was done. Participants were motivated-to-quit smokers with (n=4116) and without (n=4028) psychiatric disorders who received brief cessation counselling at each visit. In the non-psychiatric cohort, 1.3% (13/990) reported moderate and severe neuropsychiatric adverse events in the varenicline group, 2.2% (22/989) in the bupropion group, 2.5% (25/1006) in the nicotine patch group, and 2.4% (24/999) in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1.28 (95% CI -2.40 to -0.15) and -0.08 (-1.37 to 1.21), respectively; the RDs for comparisons with nicotine patch were -1.07 (-2.21 to 0.08) and 0.13 (-1.19 to 1.45), respectively. In the psychiatric cohort, 6.5% (867/1026) reported moderate and severe neuropsychiatric adverse events in the varenicline group, 6.7% (68/1017) in the bupropion group, 5.2% (53/1016) in the nicotine patch group, and 4.9% (50/1015) in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1.59 (95% CI -0.42 to 3.59) and 1.78 (-0.24 to 3.81), respectively; the RDs versus nicotine patch were 1.22 (-0.81 to 3.25) and 1.42 (-0.63 to 3.46), respectively. Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25%), insomnia (bupropion, 12%), abnormal dreams (nicotine patch, 12%), and headache (placebo, 10%).

A Cochrane review[Abstract] 3 included a network meta-analysis of 12 treatment-specific reviews (267 studies) involving 101 804 participants studying varenicline, bupropion, NRT, combination NRT, and placebo. The serious adverse events (SAEs) meta-analysis found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55 RR 1.06; 14 trials, n=6333 participants; event rates for any SAE were 2.1% in the varenicline arms and 2.0% in the placebo arms), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56).

A cohort sudy 1 included a total of 119 546 men and women aged 18 years and over who used a smoking cessation product between years 2006 and 2011. To compare the risk of suicide, self harm, and depression in patients prescribed varenicline or bupropion with those prescribed nicotine replacement therapy a prospective cohort study within the Clinical Practice Research Datalink was conducted among 349 general practices in England. There were 81 545 users of nicotine replacement products (68.2% of all users of smoking cessation medicines), 6741 bupropion (5.6%), and 31 260 varenicline (26.2%) users.Outcomes were treated depression and fatal and non-fatal self harm within three months of the first smoking cessation prescription, determined from linkage with mortality data from the Office for National Statistics (for suicide) and Hospital Episode Statistics data (for hospital admissions relating to non-fatal self harm). Hazard ratios or risk differences were estimated using Cox multivariable regression models, propensity score matching, and instrumental variable analysis using physicians' prescribing preferences as an instrument. Sensitivity analyses were performed for outcomes at six and nine months.There were 92 cases of fatal and non-fatal self harm (326.5 events per 100 000 person years) and 1094 primary care records of treated depression (6963.3 per 100 000 person years). There was no evidence that patients prescribed varenicline had higher risks of fatal or non-fatal self harm (hazard ratio (HR) 0.88, 95% CI 0.52 to 1.49) or treated depression (HR 0.75, 95% CI 0.65 to 0.87) compared with those prescribed nicotine replacement therapy. There was no evidence that patients prescribed bupropion had a higher risk of fatal or non-fatal self harm (HR 0.83, 95% CI 0.30 to 2.31) or of treated depression (HR 0.63, 95% CI 0.46 to 0.87) compared with patients prescribed nicotine replacement therapy.

A 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 4 of varenicline and bupropion with 12-week follow-up, in a subset population with a psychiatric disorder (n = 4092). Primary end-point parameters were incidence of prespecified moderate and severe neuropsychiatric adverse events (NPSAEs) and weeks 9 to 12 continuous abstinence rates. The observed NPSAE incidence across treatments was 5.1% to 6.3% in those with a psychotic disorder (n=390), 4.6% to 8.0% in those with an anxiety disorder (n = 792), and 4.6% to 6.8% in those with a mood disorder (n = 2910). 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 continuos abstinence (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 9-12 abstinence rates 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.