Efficacy Of Pharmacotherapy For Smoking Cessation Research Articles

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

Improving treatment outcomes for smokers with major depressive disorder (MDD) can have significant public health implications. To evaluate the safety and efficacy of smoking cessation pharmacotherapy among smokers with MDD. Secondary analysis of a randomized, double-blind, active- (nicotine patch) and placebo-controlled trial of 12 weeks of either varenicline or bupropion with a 12-week follow-up. Community volunteers 18-75 years of age; smoke 10+ cigarettes/day; with clinically stable MDD (N = 2635) or no psychiatric disorder (N = 4028), from 140 sites in 16 countries. Twelve weeks of pharmacotherapy (placebo[PLA], nicotine replacement therapy[NRT], bupropion[BUP], varenicline[VAR]) plus brief cessation counseling. Primary safety outcome: the occurrence of ≥1 treatment-emergent, moderate to severe neuropsychiatric adverse event (NPSAE). Primary efficacy outcome: biochemically confirmed continuous abstinence(CA) during the final 4 weeks of treatment (Weeks 9-12). A total of 6653 participants (56% female; 39% MDD) ~47 years old. Risk of NPSAEs did not differ by medication for MDD. MDD had higher risk (p < .0001) for NPSAEs than the NPC. Efficacy (6653; intent-to-treat): CA rates for MDD versus NPC respectively were 31.2% versus 38.0% VAR; 23.0% versus 26.1% BUP; 22.6% versus 26.4% NRT; and 13.4% versus 13.7% PLA but no differential treatment effect was noted within the cohorts. All active treatments differed from PLA but VAR showed the largest effect. Results suggest that for MDD smokers, inclusive of those with recurrent episode, varenicline plus counseling may be the best pharmacological option for the treatment of smoking given its greater efficacy effect size and similar risk of NPSAEs. ClinicalTrials.gov Identifier: NCT01456936. https://clinicaltrials.gov/ct2/show/NCT01456936.

The Role of Pharmacogenetics in Smoking.

Smoking continues to be the leading preventable contributor to death worldwide. Twin studies have suggested a significant genetic contribution underlying most smoking behaviors (40-70% heritability estimates). Candidate gene studies of smoking phenotypes have identified several pharmacogenes implicated in nicotine's pharmacokinetics (CYP2A6, CYP2B6, CYP2A13, FMOs, UGTs, and OCT2), and nicotine's pharmacodynamic response in the central nervous system (nicotinic acetylcholine receptors, as well as through the dopaminergic and serotonergic systems). Subsequent genome-wide association studies (GWAS) have confirmed the role of certain pharmacogenes through hypothesis-free approaches. Furthermore, pharmacogenes that alter the efficacy of smoking cessation pharmacotherapies, including nicotine replacement therapies, bupropion, and varenicline, may also impact quitting success. In this brief review we highlight the role of pharmacogenes in smoking behaviors, such as smoking status, consumption, nicotine dependence, spontaneous quitting, and altered abstinence to pharmacotherapies; We provide examples from initial candidate gene associations and subsequent GWAS. The genes CYP2A6 and the CHRNA5-A3-B4 confer the most replicated sources of genetic variation in smoking behaviors, likely due to their importance in nicotine's pharmacology. We will also provide examples of genetic scoring approaches, and the role of rare variants in explaining a portion of the missing heritability in smoking behaviors.

Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: Subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial.

BackgroundSmoking rates are high in adults with anxiety disorders (ADs), yet little is known about the safety and efficacy of smoking‐cessation pharmacotherapies in this group.MethodsPost hoc analyses in 712 smokers with AD (posttraumatic stress disorder [PTSD], n = 192; generalized anxiety disorder [GAD], n = 243; panic disorder [PD], n = 277) and in a nonpsychiatric cohort (NPC; n = 4,028). Participants were randomly assigned to varenicline, bupropion, nicotine‐replacement therapy (NRT), or placebo plus weekly smoking‐cessation counseling for 12 weeks, with 12 weeks follow‐up. General linear models were used to test the effects of treatment group, cohort, and their interaction on neuropsychiatric adverse events (NPSAEs), and continuous abstinence weeks 9–12 (treatment) and 9–24 (follow‐up).ResultsNPSAE incidence for PTSD (6.9%), GAD (5.4%), and PD (6.2%) was higher versus NPC (2.1%), regardless of treatment. Across all treatments, smokers with PTSD (odds ratio [OR] = 0.58), GAD (OR = 0.72), and PD (OR = 0.53) had lower continuous abstinence rates weeks 9–12 (CAR9–12) versus NPC. Varenicline demonstrated superior efficacy to placebo in smokers with GAD and PD, respectively (OR = 4.53; 95% confidence interval [CI] = 1.20–17.10; and OR = 8.49; 95% CI = 1.57–45.78); NRT was superior to placebo in smokers with PD (OR = 7.42; 95% CI = 1.37–40.35). While there was no statistically significant effect of any treatment on CAR9–12 for smokers with PTSD, varenicline improved 7‐day point prevalence abstinence at end of treatment in this subcohort.ConclusionIndividuals with ADs were more likely than those without psychiatric illness to experience moderate to severe NPSAEs during smoking‐cessation attempts, regardless of treatment. While the study was not powered to evaluate abstinence outcomes with these subgroups of smokers with ADs, varenicline provided significant benefit for cessation in those with GAD and PD, while NRT provided significant benefit for those with PD.

Characterising the nicotine metabolite ratio and its association with treatment choice: A cross sectional analysis of Stop Smoking Services in England

Pharmacotherapy provision based on Nicotine Metabolite Ratio (NMR) status (slow/normal metabolism) may improve smoking cessation rates. However, it is unclear whether NMR status is consistent across patient characteristics and current treatment choice. Data come from 1,826 participants attending Stop Smoking Services (SSS) across England in 2012/13. Sociodemographic, mental/physical health, smoking and treatment characteristics (nicotine replacement therapy vs. other pharmacotherapy; group vs. one-to-one behavioural support) were assessed. Salivary nicotine metabolites were measured and NMR (3-hydroxycotinine/cotinine) computed, characterising smokers as slow (NMR < 0.31) or normal (NMR ≥ 0.31) metabolisers. Normal metabolisers were older than slow metabolisers (Odds Ratio (OR) = 1.49, 95% Confidence Interval (CI) = 1.32–1.69) but no other characteristics were associated with NMR status. Overall, predictors accounted for only 7.3% of NMR variance. In adjusted analysis, pharmacotherapy type was not associated with NMR status, but normal metabolisers were less likely to use group support (OR = 0.67, 95% CI = 0.51–0.89). NMR status does not vary substantially across sociodemographic characteristics. Given its impact on pharmacotherapy efficacy, the lack of an association with pharmacotherapy choice suggests there is scope to use NMR status to optimise the selection and efficacy of smoking cessation pharmacotherapy. The unexpected association of NMR status with behavioural support should be explored further.

Gender differences in the real-world effectiveness of smoking cessation medications: Findings from the 2010–2011 Tobacco Use Supplement to the Current Population Survey

BackgroundMeta-analyses of clinical trial data have identified clinically relevant gender differences in the efficacy of smoking cessation pharmacotherapy. It is unclear whether these findings are generalizable to smokers quitting in real-world contexts. MethodsUsing Tobacco Use Supplement to the Current Population Survey (TUS-CPS) 2010–2011 cross-sectional data, we generated propensity score matched samples of smokers who quit either unassisted by medication, using only varenicline, or using only transdermal nicotine patch (TNP). We used generalized estimating equations to estimate gender differences in the comparative effectiveness of these cessation options for achieving 30-days of abstinence, adjusting for potential confounders. ResultsWhen stratified by gender, TNP was significantly more effective than unassisted quit attempts for men (OR=1.37; 95%CI=1.02,1.83; p=0.03), but not for women (OR=0.96; 95%CI=0.71,1.31; p=0.82). Varenicline was significantly more effective than unassisted quit attempts for women (OR=1.63; 95%CI=1.16, 2.31; p=0.005), but not men (OR=1.35; 95%CI=0.94,1.96; p=0.11). Varenicline was also more effective than TNP for women (OR=1.51; 95%CI=0.12,2.05; p=0.007) but not men (OR=0.92; 95%CI=0.65,1.31; p=0.64). A significant gender by medication interaction was found only for the comparison of varenicline to TNP (OR=1.64; 95%CI=1.04,2.61; p=0.04). ConclusionsFindings for varenicline vs. TNP were consistent with clinical trial data, showing greater differences in effectiveness for women compared to men. Results lend support to the generalizability of clinical trial findings, highlighting the importance of considering gender when offering treatment for smoking cessation.

Efficacy and Safety of Smoking Cessation Interventions in Patients With Cardiovascular Disease: A Network Meta-Analysis of Randomized Controlled Trials.

Although the efficacy and safety of smoking cessation interventions are well established, their efficacy and safety in patients with cardiovascular disease (CVD) remain unclear. The objective of this study was to evaluate the efficacy and safety of pharmacological and behavioral smoking cessation interventions in CVD patients via a meta-analysis of randomized controlled trials. EMBASE, PsycINFO, MEDLINE, PubMed, and the Cochrane Tobacco Addiction Specialized Register were searched for randomized controlled trials evaluating the efficacy of smoking cessation pharmacotherapies and behavioral therapies in CVD patients. Outcomes of interest were smoking abstinence at 6 and 12 months, defined using the most rigorous criteria reported. Data were pooled across studies for direct comparisons using random-effects models. Network meta-analysis using a graph-theoretical approach was used to generate the indirect comparisons. Seven pharmacotherapy randomized controlled trials (n=2809) and 17 behavioral intervention randomized controlled trials (n=4666) met our inclusion criteria. Our network meta-analysis revealed that varenicline (relative risk [RR]: 2.64; 95% confidence interval [CI], 1.34-5.21) and bupropion (RR: 1.42; 95% CI, 1.01-2.01) were associated with greater abstinence than placebo. The evidence about nicotine replacement therapies was inconclusive (RR: 1.22; 95% CI, 0.72-2.06). Telephone therapy (RR: 1.47; 95% CI: 1.15-1.88) and individual counseling (RR: 1.64, 95% CI: 1.17-2.28) were both more efficacious than usual care, whereas in-hospital behavioral interventions were not (RR: 1.05; 95% CI, 0.78-1.43). Our meta-analysis suggests varenicline and bupropion, as well as individual and telephone counseling, are efficacious for smoking cessation in CVD patients.

A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism.

Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70–0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR.

Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation

ObjectiveRecent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. MethodIn two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. ResultsFor abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X2=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. ConclusionsResults from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking.