Smoking Cessation After Initial Treatment Failure With Varenicline or Nicotine Replacement: A Randomized Clinical Trial.

Importance: Most people who smoke do not quit on their initial attempt. Objective: To determine the best subsequent strategy for nonabstinence following initial treatment with varenicline or combined nicotine replacement therapy (CNRT). Design, Setting, and Participants: Using a double-blind, placebo-controlled, sequential multiple assignment randomized trial, 490 volunteers were randomized to receive 6 weeks of varenicline or CNRT. After 6 weeks, nonabstainers were rerandomized to continue, switch, or increase medication dosage for 6 additional weeks. The study was conducted from June 2015 through October 2019 in a Texas tobacco treatment clinic. Interventions: The initial treatment was 2 mg/d of varenicline or the combined replacement therapy of a 21-mg patch plus 2-mg lozenge. The rerandomized participants either continued with their initial therapies, switched between varenicline and CNRT, or increased dosages either to 3-mg or more of varenicline or to a 42-mg patch and lozenges. All received weekly brief counseling. Main Outcomes and Measures: Biochemically verified 7-day point prevalence abstinence at the end of treatment at 12 weeks. Results: The 490 randomized participants (210 female [43%], 287 non-Hispanic White [58%], mean age, 48.1 years) smoked an average of 20 cigarettes per day. After the first phase, 54 participants in the CNRT group were abstinent and continued their therapy; of the 191 who were not abstinent, 151 were rerandomized, and the 40 who did not return for rerandomization were assigned to continue their initial CNRT condition in phase 2. The end-of-treatment abstinence rate for the 191 phase 1 nonabstainers was 8% (95% credible interval [CrI], 6% to 10%) for the 90 (47%) who continued at the dosage condition, 14% (CrI, 10% to 18%) for the 50 (33%) who increased their dosage, and 14% (95% CrI, 10% to 18%) for the 51 (34%) who switched to varenicline (absolute risk difference [RD], 6%; 95% CrI, 6% to 11%) with more than 99% posterior probability that either strategy conferred benefit over continuing the initial dosage. After the first phase, 88 participants in the varenicline group were abstinent and continued their therapy; of the 157 who were not abstinent, 122 were rerandomized and 35 who did not return for rerandomization were assigned to continue with the varenicline condition. The end-of-treatment abstinence rate for the 157 phase 1 nonabstainers was 20% (95% CrI, 16% to 26%) for the 39 (32%) who increased their varenicline dosage, 0 (95% CrI, 0 to 0) for the 41 (34%) who switched CNRT, and 3% (95% CrI, 1% to 4%) for the 77 (49%) who were assigned to the continued varenicline condition (absolute RD, -3%; 95% CrI, -4% to -1%) with more than 99% posterior probability that continuing varenicline at the initial dosage was worse than switching to a higher dosage. Furthermore, increasing the varenicline dosage had an absolute RD of 18% (95% CrI, 13% to 24%) and a more than 99% posterior probability of conferring benefit. The secondary outcome of continuous abstinence at 6 months indicated that only increased dosages of the CNRT and varenicline provided benefit over continuation of the initial treatment dosages. Conclusions and Relevance: For individuals who smoked but did not achieve abstinence after treatment with varenicline, increasing the dosage enhanced abstinence vs continuing, whereas for nonabstainers initially treated with CNRT, a dosage increase or switch to varenicline enhanced abstinence and may be viable rescue strategies. Trial Registration: ClinicalTrials.gov Identifier: NCT02271919.

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Genetic Prediction of Smoking Cessation Medication Side Effects: A Genome-Wide Investigation of Abnormal Dreams on Varenicline.

Varenicline, the most efficacious smoking cessation monotherapy, produces abnormal dreams. Although genetic contributions to varenicline-associated nausea and cessation have been identified, the role of genetics in abnormal dreams is unknown. We conducted a genomewide association study (GWAS) of abnormal dreams in 188 European ancestry smokers treated with varenicline (NCT01314001). Additive genetic models examined the likelihood of experiencing abnormal dreams 2 weeks following varenicline initiation. For the top locus, we tested for selectivity to varenicline, effects on cessation, replication, and generalizability to African ancestry (AA) individuals. The top GWAS variant associated with abnormal dreams was rs901886, mapping to intron 2 of ICAM5 on chromosome 19. The prevalence of abnormal dreams in those with rs901886 CC, CT, and TT genotypes was 15%, 36%, and 62%, respectively (odds ratio = 2.94 for T vs. C, 95% confidence interval = 1.92-4.55, P = 2.03e-7; T allele frequency = 52%). This rs901886 association was selective to varenicline (P values > 0.05 on nicotine patch and placebo). There were also positive associations for rs901886 T (vs. C allele, P = 0.03) and for abnormal dreams (P = 0.06) with varenicline-aided cessation. Neither rs901886 (P = 0.40) nor abnormal dreams (P = 0.24) were associated with adherence. A similar direction of effect of rs901886 on abnormal dreams was observed in a second varenicline trial (NCT01836276). In AA individuals (n = 137), rs901886 was not associated with abnormal dreams (P = 0.41), but there was an association for a variant located ~ 74.4 kb 5' of ICAM5 (P = 2.56e-3). Variation in ICAM5 may influence abnormal dreams and cessation on varenicline. These findings provide additional support for genetically optimized smoking cessation approaches.

Cytisinicline for Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4ß2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. Objective: To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo. Design, Setting, and Participants: A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Interventions: Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Main Outcomes and Measures: Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Results: Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Conclusions and Relevance: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04576949.

Treatment of Tobacco Smoking: A Review.

IMPORTANCE: More deaths in the US are attributed to cigarette smoking each year than to any other preventable cause. Approximately 34 million people and an estimated 14% of adults in the US smoke cigarettes. If they stopped smoking, they could reduce their risk of tobacco-related morbidity and mortality and potentially gain up to 10 years of life. OBSERVATIONS: Tobacco smoking is a chronic disorder maintained by physical nicotine dependence and learned behaviors. Approximately 70% of people who smoke cigarettes want to quit smoking. However, individuals who attempt to quit smoking make an average of approximately 6 quit attempts before achieving long-term abstinence. Both behavioral counseling and pharmacotherapy while using nicotine replacement therapy (NRT) products, varenicline, or bupropion are effective treatments when used individually, but they are most effective when combined. In a meta-analysis including 19 488 people who smoked cigarettes, the combination of medication and behavioral counseling was associated with a quit rate of 15.2% over 6 months compared with a quit rate of 8.6% with brief advice or usual care. The EAGLES trial, a randomized double-blind clinical trial of 8144 people who smoked, directly compared the efficacy and safety of varenicline, bupropion, nicotine patch, and placebo and found a significantly higher 6-month quit rate for varenicline (21.8%) than for bupropion (16.2%) and the nicotine patch (15.7%). Each therapy was more effective than placebo (9.4%). Combining a nicotine patch with other NRT products is more effective than use of a single NRT product. Combining drugs with different mechanisms of action, such as varenicline and NRT, has increased quit rates in some studies compared with use of a single product. Brief or intensive behavioral support can be delivered effectively in person or by telephone, text messages, or the internet. The combination of a clinician's brief advice to quit and assistance to obtain tobacco cessation treatment is effective when routinely administered to tobacco users in virtually all health care settings. CONCLUSIONS AND RELEVANCE: Approximately 34 million people in the US smoke cigarettes and could potentially gain up to a decade of life expectancy by stopping smoking. First-line therapy should include both pharmacotherapy and behavioral support, with varenicline or combination NRT as preferred initial interventions.

Trends in Incident Varenicline Prescribing Among Veterans Following the US Food and Drug Administration Drug Safety Warnings.

Objective: To evaluate national trends in incident varenicline and nicotine replacement therapy (NRT) prescribing among Department of Veterans Affairs (VA) beneficiaries before and after US Food and Drug Administration (FDA) warnings regarding neuropsychiatric side effects with varenicline use.Methods: All adult VA patients identified as smokers from 2007 to 2019 (N = 3,600,947) were determined and monthly counts of new varenicline and NRT users were calculated. An interrupted time-series analysis estimated the effect of the FDA warnings on varenicline and NRT prescribing overall and among Veterans with and without mental health disorders.Results: The incident use rate of varenicline decreased from a peak of 6.2 per 1,000 veteran smokers in October 2007 to 1.0 by July 2009 following the first FDA warning (pre-warning monthly slope = -0.27; P = .03). New NRT use increased from 10.7 per 1,000 veteran smokers in October 2007 to a peak of 12.6 per 1,000 in July 2009 (slope change = 0.71; P = .01), suggesting potential substitution. Following removal of the FDA boxed warning in December 2016, varenicline prescribing increased but did not return to pre-warning levels by December 2019. Among veterans with and without mental health disorders, varenicline use decreased 90% and 88%, respectively, following the first FDA warning, and both groups had comparable rates of new NRT use.Conclusions: Following the first FDA warning, incident use of varenicline declined significantly among veterans both with and without mental health disorders. Despite removal of the FDA boxed warning in December 2016, new use of varenicline had not returned to pre-warning levels 3 years following the removal.

Comparison of Cardiovascular Safety for Smoking Cessation Pharmacotherapies in a Population-Based Cohort in Australia.

Importance: Although concerns exist regarding a potential increased risk of cardiovascular events for smoking cessation pharmacotherapies, there is general consensus that any increased risk associated with their use would be outweighed by the benefits of smoking cessation; thus, clinical guidelines recommend that such pharmacotherapies be offered to everyone who wants to quit smoking. In the interest of minimizing risk to patients, prescribers need evidence indicating how these pharmacotherapies compare with one another in terms of cardiovascular safety. Objective: To compare the risk of major adverse cardiovascular events (MACE) among individuals initiating varenicline, nicotine replacement therapy (NRT) patches, or bupropion. Design, Setting, and Participants: This retrospective, population-based cohort study using linked pharmaceutical dispensing, hospital admissions, and death data was conducted in New South Wales, Australia. Participants included adults who were dispensed a prescription smoking cessation pharmacotherapy between 2008 and 2015 or between 2011 and 2015, depending on the availability of the pharmacotherapies being compared. Pairwise comparisons were conducted for risk of MACE among 122 932 varenicline vs 92 148 NRT initiators; 342 064 varenicline vs 10 457 bupropion initiators; and 102 817 NRT vs 6056 bupropion initiators. Exposure: First course of the smoking cessation pharmacotherapy of interest. Main Outcomes and Measures: The primary outcome was MACE, defined as a composite of acute coronary syndrome, stroke, and cardiovascular death. Secondary outcomes were the individual components of MACE. Inverse probability of treatment weighting with high-dimensional propensity scores was used to account for potential confounding. Cox proportional hazards regression models with robust variance were used to estimate hazard ratios (HRs) and 95% CIs. Data were analyzed January 24, 2019, to September 1, 2021. Results: The mean (SD) age of included individuals ranged from 41.9 (14.2) to 49.8 (14.9) years, and the proportion of women ranged from 42.8% (52 702 of 123 128) to 52.2% (53 693 of 102 913). The comparison of 122 932 varenicline initiators and 92 148 NRT patch initiators showed no difference in the risk of MACE (HR, 0.87; 95% CI, 0.72-1.07) nor in the risk of the secondary outcomes of acute coronary syndrome (HR, 0.96; 95% CI, 0.76-1.21) and stroke (HR, 0.72; 95% CI, 0.45-1.14). However, decreased risk of cardiovascular death was found among varenicline initiators (HR, 0.49; 95% CI, 0.30-0.79). The results of comparisons involving bupropion were inconclusive owing to wide confidence intervals (eg, risk of MACE: 342 064 varenicline vs 10 457 bupropion initiators, HR, 0.87 [95% CI, 0.53-1.41]; 102 817 NRT patch vs 6056 bupropion initiators, HR, 0.79 [95% CI, 0.39-1.62]). Conclusions and Relevance: The finding of this cohort study that varenicline and NRT patch use have similar risk of MACE suggests that varenicline, the most efficacious smoking cessation pharmacotherapy, may be prescribed instead of NRT patches without increasing risk of major cardiovascular events. Further large-scale studies of the cardiovascular safety of varenicline and NRT relative to bupropion are needed.

Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, cytisine has not been tested against the most effective smoking cessation medication, varenicline, which is associated with adverse events known to lead to discontinuation of therapy. Objective: To examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation. Design, Setting, and Participants: This noninferiority, open-label randomized clinical trial with allocation concealment and blinded outcome assessment was undertaken in Australia from November 2017 through May 2019; follow-up was completed in January 2020. A total of 1452 Australian adult daily smokers willing to make a quit attempt were included. Data collection was conducted primarily by computer-assisted telephone interview, but there was an in-person visit to validate the primary outcome. Interventions: Treatments were provided in accordance with the manufacturers' recommended dosage: cytisine (n = 725), 1.5-mg capsules taken 6 times daily initially then gradually reduced over the 25-day course; varenicline (n = 727), 0.5-mg tablets titrated to 1 mg twice daily for 84 days (12 weeks). All participants were offered referral to standard telephone behavioral support. Main Outcomes and Measures: The primary outcome was 6-month continuous abstinence verified using a carbon monoxide breath test at 7-month follow-up. The noninferiority margin was set at 5% and the 1-sided significance threshold was set at .025. Results: Among 1452 participants who were randomized (mean [SD] age, 42.9 [12.7] years; 742 [51.1%] women), 1108 (76.3%) completed the trial. Verified 6-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group (risk difference, -1.62% [1-sided 97.5% CI, -5.02% to ∞]; P = .03 for noninferiority). Self-reported adverse events occurred less frequently in the cytisine group (997 events among 482 participants) compared with the varenicline group (1206 events among 510 participants) and the incident rate ratio was 0.88 (95% CI, 0.81 to 0.95; P = .002). Conclusions and Relevance: Among daily smokers willing to quit, cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation. Trial Registration: anzctr.org.au Identifier: ACTRN12616001654448.

Cost-Effectiveness Analysis of Smoking Cessation Interventions in the United Kingdom Accounting for Major Neuropsychiatric Adverse Events.

OBJECTIVES: Smoking is a leading cause of death worldwide. Cessation aids include varenicline, bupropion, nicotine replacement therapy (NRT), and e-cigarettes at various doses (low, standard and high) and used alone or in combination with each other. Previous cost-effectiveness analyses have not fully accounted for adverse effects nor compared all cessation aids. The objective was to determine the relative cost-effectiveness of cessation aids in the United Kingdom. METHODS: An established Markov cohort model was adapted to incorporate health outcomes and costs due to depression and self-harm associated with cessation aids, alongside other health events. Relative efficacy in terms of abstinence and major adverse neuropsychiatric events was informed by a systematic review and network meta-analysis. Base case results are reported for UK-licensed interventions only. Two sensitivity analyses are reported, one including unlicensed interventions and another comparing all cessation aids but removing the impact of depression and self-harm. The sensitivity of conclusions to model inputs was assessed by calculating the expected value of partial perfect information. RESULTS: When limited to UK-licensed interventions, varenicline standard-dose and NRT standard-dose were most cost-effective. Including unlicensed interventions, e-cigarette low-dose appeared most cost-effective followed by varenicline standard-dose + bupropion standard-dose combined. When the impact of depression and self-harm was excluded, varenicline standard-dose + NRT standard-dose was most cost-effective, followed by varenicline low-dose + NRT standard-dose. CONCLUSION: Although found to be most cost-effective, combined therapy is currently unlicensed in the United Kingdom and the safety of e-cigarettes remains uncertain. The value-of-information analysis suggested researchers should continue to investigate the long-term effectiveness and safety outcomes of e-cigarettes in studies with active comparators.

Frequently Reported Adverse Events With Smoking Cessation Medications: Post Hoc Analysis of a Randomized Trial.

OBJECTIVE: To compare the incidence, severity, and clinical course of frequently reported adverse events (AEs) after treatment with smoking cessation pharmacotherapies. METHODS: This was a multinational, multicenter, post hoc analysis of frequently reported treatment-emergent AEs from a large, phase 4, double-blind, randomized, triple-dummy, placebo-controlled trial (EAGLES), conducted between November 30, 2011, and January 13, 2015, that included smokers with and without psychiatric disorders (N=8144). Treatments were varenicline 1 mg twice daily, bupropion sustained-release 150 mg twice daily, and nicotine patch 21 mg once daily with tapering (12-week treatment, 12-week nontreatment follow-up), with incidence, time to onset, and duration of frequently reported AEs (≥5% of participants in any treatment group) measured. Risk differences for AEs for varenicline and bupropion vs nicotine patch were compared. RESULTS: Across frequently reported AEs, nausea, insomnia, abnormal dreams, anxiety, irritability, dry mouth, fatigue, and application site pruritus differed significantly in active treatment vs placebo groups. Risk differences were as follows: for nausea with varenicline vs nicotine patch, 15.50% (95% CI, 13.20% to 17.80%); for insomnia with bupropion vs nicotine patch, 2.58% (CI, 0.65% to 4.51%); and for abnormal dreams with varenicline and bupropion vs nicotine patch, -2.49% (CI, -4.35% to -0.64%) and -5.60% (CI, -7.27% to -3.93%), respectively. Frequently reported AEs of severe intensity and treatment discontinuation were experienced by less than 1.5% and less than 3% of participants across all groups, respectively. CONCLUSION: Active treatments were well tolerated with comparable AE profiles. Most AEs are not clinically important, and prescribers can reassure patients that those experienced will be manageable. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01456936.

Comparative efficacy and safety of pharmacological interventions for smoking cessation in healthy adults: A network meta-analysis.

Smoking is the leading cause of morbidity and mortality in different non-communicable diseases, and cessation leads to immense health benefits. The present network meta-analysis has been conducted to evaluate and compare the effects of available pharmacological interventions for smoking cessation in adults. A standard meta-analysis protocol was developed and after performing a comprehensive literature search on MEDLINE/PubMed, Cochrane databases, and International Clinical Trials Registry Platform, reviewers extracted data from 97 randomized controlled trials. PRISMA guidelines were followed in data extraction, analysis and reporting of findings. Random effects Bayesian network meta-analysis was done to pool the effects across the interventions. Network graph was built, and for closed triangles in the network graph, node splitting analysis was performed. The primary outcome measure was self-reported biochemically verified smoking abstinence at six months. The number of participants achieving continuous abstinence was reported. Data for the number of participants reporting at least one adverse event was also extracted, if available. Combination of nicotine receptor agonist and nicotine replacement therapy had a significant odd of 4.4 (95%CrI:2.2-8.7), bupropion and nicotine receptor agonist 4.0 (95%CrI:2.1-7.7), bupropion and nicotine replacement therapy 3.8 (95%CrI:2.3-6.2), combination nicotine replacement therapy has an odd of 2.6 (95%CrI:1.8-3.8), and nicotine receptor agonist had a significant odd of 2.7 (95%CrI:2.3-3.2) when compared to placebo (moderate quality of evidence) for continuous abstinence at 6 months. When compared with behavioural therapy, the odds ratio of interventions was not statistically significant. Combination of nicotine receptor agonist and nicotine replacement therapy has the highest probability of being the best treatment for abstinence from smoking.

Interventions for Tobacco Cessation in Adults, Including Pregnant Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: It has been estimated that in 2018 nearly 20% of adults in the US were currently using a tobacco product. Objective: To systematically review the effectiveness and safety of pharmacotherapy, behavioral interventions, and electronic cigarettes for tobacco cessation among adults, including pregnant persons, to inform the US Preventive Services Task Force. Data Sources: PubMed, PsycInfo, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, Centre for Reviews and Dissemination of Health Technology Assessment; surveillance through September 25, 2020. Study Selection: Systematic reviews of tobacco cessation interventions and randomized clinical trials that evaluated the effects of electronic cigarettes (e-cigarettes) or pharmacotherapy among pregnant persons. Data Extraction and Synthesis: Independent critical appraisal and data abstraction; qualitative synthesis and random-effects meta-analyses. Main Outcomes and Measures: Health outcomes, tobacco cessation at 6 months or more, and adverse events. Results: Sixty-seven reviews addressing pharmacotherapy and behavioral interventions were included as well as 9 trials (N = 3942) addressing e-cigarettes for smoking cessation and 7 trials (N = 2285) of nicotine replacement therapy (NRT) use in pregnancy. Combined pharmacotherapy and behavioral interventions (pooled risk ratio [RR], 1.83 [95% CI, 1.68-1.98]), NRT (RR, 1.55 [95% CI, 1.49-1.61]), bupropion (RR, 1.64 [95% CI, 1.52-1.77]), varenicline (RR, 2.24 [95% CI, 2.06-2.43]), and behavioral interventions such as advice from clinicians (RR, 1.76 [95% CI, 1.58-1.96]) were all associated with increased quit rates compared with minimal support or placebo at 6 months or longer. None of the drugs were associated with serious adverse events. Five trials (n = 3117) reported inconsistent findings on the effectiveness of electronic cigarettes on smoking cessation at 6 to 12 months among smokers when compared with placebo or NRT, and none suggested higher rates of serious adverse events. Among pregnant persons, behavioral interventions were associated with greater smoking cessation during late pregnancy (RR, 1.35 [95% CI, 1.23-1.48]), compared with no intervention. Rates of validated cessation among pregnant women allocated to NRT compared with placebo were not significantly different (pooled RR, 1.11 [95% CI, 0.79-1.56], n = 2033). Conclusions and Relevance: There is strong evidence that a range of pharmacologic and behavioral interventions, both individually and in combination, are effective in increasing smoking cessation in nonpregnant adults. In pregnancy, behavioral interventions are effective for smoking cessation, but data are limited on the use of pharmacotherapy for smoking cessation. Data on the effectiveness and safety of electronic cigarettes for smoking cessation among adults are also limited and results are inconsistent.

Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Persons: US Preventive Services Task Force Recommendation Statement.

IMPORTANCE: Tobacco use is the leading preventable cause of disease, disability, and death in the US. In 2014, it was estimated that 480 000 deaths annually are attributed to cigarette smoking, including second hand smoke exposure. Smoking during pregnancy can increase the risk of numerous adverse pregnancy outcomes (eg, miscarriage and congenital anomalies) and complications in the offspring (including sudden infant death syndrome and impaired lung function in childhood). In 2019, an estimated 50.6 million US adults (20.8% of the adult population) used tobacco; 14.0% of the US adult population currently smoked cigarettes and 4.5% of the adult population used electronic cigarettes (e-cigarettes). Among pregnant US women who gave birth in 2016, 7.2% reported smoking cigarettes while pregnant. OBJECTIVE: To update its 2015 recommendation, the USPSTF commissioned a review to evaluate the benefits and harms of primary care interventions on tobacco use cessation in adults, including pregnant persons. POPULATION: This recommendation statement applies to adults 18 years or older, including pregnant persons. EVIDENCE ASSESSMENT: The USPSTF concludes with high certainty that the net benefit of behavioral interventions and US Food and Drug Associated (FDA)-approved pharmacotherapy for tobacco smoking cessation, alone or combined, in nonpregnant adults who smoke is substantial. The USPSTF concludes with high certainty that the net benefit of behavioral interventions for tobacco smoking cessation on perinatal outcomes and smoking cessation in pregnant persons is substantial. The USPSTF concludes that the evidence on pharmacotherapy interventions for tobacco smoking cessation in pregnant persons is insufficient because few studies are available, and the balance of benefits and harms cannot be determined. The USPSTF concludes that the evidence on the use of e-cigarettes for tobacco smoking cessation in adults, including pregnant persons, is insufficient, and the balance of benefits and harms cannot be determined. The USPSTF has identified the lack of well-designed, randomized clinical trials on e-cigarettes that report smoking abstinence or adverse events as a critical gap in the evidence. RECOMMENDATIONS: The USPSTF recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and FDA-approved pharmacotherapy for cessation to nonpregnant adults who use tobacco. (A recommendation) The USPSTF recommends that clinicians ask all pregnant persons about tobacco use, advise them to stop using tobacco, and provide behavioral interventions for cessation to pregnant persons who use tobacco. (A recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of pharmacotherapy interventions for tobacco cessation in pregnant persons. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of e-cigarettes for tobacco cessation in adults, including pregnant persons. The USPSTF recommends that clinicians direct patients who use tobacco to other tobacco cessation interventions with proven effectiveness and established safety. (I statement).

Development and Validation of a Model to Predict Neonatal Abstinence Syndrome.

OBJECTIVES: To develop and validate clinical risk prediction tools for neonatal abstinence syndrome (NAS). STUDY DESIGN: We developed prediction models for NAS based on a set of 30 demographic and antenatal exposure covariates collected during pregnancy. Data (outpatient prescription, vital, and administrative records), were obtained from enrollees in the Tennessee Medicaid Program from 2009 to 2014. Models were created using logistic regression and backward selection based on improvement in the Akaike information criterion, and internally validated using bootstrap cross-validation. RESULTS: A total of 218 020 maternal and infant dyads met inclusion criteria, of whom 3208 infants were diagnosed with NAS. The general population model included age, hepatitis C virus infection, days of opioid used by type, number of cigarettes used daily, and the following medications used in the last 30 day of pregnancy: bupropion, antinausea medicines, benzodiazepines, antipsychotics, and gabapentin. Infant characteristics included birthweight, small for gestational age, and infant sex. A high-risk model used a smaller number of predictive variables. Both models discriminated well with an area under the curve of 0.89 and were well-calibrated for low-risk infants. CONCLUSIONS: We developed 2 predictive models for NAS based on demographics and antenatal exposure during the last 30 days of pregnancy that were able to risk stratify infants at risk of developing the syndrome.

Effect of Sustained Smoking Cessation Counseling and Provision of Medication vs Shorter-term Counseling and Medication Advice on Smoking Abstinence in Patients Recently Diagnosed With Cancer: A Randomized Clinical Trial.

Importance: Persistent smoking may cause adverse outcomes among patients with cancer. Many cancer centers have not fully implemented evidence-based tobacco treatment into routine care. Objective: To determine the effectiveness of sustained telephone counseling and medication (intensive treatment) compared with shorter-term telephone counseling and medication advice (standard treatment) to assist patients recently diagnosed with cancer to quit smoking. Design, Setting, and Participants: This unblinded randomized clinical trial was conducted at Massachusetts General Hospital/Dana-Farber/Harvard Cancer Center and Memorial Sloan Kettering Cancer Center. Adults who had smoked 1 cigarette or more within 30 days, spoke English or Spanish, and had recently diagnosed breast, gastrointestinal, genitourinary, gynecological, head and neck, lung, lymphoma, or melanoma cancers were eligible. Enrollment occurred between November 2013 and July 2017; assessments were completed by the end of February 2018. Interventions: Participants randomized to the intensive treatment (n = 153) and the standard treatment (n = 150) received 4 weekly telephone counseling sessions and medication advice. The intensive treatment group also received 4 biweekly and 3 monthly telephone counseling sessions and choice of Food and Drug Administration-approved cessation medication (nicotine replacement therapy, bupropion, or varenicline). Main Outcome and Measures: The primary outcome was biochemically confirmed 7-day point prevalence tobacco abstinence at 6-month follow-up. Secondary outcomes were treatment utilization rates. Results: Among 303 patients who were randomized (mean age, 58.3 years; 170 women [56.1%]), 221 (78.1%) completed the trial. Six-month biochemically confirmed quit rates were 34.5% (n = 51 in the intensive treatment group) vs 21.5% (n = 29 in the standard treatment group) (difference, 13.0% [95% CI, 3.0%-23.3%]; odds ratio, 1.92 [95% CI, 1.13-3.27]; P < .02). The median number of counseling sessions completed was 8 (interquartile range, 4-11) in the intensive treatment group. A total of 97 intensive treatment participants (77.0%) vs 68 standard treatment participants (59.1%) reported cessation medication use (difference, 17.9% [95% CI, 6.3%-29.5%]; odds ratio, 2.31 [95% CI, 1.32-4.04]; P = .003). The most common adverse events in the intensive treatment and standard treatment groups, respectively, were nausea (n = 13 and n = 6), rash (n = 4 and n = 1), hiccups (n = 4 and n = 1), mouth irritation (n = 4 and n = 0), difficulty sleeping (n = 3 and n = 2), and vivid dreams (n = 3 and n = 2). Conclusions and Relevance: Among smokers recently diagnosed with cancer in 2 National Cancer Institute-designated Comprehensive Cancer Centers, sustained counseling and provision of free cessation medication compared with 4-week counseling and medication advice resulted in higher 6-month biochemically confirmed quit rates. However, the generalizability of the study findings is uncertain and requires further research. Trial Registration: ClinicalTrials.gov Identifier: NCT01871506.

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

BACKGROUND: Although cigarette smoking typically begins in adolescence, evidence for successful pharmacological smoking cessation interventions for this population is scarce. In adult smokers, varenicline is the most effective single pharmacotherapy. The aim of this study was to assess the efficacy and tolerability of varenicline for smoking cessation in adolescents. METHODS: We did a randomised, placebo-controlled trial with adolescent smokers aged 12-19 years who were seeking treatment to quit at 57 outpatient centres (in the USA, Russia, South Korea, Taiwan, Canada, and Georgia). Participants were randomly assigned (1:1:1) to receive 12 weeks of high-dose varenicline (1 mg twice daily; 0·5 mg twice daily if bodyweight ≤55 kg), low-dose varenicline (0·5 mg twice daily; 0·5 mg once daily if bodyweight ≤55 kg), or placebo, then followed up for 40 additional weeks. At all visits, participants received brief, developmentally tailored smoking cessation counselling (<10 min per session) delivered by a trained counsellor. The primary efficacy outcome was continuous abstinence from weeks 9 to 12, measured via a Nicotine Use Inventory and confirmed by urine cotinine testing. The primary tolerability outcome was frequency of treatment-emergent adverse events, including neuropsychiatric adverse events, occurring after the first dose and within 30 days of the last dose of study medication. This trial is registered with ClinicalTrials.gov, NCT01312909. FINDINGS: Between April 26, 2011, and Jan 18, 2018, 312 participants were enrolled and completed participation in the study: 109 in the high-dose varenicline group, 103 in the low-dose varenicline group, and 100 in the placebo group. The continuous abstinence rates from week 9 to 12 were 20% (22 of 109) in the high-dose varenicline group, 27% (28 of 103) in the low-dose varenicline group, and 18% (18 of 100) in the placebo group. Abstinence rates between high-dose varenicline and placebo groups (odds ratio [OR] 1·18 [95% CI 0·59-2·37]; p=0·63) and between low-dose varenicline and placebo groups (1·73 [0·88-3·39]; p=0·11) did not differ significantly. Treatment-emergent adverse events occurred in 65 (60%) of 108 participants in the high-dose group, 53 (53%) of 100 in the low-dose group, and 52 (53%) of 99 in the placebo group, and most were rated as mild. Neuropsychiatric treatment-emergent adverse events occurred in 18 (17%) of 108 participants in the high-dose group, 11 (11%) of 100 in the low-dose group, and 12 (12%) of 99 in the placebo group, and none was rated as severe. INTERPRETATION: This trial did not show an advantage in abstinence with varenicline compared with placebo among adolescent smokers. The rates of treatment-emergent adverse events were similar to those in previous trials of adult smokers, raising no new tolerability signals. These findings do not support the use of varenicline as a first-line pharmacotherapy for smoking cessation in adolescents. FUNDING: Pfizer.

A descriptive analysis of medicines safety advisories issued by national medicines regulators in Australia, Canada, the United Kingdom and the United States - 2007 to 2016.

PURPOSE: To determine the frequency and characteristics of safety advisories issued by medicines regulatory agencies in Australia, Canada, United Kingdom (UK) and the United States (US). METHODS: This retrospective analysis examines medicines safety warnings issued by the US Food and Drug Administration (FDA), Health Canada (HC), the Australian Therapeutic Goods Administration (TGA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) from January 1, 2007 until December 31, 2016. A database of warnings obtained from regulators' websites was developed and warnings were classified by communication type, drug, or therapeutic class focus, and the risk discussed. Advisories identifying the same drug or therapeutic class and risk were combined into groups termed "drug-risk issues" for comparisons between regulators. RESULTS: Over this 10-year period, 1441 advisories were identified, with the MHRA issuing the most advisories (MHRA = 469, FDA = 382, HC = 370 TGA = 220). Seventy two percent focussed on single drugs (1034/1441) and 58.7% were alerts (846/1441) posted on the regulators' websites. Diabetes drugs, smoking cessation drugs and immunomodulatory agents were the individual drug types most often subject to safety advisories, while antidepressants, antipsychotics, and proton-pump inhibitors were the top three therapeutic classes. Of 680 identified drug-risk issues, 3.8% (26/680) described a risk of death. By body system, cardiac effects were the most frequent: 10.4% (71/680). CONCLUSION: We found considerable differences in the use of advisories including frequency, communication type, and focus. Disparities in communication about emergent evidence on risks may mean that clinicians and patients in some countries are less well informed about medicine safety concerns than others.