Economic Evaluation of Enhanced vs Standard Varenicline Treatment for Tobacco Cessation.

Importance: Smoking is the leading preventable cause of death and illness in the US. Identifying cost-effective smoking cessation treatment may increase the likelihood that health systems deliver such treatment to their patients who smoke. Objective: To evaluate the cost-effectiveness of standard vs enhanced varenicline use (extended varenicline treatment or varenicline in combination with nicotine replacement therapy) among individuals trying to quit smoking. Design, Setting, and Participants: This economic evaluation assesses the Quitting Using Intensive Treatments Study (QUITS), which randomized 1251 study participants who smoked into 4 conditions: (1) 12-week varenicline monotherapy (n = 315); (2) 24-week varenicline monotherapy (n = 311); (3) 12-week varenicline combination treatment with nicotine replacement therapy patch (n = 314); or (4) 24-week varenicline combination treatment with nicotine replacement therapy patch (n = 311). Study enrollment occurred in Madison and Milwaukee, Wisconsin, between November 11, 2017, and July 2, 2020. Statistical analysis took place from May to October 2023. Main Outcomes and Measures: The primary outcome was 7-day point prevalence abstinence (biochemically confirmed with exhaled carbon monoxide level ≤5 ppm) at 52 weeks. The incremental cost-effectiveness ratio (ICER), or cost per additional person who quit smoking, was calculated using decision tree analysis based on abstinence and cost for each arm of the trial. Results: Of the 1251 participants, mean (SD) age was 49.1 (11.9) years, 675 (54.0%) were women, and 881 (70.4%) completed the 52-week follow-up. Tobacco cessation at 52 weeks was 25.1% (79 of 315) for 12-week monotherapy, 24.4% (76 of 311) for 24-week monotherapy, 23.6% (74 of 314) for 12-week combination therapy, and 25.1% (78 of 311) for 24-week combination therapy, respectively. The total mean (SD) cost was $1175 ($365) for 12-week monotherapy, $1374 ($412) for 12-week combination therapy, $2022 ($813) for 24-week monotherapy, and $2118 ($1058) for 24-week combination therapy. The ICER for 12-week varenicline monotherapy was $4681 per individual who quit smoking and $4579 per quality-adjusted life-year (QALY) added. The ICER for 24-week varenicline combination therapy relative to 12-week monotherapy was $92 000 000 per additional individual who quit smoking and $90 000 000 (95% CI, $15 703 to dominated or more costly and less efficacious) per additional QALY. Conclusions and Relevance: This economic evaluation of standard vs enhanced varenicline treatment for smoking cessation suggests that 12-week varenicline monotherapy was the most cost-effective treatment option at the commonly cited threshold of $100 000/QALY. This study provides patients, health care professionals, and other stakeholders with increased understanding of the health and economic impact of more intensive varenicline treatment options.

Incremental net monetary benefit of using varenicline for smoking cessation: A systematic review and meta-analysis of economic evaluation studies.

AIMS: To conduct a systematic review and meta-analysis and pool the incremental net benefits (INBs) of varenicline compared with behaviour support with bupropion or nicotine replacement therapy (NRT), behaviour support alone and unaided cessation in adult smokers making a first-time attempt to quit. METHODS: A search for economic evaluation studies was conducted from inception to 30 September 2022, on PubMed, Embase, Cost-Effectiveness Analysis (CEA) Registry by Tufts Medical Centre, EconLit and the NHS Economic Evaluation Database (NHS EED). Eligible studies were included if they were (1) conducted among adults ages 18 years old and older who were smokers attempting to quit for the first time; (2) compared varenicline to behaviour support with bupropion or NRT, behaviour support alone and unaided cessation; and (3) performed a CEA or cost-utility analysis. The INBs were calculated and pooled across studies stratified by country income level and study perspective using the random-effects model. Statistical heterogeneity between studies was assessed using the I2 statistic and Cochrane Q statistic. RESULTS: Of the 1433 identified studies, 18 studies were included in our review. Our findings from healthcare system/payer perspective suggested that the use of varenicline is statistically significantly cost-effective compared with bupropion (pooled INB, $830.75 [95% confidence interval, $208.23, $1453.28]), NRTs ($636.16 [$192.48, $1079.84]) and unaided cessation ($4212.35 [$1755.79, $6668.92]) in high-income countries. Similarly, varenicline is also found to be cost-effective compared to bupropion ($2706.27 [$1284.44, $4128.11]), NRTs ($3310.01 [$1781.53, $4838.50]) and behavioural support alone ($5438.22 [$4105.99, $6770.46]) in low- and middle-income countries. CONCLUSION: Varenicline is cost-effective as a smoking cessation aid when compared with behavioural support with bupropion or nicotine replacement therapies and behavioural support alone in both high-income countries and low- and middle-income countries, from the healthcare system/payer perspective in adult smokers who attempt to quit for the first time.

[Cost-effectiveness of pharmaceutical smoking cessation intervention in China primary cancer prevention].

Objectives: To evaluate the cost-effectiveness of typical pharmaceutical smoking cessation intervention strategies in China in the context of primary cancer prevention. Methods: Markov cohort simulation models were established to simulate the burden of 12 smoking caused cancer, including lung cancer, oral cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, kidney cancer, bladder cancer, cervical cancer, and acute myeloid leukemia. Taking incremental cost effectiveness ratio (ICER) as the main indicator, the model sets one year as the cycling period for 50 periods and simulates the cohort of 10 000 thirty-five-year-old current smokers with various smoking cessation strategies. To ensure the robustness of conclusion, univariate sensitivity analysis, probability sensitivity analysis, and age-group sensitivity analysis were conducted. Results: The results showed that varenicline intervention was the most cost-effective intervention. Compared to the next most effective option, incremental cost of each additional quality-adjusted life year is 11 140.28 yuan, which is below the threshold of willingness to pay (1 year GDP per capita). The value of ICER increased as the increasing age group of adopting intervention, but neither exceeded the threshold of willingness to pay. One-way sensitivity analysis showed that the value of discount rate, the hazard ratio and cost of intervention strategy had a greater impact on the result of ICER. Conclusion: In China, the use of varenicline to quit smoking is highly cost effective in the context of cancer primary prevention, especially for younger smokers.

Cost-Effectiveness of Smoking Cessation Interventions in Patients With Ischemic Stroke and Transient Ischemic Attack.

BACKGROUND: Smoking cessation rates after stroke and transient ischemic attack are suboptimal, and smoking cessation interventions are underutilized. We performed a cost-effectiveness analysis of smoking cessation interventions in this population. METHODS: We constructed a decision tree and used Markov models that aimed to assess the cost-effectiveness of varenicline, any pharmacotherapy with intensive counseling, and monetary incentives, compared with brief counseling alone in the secondary stroke prevention setting. Payer and societal costs of interventions and outcomes were modeled. The outcomes were recurrent stroke, myocardial infarction, and death using a lifetime horizon. Estimates and variance for the base case (35% cessation), costs and effectiveness of interventions, and outcome rates were imputed from the stroke literature. We calculated incremental cost-effectiveness ratios and incremental net monetary benefits. An intervention was considered cost-effective if the incremental cost-effectiveness ratio was less than the willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY) or when the incremental net monetary benefit was positive. Probabilistic Monte Carlo simulations modeled the impact of parameter uncertainty. RESULTS: From the payer perspective, varenicline and pharmacotherapy with intensive counseling were associated with more QALYs (0.67 and 1.00, respectively) at less total lifetime costs compared with brief counseling alone. Monetary incentives were associated with 0.71 more QALYs at an additional cost of $120 compared with brief counseling alone, yielding an incremental cost-effectiveness ratio of $168/QALY. From the societal perspective, all 3 interventions provided more QALYs at less total costs compared with brief counseling alone. In 10 000 Monte Carlo simulations, all 3 smoking cessation interventions were cost-effective in >89% of runs. CONCLUSIONS: For secondary stroke prevention, it is cost-effective and potentially cost-saving to deliver smoking cessation therapy beyond brief counseling alone.

Cost-Effectiveness Analysis of Tobacco Control Strategies in Indonesia.

OBJECTIVES: In Indonesia, tobacco smoking is a significant public health problem that continues to grow, with a prevalence among the highest worldwide. This study aimed to assess the cost-effectiveness of government-funded varenicline, smoking bans in public places, and an additional 10% tobacco tax in Indonesia. METHODS: Markov modeling of Indonesians aged 15 to 84 years was undertaken, with simulated follow-up until age 85 years. Data on demographics, smoking prevalence, and mortality were drawn from the Global Burden of Disease Study 2017. Data regarding the efficacy and costs of the 3 interventions were gathered from published sources. Costs and benefits accrued beyond one year were discounted at 3% per annum. The year value of costing data was 2020. RESULTS: Government-funded varenicline, smoking bans in public places, and an additional 10% tobacco tax were predicted to save 5.5 million, 1.6 million, and 1.7 million years of life, respectively (all discounted). In terms of quality-adjusted life-years, 3 tobacco interventions were predicted to gain 11.9 million, 3.47 million, and 3.78 million in quality-adjusted life-years, respectively. The savings in smoking-related healthcare costs amounted to US $313.8 billion, US $97.5 billion, and US $106 billion, respectively. Hence, from the perspective of the healthcare system, all 3 interventions were cost saving (dominant). CONCLUSIONS: In Indonesia, tobacco control measures are likely to be highly cost-effective and even cost saving from the healthcare system's perspective. These cost savings can be balanced against economic losses that would result from the impact on the sizable Indonesian tobacco industry.

Cost-Effectiveness Analysis of Smoking Cessation Interventions With Behavioral Support: A Study Based on the Benefits of Smoking Cessation on Outcomes (BENESCO) Model.

INTRODUCTION: Few studies have compared cost-effectiveness of different smoking cessation interventions (SCIs) that include behavioral support, considering smoking-related diseases. Therefore, we compare the cost-effectiveness of SCIs with behavioral support in South Korea using the Benefits of Smoking Cessation on Outcomes (BENESCO) model. AIMS AND METHODS: We used the BENESCO model to estimate the cost and utility of the SCIs with behavioral support, including pharmacist counseling with nicotine replacement therapy (pharmacist+NRT), expert counseling with NRT (expert+NRT), and expert counseling with varenicline (expert+varenicline). The target population was adult smokers who wanted to cease smoking within 1 month. We applied transitional probabilities and epidemiological data from the literature. Medical costs and utilities were calculated using claims and national survey data, respectively. Cost-effectiveness was evaluated within the threshold (17 926 USD per quality-adjusted life years [QALYs]) by incremental cost-effectiveness ratio (ICER). RESULTS: The model cohort included 1 219 390 male and 298 511 female smokers. The pharmacist+NRT group had 32 842 more QALYs gained and 26 689 958 USD less expended than the expert+NRT group. The ICER for the expert+varenicline group versus the pharmacist+NRT and expert+NRT groups was 27 247 and 4074 USD per QALY, respectively. The robustness of the results was confirmed by sensitivity analyses, except for the discount rate and cost of the expert+varenicline group. CONCLUSIONS: In Korea, pharmacist counseling with NRT showed higher QALY gains and lower costs than expert counseling with NRT. Expert counseling with varenicline was more effective for smoking cessation and more cost-effective than expert counseling with NRT but was not cost-effective compared with pharmacist counseling with NRT. IMPLICATIONS: This study provides evidence for decision-making on smoking cessation programs by evaluating the cost-effectiveness of SCIs. Furthermore, we attempted to use the BENESCO model to compare and evaluate the cost-effectiveness of SCIs with behavioral support. It is meaningful because this study showed the availability of using the BENESCO model in the future cost-effectiveness analysis of various SCIs.

Information shocks and pharmaceutical firms' marketing efforts: Evidence from the Chantix black box warning removal.

We study how pharmaceutical firm marketing responds to a regulatory decision that represents a positive information shock about drug safety. In the context of the smoking cessation drug Chantix, we estimate the effects of a Food and Drug Administration (FDA) decision to remove the drug's black box warning on two forms of marketing: monetary and in-kind payments to physicians (detailing) and direct-to-consumer advertising. Using identification strategies that leverage geographic variation in latent demand for smoking cessation therapy and the targeted nature of the information shock, we find that the removal of the warning significantly increased Chantix-related detailing payments and increased expenditures on national television advertising of Chantix. Understanding these firm-level strategic promotion responses is important, as they have implications for the dissemination of new drug information and the behaviors of physicians and consumers.

What Factors are Associated With Waterpipe Smoking Cessation? A Secondary Data Analysis.

INTRODUCTION: Waterpipe smoking is gaining popularity and becoming a major global public health concern. An understanding of factors that predict waterpipe smoking cessation is necessary for targeting tobacco control efforts. METHODS: This is a secondary data analysis of a randomized controlled trial comparing the efficacy of varenicline against placebo in helping waterpipe smokers to quit. A total of 510 adult daily waterpipe smokers were recruited to the trial in 2016. Logistic regression models were applied to assess factors (i.e., demographic, environmental, behavioral, and physiological) associated with primary outcome (waterpipe smoking cessation) and secondary outcomes (waterpipe cessation alongside abstinence from cigarette and short-term and long-term waterpipe smoking cessation). Cessation was defined as 7-day point prevalence abstinence from smoking reported at 5,12, and/or 25 weeks follow-ups. RESULTS: Over a period of six months, 189 (39.2%) participants abstained from waterpipe smoking for at least one week. Being male (adjusted odds ratio (aOR):2.99 (95%CI:1.47-6.08)), dual smoker (waterpipe and cigarettes) (aOR:2.98 (95%CI:1.87-4.74)), more withdrawal symptoms measured by the Mood and Physical Symptoms Scale (aOR:1.08 (95%CI:1.02-1.13)), less nicotine dependency measured by Lebanon Waterpipe Dependency Scale (aOR:0.90 (95%CI:0.85-0.96)), having a history of quit attempt (aOR:2.14 (95%CI:1.16-3.96)), smoking restriction in the house (aOR:2.69 (95%CI:1.01-7.14)), and not sharing waterpipe with others (aOR:2.72 (95%CI:1.31-5.66)) predicted waterpipe smoking cessation. CONCLUSIONS: In addition to nicotine dependency, social factors such as home restrictions on smoking, and not sharing waterpipe were identified as predictors of waterpipe smoking cessation. To help waterpipe smokers quit, social environment may be just as or even more important than well-known physical and psychological factors. IMPLICATIONS: A range of factors, predominantly social factors play a significant role in facilitating or deterring waterpipe smokers from quitting smoking. Our findings suggest that interventions that focus on social as well as physical/psychological factors may encourage waterpipe smokers in achieving abstinence.

Cost-Effectiveness Analysis of Varenicline Versus Currently Funded Smoking Cessation Strategies in Brazil.

OBJECTIVES: To assess the cost-effectiveness of varenicline in comparison to currently funded smoking cessation strategies in Brazil. METHODS: We modeled the lifetime direct costs and health-related quality of life of a hypothetical cohort of smokers with a single attempt to quit smoking using one of the following: (1) cognitive behavioral therapy (CBT) without any pharmacological intervention, (2) varenicline, (3) bupropion, (4) nicotine replacement therapy (NRT) with transdermal patch, (5) bupropion in combination with NRT transdermal patch, and (6) combined NRT (oral plus transdermal). All drug alternatives were considered with concomitant CBT. The analysis relied on a Markov model based on the Benefits of Smoking Cessation and Outcomes study and used different age and sex categories in the consideration of relative risks and incidence rates of the diseases included in the model. The analysis was conducted from the healthcare system perspective, and a 3% discounting rate for costs and outcomes was applied. Model parameter values were sourced from published literature. Probabilistic and deterministic sensitivity analyses assessed robustness. RESULTS: Among the smoking cessation alternatives available in Brazil, varenicline and combined NRT were estimated to have higher effectiveness; varenicline, however, was dominated due to its higher average cost. In the base-case analysis, combined NRT had an incremental gain of 0.25 quality-adjusted life-years (QALYs) in comparison to the second-best option (bupropion in combination with NRT transdermal patch) and an incremental cost-effectiveness ratio of R$2173.47/QALY ($595.45/QALY). CONCLUSIONS: Combination of oral and transdermal NRT (coupled with CBT) was the most effective smoking cessation option and was 100% cost-effective within a conservative willingness-to-pay threshold.

The Structured Process to Identify Fit-For-Purpose Data: A Data Feasibility Assessment Framework.

To complement real-world evidence (RWE) guidelines, the 2019 Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) framework elucidated a process for designing valid and transparent real-world studies. As an extension to SPACE, here, we provide a structured framework for conducting feasibility assessments-a step-by-step guide to identify decision grade, fit-for-purpose data, which complements the United States Food and Drug Administration (FDA)'s framework for a RWE program. The process was informed by our collective experience conducting systematic feasibility assessments of existing data sources for pharmacoepidemiology studies to support regulatory decisions. Used with the SPACE framework, the Structured Process to Identify Fit-For-Purpose Data (SPIFD) provides a systematic process for conducting feasibility assessments to determine if a data source is fit for decision making, helping ensure justification and transparency throughout study development, from articulation of a specific and meaningful research question to identification of fit-for-purpose data and study design.

The prevalence, odds, predictors, and management of tobacco use disorder or nicotine dependence among people with severe mental illness: Systematic review and meta-analysis.

The prevalence, correlates, and management of tobacco use disorder (TUD) or nicotine dependence (ND) among people with severe mental illness (SMI), namely schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), remain unclear. Therefore, a systematic review and meta-analysis was conducted. Electronic databases were systematically searched from inception to July 12, 2020, for observational studies documenting the prevalence, odds, and correlates of TUD/ND among people with SMI; randomized controlled trials (RCTs) informing the management of TUD/ND in people with SMI were also included. Random-effects meta-analyses were conducted. Sources of heterogeneity were explored. Nineteen observational studies, including 7527 participants with SMI met inclusion criteria. TUD/ND co-occurred in 33.4-65% of people with SMI. Rates were higher among males. While bupropion and varenicline represent promising treatment opportunities for schizophrenia with TUD/ND, non-pharmacological interventions require further research, mainly for people with primary mood disorders. TUD/ND represent prevalent co-occurring conditions among people with SMI. Further well-designed RCTs are warranted to inform their management.

Cost-effectiveness analysis of treatment with varenicline for nicotine dependence compared with smoking cessation without pharmacotherapy in the real world.

PURPOSE: Smoking is an important public health issue. Although measures to support smoking cessation have been implemented worldwide, smokers often fail to quit smoking after receiving pharmacotherapies for nicotine dependence. The present study evaluated the cost-effectiveness of varenicline for smoking cessation compared with no pharmacotherapy using actual paid medical cost data in Japan. METHODS: This was a retrospective cohort study of 3657 subjects who had quit smoking with varenicline or no pharmacotherapy. We extracted health examination and medical claim data from a health insurer database for the period 2012-2015. We calculated the incremental cost-effective ratio (ICER) of varenicline using actual paid medical costs for nicotine dependence and the number needed to treat to maintain smoking cessation compared with no pharmacotherapy, considering sex, age, income, and occupation. RESULTS: The 1- and 2-year smoking cessation maintenance rates were 69.7% and 62.4%, respectively. We found that 8.8% of subjects who quit smoking used varenicline for nicotine dependence and the cost per person was Japanese Yen (JPY) 52 177 (U.S. dollars [USD] 474; USD 1 = JPY 110). The ICER of varenicline was dominant when comparing 2-year cessation with 1-year cessation. Male, age <40 years, low income, and manufacturing workers were the most cost-effective variables. CONCLUSIONS: The cost-effective variables of varenicline in the real world were investigated. The results of this study strengthen the evidence regarding which type of people should be targeted for measures to support smoking cessation using varenicline.

Association Between Conflicts of Interest and Authors' Positions on Harms of Varenicline: a Cross-Sectional Analysis.

BACKGROUND: Few studies have investigated the relationship between industry funding/conflicts of interest and authors' positions in opinion pieces on drug safety. Harmful effects of varenicline, a treatment for smoking cessation, have been highly contested. OBJECTIVE: To examine the association between pharmaceutical industry funding/authors' financial conflicts of interest and position on varenicline in opinion articles, especially in relation to the minimization of harms; to assess whether opinion pieces on drug safety issues written by authors with conflicts of interest are more frequently cited in the news or social media. DESIGN: Cross-sectional analysis. PARTICIPANTS: English language opinion pieces and narrative reviews about varenicline published between May 2006 and February 2019. MAIN MEASURES: Odds ratios and 95% confidence intervals; the Mann-Whitney two-sample statistic was used to test for differences in Altmetric scores, a measure of media attention. KEY RESULTS: Of the 221 included articles, 30.3% (67) disclosed the funding source and 62.9% (139) disclosed authors' conflicts of interest. Authors of opinion pieces on varenicline who reported financial ties to the pharmaceutical industry (as a conflict of interest or funding source) were more likely to minimise the cardiovascular and psychiatric risk of varenicline compared to those without conflicts of interest or industry funding (OR: 4.00; 95% CI: 1.32 to 12.16 for cardiovascular risk; OR: 8.51; 95% CI: 3.79 to 19.11 for psychiatric risk). These associations persisted in sensitivity analyses. No statistically significant difference in Altmetric score was found between articles with (mean 15.83, median 3) and without (mean 11.90, median 1) conflicts of interest, indicating similar media attention (p-value=0.11). CONCLUSIONS: We found that authors with financial ties to drug companies were more likely to publish opinion pieces that minimised harms of varenicline. These results raise questions about journals' editorial policies to accept reviews of treatments from authors with financial relationships with manufacturers.

Smoking cessation medicines and e-cigarettes: a systematic review, network meta-analysis and cost-effectiveness analysis.

BACKGROUND: Cigarette smoking is one of the leading causes of early death. Varenicline [Champix (UK), Pfizer Europe MA EEIG, Brussels, Belgium; or Chantix (USA), Pfizer Inc., Mission, KS, USA], bupropion (Zyban; GlaxoSmithKline, Brentford, UK) and nicotine replacement therapy are licensed aids for quitting smoking in the UK. Although not licensed, e-cigarettes may also be used in English smoking cessation services. Concerns have been raised about the safety of these medicines and e-cigarettes. OBJECTIVES: To determine the clinical effectiveness, safety and cost-effectiveness of smoking cessation medicines and e-cigarettes. DESIGN: Systematic reviews, network meta-analyses and cost-effectiveness analysis informed by the network meta-analysis results. SETTING: Primary care practices, hospitals, clinics, universities, workplaces, nursing or residential homes. PARTICIPANTS: Smokers aged ≥ 18 years of all ethnicities using UK-licensed smoking cessation therapies and/or e-cigarettes. INTERVENTIONS: Varenicline, bupropion and nicotine replacement therapy as monotherapies and in combination treatments at standard, low or high dose, combination nicotine replacement therapy and e-cigarette monotherapies. MAIN OUTCOME MEASURES: Effectiveness - continuous or sustained abstinence. Safety - serious adverse events, major adverse cardiovascular events and major adverse neuropsychiatric events. DATA SOURCES: Ten databases, reference lists of relevant research articles and previous reviews. Searches were performed from inception until 16 March 2017 and updated on 19 February 2019. REVIEW METHODS: Three reviewers screened the search results. Data were extracted and risk of bias was assessed by one reviewer and checked by the other reviewers. Network meta-analyses were conducted for effectiveness and safety outcomes. Cost-effectiveness was evaluated using an amended version of the Benefits of Smoking Cessation on Outcomes model. RESULTS: Most monotherapies and combination treatments were more effective than placebo at achieving sustained abstinence. Varenicline standard plus nicotine replacement therapy standard (odds ratio 5.75, 95% credible interval 2.27 to 14.90) was ranked first for sustained abstinence, followed by e-cigarette low (odds ratio 3.22, 95% credible interval 0.97 to 12.60), although these estimates have high uncertainty. We found effect modification for counselling and dependence, with a higher proportion of smokers who received counselling achieving sustained abstinence than those who did not receive counselling, and higher odds of sustained abstinence among participants with higher average dependence scores. We found that bupropion standard increased odds of serious adverse events compared with placebo (odds ratio 1.27, 95% credible interval 1.04 to 1.58). There were no differences between interventions in terms of major adverse cardiovascular events. There was evidence of increased odds of major adverse neuropsychiatric events for smokers randomised to varenicline standard compared with those randomised to bupropion standard (odds ratio 1.43, 95% credible interval 1.02 to 2.09). There was a high level of uncertainty about the most cost-effective intervention, although all were cost-effective compared with nicotine replacement therapy low at the £20,000 per quality-adjusted life-year threshold. E-cigarette low appeared to be most cost-effective in the base case, followed by varenicline standard plus nicotine replacement therapy standard. When the impact of major adverse neuropsychiatric events was excluded, varenicline standard plus nicotine replacement therapy standard was most cost-effective, followed by varenicline low plus nicotine replacement therapy standard. When limited to licensed interventions in the UK, nicotine replacement therapy standard was most cost-effective, followed by varenicline standard. LIMITATIONS: Comparisons between active interventions were informed almost exclusively by indirect evidence. Findings were imprecise because of the small numbers of adverse events identified. CONCLUSIONS: Combined therapies of medicines are among the most clinically effective, safe and cost-effective treatment options for smokers. Although the combined therapy of nicotine replacement therapy and varenicline at standard doses was the most effective treatment, this is currently unlicensed for use in the UK. FUTURE WORK: Researchers should examine the use of these treatments alongside counselling and continue investigating the long-term effectiveness and safety of e-cigarettes for smoking cessation compared with active interventions such as nicotine replacement therapy. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016041302. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 59. See the NIHR Journals Library website for further project information.

Cigarette smoking is one of the main causes of early death both in the UK and worldwide. Three medicines, varenicline, bupropion and nicotine replacement therapy, are licensed in the UK to help people stop smoking. E-cigarettes can also be used as a stop smoking aid. We combined information from previous studies, including clinical trials, to determine which product was the safest, most effective and best value for money for the NHS. We compared treatments that were given alone as well as treatments that were combined with others, such as combination nicotine replacement therapy, varenicline combined with nicotine replacement therapy, varenicline combined with bupropion and bupropion combined with nicotine replacement therapy. The last three combined treatments are not currently licensed in the UK for smoking cessation. We also compared different treatment doses (low, high and standard doses). We found that most treatments were more effective than placebo in helping people to quit smoking. One of the combination treatments (varenicline at standard dose combined with nicotine replacement therapy at standard dose) was the most effective at getting people to quit smoking, followed by e-cigarette at low dose, varenicline at standard dose combined with bupropion at standard dose, and e-cigarette at high dose. We also found that smokers with higher tobacco dependence and smokers treated with counselling alongside medicines achieved a higher proportion of continuous quitting. We also found evidence that the standard dose of bupropion was associated with an increased risk of serious side effects compared with placebo. There was inconclusive evidence that any of the treatments increased the risk of major cardiovascular side effects. There was some evidence that smokers who received a standard dose of varenicline had an increased risk of major neurological and psychiatric side effects compared with those receiving a standard dose of bupropion. E-cigarette at low dose, varenicline standard plus nicotine replacement therapy standard and varenicline standard plus bupropion standard were the best value for money interventions, but further clinical trials comparing treatments against each other are needed to increase confidence in these findings.

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.

Assessment of Racial Differences in Pharmacotherapy Efficacy for Smoking Cessation: Secondary Analysis of the EAGLES Randomized Clinical Trial.

Importance: Understanding Black vs White differences in pharmacotherapy efficacy and the underlying reasons is critically important to reducing tobacco-related health disparities. Objective: To compare pharmacotherapy efficacy and examine variables to explain Black vs White differences in smoking abstinence. Design, Setting, and Participants: This study is a secondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) double-blind, placebo-controlled, randomized clinical trial, which took place at clinical trial centers, academic centers, and outpatient clinics in 29 states in the US. US Black and White smokers who smoked 10 or more cigarettes per day with and without psychiatric comorbidity were enrolled between November 2011 and January 2015. Data analysis was performed from July 2019 to January 2020. Interventions: Participants were randomized (1:1:1:1) in a double-blind, triple-dummy, placebo- and active-controlled (nicotine patch) trial of varenicline and bupropion for 12 weeks with follow-up through week 24. Main Outcomes and Measures: Biochemically verified continuous cigarette abstinence rate (CAR) from weeks 9 to 24. Baseline, postbaseline treatment, and safety characteristics were examined as variables to explain race differences in abstinence. Results: Of the 1065 Black smokers enrolled, 255 were randomized to receive varenicline, 259 received bupropion, 286 received nicotine replacement therapy (NRT [ie, nicotine patch]), and 265 received placebo. Among the 3044 White smokers enrolled, 778 were randomized to receive varenicline, 769 received bupropion, 738 received NRT, and 759 received placebo. Participants were predominantly female (614 Black [57.7%] and 1786 White [58.7%] women) and heavy smokers (mean [SD] cigarettes per day, 18.2 [7.9] for Black and 20.0 [7.5] for White smokers), with a mean (SD) age of 47.2 (11.2) years for Black and 46.5 (12.7) years for White participants. Treatment and race were associated with CAR for weeks 9 to 24. The CAR was 4.9% lower for Black vs White participants (odds ratio [OR], 0.53; 95% CI, 0.41-0.69; P < .001); differences were found across all treatments. Pooling psychiatric and nonpsychiatric cohorts, varenicline (OR, 2.63; 95% CI, 1.90-3.63; P < .001), bupropion (OR, 1.75; 95% CI, 1.25-2.46; P = .001), and NRT (OR, 1.52; 95% CI, 1.07-2.16; P = .02) had greater efficacy than placebo for White participants. Only varenicline (OR, 2.63; 95% CI, 1.26-5.48; P = .01) had greater efficacy than placebo for Black participants. Baseline, postbaseline, and safety characteristics differed by race, but these variables did not eliminate the association of race with CAR. Black participants had 49% reduced odds of CAR for weeks 9 to 24 compared with White participants in the adjusted model (OR, 0.51; 95% CI, 0.39-0.66; P < .001). Conclusions and Relevance: Black and White smokers achieved the highest rate of abstinence while taking varenicline, suggesting that it is the best first-line therapy for these groups. However, Black smokers were less responsive to all therapies, including placebo. Understanding variables (eg, socioeconomic or biological) beyond those may lead to improved treatment outcomes for Black smokers. Trial Registration: ClinicalTrials.gov Identifier: NCT01456936.

Varenicline rescues nicotine-induced decrease in motivation for sucrose reinforcement.

Varenicline is one of the top medications used for smoking cessation and is often prescribed before termination of nicotine use. The effect of this combined nicotine and varenicline use on the reward system and motivation for primary reinforcement is underexplored. The goal of this study was to assess the effects of nicotine and varenicline on motivation for a food reinforcer. In Experiment 1, we first assessed the responding for sucrose after pretreatment with nicotine (0, 0.1, or 0.4 mg/kg) and varenicline (0.0, 0.1, 1.0 mg/kg) using a behavioral economics approach. The responding for sucrose was then assessed using a progressive ratio schedule of reinforcement after pretreatment with all possible combinations of nicotine and varenicline doses. In Experiment 2, rats were assessed for the consumption of sucrose in home cages after pretreatment with nicotine and varenicline. We found that (a) nicotine decreased economic demand for sucrose, (b) varenicline rescued nicotine-induced reduction in economic demand for sucrose, and (c) history of varenicline treatment predicted responding for sucrose on a progressive ratio schedule of reinforcement where rats with a history of varenicline treatment responded significantly lower for sucrose across nicotine doses than rats that had not been exposed to varenicline. The results of Experiment 2 largely confirmed that nicotine decreases motivation for sucrose using a passive consumption protocol and that varenicline rescues this effect. Overall, these findings suggest that varenicline interacts with the effects of nicotine by restoring nicotine-induced reduction in motivation for appetitive rewards.

Clinical impact and cost-effectiveness of integrating smoking cessation into lung cancer screening: a microsimulation model.

BACKGROUND: Low-dose computed tomography (CT) screening can reduce lung cancer mortality in people at high risk; adding a smoking cessation intervention to screening could further improve screening program outcomes. This study aimed to assess the impact of adding a smoking cessation intervention to lung cancer screening on clinical outcomes, costs and cost-effectiveness. METHODS: Using the OncoSim-Lung mathematical microsimulation model, we compared the projected lifetime impact of a smoking cessation intervention (nicotine replacement therapy, varenicline and 12 wk of counselling) in the context of annual low-dose CT screening for lung cancer in people at high risk to lung cancer screening without a cessation intervention in Canada. The simulated population consisted of Canadians born in 1940-1974; lung cancer screening was offered to eligible people in 2020. In the base-case scenario, we assumed that the intervention would be offered to smokers up to 10 times; each intervention would achieve a 2.5% permanent quit rate. Sensitivity analyses varied key model inputs. We calculated incremental cost-effectiveness ratios with a lifetime horizon from the health system's perspective, discounted at 1.5% per year. Costs are in 2019 Canadian dollars. RESULTS: Offering a smoking cessation intervention in the context of lung cancer screening could lead to an additional 13% of smokers quitting smoking. It could potentially prevent 12 more lung cancers and save 200 more life-years for every 1000 smokers screened, at a cost of $22 000 per quality-adjusted life-year (QALY) gained. The results were most sensitive to quit rate. The intervention would cost over $50 000 per QALY gained with a permanent quit rate of less than 1.25% per attempt. INTERPRETATION: Adding a smoking cessation intervention to lung cancer screening is likely cost-effective. To optimize the benefits of lung cancer screening, health care providers should encourage participants who still smoke to quit smoking.

Pharmacovigilance Assessment of Cardiac Implications of Nicotine Replacement Therapy Among Smokers.

PURPOSE: The purpose of this quantitative comparative study was to examine the possible relationship between nicotine replacement therapy (NRT) and cardiac disorder risk by comparing the rates of cardiac disorder risk of NRT with cardiac disorder risk of non-replacement drugs among smokers seeking smoking cessation. METHODS: The study used retrospective quantitative design, which involved the collection of secondary data from the adverse event reporting system (FAERS) database of the U.S Food and Drug Administration (FDA). Rates of cardiac disorder were compared between the NRT group and non- NRT (varenicline and bupropion) group. Statistical analyses involved using a 2x2 contingency table and logistic regression to calculate odds ratio (reporting odds ratio (ROR)). RESULTS AND DISCUSSION: Unadjusted ROR was 0.45 (95% confidence interval [CI] 0.28, 0.70). With age and sex as confounding factors, the smokers in the NRT group still had lower odds of having cardiac disorder risk than the non-NRT group (adjusted ROR=0.44, 95% CI 0.28, 0.70). CONCLUSION: Our study findings showed lower cardiac disorder risk with the NRT group compared to the non-NRT (varenicline and bupropion) group. While the study did not aim to undermine either using NRT or non-NRT for smoking cessation therapy to prevent smoking illness, the study results offer informed findings that could potentially improve current smoking cessation management using NRT intervention among smokers and enhance smokers' health outcome. Despite the negative signal detection of cardiac disorder risk with NRT as compared to non-NRT in final findings, we still recommend further research on the causal relationship between NRT and non-NRT and cardiac disorder risk.