Evidence Summary

Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Persons

January 19, 2021

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

By Carrie D. Patnode, PhD, MPH; Jillian T. Henderson, PhD, MPH; Erin L. Coppola, MPH; Joy Melnikow, MD, MPH; Shauna Durbin, MPH; Rachel G. Thomas, MPH

The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was published in JAMA on January 19, 2021 (JAMA. 2021;325(3):280-298. doi:10.1001/jama.2020.23541).

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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.

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Despite progress in reducing the use of tobacco products by US adults, in 2019 an estimated 20.8% of adults in the US currently used any tobacco product and there are persistent differences in rates of smoking by age, sex, and race/ethnicity.1 A large range of pharmacologic and behavioral methods are available to help adults quit tobacco use;2 however in a 2015 survey, among those who tried quitting in the previous year, only 31.2% reported using evidence-based cessation treatments and 7.4% were successful in quitting.3

In 2015, the US Preventive Services Task Force (USPSTF) issued 4 recommendations related to tobacco cessation interventions among adults. Two A recommendations were given for behavioral and pharmacotherapy interventions for adults and for behavioral interventions for pregnant women, and 2 I statements were issued: one for pharmacotherapy interventions for pregnant women and one on the use of electronic cigarettes (e-cigarettes) for tobacco cessation among adults and pregnant women.4 The objective of this review was to inform updated recommendations by the USPSTF.

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Scope of Review

This is an update of a 2015 overview of reviews that supported the 2015 USPSTF recommendation.5,6 An analytic framework and 3 key questions (KQs) guided the review (Figure). Consistent with the 2015 review, an overview of reviews method was primarily used for this update. However, given the insufficient evidence found in 2015, original searches and syntheses of primary evidence were conducted for the benefits and harms of e-cigarettes for smoking cessation and for the benefits and harms of pharmacologic smoking cessation interventions among pregnant women. Details are available in the full report.8 All main results presented in the full report are also presented in this article; more detailed methods, including review selection and determination of overall credibility and quality of individual reviews and studies, and additional effect estimates for specific types of interventions and comparative effectiveness outcomes, are provided in the full report.

Data Sources and Searches

Three separate literature searches were conducted. All searches were restricted to articles in the English language published since January 2014. For reviews, the following databases were searched through April 2019: PubMed, PsycINFO, the Database of Abstracts of Reviews of Effects, the Cochrane Database of Systematic Reviews (CDSR), and the Centre for Reviews and Dissemination Health Technology Assessment. For primary evidence on e-cigarettes, the CDSR, Cochrane Central Register of Controlled Clinical Trials (CENTRAL), PsycInfo, PubMed, and Scopus were searched through May 2020. For studies of pharmacotherapy tobacco cessation interventions among pregnant women, Medline, CENTRAL, PubMed, and PsycInfo were searched through May 2020. Ongoing surveillance for relevant primary literature and Cochrane systematic reviews was completed through September 25, 2020.

Study Selection

Two researchers independently reviewed all identified abstracts and full-text articles against prespecified eligibility criteria. Studies were included if they were systematic reviews, with or without meta-analysis, that examined the effectiveness of tobacco cessation interventions for adults. Interventions targeting cessation of any tobacco product, including e-cigarettes, were included and reviews that focused on specific interventions (eg, nicotine replacement therapy [NRT], group counseling) and specific subpopulations (eg, persons with serious mental illness) were eligible. Reviews published by Cochrane and non-Cochrane reviews were included. Narrative (nonsystematic) reviews and other overviews of reviews were excluded. Only the most recent version of updated reviews was included. Separate inclusion criteria were outlined when considering primary evidence related to e-cigarettes and pharmacotherapy interventions among pregnant women.

Data Extraction and Quality Assessment

One reviewer completed the AMSTAR-2 (Assessment of Multiple Systematic Reviews 2) tool9 to rate the credibility of the systematic reviews under consideration for inclusion, and a second reviewer provided an independent assessment using the same tool for all reviews rated critically low. For primary studies, 2 reviewers independently assessed the risk of bias of included evidence using study-design specific criteria. Each review and study were assigned a quality rating of “good,” fair,” or “poor” according to the USPSTF study design–specific criteria.7 Reviews rated as having critically low credibility and primary studies rated as poor quality were excluded. Data from each included review and primary study were abstracted into detailed abstraction forms using DistillerSR. For all included evidence, one reviewer completed primary data abstraction and a second reviewer checked all data for accuracy and completeness.

Data Synthesis and Analysis

Given the large number of reviews that met eligibility criteria and the overlapping scope and evidence between many of them, a method was developed to identify 1 or more reviews within each population and intervention group that represented the most current and applicable evidence. These reviews served as the basis for the main findings. All other reviews were examined for complementary or discordant findings. Pooled point estimates presented in the included reviews were reported when appropriate; none of the individual study evidence was reanalyzed. Data from trials of e-cigarette use were not meta-analyzed, given the few number of studies and data reporting. Methods for the meta-analyses of data from trials of pharmacotherapy among pregnant women are described in the full evidence report.

For the overview of reviews method, the strength of the overall body of evidence assigned within the primary systematic review was reported. In most cases, these grades were based on the Grading of Recommendations Assessment, Development and Evaluation working group definitions, which consider study limitations, consistency of effect, imprecision, indirectness, and publication bias. Where strength of evidence grades were not available, including for the primary evidence syntheses, an overall strength of evidence grade was assigned based on consensus discussions involving at least 2 reviewers.10

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This review addressed 2 populations of interest: the general adult population and pregnant women. Within each population, results are organized by KQ.

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For the overview of reviews, investigators reviewed 1173 abstracts and 210 full-text articles for possible inclusion for all KQs. Sixty-four reviews were identified that met eligibility criteria, including those among an unselected population of adults and those limited to a specific subgroup of adults (Table 1).11-53,57-77 Thirty-two reviews were designated as primary reviews.11-16,18-20,22,24-30,32-34,38,41,43,45,46,48-53,78 Eleven additional reviews had overlapping evidence with the primary reviews.17,21,23,31,35,37,39,40,42,44,47 Results of these reviews were consistent with the primary reviews in terms of effect magnitude and statistical significance and are not discussed further. Twenty-one reviews focused on specific subpopulations of adults (eg, people with severe mental illness, smokeless tobacco users).57-77 These 21 reviews are not discussed here but are included in the full report.8

The review of primary evidence on the use of e-cigarettes for smoking cessation resulted in 9 included randomized clinical trials (RCTs) reported in 16 publications; 5 of these RCTs addressed smoking cessation (KQ2) and all addressed potential harms (KQ3).79-94 None of the e-cigarette trials reported results related to health outcomes (KQ1).

Health Benefits of Interventions

Key Question 1. Do tobacco cessation interventions improve mortality, morbidity, and other health outcomes in adults who currently use tobacco?

One RCT (n = 1445) reported the results of a behavioral tobacco cessation intervention on health outcomes.95 This study reported no statistically significant differences between intervention and control groups in rates of total mortality (41.5% vs 44.%, P = .93), coronary heart disease mortality (17.3% vs 19.9%, P = .87), and lung cancer incidence (7.8% vs 8.8%, P = .89) at 20-year follow-up among men at high risk for cardiorespiratory disease.96

Cessation Benefits of Interventions

Key Question 2. Do tobacco cessation interventions increase tobacco abstinence in adults who currently use tobacco?

Among the general adult population, there was strong evidence from systematic reviews that the combination of pharmacotherapy and behavioral support, all 7 US Food and Drug Administration–approved medications (all forms of NRT, bupropion, varenicline), and a variety of behavioral interventions were statistically significantly associated with an increase in smokers’ relative likelihood to quit smoking at 6 or more months as compared with smokers receiving usual care or a minimal stop-smoking intervention (Table 2).

The pooled risk ratio (RR) for smoking abstinence at 6 months or more for combined pharmacotherapy plus behavioral support vs usual care or minimal support control groups was 1.83 (95% CI, 1.68- 1.98; 52 trials; n = 19,488).11 Average quit rates in these trials ranged from 2% to 50% (mean, 15.2%) among participants receiving pharmacotherapy and behavioral support vs 0% to 36% (mean, 8.6%) among participants randomized to a control group.

There was also evidence of an association between the use of NRTs, bupropion, and varenicline and smoking abstinence at 6 months or more (Table 2). The pooled RR for abstinence for NRT was 1.55 (95% CI, 1.49-1.61; 133 trials; n = 64,640);12 for bupropion, 1.64 (95% CI, 1.52-1.77; 46 trials; n = 17,866);15 and for varenicline, 2.24 (95% CI, 2.06-2.43; 27 trials; n = 12,625)16 when compared with placebo or no drug. In all cases, behavioral support to quit smoking was provided to both intervention and control participants. There was also an association between combined NRT (typically a long- and short-acting therapy) and quitting at 6 months or more (RR, 1.25 [95% CI, 1.15-1.36]; 14 trials; n = 11,356) compared with a single form of NRT.13 Pooled analysis of trials directly comparing NRT and bupropion did not suggest a difference between the 2 types of pharmacotherapy (RR, 0.99 [95% CI, 0.91-1.09]; 10 trials; n = 8230);15 however, varenicline has been shown to be superior to both NRT (RR, 1.25 [95% CI, 1.14-1.37]; 8 trials; n = 6264)16 and bupropion (RR [bupropion vs varenicline], 0.71 [95% CI, 0.64-0.79]; 6 trials; n = 6286)15 in achieving abstinence at 6 months or more, although there are fewer trials testing these differences. There is limited evidence for the use of other antidepressants and nicotine receptor partial agonists for their effectiveness in helping people stop smoking.15,16

Compared with various controls, behavioral interventions such as in-person advice and support from clinicians;26,27 individual-,28 group-,29 telephone-,34 and mobile phone–based38 support; interactive and tailored internet-based interventions;41 and the use of incentives43 were associated with increased relative smoking cessation at 6 or more months (15% to 88% range of relative effects). Pooled results for all comparisons are reported in Table 2. For example, smoking cessation advice from a physician or nurse was associated with pooled RRs of 1.76 (95% CI, 1.58-1.96; 28 trials; n = 22,239)26 and 1.29 (95% CI, 1.21- 1.38; 44 trials; n = 20,881),27 respectively. Behavioral support, when added to pharmacotherapy, was also associated with increased rates of smoking cessation when compared with pharmacotherapy alone (RR, 1.15 [95% CI, 1.08-1.22]; 65 trials; n = 23,331).25 There was a lack of clear benefit of motivational interviewing;30 decision aids;32 real-time video counseling;36 print-based, nontailored self-help materials;33 biomedical risk assessment;45 exercise;46 acupuncture;48 hypnotherapy;49 and systems-level interventions50,51 compared with controls; however, there was substantially less evidence related to each of these interventions, and many individual trials of these interventions showed positive effects.

There was no evidence to suggest that the benefits and harms of pharmacotherapy and behavioral interventions, alone and combined, differed when offered to specific subpopulations of adults, including those with mental health conditions, ethnic minorities, or smokeless tobacco users. Where pooled results were presented, the direction and magnitude of effects were almost identical to those seen with the broader evidence base, although very few direct comparisons between subgroups were presented. While some reviews found evidence of potential effect modification by specific intervention, population, or study design characteristics, there was no individual factor that consistently predicted greater treatment effects across reviews.

Five trials (n = 3117)80,81,90,91,93 were included that evaluated the effectiveness of using e-cigarettes to help current conventional smokers stop or reduce smoking compared with placebo or nicotine replacement therapy. The types of e-cigarettes, nicotine content, delivery of the intervention, and additional intervention components differed across all 5 trials, as did the comparisons. Mixed findings were reported on the effectiveness of e-cigarettes on smoking cessation at 6 to 12 months among adult smokers when compared with placebo devices or NRT. In 2 of the 5 trials (n = 2008), smokers randomized to e-cigarettes containing nicotine (with or without the co-use of NRT) were found to have statistically significantly greater rates of abstinence than those randomized to NRT alone90 or NRT plus nonnicotine e-cigarettes91 at 6- to 12-month follow-up. In both trials, continued use of e-cigarettes was high at 6- and 12-month follow-up (approximately 3-9 months after the treatment phase), with 45% to 80% of participants still using nicotine-based e-cigarettes as opposed to approximately 9% to 40% of participants still using NRT. Another trial (n = 300) compared the use of e-cigarettes (2 groups using different nicotine concentrations) with placebo at 12 months and found 11% abstinence in the nicotine-containing e-cigarette groups compared with 4% abstinence in the placebo group (P = .04), but 27% of those who quit smoking continued to use e-cigarettes at 1 year.81 The remaining 2 trials (n = 807) reported no clear difference in the rates of smoking cessation among those randomized to nicotine e-cigarettes vs placebo e-cigarettes80 or nicotine gum at 6 to 12 months’ follow-up.93

Harms of Interventions

Key Question 3. What harms are associated with tobacco cessation interventions in adults? 

Nine primary reviews reported adverse events related to pharmacotherapy interventions for smoking cessation in general adult populations.12-16,18-20,22 There was no association between the use of NRT, bupropion, or varenicline and serious adverse events, including major cardiovascular adverse events or serious neuropsychiatric events, as compared with placebo or nondrug control groups. Few reviews on behavioral interventions captured information on potential harms, and none suggested serious adverse events that arose. Nine trials reported on the potential short-term harms of e-cigarette use for cessation; none suggested relatively higher rates of serious adverse events.80-84,86,90,91,93

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Based on a primary literature review of 64 full-text articles, 7 RCTs (n = 2285) (reported in 12 publications)98-109 that evaluated the use of NRT among pregnant women were included. Additionally, 5 large observational studies (n = 1,293,379) (reported in 6 publications)110-115 were included that reported on the harms of NRT, bupropion, or varenicline use.

Using the overview of reviews approach, 5 reviews were identified that addressed the benefits and harms of behavioral interventions for supporting women to stop smoking during pregnancy (Table 1).43,53-56 A 2017 Cochrane review included the most comprehensive evidence synthesis of tobacco cessation behavioral support interventions for pregnant women and was used as the basis for the findings presented here.54 The other identified reviews were mostly duplicative and the results were entirely consistent with the Cochrane review.

No studies were identified that addressed the benefits or harms of the use of e-cigarettes to help pregnant women quit smoking.

Health Benefits of Interventions

Key Question 1. Do tobacco cessation interventions improve mortality, morbidity,and other health outcomes in pregnant women who currently use tobacco?

All 7 included RCTs (n = 2285) were designed to test the effectiveness of NRT on smoking cessation and reported infant, child, and maternal health.98,99,102,105-107,109 Five placebo-controlled trials reported on preterm birth (delivery at <37 weeks’ gestation).98,99,105,106,109 The most recent study, conducted in 2017, reported a statistically significant lower incidence of preterm delivery among those in the NRT inhaler group (3/67 [4.5%]) compared with the placebo group (10/67 [14.9%]) (P = .03) after controlling for history of preterm birth.106 Within the other trials, 1 (n = 403) reported similar numbers of women with preterm birth in the NRT and placebo groups (14.0% vs 13.5%, respectively),98 2 (n = 1301) reported only slightly fewer women with preterm birth in the NRT group,99,109 and the study with the fewest patients (n = 194) reported reduced incidence of preterm birth with NRT compared with placebo (RR, 0.39 [95% CI, 0.17-0.91]).105 The 3 placebo-controlled trials that did not report statistically significant differences had larger samples and estimated effects closer to null, with RRs ranging from 0.85 to 1.04.98,99,109 Two trials without placebo controls were imprecise (very wide CIs) and estimated effects in opposite directions.102,107

All 7 trials reported the association between NRT and mean birth weight.98,99,102,105-107,109 Two placebo-controlled trials found significantly higher mean birth weights among women allocated to the NRT group,105,109 and only one of these trials105 reported similar effect for the proportion of infants categorized as having low birth weight. The 2 largest, good-quality, placebo-controlled trials of NRT patch interventions (n = 403 and n = 1051) did not find evidence of increased infant birth weight with NRT treatment.98,99

One hundred two RCTs were included in a 2017 review that addressed the effects of behavioral smoking cessation interventions during pregnancy on smoking behavior and perinatal health outcomes.54 Of the 102 included trials, 19 study groups reported rates of preterm birth (<37 weeks’ gestation), 26 study groups reported mean birth weight, and 17 groups reported rates of low birth- weight infants (<2500 g).54 Other, less commonly reported data included stillbirths (8 trials), perinatal deaths (4 trials), and neonatal deaths (5 trials) (results related to these outcomes are included in the full report).

Of the 19 trials reporting the effects of a behavioral intervention on preterm birth (less than 37 weeks’ gestation), results were mixed, although the majority reported a reduced risk of preterm birth among women within the behavioral interventions vs control groups.54 The review’s meta-analysis of these trials found no significant association with behavioral interventions compared with controls on rates of preterm birth (RR, 0.93 [95% CI 0.77- 1.11]; 19 trials; n = 9222). When all 26 studies that reported mean birth weight were combined, there was evidence that behavioral smoking cessation interventions were associated with a higher mean birth weight (55.60 g, compared with usual care control interventions; mean difference, 55.60 g [95% CI, 29.82-81.38]; 26 trials; n = 11,338).54 A pooled analysis of 18 RCTs also found a 17% risk reduction for delivery of a low-birth-weight infant (<2500 g) (RR, 0.83 [95% CI, 072-0.94]; 18 trials; n = 9402).

Cessation Benefits of Interventions

Key Question 2. Do tobacco cessation interventions increase tobacco abstinence in pregnant women who currently use tobacco?

There was no evidence of differences in rates of smoking cessation among pregnant women randomized to NRT vs placebo or no intervention within the included trials. Meta-analysis of 5 placebo-controlled trials found a pooled RR of 1.11 (95% CI, 0.79- 1.56]; n = 2033) for NRT vs placebo.98,99,105,106,109 Quit rates in these trials ranged from 5% to 28% in the intervention groups and 5% to 25% in the control groups (mean, 11.8% vs 10.6%). The results of the 2 smaller trials with no treatment controls102,107 were not statistically significant, and estimates of efficacy were greater than for the placebo-controlled trials.

Within the Cochrane review on behavioral interventions among pregnant women, of the 120 study groups included in the review, 97 groups reported the primary outcome measure of smoking abstinence in late pregnancy, up to and including the period of hospitalization for birth.54 Pooled analyses of all behavioral interventions, regardless of type of behavioral support and including self-reported outcomes, indicated a statistically significant association with smoking cessation in late pregnancy when compared with usual care or a minimal intervention (RR, 1.35 [95% CI, 1.23-1.48]; 97 trials; n = 26,637). The results were similarly associated with a beneficial effect when restricted to trials comparing counseling with usual care (RR, 1.44 [95% CI, 1.19-1.73]; 30 trials; n = 12,432). There was some evidence that the positive association of behavioral interventions on smoking cessation in late pregnancy continued into the postpartum period, up until approximately 18 months postpartum. For instance, in an examination of counseling interventions compared with usual care, the average RR was 1.59 (95% CI, 1.26-2.01; 11 trials) at 0 to 5 months postpartum, 1.33 (95% CI, 1.00-1.77; 6 trials) at 6 to 11 months postpartum, and 2.20 (95% CI, 1.23-3.96; 2 trials) at 12 to 17 months.54

Harms of Interventions

Key Question 3. What harms are associated with tobacco cessation interventions in pregnant women?

There was no evidence of perinatal harms related to NRT use among pregnant women, but data for assessing rare harms were very limited.98,99,102,105-107,109 Two larger trials reported stillbirths and congenital malformations and reported few events and no differences in the outcome between study groups.98,99 Trials reporting miscarriage98,99,106 and neonatal deaths98,99,105 reported few events and no difference between study groups. One trial provided extended follow-up and did not find differences in longer-term developmental or respiratory harms associated with NRT use during pregnancy.101 Evidence from 5 large cohort studies did not find differences in stillbirth, birth outcomes, or any congenital anomaly for infants born to mothers with exposure to NRT, bupropion, or varenicline vs those unexposed to medications but whose mothers smoked.110-115 Behavioral smoking cessation interventions were found to have minimal adverse effects.54

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This evidence review evaluated interventions for tobacco cessation in adults; the evidence is summarized in Table 3. The results are generally consistent with the conclusions of the 2020 Surgeon General’s report on smoking cessation.2 There is moderate to high-certainty evidence that all 7 US Food and Drug Administration–approved medications for smoking cessation, a variety of behavioral support and counseling approaches, and the combination of pharmacotherapy plus behavioral support—all interventions that may be readily available to primary care patients and clinicians—can significantly increase the rate of smoking cessation among adults at 6 months and longer compared with usual care or brief self-help materials. Treatment effects appear to be comparable in a range of populations, settings, and types of behavioral support. Furthermore, despite adding nearly 5 more years of research since the previous review,5,6 the effect estimates for each pooled comparison have been remarkably stable for at least the past 3 decades.

Nevertheless, various questions about tobacco cessation interventions have not yet been answered. Evidence is still needed to compare different forms, doses, and durations of drugs; to compare drugs with one another; to evaluate remotely delivered interventions vs minimal support; and to test interventions in special populations for which the effectiveness may differ from that in the general population (eg, pregnant women, persons with current severe mental illness, those with physical disabilities, nondaily and intermittent smokers), including direct subgroup comparisons.

Evidence on the potential benefits and harms of pharmacotherapy for smoking cessation during pregnancy is limited, with few placebo-controlled trials and limited power for detecting both potential benefits and harms (Table 3). In contrast to the findings in this review, a recent Cochrane review concluded that there was low-quality evidence suggesting that NRT may be more effective than placebo and nonplacebo controls.117 There was unclear evidence of an association when limited to only placebo-controlled trials,117 however, a finding similar to this review. Careful collection of adverse events information, including long-term consequences of stop-smoking medications, is important in future trials, and data on adherence to medications and levels of nicotine exposure from NRT relative to what occurs with smoking would also be valuable.

In contrast to the robust evidence on pharmacotherapy and behavioral interventions for smoking cessation, evidence on the use of e-cigarettes as an intervention to quit conventional smoking is lacking (Table 3). No studies on the use of e-cigarettes as tobacco cessation interventions reported health outcomes, and few trials reported on the potential adverse events of e-cigarette use when used in attempts to quit smoking. This is particularly concerning given the apparent longer-term use of e-cigarettes for cessation compared to pharmacotherapy in addition to the recent outbreak of e-cigarette, or vaping, product use–associated lung injury.118 Furthermore, there is lack of long-term epidemiologic studies and large clinical trials examining the associations between e-cigarette use and morbidity and mortality, especially in the long term.119

Although this review was scoped to include interventions focused on quitting any tobacco product, most published trials have targeted (and reported) quitting combustible cigarette use. More research is needed on interventions to help people quit other tobacco products such as cigars, smokeless tobacco, and e-cigarettes. Given the high prevalence of dual use of combustible and electronic cigarettes,120 there is a need for research on interventions to help dual users of conventional cigarettes and e-cigarettes quit both products, as well as research on potential relapse back to cigarette use among former smokers who use e-cigarettes.

Limitations

The primary limitation of the evidence report relates to the overview of reviews approach. The comprehensiveness of the overview of reviews is inevitably limited by the recency and quality of the source reviews. Although most of the reviews included evidence at least through 2015, there may be evidence on specific population and intervention subsets that has been published after each review’s last search date. If this occurred, the respective bodies of evidence may not reflect these newer studies. Given the consistency of the effects within each group over time, however, it appears unlikely that any new trials, regardless of their sample size and effect estimates, would have substantial bearing on the overall results of this overview of reviews.

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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.

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Source:This article was published in JAMA on January 19, 2021 (JAMA. 2021;325(3):280-298. doi:10.1001/jama.2020.23541).

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was funded under contract HHSA-290-2015-00007-I-EPC5, Task Order 5, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Information: A draft version of this evidence report underwent external peer review from 6 content experts (Brian King, PhD, MPH [Centers for Disease Control and Prevention], Janet Wright, MD [Office of the Surgeon General], Nicola Lindson, BSc, MSc, CPsychol, PhD [University of Oxford], Stephen Fortmann, MD [Kaiser Permanente Center for Health Research], Nancy Rigotti, MD [Harvard Medical School], and Michele Levine, PhD [University of Pittsburgh]) and 3 federal partners (Centers for Disease Control and Prevention, National Institutes of Health, and US Food and Drug Administration). Comments were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

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Figure is an analytic framework that depicts three Key Questions to be addressed in the systematic review. The figure illustrates how tobacco cessation interventions may result in improved mortality, morbidity, and other health outcomes in adults who currently use tobacco, including pregnant women (Key Question 1), and how tobacco cessation interventions may result in increased tobacco abstinence in adults who currently use tobacco, including pregnant women (Key Question 2). Additionally, the figure addresses how tobacco cessation interventions may be associated with any harms in adults, including pregnant women (Key Question 3).

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. A dashed line indicates a health outcome that immediately follows an intermediate outcome. Additional Information available in the USPSTF Procedure Manual.7

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Source Primary reviewa Qualityb Specific intervention or subgroup Last search date Total No. of included studies KQ1 (health outcomes) KQ2 (cessation) KQ3 (harms)
Benefits of combined pharmacotherapy and behavioral support (1 review)
Stead et al, 11 2016 ? c Combined pharmacotherapy and behavioral support July 2015     ?  
Benefits and harms of pharmacotherapy (13 reviews)
Hartmann-Boyce et al,12 2018 ? High NRT July 2017 136   ? ?
Lindson et al,13 2019 ? High NRT, different doses, durations, and combinations April 2018 63   ? ?
Mills et al,14 2010c ? Moderate NRT (harms only) November 2009 120     ?
Howes et al,15 2020 ? High Bupropion April 2019 115   ? ?
Cahill et al,16 2016 ? Moderate Varenicline May 2015 44   ? ?
Agboola et al,17 2015   Low Varenicline September 2013 19   ?  
Sterling et al,18 2016 ? Low Varenicline (harms only) June 2015 38     ?
Thomas et al,19 2015 ? High Varenicline (harms only) May 2014 44     ?
Chang et al,20 2015 ? Moderate Varenicline + NRT November 2014 3   ? ?
Windle et al,21 2016   Moderate NRT, bupropion, varenicline July 2015 123   ? ?
Mills et al,22 2014c ? Moderate NRT, bupropion, varenicline (harms only) March 2013 63     ?
Rosen et al,23 2018   Low NRT, bupropion, varenicline December 11, July 12, July 13 61   ?  
Hollands et al,24 2019 ? High Support for medication adherence September 2018 10   ? ?
Benefits and harms of behavioral interventions (25 reviews)
Hartmann-Boyce et al,25 2019 ? High Behavioral support as an adjunct to pharmacotherapy June 2018 83   ?  
Stead et al,26 2013c ? High Physician advice January 2013 42 ? ?  
Rice et al,27 2017 ? High Nurse support January 2017 59   ?  
Lancaster and Stead,28 2017 ? High Individual behavioral counseling May 2016 49   ?  
Stead et al,29 2017 ? Moderate Group behavioral therapy May 2016 66   ?  
Lindson et al,30 2019 ? High Motivational interviewing August 2018 37   ?  
Denison et al,31 2017   Moderate Cognitive therapy November 2016 21   ?  
Moyo et al,32 2018 ? Moderate Decision aids July 2017 7   ?  
Livingstone-Banks et al,33 2019 ? Moderate Print-based interventions March 2018 75   ?  
Matkin et al,34 2019 ? Moderate Telephone counseling May 2018 104   ?  
Danielsson et al,35 2014   Low Telephone- or internet-based support May 2013 74   ?  
Tzelepis et al,36 2019 ? High Real-time video counseling August 2019 2   ?  
Palmer et al,37 2018   Moderate Mobile phone–based support January 2016 18   ?  
Whittaker et al,38 2019 ? High Mobile phone text messaging and app-based interventions October 2018 26   ?  
Do et al,39 2018   Moderate Mobile phone– and internet-based interventions March 2017 108   ?  
McCrabb et al,40 2019   Moderate Internet-based interventions September 2017 45   ?  
Taylor et al,41 2017 ? High Internet-based interventions August 2016 77   ? ?
Graham et al,42 2016   Moderate Internet-based interventions April 2015 40   ?  
Notley et al,43 2019 ? Moderate Incentives July 2018 33   ? ?
Giles et al,44 2014     Financial-based incentives April 2012 8   ?  
Clair et al,45 2019 ? Moderate Biomedical risk assessment September 2018 20   ?  
Ussher et al,46 2019 ? High Exercise May 2019 24   ?  
Klinsophon et al,47 2017   High Exercise November 2016 19   ?  
White et al,48 2014c ? High Acupuncture October 2013 38   ?  
Barnes et al,49 2019 ? High Hypnotherapy July 2018 14   ? ?
Boyle et al,50 2014 ? High Electronic health records support July 2014 16   ?  
Thomas et al,51 2017 ? High System change interventions February 2016 7   ?  
Benefits and harms of reduction-to-quit interventions (1 review)
Lindson et al,52 2019c ? High Reduce-to-quit interventions October 2018 51   ? ?
Benefits and harms of relapse prevention interventions (1 review)
Livingstone-Banks et al,53 2019 ? Moderate Relapse prevention February 2018 77   ?  
Benefits and harms of behavioral interventions in pregnant persons (5 reviews)
Chamberlain et al,54 2017 ? High Any behavioral support among pregnant persons November 2015 102 ? ? ?
Griffiths et al,55 2018   Moderate Digital interventions among pregnant persons May 2017 12   ?  
Livingstone-Banks et al,53 2019 ? Moderate Relapse prevention among pregnant persons February 2018 77   ?  
Notley et al,43 2019   High Incentives among pregnant persons July 2018 10   ? ?
Wilson et al,56 2018   Moderate Psychotherapy or incentive-based interventions July 2017 22   ?  
Reviews limited to other subgroups (21 reviews)
Wu et al,57 2015   Moderate Subgroup: adults not motivated to quit
Any tobacco cessation intervention
April 2015 14   ? ?
Appolonio et al,58 2016   High Subgroup: adults with alcohol or drug dependence
Any tobacco cessation intervention
August 2016 34   ?  
Thurgood et al,59 2016   High Subgroup: adults with alcohol or drug dependence
Any tobacco cessation intervention
August 2014 17   ?  
Wilson et al,60 2017   Moderate Subgroup: disadvantaged persons
Any behavioral support
January 2017 24   ?  
Boland et al,61 2018   Low Subgroup: disadvantaged persons
Mobile phone– or internet-based support
May 2016 13   ?  
Liu et al,62 2013c   Low Subgroup: ethnic minorities
Adapted interventions for ethnic minorities
April 2013 28   ?  
Johnston et al,63 2013c   Low Subgroup: ethnic minorities
Any tobacco cessation intervention
May 2012 5   ?  
Carson et al,64 2012c   High Subgroup: ethnic minorities
Any tobacco cessation intervention
April 2011 4   ? ?
Schuit et al,65 2017   High Subgroup: genetic biomarker differences
NRT, bupropion, varenicline
August 2016 18   ?  
Khanna et al,66 2016   High Subgroup: persons with SMI
Advice
April 2015 0   ?  
Tsoi et al,67 2013c   High Subgroup: persons with SMI
Any tobacco cessation intervention
October 2012 34   ?  
van der Meer et al,68 2013c   Moderate Subgroup: persons with SMI
Any tobacco cessation intervention
April 2013 49   ?  
Peckham et al,69 2017   Moderate Subgroup: persons with SMI
Any tobacco cessation intervention
September 2016 26   ? ?
Roberts et al,70 2016   Moderate Subgroup: persons with SMI
NRT, bupropion, varenicline
December 2014 14   ? ?
Ahmed et al,71 2018   Moderate Subgroup: persons with SMI
Varenicline
July 2018 4   ? ?
Kishi and Iwata,72 2015   Moderate Subgroup: persons with SMI
Varenicline (harms only)
August 2014 7     ?
Wu et al,73 2016   High Subgroup: persons with SMI
Varenicline (harms only)
September 2015 8     ?
Smith et al,74 2017   Low Subgroup: sex differences
NRT, bupropion, varenicline
December 2015 28   ?  
McKee et al,75 2016   High Subgroup: sex differences
Varenicline
December 2014 16   ?  
Ebbert et al,76 2015   High Subgroup: smokeless tobacco users
Any tobacco cessation intervention
June 2015 34   ? ?
Schwartz et al,77 2016   Low Subgroup: smokeless tobacco users
Varenicline
February 2014 3   ? ?

Abbreviations: KQ, key question; NRT, nicotine replacement therapy; SMI, severe mental illness.
a Primary reviews are those that represented the most current evidence, most applicable evidence, or both within each population and intervention subgroup and served as the basis for the main findings of this report.
b Review credibility assessed using AMSTAR-2 (Assessment of Multiple Systemic Reviews 2).9
c Included in previous US Preventive Services Task Force review; has not been updated.

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Source Intervention Control No. of RCTs No. analyzed Intervention Control Risk ratio (95% CI) I2, %
Control No. Quit rate,
%c
Control No. Quit rate, %c
Stead et al,11 2016 Combined pharmacotherapy and behavioral support Brief advice or usual care 52 19,488 1529 10,070 15.2 808 9418 8.6 1.83 (1.68-1.98) 36
Hartmann-Boyce et al,12 2018 NRT, any form Placebo or no drug 133 64,640 5574 32,918 16.9 3315 31,722 10.5 1.55 (1.49-1.61) 39
NRT, gum Placebo or no drug 56 22,581 1732 10,596 16.3 1196 11,985 10.0 1.49 (1.40-1.60) 40
NRT, patch Placebo or no drug 51 25,754 2160 13,773 15.7 1131 11,981 9.4 1.64 (1.53-1.75) 24
NRT, inhaler Placebo or no drug 4 976 84 490 17.1 44 486 9.1 1.90 (1.36-2.67) 0
NRT, intranasal spray Placebo or no drug 4 887 107 448 23.9 52 439 11.8 2.02 (1.49-2.73) 0
NRT, tablets Placebo or no drug 8 4439 488 2326 20.9 273 2113 12.9 1.52 (1.32-1.74) 71
NRT, participant's choice Placebo or no drug 7 8288 793 4179 19.0 569 4109 13.8 1.37 (1.25-1.52) 42
Lindson et al,13 2019 NRT combination NRT single form 14 11,356 881 5218 16.9 852 6138 13.9 1.25 (1.15-1.36) 4
Howes et al,15 2020 Bupropion Placebo or no drug 46 17,866 1846 9714 19.0 900 8152 11.0 1.64 (1.52-1.77) 15
Cahill et al,16 2016 Varenicline Placebo 27 12,625 1695 6632 25.6 668 5993 11.1 2.24 (2.06-2.43) 60
Hughes et al,97 2014 Nortriptyline Placebo 6 975 96 480 20.0 49 495 9.9 2.03 (1.48-2.78) 16
Howes et al,15 2020 Bupropion NRT, any form 10 9230 681 3563 19.1 987 4667 21.1 0.99 (0.91-1.09) 18
Howes et al,15 2020 Bupropion Varenicline 6 6286 474 3096 15.3 677 3190 21.2 0.71 (0.64-0.79) 0
Cahill et al,16 2016 Varenicline NRT, any form 8 6264 767 3227 23.8 575 3037 18.9 1.25 (1.14-1.37) 39
Hollands et al,24 2019 Support for medication adherence Usual care 5 3593 412 1816 22.7 361 1777 20.3 1.16 (0.96-1.40) 48
Hartmann-Boyce
et al,25 2019
Behavioral therapy as an adjunct to pharmacotherapy Pharmacotherapy 65 23,331 2291 11,630 19.5 2006 11,701 17.1 1.15 (1.08-1.22) 8
Stead et al,26 2013 Physician advice Usual care 26 22,239 1008 12,583 8.0 462 9656 4.8 1.76 (1.58-1.96) 40
Rice et al,27 2017 Nurse advice Usual care 44 20,881 1607 11,319 14.2 1165 9562 12.2 1.29 (1.21-1.38) 50
Lancaster et al,28 2017 Individual counselling with cessation specialist Minimal contact control 33 13,762 765 6715 11.4 546 7047 7.7 1.48 (1.34-1.64) 46
Stead et al,29 2017 Group behavioral intervention Self-help program 13 4395 249 2388 10.4 116 2007 5.8 1.88 (1.52-2.33) 0
Lindson et al,30 2019b Motivational interviewing + another smoking cessation intervention Smoking cessation intervention alone 12 4167 399 2134 18.7 306 2033 15.1 1.07 (0.85-1.36) 47
Moyo et al,32 2018 Decision aid Usual care without decision aid 7d 1772 NA NA NA NA NA NA NAe NA
Livingstone-Banks et al,33 2019b Print-based, non-tailored self-help materialsf No self-help 32 28,451 983 11,114 8.8 794 13,337 6.0 1.06 (0.95. 1.19) 25
Print-based, non-tailored self-help materials with no face-to-face contact No self-help 11 13,241 416 6723 6.2 331 6518 5.1 1.19 (1.03-1.37) 0
Print-based, non-tailored self-help materialsf No self-help 10 14,359 501 6786 7.4 455 7573 6.1 1.34 (1.19-1.51) 0
Matkin et al,34 2019 Proactive telephone counseling (quitline callers) Control (various) 14 32,484 2123 19,600 10.8 1004 12,884 7.8 1.38 (1.19-1.61) 72
Proactive telephone counseling (not initiated by quitline) Control (various) 65 41,233 2924 21,001 13.9 2229 20,232 11.0 1.25 (1.15-1.35) 52
Whittaker et al,38 2019 Mobile phone-based interventions Usual care of minimal intervention 13 14,133 694 7324 9.5 382 6809 5.6 1.54 (1.19-2.00) 71
Mobile phone-based interventions No intervention 4 997 64 497 12.9 39 500 7.8 1.59 (1.09-2.33) 0
Tzelepis et al,36 2019 Real-time video counselling Telephone counselling 2 608 30 301 10.0 22 307 7.2 2.15 (0.38-12.04) 66
Taylor et al,41 2017 Internet (interactive and tailored) Self-help or usual care 8 6786 516 4020 12.8 356 2766 12.9 1.15 (1.01-1.30) 58
Notley et al,43 2019 Incentives Usual care or non-incentive-based intervention 30 20,060 1336 12,800 10.4 516 7260 7.1 1.49 (1.28-1.73) 33
Clair et al,45 2019 Feedback on smoking exposure Usual care or minimal intervention 5 2368 183 1199 15.3 179 1169 15.3 1.00 (0.83-1.21) 0
Feedback on smoking-related disease risk Usual care or minimal intervention 5 2064 106 1018 10.4 136 1046 13.0 0.80 (0.63-1.01) 0
Feedback on smoking-related harms Usual care or minimal intervention 11 3314 239 1646 14.5 195 1668 11.7 1.26 (0.99-1.61) 34
Ussher et al,46 2019 Exercise No exercise 21 6607 457 3326 13.7 407 3281 12.4 1.08 (0.96-1.22) 0
White et al,48 2014 Acupuncture Sham acupuncture 9 1892 122 997 12.2 97 895 10.8 1.10 (0.86-1.40) 23
Barnes et al,49 2019 Hypnotherapy No intervention or other cessation intervention 14 1926 NA NA NA NA NA NAh   NA
Boyle et al,50 2014 EHR-facilitated interventions No change to EHR 16g NAh NA NA NA NA NA NAi   NA
Thomas et al,51 2017 System change interventions No system changes 7 NAi NA NA NA NA NA NAj   NA
Lindson et al,52 2019c Reduction-to-quit interventions No cessation intervention 6 1599 87 915 9.5 25 684 3.7 1.74 (0.90-3.38) 45
Reduction-to-quit interventions Abrupt quitting
interventions
22 9219 584 4922 11.9 528 4297 12.3 1.01 (0.87-1.17) 29

Abbreviations: EHR, electronic health record; NA, not applicable; NRT, nicotine replacement therapy; RCT, randomized clinical trial; RR, risk ratio.
a Used strictest available criterion to define abstinence (ie, continuous, sustained, or prolonged abstinence was preferred over point prevalence abstinence, and biochemically validated rates were used when available).
b Each review pooled data from the longest follow-up point reported at 6 or more months of follow-up.
c Weighted average quit rates.
d Includes 3 RCTs and 4 quasi-experimental studies.
e No meta-analysis performed. Six studies reported the effects of the intervention on smoking cessation. Only 1 study reported a statistically significant benefit of the use of a decision aid vs usual care on smoking cessation at 6 months.
f Irrespective of level of contact and support common to control group.
g Includes 7 RCTs and 9 nonrandomized observational studies.
h In general, this review found no evidence of a difference in smoking cessation at 6 months’ or greater follow-up among trials that compared hypnotherapy vs no intervention or other smoking cessation interventions. In the group with the most trials, there was no overall difference in smoking cessation rates between groups at 6 months or greater follow-up between hypnotherapy vs attention-matched smoking cessation behavioral intervention (RR, 1.21 [95% CI, 0.91-1.61]; 6 studies; n = 957; I2 = 36%).
i Only 1 RCT (n = 9589) reported effects on smoking cessation, as captured in the EHR, and found that more intervention vs control clinic smokers quit (5.3% vs 1.9%, P < .001). The remaining studies focused on the impact of EHR changes on smoking support actions by clinicians, clinics, and health systems, with most studies reporting improved processes following EHR-facilitated intervention implementation.
j Four trials (n = 7142) reported the effects of the intervention on smoking cessation, finding mixed results. Across all 7 trials, there was mixed evidence on secondary process outcomes such as documentation of smoking status and provision of counseling.

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Intervention No. of included studies and participantsa Summary of findings Consistency and precision Other limitations Strength of evidenceb
KQ1: health outcomes (general adults)
Combined pharmacotherapy and behavioral 0 NA NA NA Insufficient
Pharmacotherapy 0 NA NA NA Insufficient
Behavioral 1 review (1 RCT, n = 1445) One trial found favorable effects on all-cause and coronary disease mortality and lung cancer incidence and mortality 20 y after an intensive behavioral intervention, although results were not statistically significant NA Only 1 review reported the results of 1 intervention in men; within that trial, the rate of smoking among control group participants declined steadily over the follow-up period, narrowing the intervention effect Low evidence of potential benefit
Electronic cigarettes 0 RCTs NA NA NA Insufficient
KQ2: cessation outcomes (general adults)
Combined pharmacotherapy and behavioral 1 review (53 RCTs, n = 25,375) Combined pharmacotherapy and behavioral interventions increased smoking quit rates by 68% to 98% compared with no or minimal treatment (RR, 1.83 [95% CI, 1.68-1.98]) at ≥6 mo follow-up Reasonably consistent; reasonably precise May be risk of bias due to lack of blinding of participants High evidence of benefitc
Pharmacotherapy 5 reviews (336 RCTs, n > 159,000) NRT, bupropion, and varenicline significantly increased the chances of quitting smoking compared with placebo or no medication

Reviews suggested that NRT might increase smoking abstinence at 6 mo or longer by 49% to 61% (RR, 1.55 [95% CI, 1.49-1.61]); bupropion by 49% to 76% (RR, 1.62 [95% CI, 1.49-1.76]); and varenicline by 106% to 143% (RR, 2.24 [95% CI, 2.06-2.43])

Absolute quit differences averaged 6.4% for NRT, 8.2% for bupropion, and 14.5% for varenicline

Using a combination of NRT products increased quitting more than the use of a single NRT product (RR, 1.25 [95% CI, 1.15-1.36])

Direct comparisons between drugs suggested that varenicline may be superior to NRT and bupropion in achieving smoking abstinence at ≥6 moe

Reasonably consistent; reasonably precise Possibility of publication bias but unlikely that the presence of additional studies with lower relative risks would alter the findings, given large number of studies and consistency in findings for each type of drug High evidence of benefitd
Behavioral 20 reviews (830 RCTs, n > 500,000) Clinician advice and counseling, individual counseling, group-based interventions, telephone counseling, mobile phone–based interventions, tailored and interactive internet-based interventions, and incentives showed significant increased smoking cessation at 6 mo or more relative to controls (15%-88%); for example, RR, 1.76 (95% CI, 1.58-1.96) for physician advice vs minimal controls or usual care

Providing more intense adjunctive behavioral support to smokers receiving pharmacotherapy may increase cessation by 8% to 22% (RR, 1.15 [95% CI, 1.08-1.22])

Evidence on the use of motivational interviewing, decision aids, print-based, nontailored self-help materials, real-time video counseling, biomedical risk assessment, exercise, complementary and alternative therapies, and system-level interventions was limited and not definitive in the effects on cessation

Reasonably consistent; reasonably precise Individual trials may be represented in more than 1 review and/or meta-analysis

Indication of possible publication bias for evidence related to motivational interviewing and acupuncture

Fixed-effects models were used in nearly all meta-analyses

Moderate to high evidence of benefitf
Relapse prevention 1 review (77 RCTs, n = 67,285) Analyses of behavioral interventions among abstainers did not detect an effect in studies of both assisted abstainers (RR, 0.99 [95% CI, 0.87-1.13]; I2 = 56%; 10 studies; n = 5408) and unaided abstainers (RR, 1.06 [95% CI, 0.96-1.16]; I2 = 1%; 5 studies; n = 3561) from the general population

There was some evidence that extending varenicline could be beneficial in preventing relapse, but it was only reported by 2 studies NRT was found to help in unassisted abstainers, but no difference was seen among those who achieved abstinence with NRT

None of the 6 studies that examined the use of bupropion to prevent relapse found a statistically significant effect

Inconsistent; imprecise Highly variable study designs and included interventions Moderate evidence of no benefit of behavioral intervention; moderate evidence of benefit of varenicline; low evidence of no benefit of bupropion or NRT
e-Cigarettes 5 RCTs (n = 3117) Two trials (n = 2008) found statistically significantly greater rates of smoking abstinence in those using e-cigarettes containing nicotine (with or without the co-use of NRT) compared with NRT alone or NRT plus nonnicotine e-cigarettes at 6- to 12-mo follow-up, although continued use of e-cigarettes remained high after the treatment phase

Another trial (n = 300) found a borderline statistically significant higher quit rate among persons receiving nicotine-containing e-cigarettes (11%) vs nonnicotine e-cigarettes (4%) at 12 mo (P = .04), but 27% of those who quit smoking continued to use e-cigarettes at 1 y

The remaining 2 trials found no statistically significant difference in biochemically verified abstinence at 6 mo between those receiving e-cigarettes vs nicotine patch or placebo e-cigarettes (n = 807)

Inconsistent; imprecise Limited statistical power to detect differences and differential loss to follow-up in all 5 trials (22%-50%)

Wide variance of nicotine concentrations in e-cigarette interventions (7.8 mg vs 18 mg)

Insufficient
KQ3: harms (general adults)
Combined pharmacotherapy and behavioral 0 reviews NA NA NA Moderate evidence of no harmsg
Pharmacotherapy 15 reviews NRT, bupropion, and varenicline were not associated with an increased risk in major cardiovascular or neuropsychiatric adverse events

NRT was associated with a higher rate of any cardiovascular adverse events, largely driven by low-risk events, typically bradycardia and arrhythmia

There was no evidence of a difference in harms associated with medications for those with vs without severe mental illness

Reasonably consistent; reasonably precise Many trials that report cessation effectiveness do not report adverse events, particularly cardiovascular- or neuropsychiatric-specific adverse events

Adverse events typically measured through passive reporting and therefore susceptible to underreporting

Moderate evidence of no harmsg
Behavioral 3 reviews There was no evidence that behavioral tobacco cessation interventions are associated with serious adverse events NA Very few reviews assessed adverse events related to behavioral interventions Moderate evidence of no harmsg,h
Electronic cigarettes 9 RCTs (n = 3942) No trials reported serious adverse events in either the intervention or the control groups related to product use and no significant differences in the frequency of adverse events among study groups

Coughing, nausea, throat irritation and sleep disruption were the most reported adverse effects of e-cigarette use

Reasonably consistent; imprecise Limited statistical power to detect differences and differential loss to follow-up in all 3 trials (22%-39%)

One study did not report methods for reporting adverse events

Insufficient
KQ1: health outcomes (pregnant persons)
Pharmacotherapy 7 RCTs (n = 2285) Limited evidence of NRT on perinatal and child health benefits

Five placebo-controlled NRT trials reported preterm births with the 3 largest trials reporting effects close to null and 2 reporting reduced risk with NRT

These 5 trials also reported birth weight; the 2 largest placebo-controlled trials reported no difference with NRT, and 2 trials reported higher mean birth weights associated with NRT

The risk for low birth weight was lower in the smallest trial, and results were mixed but null for the others

Follow-up data from the largest NRT trial found higher rate of “survival with no impairment” at 2 y among children of women assigned to NRT intervention vs placebo (73% vs 65%; OR, 1.40 [95% CI 1.05-1.86])

No trials of bupropion or varenicline among pregnant women

Inconsistent; imprecise Rare health outcomes and few trials of NRT limited statistical precision and ability to draw conclusions

Limited information on the women approached for participation that declined, and low participation rates

Timing of the final antenatal assessment varied considerably among trials, which may affect the amount of time women were exposed to the intervention as well as those lost to follow-up and measurement of perinatal outcomes

Insufficient evidence for birth outcomes and child health outcomes
Behavioral 1 review (26 RCTs, n = 12,338) Suggestive benefit of behavioral interventions on mean birth weight (mean difference, 55.60 [95% CI, 29.82-81.38]) and low birth weight (RR, 0.83 [95% CI, 0.72-0.94]), vs usual care or control

Uncertain evidence on the effect of behavioral interventions on preterm birth (RR, 0.93 [95% CI, 0.77-1.11]) and stillbirths (RR, 1.20 [95% CI, 0.76-1.90])

Reasonably consistent; reasonably precise   High evidence of potential benefit on mean birth weight and risk of preterm birth
Electronic cigarettes 0 NA NA NA Insufficient
KQ2: cessation outcomes (pregnant persons)
Pharmacotherapy 7 RCTs (n = 2285) No statistical evidence of NRT efficacy for validated smoking cessation in late pregnancy (RR, 1.11, 95% CI,0.79-1.56) in pooled analysis of 5 placebo-controlled trials

Limited power and all trials in the direction of benefit, including 2 trials with no NRT control conditions

No trials of bupropion or varenicline among pregnant women

Reasonably consistent; imprecise Limited information on the women approached for participation who declined, and low participation rates Low evidence of no benefit
Behavioral 1 review (97 RCTs, n = 26,637) The pooled estimate from 97 trials suggested an increased risk of quitting smoking in late pregnancy for psychosocial interventions compared with controls (RR, 1.35 [95% CI, 1.23-1.48]), with a similar benefit when limited to the most common intervention (counseling) vs usual care (RR, 1.44 [95% CI, 1.19-1.73])

Heterogeneity was moderate for the pooled effect (44%), but there was no definitive evidence of subgroup effects by study, population, or intervention characteristics

Reasonably consistent; reasonably precise Minimal information on the number of women who were eligible for inclusion or approached to take part in the trials

Timing of the final antenatal assessment of smoking status varied considerably among trials, which may affect the amount of time women were exposed to the intervention as well as those lost to follow-up

Moderate evidence of benefit
Relapse prevention 1 review (18 RCTs, n = 5545) No clear benefit on relapse prevention at the end of pregnancy (RR, 1.05 [95% CI, 0.99-1.11]; 8 studies; n = 1523; I2 = 0%) or during the postpartum period (RR, 1.02 [95% CI, 0.94-1.09]; 15 studies; n = 4606; I2 = 3%) Inconsistent; imprecise Variable interventions tested Low evidence of no benefit of behavioral interventions
e-Cigarettes 0 NA NA NA Insufficient
KQ3: harms (pregnant persons)
Pharmacotherapy 7 RCTs (n = 2285); 5 cohort studies (n = 1,293,379) Limited evidence of perinatal harms from NRT; mixed findings on birth outcomes from trials but most in direction of benefit rather than harm (KQ1)

Two-year follow-up from 1 NRT trial did not suggest harms (KQ1)

No trials of bupropion or varenicline among pregnant women

Observational evidence did not indicate harms of major congenital anomalies, stillbirth, premature birth, or low birth weight associated with NRT, bupropion, or varenicline

Inconsistent; imprecise

Few trials of NRT and not all reported consistently on health outcomes and adverse events

Observational studies may not be able to fully account for confounding; substantial differences across a range of population characteristics among comparison groups

Low evidence of no harm
Behavioral 1 review (13 RCTs, n = 5831) There did not appear to be any adverse effects from the psychosocial interventions

Five of 13 trials evaluating psychological effects reported an improvement in women’s psychological well-being, and none reported negative effects

Reasonably consistent; reasonably precise Measures of adverse events rarely reported; most reliant on passive reporting Moderate evidence of no harm
e-Cigarettes 0 NA NA NA Insufficient

Abbreviations: e-cigarette, electronic cigarette; NA, not applicable; NRT, nicotine replacement therapy; OR, odds ratio; RCT, randomized clinical trial; RR, risk ratio.
a Number of included studies reflects the number of systematic reviews designated as primary evidence for that body of evidence as well as the summed total number of included studies and observations from each review.
b For the review-of-reviews method, the strength of the overall body of evidence assigned within the primary systematic review was adopted. In most cases, these grades were based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group definitions, which consider study limitations, consistency of effect, imprecision, indirectness, and publication bias. Where strength of evidence grades were not available, the Evidence-based Practice Center approach was adapted to assign an overall strength of evidence grade based on consensus discussions involving at least 2 reviewers.10
c Some evidence of asymmetry in a funnel plot; excess of small trials detecting larger effects. However, in a sensitivity analysis, removing smaller studies did not markedly decrease the pooled estimate.
d Sensitivity analysis including only those studies judged to have a low risk of bias did not affect the pooled results for any comparison; for NRT and bupropion, the funnel plots showed some evidence of asymmetry. However, given the large number of trials in these reviews, this does not suggest the results would be altered significantly were smaller studies with lower RRs included.
e Evidence from existing systematic reviews as well as the EAGLES trial indicate that adult smokers randomized to varenicline have a statistically significant higher likelihood of quitting smoking at 6 months compared with those randomized to NRT or bupropion. In the EAGLES trial (n = 8144) 21.8% of smokers randomized to varenicline quit smoking at 6 months compared with 15.7% randomized to NRT (odds ratio, 1.52 [95% 1.29-1.78]) and 16.2% randomized to bupropion (odds ratio, 1.45 [95% CI, 1.24-1.70]).116
f Quality of the evidence differs for each specific type of intervention but generally reflects moderate to high certainty grades. Most common reasons for downgraded the quality of evidence were unexplained statistical heterogeneity, several studies with high or unclear risk of bias, or inconsistency in the evidence base.
g Total number of studies and observations not estimated.
h Despite the relatively limited number of reviews that reported harms related to interventions, it appears likely that there are no serious harms related to combined pharmacotherapy and behavioral counseling interventions or behavioral counseling alone for tobacco cessation.

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