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Public Health Consequences of E-Cigarettes (2018)

Chapter: 17 Smoking Cessation Among Adults

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Suggested Citation:"17 Smoking Cessation Among Adults." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"17 Smoking Cessation Among Adults." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"17 Smoking Cessation Among Adults." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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Suggested Citation:"17 Smoking Cessation Among Adults." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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17 Smoking Cessation Among Adults For both individuals and for public health, the central potential ben- efit of e-cigarettes is to promote smoking cessation among established cigarette smokers or at least to reduce smokers’ exposure to combustible tobacco products. Although all tobacco use has health risks, the risk is highest when the user inhales the smoke produced by burning tobacco. Because e-cigarettes do not burn tobacco or generate smoke, the use of e-cigarettes likely confers a lower overall health risk than does smoking combustible tobacco products (see Chapter 18). Established combustible tobacco smokers who completely switch to using e-cigarettes therefore would be expected to reduce their tobacco-related health risks. Additional benefit would be expected if e-cigarette users subsequently stopped using both e-cigarettes and combustible tobacco products. This section addresses the question: Do e-cigarettes help smokers quit smoking combustible tobacco cigarettes? In short, are e-cigarettes effective smoking cessation aids capable of increasing abstinence from combustible tobacco products compared with no treatment, a placebo treatment (usu- ally a non-nicotine–containing e-cigarette), or a Food and Drug Adminis- tration (FDA)-approved smoking cessation aid such as a nicotine replace- ment product, varenicline, or bupropion? A related but broader question is the following: What is the impact of the availability of e-cigarettes on population smoking cessation rates? The population impact of e-cigarettes will be a product not only of their effectiveness in an individual smoker but also of their reach, defined as the proportion of smokers who use them. E-cigarettes’ current status as 541

542 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES easily accessible consumer products may contribute to their appeal. If e-cigarettes have greater appeal to smokers than current FDA cessation aids, they could enhance population cessation rates simply by encourag- ing more current combustible tobacco cigarette smokers to make a quit attempt when they would not otherwise have attempted to quit tobacco. CONCEPTUAL FRAMEWORK: PATTERNS OF E-CIGARETTE USE AMONG ESTABLISHED SMOKERS Ultimately, the potential health benefit of e-cigarette use for cigarette smokers will depend on the characteristics of the smoker, the product (including both the e-cigarette device and e-liquid), and how the device is used. The pattern of e-cigarette use is likely to vary among individual smokers and over time as regular combustible tobacco cigarette smokers experiment with and perhaps transition to e-cigarettes. Figure 17-1 illus- trates a conceptual model of these transitions. The extent of risk reduction will depend on several factors that are defined by the answers to the following questions: 1. Does the smoker switch completely to e-cigarettes (1a in Figure 17-1) or use both combustible tobacco cigarettes and e-cigarettes, a pattern referred to as dual use (1b in Figure 17-1)? The extent of harm reduction should be much greater for a smoker who switches completely to e-cigarettes than for a smoker who uses e-cigarettes to replace FIGURE 17-1  Conceptual framework of smoking cessation and e-cigarette use.

SMOKING CESSATION AMONG ADULTS 543 some, but not all, combustible tobacco cigarettes with e-cigarettes (dual use) because even small exposures to tobacco smoke increase health risks, especially the risk of cardiovascular disease (HHS, 2014). Because the risk of even small exposures to tobacco smoke may not be widely appreciated by the public, dual users may overestimate the degree to which they are reducing their tobacco- related risk and perhaps be less likely to continue efforts to stop combustible tobacco use altogether (Kasza et al., 2017). 2. If the smoker switches completely to e-cigarettes, is the use of e-cigarettes: a.  temporary state leading to abstinence from both combustible A tobacco cigarettes and e-cigarettes? (2a) b.  persistent state, in which exposure to e-cigarettes is sustained A long-term? (2b) c.  temporary state followed by relapse to combustible tobacco prod- A ucts, with or without continued e-cigarette use? (2c) E-cigarettes should have the greatest benefit for the cigarette smoker who switches completely from combustible tobacco cigarettes to e-cigarettes or uses e-cigarettes for a limited time and then quits using both cigarettes and e-cigarettes (2a in Figure 17-1), producing abstinence from both tobacco smoke and nicotine, as well as any other potentially harmful constituents of e-cigarette aerosol. However, a complete switch from combustible tobacco cigarettes to e-cigarettes, with e-cigarette use persisting indefinitely, is still likely to reduce harm (2b). By contrast, a temporary switch to e-cigarettes followed by relapse to combustible tobacco use (2c) is unlikely to confer meaningful long-term reduction in health risk and could add whatever risk is conveyed by e-cigarette use. 3. If the smoker becomes a dual user of cigarettes and e-cigarettes, is e-cigarette use: a.  persistent state of continued exposure to both tobacco smoke and A to e-cigarette constituents? (3a) b.  temporary state en route to exclusive and persistent use of A e-cigarettes? (3b) c.  temporary state followed by relapse to smoking combustible A tobacco products? (3c) d.  temporary state on route to abstinence from all nicotine products? A (3d) If dual use is a transitional state only, the extent of harm will depend on whether the individual returns to smoking only combustible tobacco cigarettes (relapse, 3c in Figure 17-1); transitions completely to e-cigarettes,

544 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES further reducing harm by reducing exposure to tobacco smoke (3b); con- tinues dual use indefinitely (3a); or stops using both combustible tobacco cigarettes and e-cigarettes (3d). The last option, abstinence from tobacco smoke, nicotine, and other constituents of e-cigarette aerosol, is optimal. By contrast, a temporary switch to dual use followed by relapse to com- bustible tobacco use (3c in Figure 17-1) is likely to confer minimal long- term reduction in health risk. Stopping smoking reduces the risk of tobacco-related diseases and extends life expectancy by up to a decade (Jha and Peto, 2014). The risks of cigarette smoking are well described, while the risks of e-cigarette use are just beginning to be assessed and much uncertainty remains. If e-cigarette use helps a smoker to completely quit combustible tobacco use (2a and 3d in Figure 17-1), some degree of e-cigarette risk could still generate a net health benefit, as long as exposure to e-cigarettes is temporary and the benefit exceeds net short-term risk. However, if the final state is persistent e-cigarette use replacing combustible tobacco cigarette use (2b and 3b in Figure 17-1), a lower level of e-cigarette risk would be required to gener- ate an overall net benefit to the individual. Temporary e-cigarette use with return to combustible tobacco use (2c and 3c in Figure 17-1) would likely have no net individual health benefit. Currently, little information is available about the relative frequency at which smokers using e-cigarettes follow each path or about how the risks and benefits of each path compare. For the purposes of this chapter, the committee defines smoking cessation as stopping all combustible tobacco product use. It could be achieved following paths 2a, 2b, 3b, or 3d in Figure 17-1. This definition allows for sustained exposure to nicotine and other constituents in e-cigarettes. A more stringent criterion requiring nicotine abstinence from all sources is represented by paths 2a and 3d in Figure 17-1. EVIDENCE REVIEW: LEVELS OF EVIDENCE AVAILABLE The interpretation of epidemiological evidence must consider both its internal and external validity. Internal validity is a measure of how likely the finding of an association or causal relationship is accurate, which is determined by the degree to which a study minimizes systematic error (bias). Self-selection and confounding are important threats to internal validity. External validity addresses the extent to which a finding can be generalized to another context or to the general population. To assess the efficacy of e-cigarettes for smoking cessation, the ran- domized controlled trial (RCT) provides the strongest study design to protect against threats to internal validity. Ideally, an RCT would enroll cigarette smokers seeking to quit and randomly assign them to switch

SMOKING CESSATION AMONG ADULTS 545 from smoking combustible tobacco cigarettes to either using e-cigarettes or a comparison condition. The comparison condition could be no e-cigarettes (i.e., no treatment); a placebo (non-nicotine e-cigarette); an FDA-approved smoking-cessation pharmacotherapy, such as nicotine replacement, varenicline, or bupropion; or some other evidence-based ­ cessation intervention, such as behavioral counseling. Each comparison condition would answer a slightly different variant of the question about e-cigarettes’ effectiveness. Ideally, the RCT’s primary outcome would be biochemically confirmed abstinence from combustible tobacco prod- ucts 6 to 12 months later. Repeated assessments of adverse events occur- ring during the period of the study would allow for assessment of risks of ­ -cigarette use. As described below, the committee found that few e RCTs have been conducted to address the question about effectiveness of e-cigarettes. Prospective observational (cohort) studies offer less protection from threats to internal validity, but can provide valuable supporting evidence, especially when data from RCTs are limited (as in the current situation) or when randomization is unethical. A cohort study that could address the question could compare smokers who use e-cigarettes in a quit attempt with those who do not and assess the association between exposure to e-cigarettes and abstinence from tobacco products. An optimal prospective observational study design would identify and follow a large cohort of smokers who want to quit or are making a quit attempt, assess e-cigarette exposure in detail before the smoking cessation outcome is assessed, biochemically confirm self-reported tobacco abstinence, and adjust for multiple potential confounding factors associated with e-cigarette use and with smoking cessation. The limitation inherent in this study design is that smokers choose whether or not to use e-cigarettes. Those who do and do not choose to use e-cigarettes may differ in ways that independently influence a smoker’s likelihood of success, confounding the observed association of e-cigarettes to quitting. Statistical methods can adjust for these factors, but unmeasured confounding remains a potential threat and makes it difficult to infer causality to an observed relationship between e-cigarette use and smoking cessation success. Cross-sectional studies compare the prevalence of current or past e-cigarette use between current and former smokers. They provide a lower level of evidence and generally cannot be used to ascertain causality. External validity depends on the representativeness of the study sam- ple to the overall population to which a scientist or policy maker may wish to apply the study’s findings. Studies that recruit or include nation- ally representative samples of smokers allow for broad generalizability of study findings and therefore maximize external validity. However, RCTs, which have the best internal validity, can rarely be conducted using large,

546 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES nationally representative samples of individuals that maximize external validity. There is usually a trade-off of internal and external validity in any study. The committee considered both factors in its review of the evi- dence to address questions about the efficacy of e-cigarettes for smoking cessation. The public health impact of an intervention is a broader question that is a function of both the intervention’s efficacy and its reach (e.g., propor- tion of the at-risk population that uses it). As consumer products already easily accessible to smokers, e-cigarettes therefore have the potential to alter population cessation rates as a function of their efficacy as cessation aids and/or as a consequence of their appeal to smokers. RCTs measure the relative effectiveness of e-cigarettes in specific groups of smokers. However, the impact of e-cigarettes on population-level cessation rates will also depend on the proportion of smokers who use the products (i.e., reach) as well as characteristics of the products and how they are used (e.g., extent of nicotine delivery to the user). Population-level studies therefore provide an important additional type of evidence to evaluate in addressing the overall impact of e-cigarettes in a real-world setting. For studies of populations, prospective cohort and cross-sectional study designs are commonly used, with the former providing stronger internal validity to the latter. EVIDENCE REVIEW: METHODS The committee’s initial scan of the evidence identified individual studies with varying designs and rigor and also identified multiple pub- lished reviews. Most of the latter were systematic reviews that sum- marized the evidence either qualitatively in a narrative format or quan- titatively using meta-analysis. Many of them were very recent, having been published between 2016 and 2017. Given the availability of multiple recent systematic reviews, the committee chose as its principal strategy to conduct a review of the existing reviews. Committee staff conducted a formal literature search to identify evi- dence reviews that were published through August 31, 2017, and that addressed the effectiveness of e-cigarettes for smoking cessation. The search strategy is described in Appendix B. The search identified 21 review articles published between 2014 and 2017 (El Dib et al., 2017; Franck et al., 2014; Hajek et al., 2014; Harrell et al., 2014; Hartmann-Boyce et al., 2016; Heydari et al., 2014, 2017; Ioakeimidis et al., 2016; Kalkhoran and Glantz, 2016; Khoudigian et al., 2016; Knight- West and Bullen, 2016; Lam and West, 2015; MacDonald et al., 2016; Malas et al., 2016; McRobbie et al., 2014; Orr and Asal, 2014; Patnode et al., 2015; Rahman et al., 2014, 2015; Vanderkam et al., 2016; Waghel et al., 2015).

SMOKING CESSATION AMONG ADULTS 547 Table 17-1 summarizes characteristics of the studies that were identified by the literature search. One committee member reviewed the results and excluded four publications. One report (MacDonald et al., 2016) was a protocol for an ongoing review that was not yet completed. A second review was an earlier version of a review from the Cochrane Collabora- tion (McRobbie et al., 2014), whose update is included. Two reviews were excluded because they did not provide specific data on e-cigarettes and cessation; in both cases, the same lead author subsequently published a review of e-cigarettes and cessation that is included in this review (Heydari et al., 2017; Rahman et al., 2015). One committee member reviewed each of the remaining 17 studies to determine whether they met criteria as systematic reviews, using criteria developed for a previous report (NASEM, 2017): 1. Does the article describe a search involving at least two databases? 2. Does the article describe a search involving appropriate search terms? 3. Does the article describe a search involving pre-specified eligibil- ity criteria? 4. Does the article include a risk-of-bias discussion and/or quality assessment? 5. Does the article include a meta-analysis or qualitative synthesis of findings? Of the remaining reviews, 17 met these criteria. Four were published in 2014, four in 2015, seven in 2016, and two in 2017. Six of the reviews conducted a formal meta-analysis, pooling data from at least some of the identified studies (El Dib et al., 2017; Hartmann-Boyce et al., 2016; Kalkhoran and Glantz, 2016; Khoudigian et al., 2016; Rahman et al., 2014; Vanderkam et al., 2016). Two other reviews cited the results of a meta- analysis that had previously been published elsewhere (Ioakeimidis et al., 2016; Knight-West and Bullen, 2016). All assessed a smoking cessation endpoint and some of them also assessed other endpoints such as smok- ing reduction (see Chapter 18 on Harm Reduction). The scan of the studies that were not included in the systematic reviews and were published through August 31, 2017, identified several population studies, whose results are described below. No new RCTs were identified. Additional observational and cohort studies were identified, but their results were generally consistent with studies in the systematic reviews.

548 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-1  Systematic Reviews of E-Cigarettes and Smoking Cessation Identified by Literature Search Systematic Search Studies Reference Review Meta-Analysis Through Included El Dib et al., Yes Yes 12/29/2015 12 (3 RCT, 2017 (updated until 9 cohort) 5/2016) Franck et al., Yes No 9/15/2013 7 2014 Hajek et al., Yes No 2/2014 Not specified 2014 Harrell et al., Yes No 11/2013 15 2014 Hartmann- Yes Yes 1/2016 24 (3 RCT, 21 Boyce et al., cohort) 2016

SMOKING CESSATION AMONG ADULTS 549 Explicit Quality Conclusion Regarding Assessment? E-Cigarettes and Cessation Comments Yes “There is very limited evidence regarding the impact of e-cigarettes on tobacco smoking cessation, reduction or adverse effects: data from RCTs are of low certainty and observational studies of very low certainty…. This review underlines the need to conduct well-designed trials measuring biochemically validated outcomes and adverse effects” (El Dib et al., 2017, p. 1). Yes “Given the limited available evidence on the risks and benefits of e-cigarette use, large, randomized, controlled trials are urgently needed to definitively establish their potential for smoking cessation” (Franck et al., 2014, p. 1945). No None Broad general review No “Data on the use of e-cigarettes for quitting smoking are suggestive but ultimately inconclusive” (Harrell et al., 2014, p. 381). Yes “There is evidence from two Update of 2014 Cochrane review trials that e-cigarettes help (see McRobbie et al., 2014) smokers to stop smoking in the long term compared with placebo e-cigarettes. However, the small number of trials, low event rates, and wide confidence intervals around the estimates mean that our confidence in the result is rated low” (Hartmann-Boyce et al., 2016, p. 2). continued

550 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-1 Continued Systematic Search Studies Reference Review Meta-Analysis Through Included Heydari et al., Yes No 9/2014 69 2017 Ioakeimidis et Yes Yes (report 6/2015 2 RCT al., 2016 result of other meta-analyses) Kalkhoran and Yes Yes 6/17/2015 20 (1 RCT, Glantz, 2016 1 NRCT, 15 cohort, 3 cross- sectional) Khoudigian et Yes Yes 5/2014 5 al., 2016

SMOKING CESSATION AMONG ADULTS 551 Explicit Quality Conclusion Regarding Assessment? E-Cigarettes and Cessation Comments No “Enough evidence to suggest Non-standard methods to that e-cigarettes are effective synthesize results for quitting smoking is lacking, as is the evidence for the lack of their harm for respiratory system and thus being alternatives for smoking. However, further studies are needed” (Heydari et al., 2017, p. 27). Yes “Further research is needed to examine the longer term safety, potential for long-term use and efficacy as a cessation aid” (Ioakeimidis et al., 2016, p. 5). Yes “As currently being used, e-cigarettes are associated with significantly less quitting among smokers” (Kalkhoran and Glantz, 2016, p. 2). Yes “Limited low-quality evidence of a non-statistically significant trend toward smoking cessation in adults using nicotine e-cigarettes exists compared with other therapies or placebo. Larger, high-quality studies are needed to inform policy decisions” (Khoudigian et al., 2016, p. 257). continued

552 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-1 Continued Systematic Search Studies Reference Review Meta-Analysis Through Included Knight-West Yes Yes (report 9/2015 11 (3 RCT, 8 and Bullen, result of other cohort) 2016 meta-analyses) Lam and West, Yes No 2/2015 4 2015 Malas et al., Yes No 2/1/2016 62 2016

SMOKING CESSATION AMONG ADULTS 553 Explicit Quality Conclusion Regarding Assessment? E-Cigarettes and Cessation Comments No “Collectively, these studies suggest modest cessation efficacy … at least with the short-term use. More research, specifically well- conducted large efficacy trials comparing e-cigarettes with standard smoking cessation management (e.g., nicotine replacement therapy plus behavioral support) and long-term prospective studies for adverse events, is urgently needed to fill critical knowledge gaps on these products” (Knight-West and Bullen, 2016, p. 111). Yes “Based on the current Limited to RCTs of e-cigarettes available literature, and cessation e-cigarettes may constitute an effective smoking cessation tool” (Lam and West, 2015, p. 98). Yes “While inconclusive due to low quality, overall the existing literature suggests e-cigarettes may be helpful for some smokers for quitting or reducing smoking. However, more carefully designed and scientifically sound studies are urgently needed to establish unequivocally the long-term cessation effects of e-cigarettes” (Malas et al., 2016, p. 1926). continued

554 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-1 Continued Systematic Search Studies Reference Review Meta-Analysis Through Included Orr and Asal, Yes No 3/2014 6 2014 Patnode et al., Yes (of reviews, No (for 3/1/2015 2 2015 not original e-cigarettes) studies) Rahman et al., Yes Yes 5/2014 6 (2 RCT, 2015 2 cohort, 2 cross-sectional) Vanderkam et Yes Yes 6/14/2015 13 (2 RCT, 2 al., 2016 NRCT, 9 cohort)

SMOKING CESSATION AMONG ADULTS 555 Explicit Quality Conclusion Regarding Assessment? E-Cigarettes and Cessation Comments No “There is limited evidence for the effectiveness of e-cigarettes in smoking cessation…. Additional well- designed, long-term cessation studies are warranted, especially in comparison to current FDA-approved products” (Orr and Asal, 2014, pp. 1502, 1505). Yes “Only two trials addressed Review of reviews only. Done for the efficacy and harms related the update of the U.S. Preventive to the use of electronic Services Task Force review of cigarettes and these trials smoking cessation therapies suggested no benefit on smoking cessation among smokers intending to quit” (Patnode et al., 2015, p. v). Yes “Use of e-cigarettes is Update of Rahman et al., 2014, associated with smoking a narrative review of multiple cessation and reduction. endpoints, not just tobacco More randomized controlled cessation trials are needed to assess effectiveness against other cessation methods” (Rahman et al., 2015, p. 2). Yes “The use of electronic Text in French. Primary outcome cigarettes with nicotine was smoking reduction, but decreases tobacco cessation was a secondary consumption among regular outcome smokers. Further studies are needed to specify electronic cigarettes’ safety profile and its ability to cause a reduction in consumption and long- term cessation in smokers” (Vanderkam et al., 2016, p. 972). continued

556 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-1 Continued Systematic Search Studies Reference Review Meta-Analysis Through Included Waghel et al., Yes No 5/2014 7 2015 Excluded Reviews Heydari et al., Yes, but not No n/a n/a 2014 specific to e-cigarettes MacDonald et Yes Not at present Ongoing 13 (in initial al., 2016 time scoping of the literature in April 2014; ongoing at the time of publication) McRobbie et Yes Yes 7/2014 13 (2 RCT, al., 2014 11 cohort)

SMOKING CESSATION AMONG ADULTS 557 Explicit Quality Conclusion Regarding Assessment? E-Cigarettes and Cessation Comments No “The limited evidence available supports that e-cigarettes may be effective as monotherapy for smoking cessation and reduction. However, superiority to nicotine replacement therapy was not proven” (Waghel et al., 2015, p. 8). n/a n/a Systematic review of all cessation methods, little focus on e-cigarettes Yes Ongoing project; no Protocol paper for an ongoing conclusions yet meta-narrative review yes “There is evidence from two Updated as Hartmann-Boyce et trials that e-cigarettes help al., 2016 smokers to stop smoking long-term compared with placebo e-cigarettes. However, the small number of trials, low event rates and wide confidence intervals around the estimates mean that our confidence in the result is rated ‘low’ by GRADE standards. The lack of difference between the effect of e-cigarettes compared with nicotine patches found in one trial is uncertain for similar reasons” (McRobbie et al., 2014, p. 2). continued

558 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-1 Continued Systematic Search Studies Reference Review Meta-Analysis Through Included Rahman et al., Yes No 1/2014 5 (for cessation 2014 endpoint) NOTE: FDA = Food and Drug Administration; NRCT = non-randomized controlled trial; RCT = randomized controlled trial. EVIDENCE REVIEW: RESULTS Systematic Reviews Overall, the reviews report on a small and overlapping evidence base. They consistently identified the same three RCTs whose characteristics and results are summarized in Table 17-2. The reviews also identified a few non-randomized interventional trials and a larger number of prospec- tive observational trials and cross-sectional analyses. The reviews varied in the criteria used to include or exclude studies other than RCTs, with the result that the reviews summarized non-identical groups of observa- tional cohort or cross-sectional studies. The committee reviewed in detail the most recent systematic reviews, defined as those published in 2016 or 2017, reasoning that these would be the most complete, and focused on those that conducted an independent formal meta-analysis. A total of five reviews met both criteria (El Dib et al., 2017; Hartmann-Boyce et al., 2016; Kalkhoran and Glantz, 2016; Khoudigian et al., 2016; Vanderkam et al., 2016). In addition, the committee examined in detail a 2016 systematic review that attempted a meta-analysis (Malas et al., 2016), but judged the studies to be too heterogeneous for this to be appropriate. From this group, the committee identified two systematic reviews as those that provided the most comprehensive, most rigorous, and most recent summary of the available data (El Dib et al., 2017; Hartmann-Boyce et al., 2016). These two reviews were conducted independently by differ- ent groups of authors. Table 17-3 summarizes the two reviews’ methods, results, and conclusions and illustrates that the two reviews shared many similarities. Both were systematic reviews with meta-analysis. The search strategy for each began with the results of the search done for the 2014 Cochrane Collaboration review (McRobbie et al., 2014) and updated it,

SMOKING CESSATION AMONG ADULTS 559 Explicit Quality Conclusion Regarding Assessment? E-Cigarettes and Cessation Comments No “E-cigarettes may have Narrative review that aims to some potential as smoking cover multiple topics, not just cessation aids and, in the cessation. Excluded because researchers’ view, should authors published an updated therefore be subject to further review focused on cessation research and regulation (Rahman et al., 2015) similar to other nicotine replacement therapies” (Rahman et al., 2014, p. 1). adding studies that were published through December 2015 (El Dib et al., 2017) or January 2016 (Hartmann-Boyce et al., 2016). Both used comparable methods that are described in the Cochrane Handbook to screen studies, extract data, assess risk of bias, and assess the certainty of the overall body of evidence. Both included RCTs and prospective cohort ­tudies s that enrolled current combustible tobacco cigarette ­mokers regardless s of intention to quit. They compared nicotine-containing e-cigarettes with non-nicotine e-cigarettes, other smoking cessation aids, or no aid. Both excluded cross-sectional studies. The primary measure of treatment effect was tobacco smoking cessation at the longest follow-up available (a mini- mum of 6 months) using biochemically validated cessation where avail- able. There was general agreement about the results of the meta-analysis of RCTs and about the overall quality of the evidence. However, there were some differences between the methods used. The two reviews dif- fered in their handling of missing outcome data in the statistical test used in the meta-analysis (fixed-effect or random-effect Mantel-Haenszel [MH] test), and the synthesis method used for non-randomized cohort studies (narrative review versus meta-analysis). They obtained similar results, but differed slightly in their interpretation of these results. El Dib and colleagues (2017) conducted a systematic review and meta-analysis of the effect of e-cigarettes on tobacco use among cigarette smokers that was commissioned by the World Health Organization. The review compared nicotine-containing devices to non-nicotine e-cigarettes, no smoking cessation aid, or alternative smoking cessation aids. RCTs and prospective observational studies published up to December 2015 were screened independently by two independent reviewers who also extracted data and assessed studies’ risk of bias. The review identified three eligible randomized trials with a total of 1,007 participants. Results

560 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-2  Characteristics of Three Randomized Controlled Trials Testing the Efficacy of E-Cigarettes for Smoking Cessation Duration No. of Plan to of Reference Country Subjects Quit? Study Arms Treatment Bullen et al., New 657 Yes (1) INT:1st-generation 12 weeks 2013 Zealand e-cigarette (ASCEND) (Elusion) (16 mg nicotine); (2) CTL: Placebo e-cigarette; (3) Active comparator: Nicotine patch (21 mg). Caponnetto et Italy 300 No (1) INT: 1st-generation 12 weeks al., 2013 e-cigarette (Categoria) (ECLAT) (7.2 mg nicotine); (2) INT: Same e-cigarette (7.2 mg × 6 weeks, 5.2 mg × 6 weeks); (3) CTL: Placebo e-cigarette. Adriaens et al., Belgium 50 No (1) INT: 2nd generation 8 weeks 2014 (Joyetech, 18 mg/ml nicotine); (2) INT: 2nd generation (Kanger T2, 18 mg/ml nicotine); (3) CTL: Delayed e-cigarette (offered weeks 8–16). a El Dib et al., 2017. b Hartmann-Boyce et al., 2016. NOTE: ASCEND = A Study of Cessation Using Electronic Nicotine Devices; CO = carbon monoxide; CTL = control; ECLAT = EffiCiency and Safety of an eLectronic CigAreTte; INT = intervention; RR = relative risk.

SMOKING CESSATION AMONG ADULTS 561 Outcome Assessment Data Pooled Behavioral Abstinence for Meta- Support Follow-Up Measure Rate Difference Analysis?a,b Offered 6 months CO-validated (1) INT = 1 versus 2: Yes phone or continuous 7.3%; 7.3% versus text (few abstinence (2) CTL = 4.1%, used). 4.1%; RR = 1.77, No (3) CTL = 95% CI = training 5.8%. 0.54–5.77 in use of n = 362. e-cigarette. 1 versus 3: 7.3% versus 5.8%, RR = 1.26, 95% CI = 0.68–2.34, n = 584. No quit 12 months CO-validated (1) INT = Pooling INT Yes assistance continuous 13%; 1 + 2, versus or training 6–12 months (2) INT = CTL: 11% in use of 9%; versus 4%, e-cigarette. (3) PCB = RR = 2.75, 4%. 95% CI = 0.97–7.76, n = 300. (1) and (2) 2 months CO-validated At 2 No Training in abstinence months: INT e-cigarette (no definition) (1+2) = 34%; use; (3) No CTL = 0%. e-cigarette training.

562 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-3  Selected Systematic Reviews: Part 1 Hartmann-Boyce et al., 2016 El Dib et al., 2017 Characteristic (Cochrane Collaboration) (WHO commissioned) Study designs included RCTs and prospective RCTs and prospective cohort studies cohort studies Participants Current smokers Current cigarette smokers Motivated or Motivated or unmotivated unmotivated to quit to quit Interventions E-cigarettes E-cigarettes (with or without nicotine) Comparison conditions Placebo e-cigarettes, Placebo e-cigarettes, other other smoking cessation smoking cessation aid, or no aid, or no cessation aid cessation aid Search strategy: Updated results of Included results of 2014 databases used 2014 Cochrane review Cochrane review, searched using Cochrane Tobacco MEDLINE, CINHAL, Addiction Group EMBASE, CENTRAL, Specialized Register, PsycINFO, Web of Science, Cochrane Central ClinicalTrials.gov, PubMed Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO Search strategy: terms e-cig$ OR elect$ cigar$ MeSH subject headings: used OR electronic nicotine electronic nicotine, OR vape OR vaper OR smoking-cessation, tobacco- vapers OR vaping use-disorder, tobacco- smoking, quit Literature search ended January 2016 December 29, 2015 (updated until submission, May 2016) Study selection and data Independently by two Independently by three extraction authors pairs of two authors Risk of bias assessment Cochrane Handbook for Modified version of Systematic Reviews of Cochrane Handbook for Interventionsa Systematic Reviews of Interventionsb (RCTs); Ottawa-Newcastle instrument (cohort studies)c Certainty of evidence GRADE methodology GRADE methodologyd assessment Outcome measures Cessation at longest Tobacco smoking cessation follow-up point (6-month at longest follow-up minimum), prefer (6-month minimum), prefer biochemically validated biochemically validated outcome measure measure; or 50 percent or more reduction in cigarette use

SMOKING CESSATION AMONG ADULTS 563 TABLE 17-3  Continued Hartmann-Boyce et al., 2016 El Dib et al., 2017 Characteristic (Cochrane Collaboration) (WHO commissioned) Measure of treatment ITT analysis, calculate ITT analysis, calculate risk effect risk ratio at the longest ratio at longest follow-up follow-up Missing data Missing outcome = Complete case analysis smoker (excluded missing data); “worst case” sensitivity analysis done RCTs Identified meeting 3 (1,007 participants) 3 (1,007 participants) criteria Pooled for meta-analysis 2 (n = 662 subjects) 2 (n = 481 subjects) Calculation of effect size Fixed-effect Mantel- Random-effect Mantel- Haenszel model Haenszel model Result (smoking cessation): RR = 2.29, 95% RR = 2.03, 95% E-cigarette versus CI = 1.05–4.96; CI = 0.94–4.38; placebo e-cigarette RR = 1.26, 95% RR = 1.10, 95% E-cigarette versus CI = 0.68–2.34; CI = 0.60–2.03 nicotine patch (1 study, no pooling) (1 study, no pooling) Result (50% reduction or Not done RR = 0.97, 95% more) CI = 0.57–1.66 Risk of bias in included Low Low studies Overall quality of Low certainty (small Low certainty evidence (GRADE) number of studies) Prospective Cohort Studies Identified meeting 21 9 (13,115 participants) criteria Pooled for meta-analysis 0 8 Data synthesis method Narrative review only Random-effect Mantel- Haenszel model Result (e-cigarette versus Pooled analysis not done OR = 0.74, 95% no e-cigarette) CI = 0.55–1.001, p = 0.051 Risk of bias in studies High (selection bias) High (missing data, imprecision in outcomes and prognostic factors) Overall quality of Low certainty Very low certainty evidence continued

564 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-3 Continued Hartmann-Boyce et al., 2016 El Dib et al., 2017 Characteristic (Cochrane Collaboration) (WHO commissioned) Conclusions “There is evidence “Results from 2 RCTs from two trials that suggest a possible increase e-cigarettes help smokers in smoking cessation with to stop smoking in the ENDS in comparison with long term compared ENNDS....”f with placebo e-cigarettes. “There is very limited However, the small evidence regarding the number of trials, low impact of ENDS or ENNDS event rates and wide on tobacco smoking confidence intervals cessation, reduction or around the estimates adverse effects: data from mean that our confidence RCTs are of low certainty in the result is rated low and observational studies of by GRADE standards. very low certainty … from The lack of difference which no credible inferences between the effect of can be drawn…. This review e-cigarettes compared underlines the need to with nicotine patches conduct well-designed trials found in one trial is measuring biochemically uncertain for similar validated outcomes and reasons.”e adverse effects.”g a Higgins et al., 2011. b El Dib et al., 2017. The authors (El Dib et al., 2017) cite the following reference, which has been modified: Guyatt, G. H., and J. W. Busse. n.d. Modification of Cochrane tool to assess risk of bias in randomized controlled trials. https://www.evidencepartners.com/resources/ methodological-resources (accessed September 20, 2017). c El Dib et al., 2017. The authors (El Dib et al., 2017) cite the following reference, which has been modified: Guyatt, G. H., and J. W. Busse. n.d. Modification of Ottawa-Newcastle to assess risk of bias in nonrandomized trials. https://www.evidencepartners.com/resources/ methodological-resources (accessed September 20, 2017). d Guyatt et al., 2011a–e. e Hartmann-Boyce et al., 2016, p. 2. f El Dib et al., 2017, p. 12. g El Dib et al., 2017, p. 1. NOTE: GRADE = Grading of Recommendations Assessment, Development, and Evaluation; ITT = intent-to-treat; OR = odds ratio; RCT = randomized controlled trial; RR = relative risk; WHO = World Health Organization.

SMOKING CESSATION AMONG ADULTS 565 from two of the three RCTs were appropriate for pooled analysis (Bullen et al., 2013; Caponnetto et al., 2013). The third was excluded because the effect of e-cigarettes versus no e-cigarettes could be compared for only 8 weeks (Adriaens et al., 2014). The treatment effect was calculated using the random-effect MH test and using complete case analysis (excluding cases with missing outcome data), producing a total sample of 481 partici- pants. The result was a non-significant increase in smoking cessation with nicotine-containing e-cigarettes compared with non-nicotine e-cigarettes (RR = 2.03; 95% CI = 0.94–4.38; p = 0.07; quit rate = 11.7 percent nicotine, 6.3 percent non-nicotine; risk difference = 64/1,000 over 6 to 12 months). Combining the data on reduction in cigarettes per day, the two RCTs found no difference between the e-cigarette group and the non-nicotine e-cigarette group (RR = 0.97; 95% CI = 0.57–1.66; p = 0.92). The individual studies were judged to have low risk of bias, but the overall body of evi- dence was rated as low certainty due to the small number of trials and the extent of missing data. The review also identified nine eligible cohort studies with a total of 13,115 participants. In contrast to the RCTs, combining the results from cohort studies produced a nearly significant reduction in quit rates with use of e-cigarettes compared with no use of e-cigarettes (OR = 0.74; 95% CI = 0.55–1.001; p = 0.051). Limitations of the cohort studies noted by the authors included the fact that not all participants were using e-cigarettes to quit. Additionally, missing outcome data and an imprecise assessment of prognostic factors and outcomes were judged to have produced a risk of bias. Consequently, the evidence provided by the cohort studies was judged to be very low certainty “from which no credible inferences can be drawn” (El Dib et al., 2017, p. 1). Because of the low-quality evidence, the review made no conclusion about the effectiveness of e-cigarettes as cessation aids. Instead, it identified the need for well-designed RCTs mea- suring biochemically validated outcomes to answer the question. In 2016, Hartmann-Boyce and colleagues updated the Cochrane Tobacco Addiction Group’s 2014 systematic review and meta-analysis of the effectiveness of e-cigarettes for smoking cessation (Hartmann-Boyce et al., 2016; ­ cRobbie M et al., 2014). The authors identified RCTs in which current smokers (moti- vated or unmotivated to quit) were randomly assigned to e-cigarettes or to a control condition and followed for 6 months or longer. They also included prospective observational studies with at least 6-month follow- up. To assess treatment effect, authors used the most rigorous definition of tobacco abstinence available, ideally, biochemically validated abstinence. In contrast to the El Dib and colleagues (2017) review, the Hartmann-Boyce (2016) review included participants with missing outcome data as con- tinued smokers for the pooled analysis. Standard Cochrane methods for screening studies and extracting data were used. Risk ratios and 95% CIs

566 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES were calculated using a fixed-effect MH model for each study, and pooled where appropriate. The review identified 24 completed studies (3 RCTs and 21 cohort studies) and 27 ongoing studies. It specifically excluded cross-sectional studies that collected data at only one time point due to the potential for confounding and recall bias. The same two RCTs that were judged appropriate for pooling by the El Dib and colleagues (2017) analysis were also pooled in the Hartmann- Boyce and colleagues (2016) analysis. Both studies compared nicotine- containing e-cigarettes with non-nicotine e-cigarettes. However, because Hartmann-Boyce included participants with missing data as smokers (rather than excluding them, as El Dib did), its pooled analysis had a larger combined sample size of 662 participants. In the meta-analysis of the two studies, e-cigarettes produced a higher smoking abstinence rate compared with non-nicotine–containing e-cigarettes and one that achieved statistical significance (RR = 2.29; 95% CI = 1.05–4.96; e-cigarette 9 percent versus placebo 4 percent). The one study that compared an e-cigarette to nicotine patch found no significant difference in 6-month abstinence rates (RR = 1.26; 95% CI = 0.68–2.34; 584 participants). Indi- vidual RCTs were assessed to be at low risk of bias but the overall quality of the evidence was rated as “low” or “very low” because of imprecision due to the small number of trials. The authors concluded that evidence from two trials indicated that “ECs help smokers to stop smoking in the long term compared with placebo ECs” (Hartmann-Boyce et al., 2016, p. 2), although they also acknowledged that their confidence in the result was low by GRADE standards. Only one trial compared e-cigarettes to a proven smoking cessation aid, nicotine patches. The authors interpreted the lack of difference between the effects of e-cigarettes and nicotine patches for cessation in that trial as inconclusive. The Hartmann-Boyce review also described the non-randomized pro- spective observational studies it had identified, separating them into two categories, intervention versus non-intervention. Studies in which e-cigarettes were given to participant smokers as part of the study proto- col were categorized as non-randomized intervention studies. Studies that simply recorded smokers’ use of e-cigarettes at baseline and follow-up were termed “non-intervention studies.” The review did not attempt to pool data from any of the non-randomized observational studies because, it stated, “these studies are heavily confounded due to the nature of their design” (Hartmann-Boyce et al., 2016, p. 8). Specifically, the authors noted that smokers who have already succeeded in quitting with e-cigarettes would not be eligible for non-randomized observational studies, which recruit only current smokers. They argued that enrolling only “e-cigarette treatment failures” into an e-cigarette intervention study would bias the result toward a null finding.

SMOKING CESSATION AMONG ADULTS 567 Summary of These Two Systematic Reviews The two systematic reviews identified a similar group of studies and generally came to similar conclusions, specifically that the body of avail- able evidence was small and that a critical need existed for additional evidence to provide definitive answers to the questions posed. However, the reviews differed slightly in their interpretation. The Cochrane review found a statistically significant effect of nicotine e-cigarettes compared with non-nicotine e-cigarettes and interpreted this as demonstrating a positive effect of e-cigarettes on quitting, albeit with low confidence that the estimate would not change when more evidence became available. It judged that the risk of confounding from observational data was so high that it did not pool those data. Using the same two RCTs, the El Dib review produced a similar but not quite significant effect of e-cigarettes versus non-nicotine e-cigarettes. El Dib and colleagues (2017) judged the low confidence in the evidence base and the opposite result of the cohort studies to be sufficient to preclude any conclusion about effectiveness of e-cigarettes at this time. Other Systematic Reviews Table 17-4 describes four of the five other systematic reviews that were published during 2016–2017 (Kalkhoran and Glantz, 2016; Khoudigian et al., 2016; Malas et al., 2016; Vanderkam et al., 2016). A fifth systematic review from this period is not discussed because it was of lower quality and used non-standard methods to summarize the search results (Heydari et al., 2017). In addition, Table 17-4 includes one earlier systematic review that included an independent meta-analysis (Rahman et al., 2015). Khoudigian and colleagues (2016) conducted a systematic review and meta-analysis of RCTs and observational studies that were published through May 2014 and compared e-cigarettes with other non-­ andomized r trials or placebo e-cigarettes. It included smokers regardless of their inten- tion to quit smoking. The outcome of interest for this analysis was smok- ing abstinence for at least 6 months after the start of e-cigarette use. The literature search and data extraction were well conducted. The review identified five eligible studies, but only two of these had cessation out- comes. These were the same two RCTs that are included and pooled in the reviews described above (El Dib et al., 2017; Hartmann-Boyce et al., 2016). Pooling of these two studies produced a non-significant RR of 2.02 (95% CI = 0.97–4.21). Despite this, the authors observed that their results “suggest that the use of nicotine e-cigarettes increased the pro- portion of patients who stopped smoking, although this change was not statistically significant” (Khoudigian et al., 2016, p. 265). Overall, they concluded, “limited low-quality evidence of a non-statistically significant

568 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-4  Selected Systematic Reviews: Part 2 Characteristic Khoudigian et al., 2016 Malas et al., 2016 Study designs included RCT and prospective RCTs, prospective cohort, cohort studies experimental, and cross- sectional Participants Current smokers Current smokers Motivated or Motivated or unmotivated unmotivated to quit to quit Interventions E-cigarettes (with E-cigarettes (with nicotine) nicotine) Comparison conditions Placebo e-cigarettes or Not specified NRT Search strategy: MEDLINE, Embase, PubMed, MEDLINE, databases used PsycINFO, Cochrane PsycINFO, CINAHL, Central Registry of ERIC, ROVER, Scopus, ISI Controlled Trials; also Web of Science, Cochrane found gray literature Library, Ontario Tobacco through searching Research Unit library websites of health catalogue; gray literature technology assessment identified using Grey and related agencies, in Matters, OAIster, OpenGrey, addition to reports of NYAM website, Legacy major smoking cessation Library, BIOSIS Previews, conference proceedings; Conference Papers Index, also used Google ISI Proceedings, Dissertation for more Web-based Abstracts International, materials CIHI, GreyNet International Search strategy: terms Searched controlled Electronic nicotine delivery used vocabularies (MeSH system, ENDS, electronic and EMTREE) and cigarette, e-cigarette, e-cig, keywords on concept of e-juice, e-liquid, e-hookah, “electronic cigarette” or cartomizer, alternative “e-nicotine”: tobacco product, tobacco use cessation product, 1.  electr*adj (cigar* or ( smoking cessation aid, vape, nicotine*)).mp vaping, vaporizer, vape-pen 2.  e-cig* or ecig* ( or e-cigarette* or ecigarette*).mp 3.  e-nicotine* or ( enicotine*).mp 4. or/1-3 Literature search ended May 2014 February 1, 2016

SMOKING CESSATION AMONG ADULTS 569 Kalkhoran et al., 2016 Vanderkam et al., 2016 Rahman et al., 2015 RCTs, prospective cohort, Interventional trials RCTs, prospective cohort, and cross-sectional (RCTs and non-RCTs), and cross-sectional studies studies prospective cohort Current smokers Current smokers, 10 Current smokers Motivated or cigarettes per day or Motivated or unmotivated unmotivated to quit more, ages 18–60, no to quit severe comorbidity or psychiatric illness E-cigarettes (with E-cigarettes (with E-cigarettes (with nicotine) nicotine) nicotine) Not using e-cigarettes Placebo e-cigarette Placebo e-cigarette or other PubMed, Web of Science MEDLINE, Cochrane PubMed, Web of Core Collection Knowledge, Scopus Electronic cigarette, Electronic cigarette, “electronic cigarettes OR e-cigarette, electronic nicotine e-cigarettes” AND “smoking electronic nicotine delivery device, cessation OR quit smoking” delivery, electronic nicotine 1 or 2 or 3, delivery system, vaping, stop, e-cigarette quit, cessation, abstain, abstinence, 5 or 6 or 7 or 8 or 9, 4 and 10 June 17, 2015 June 14, 2015 May 2014 continued

570 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-4 Continued Characteristic Khoudigian et al., 2016 Malas et al., 2016 Study selection and data 2 authors 2 authors extraction Risk of bias assessment Yes Yes Cochrane Risk of Bias Modified version of tool (RCTs); same QualSysta tool by combining criteria for controlled quantitative and qualitative before–after studies, checklists and revising but “random sequence criteria based on Cochrane generation” and Handbook guidelines “allocation concealment” domains were reported as “high risk of bias” Outcome measures Smoking abstinence for Smoking abstinence for 6 months or more; also 30 days; also reduction, desire to smoke, number withdrawal symptoms, of cigarettes smoked, craving withdrawal symptoms Studies identified 5 (4 RCTs [2 of which 62 used in meta-analysis], 1 controlled before–after study) Meta-analysis done Yes (2 RCTs) No (attempted, but data considered too heterogeneous) Result (cessation): E-cigarette versus RR = 2.02; 95% CI = n/a placebo e-cigarette 0.97–4.21 E-cigarette versus no n/a n/a e-cigarette

SMOKING CESSATION AMONG ADULTS 571 Kalkhoran et al., 2016 Vanderkam et al., 2016 Rahman et al., 2015 1 author, with review by 2 authors 2 authors a second author Yes Yes Yes ACROBAT-NRSI Cochrane risk of bias Cochrane risk of bias tool (observational) tool (RCTs), Downs and Black Cochrane Risk of Bias instrument (observational tool (clinical trials) studies) Cigarette smoking Reduction of 50% in Smoking abstinence of any abstinence of any cigarettes/day for at duration duration. E-cigarette use least 3 months (primary explicitly allowed outcome). Smoking abstinence for 3 months or more, validated biochemically (secondary outcome). 38 (20 used in meta- 13 (2 RCTs used in meta- 6 (2 RCTs, 2 cohort, 2 cross- analysis) analysis) sectional) Yes (20 studies: RCT, Yes (2 RCTs) Yes (2 RCTs) cohort, cross-sectional designs) n/a RR = 1.91; 95% CI = RR = 2.29; 95% CI = 1.05– 0.93–3.89 4.97 OR = 0.72; 95% CI = n/a n/a 0.57–0.91 continued

572 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 17-4 Continued Characteristic Khoudigian et al., 2016 Malas et al., 2016 Conclusions “Limited low-quality “The results of this evidence of a non- systematic review lead us statistically significant to conclude that evidence trend toward smoking for the effectiveness of cessation in adults using e-cigarettes as a cessation nicotine e-cigarettes aid is inconclusive. There exists compared with is too much uncontrolled other therapies or variation to allow for any placebo. Larger, high- general conclusion to be quality studies are made.”c needed to inform policy “While inconclusive due decisions.”b to low quality, overall the existing literature suggests e-cigarettes may be helpful for some smokers for quitting or reducing smoking. However, more carefully designed and scientifically sound studies are urgently needed to establish unequivocally the long-term cessation effects of e-cigarettes”d a Kmet et al., 2004. b Khoudigian et al., 2016. c Malas et al., 2016, p. 1931. d Malas et al., 2016, p. 1926. e Kalkhoran and Glantz, 2016, p. 2. f Vanderkam et al., 2016, p. 972. trend toward smoking cessation in adults using nicotine e-cigarettes exists compared with other therapies or placebo. Larger, high-quality studies are needed to inform policy decisions” (Khoudigian et al., 2016, p. 257). Overall, this review was carefully conducted, but did not identify studies published after May 2014. Malas and colleagues (2016, p. 1927) conducted a systematic review of English-language studies containing “original data related to e-ciga- rettes and smoking cessation” that were identified from database searches through February 1, 2016, or a search of unpublished studies or abstracts (i.e., “gray literature”). Comparison conditions were not specified. Eli- gible study designs included RCTs, experimental studies, prospective observational studies, and cross-sectional studies. The primary outcome was cessation, defined as smoking abstinence or reduction with at least a

SMOKING CESSATION AMONG ADULTS 573 Kalkhoran et al., 2016 Vanderkam et al., 2016 Rahman et al., 2015 “As currently being “The use of electronic “Use of e-cigarettes is used, e-cigarettes cigarette with nicotine associated with smoking are associated with decreases tobacco cessation and reduction. significantly less quitting consumption among More randomized among smokers.”e regular smokers. Further controlled trials are needed studies are needed to to assess effectiveness specify an electronic against other cessation cigarette’s safety methods.”g profile and its ability “Limitations: Included to cause a reduction studies were heterogeneous, in consumption and due to different study long-term cessation in designs and gender smokers.”f variation.”h g Rahman et al., 2015, p. 2. h Rahman et al., 2015, p. 2. NOTE: NRT = nicotine replacement therapy; OR = odds ratio; RCT = randomized controlled trial; RR = relative risk. 30-day follow-up period. Identified studies underwent a systematic qual- ity assessment and received a rating of weak, moderate, or strong. The review identified 11 relevant studies with moderate or strong results that enrolled smokers from the general population. The authors summarized the studies qualitatively and attempted to do a quantitative synthesis, combining all study designs, but they concluded it could not be done due to heterogeneity of outcome measures and study designs. They stated, “The results of this systematic review lead us to conclude that evidence for the effectiveness of e-cigarettes as a cessation aid is inconclusive. There is too much uncontrolled variation to allow for any general conclusion to be made” (Malas et al., 2016, p. 1931). The authors identified an urgent need for “more carefully designed and scientifically sound studies ... to establish unequivocally the long-term cessation effects of e-cigarettes and

574 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES to better understand how and when e-cigarettes may be helpful” (Malas et al., 2016, p. 1926). Kalkhoran and Glantz (2016) conducted a systematic review and meta-analysis of English-language studies that assessed the relationship between e-cigarette use and cigarette smoking cessation among adult smokers, regardless of their interest in quitting smoking. They included RCTs and non-RCTs, cohort studies, and cross-sectional studies that were identified by a search ending June 17, 2015. The authors also monitored the literature for studies published before publication of their paper in January 2016 and added two studies. Outcomes were either self-reported or biochemically confirmed combustible tobacco cigarette smoking abstinence, with no required minimum duration of abstinence required. E-cigarette use was permitted under the definition of smoking abstinence. A total of 38 eligible studies were identified. They were heterogeneous in study design, duration, and definition of the e-cigarette exposure measure and the smoking cessation outcome. Twenty studies with control groups were included in a random-effects meta-analysis that found a negative effect of e-cigarette use on cessation (OR = 0.72; 95% CI = 0.57–0.91). Unlike other meta-analyses that separated RCTs and observational stud- ies, this meta-analysis combined all study designs (15 cohort studies, 3 cross-sectional studies, and 2 clinical trials [only 1 randomized]). Sensitiv- ity analyses compared the results of meta-analyses stratified by several factors, including interest in quitting, study design (clinical trial versus observational, longitudinal versus cross-sectional), biochemical verifica- tion, and recent e-cigarette use. The ORs generated in the sensitivity analysis for each of the different factors were not statistically significantly different from one another. The authors concluded, “As currently being used, e-cigarettes are associated with significantly less quitting among smokers” (Kalkhoran and Glantz, 2016, p. 2). They suggest that one expla- nation may be that e-cigarettes are used differently in a controlled clinical trial than in the real world, where e-cigarettes are readily available con- sumer products without clear instructions for use. They suggest that the results of observational trials provide insight into the effect of real-world e-cigarette use on cessation. Vanderkam and colleagues (2016) conducted a systematic review and meta-analysis of randomized and non-randomized intervention trials and prospective cohort studies that were published up to June 14, 2015. They compared nicotine-containing e-cigarettes to non-nicotine–­ontainingc e-cigarettes. The primary endpoint was 50 percent reduction of com- bustible tobacco cigarettes or more for at least 3 months, confirmed by a biochemical measure. However, they also included as a secondary mea- sure of smoking cessation for at least 3 months, confirmed by biomarker. Their search identified 13 papers, of which 2 were the same 2 RCTs

SMOKING CESSATION AMONG ADULTS 575 identified by other reviews (El Dib et al., 2017; Hartmann-Boyce et al., 2016; Khoudigian et al., 2016). In these authors’ hands, pooling the cessa­ tion data produced a non-significant effect of e-cigarettes over placebo e-cigarettes (RR = 1.91; 95% CI = 0.93–3.89). They did find a significant increase in the proportion of smokers with a validated self-report of 50 percent or greater reduction in daily cigarette consumption (RR = 1.30; 95% CI = 1.02–1.66). The authors concluded that evidence was insufficient to determine effectiveness of e-cigarettes for quitting smoking. The committee identified only one earlier systematic review that included a meta-analysis. Rahman and colleagues (2015) reviewed con- trolled trials, prospective cohort studies, and cross-sectional studies of e-cigarette use that were published up to May 2014. The review included studies that compared current smokers (variously defined and irrespec- tive of interest in quitting) who used e-cigarettes for at least 3 months with those who used any other method. The outcome measure was smoking cessation, not necessarily biochemically validated. The search and data extraction were carefully done and risk of bias was assessed. The search identified six studies, including the same two RCTs (Bullen et al., 2013; Caponnetto et al., 2013) that were identified in other reviews. A meta- analysis of these two studies, including missing data on smokers and using a random-effects MH test, produced an identical relative risk of quitting as that reported in the Hartmann-Boyce and colleagues (2016) review (RR = 2.29; 95% CI = 1.05–4.96). However, Rahman and colleagues’ interpretation of this finding was stated more positively than that of the Hartmann-Boyce and colleagues (2016) review; they concluded that the “use of e-cigarettes is associated with smoking cessation and reduction” (Rahman et al., 2015, p. 2). However, the review did acknowledge the small size and heterogeneity of the evidence base and called for more RCTs to be done to answer the question. Additionally, reduction in rate of smoking does not ensure reduction in tobacco-related harm. Evaluation of the Evidence from Systematic Reviews Overall, the systematic reviews identified by the committee generally came to similar conclusions, despite some methodological differences in the conduct of the meta-analyses. Table 17-1 includes the verbatim conclu- sions of all the systematic reviews to illustrate this similarity. Furthermore, the same two RCTs were consistently identified by most authors and were included in a formal meta-analysis by five of the systematic reviews. Both RCTs compared nicotine-containing e-cigarettes to non-nicotine placebo e-cigarettes. The relative risks generated in the meta-analyses ranged from 1.91 to 2.29, with 95% confidence limits falling near a relative risk of 1.0 in all cases. In two reviews (Hartmann-Boyce et al., 2016; Rahman

576 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES et al., 2015), the 95% CI around the estimate excluded 1.0, indicating that the superiority of e-cigarettes over placebo e-cigarettes was statistically significant, but in three other reviews, the 95% CI included 1.0, ranging from 0.93 to 0.97, thereby missing statistical significance. Although this difference led to slightly different interpretations, all reviews agreed that their confidence in their conclusion was low and that additional evidence might shift their conclusions. In contrast to RCTs, different groups of observational studies, pri- marily longitudinal cohort studies, were included in the systematic reviews. Only two systematic reviews conducted a meta-analysis of the cohort studies that they had identified (El Dib et al., 2017; Kalkhoran and Glantz, 2016). In contrast to the results of meta-analyses of RCTs, both meta-analyses of cohort studies found a negative association between e-cigarette use and cessation. Most other systematic reviews provided only a narrative summary of their observational studies. This summary identified limitations that may account for some of the discrepancy. These limitations include imprecision in measurement of e-cigarette exposure, inclusion of smokers not using e-cigarettes to quit, limited adjustment for confounding factors, and variable outcome measures of cessation (Levy et al., 2017). In particular, observational studies included in systematic reviews consistently noted an apparent association between the measure of expo- sure to e-cigarettes and likelihood of smoking cessation. Several obser- vational studies found an association between frequent (i.e., daily or at least 20 of the past 30 days) e-cigarette use and smoking cessation success (Beard et al., 2015; Biener and Hargraves, 2015; Brose et al., 2015; Hitchman et al., 2015) or quit attempts made (Brose et al., 2015), while measures of less frequent e-cigarette use were associated with less smok- ing cessation than non-use of e-cigarettes (Beard et al., 2016; Biener and Hargraves, 2015; Brose et al., 2015; Hitchman et al., 2015). In summary, the existing systematic reviews consistently agreed that the available evidence base was insufficient to definitively answer the question of whether e-cigarettes helped smokers to quit. They uniformly identified the urgent need for additional studies of high scientific quality, especially RCTs. Effect of E-Cigarettes on Population-Level Cessation Rates The committee identified only a small number of studies that enrolled nationally representative samples of individuals to assess the effect of e-cigarette availability on population cessation rates. Available studies used prospective cohort or repeat cross-sectional study designs. No RCTs are available. Few studies are available because e-cigarettes have been

SMOKING CESSATION AMONG ADULTS 577 broadly available consumer products for only a few years and national surveys, from which study data were drawn, started to collect data on e-cigarette use only recently. The most recent and largest study in the United States provides evi- dence of an association between e-cigarette use and smoking cessation rates at the population level. Zhu and colleagues (2017) analyzed data from five waves (i.e., repeated cross-sections) of the large, nationally representative U.S. Current Population Survey–Tobacco Use Supplement (CPS-TUS). The authors used these cross-sectional data to create a retro- spective cohort of individuals who reported having been smokers one year prior to the survey. The analysis compared the quit rate (defined as the proportion who reported having been abstinent for at least 3 months at the time of the survey among those who were smoking 1 year earlier) between those who had ever used or currently used (defined as now used every day or some days) an e-cigarette. In the most recent survey of more than 160,000 respondents conducted in 2014–2015, smokers who used e-cigarettes in the previous 12 months were more likely to have made a quit attempt during that period and to have achieved at least 3 months of tobacco cessation than smokers who were not e-cigarette users. In the same publication, Zhu and colleagues (2017) also used repeated cross-sectional CPS-TUS surveys to examine the population-level rates of making a quit attempt in the past year and of quitting smoking. Both mea- sures increased significantly in 2014–2015 after remaining stable in four previous surveys beginning in 2001–2002. The population-level smoking cessation rate increased by 1.1 percentage points (4.5 percent to 5.6 per- cent) between 2010–2011 and 2014–2015. This coincided with the increase in e-cigarette use in the population, but it could also have been the result of other broad population-level influences on smoking cessation rates. The authors carefully considered concurrent factors, including an increase in federal tobacco excise tax in 2009 and annual national media campaigns beginning in 2012. They argue that these are not likely to have caused the change in quit rates. The study findings are consistent with findings of a study from England that also analyzed repeated cross-sections of nation- ally representative population samples (Beard et al., 2016). That study found a higher success rate of quit attempts among smokers who used e-cigarettes during a quit attempt, compared with those who did not use e-cigarettes during a quit attempt. It did not, however, find an associa- tion between e-cigarette use and the likelihood of a smoker making a quit attempt, as the Zhu and colleagues (2017) study did. It may also have been confounded by secular changes in the availability of treatment in the National Health Service (Britton, 2016). Like Zhu and colleagues (2017), Levy and colleagues (2017) also ana- lyzed data from the cross-sectional 2014–2015 CPS-TUS. They retrospec-

578 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES tively created a cohort of individuals who were smoking 1 year prior to the survey. Their analysis focused on the relationship between the frequency of e-cigarette use at the time of the survey and two outcomes: (1) having made a quit attempt in the past year, and (2) having been abstinent from cigarettes for at least 3 months at the time of the survey if a quit attempt was made. Using multiple logistic regression analysis, the authors found consistent evidence between the frequency of e-cigarette use and both outcomes. Having made a quit attempt in the past year was associated with having ever used or currently using e-cigarettes, and the strength of this association increased with increasing number of days of e-cigarette use in the 30 days before the survey was conducted. Further- more, among smokers who had made a quit attempt in the past year, the likelihood of having quit for 3 months or more at the time of the survey was significantly associated with current e-cigarette use. The strength of the relationship increased in a dose–response relationship with the number of days of e-cigarette use in the past 30 days. The adjusted odds ratio (AOR) for smokers who had used e-cigarettes on 20 or more days in the past 30 days (versus no use) was 2.81 (95% CI = 2.26–3.49), compared with 1.59 (95% CI = 1.31–1.92) for 5 or more days of use and 1.22 (95% CI = 1.02–1.46) for any number of days of current use. By contrast, there was an inverse relationship between being abstinent and ever use of an e-cigarette (AOR = 0.80; 95% CI = 0.69–0.92). Giovenco and Delnevo (2018) used a similar approach to analyze a different large nationally representative annual cross-sectional survey, the National Health Interview Survey. They pooled data from the 2014 and 2015 surveys, which were the first to collect data on e-cigarette use. They constructed a retrospective cohort by including current smokers and any former smoker who quit in 2010 or later. They chose this date because e-cigarettes were rarely used in the United States prior to that date. Among this group of current and former smokers, daily e-cigarette users at the time of the survey (2014–2015) were more likely to be former smok- ers than e-cigarette–never users (52 percent versus 28 percent, adjusted prevalence ratio [aPR] = 3.15; 95% CI = 2.66–3.73). By contrast, those who previously tried e-cigarettes but did not use them currently and those who used them on only some days were less likely to be former smokers at the time of the survey than those who never used e-cigarettes (aPR = 0.67 [95% CI = 0.61–0.75] and 0.38 [95% CI = 0.32–0.47], respectively). Recall bias of e-cigarette use and quit attempts is a limitation of the Giovenco and Delnevo (2018), Levy and colleagues (2017), and Zhu and colleagues (2017) studies’ retrospective cohort design, as the authors acknowledge. They also recognize that reverse causation (i.e., quitting led to e-cigarette use to prevent relapse) also cannot be excluded. Other limi- tations include lack of information on potential confounders such as the

SMOKING CESSATION AMONG ADULTS 579 type of e-cigarette used, the reason for e-cigarette use, or factors reflecting motivation or confidence in the ability to quit or past quit attempts. For example, smokers who use e-cigarettes daily could also be the ones most motivated to quit and therefore most likely to succeed. A strength of the Giovenco and Delnevo (2018) study was its unique ability to adjust for one potential confounder, serious psychological distress, which is asso- ciated with a lower success in quit attempts. This information is rarely available from population-based surveys. Using the stronger prospective longitudinal cohort design that avoids recall bias and reverse causation, Zhuang and colleagues (2016) conducted a U.S. population-based study of 2,028 smokers who were interviewed in 2012 and followed for 2 years. Smokers who reported using e-cigarettes at both points were defined as long-term users, while smokers reporting use at only one time were defined as short-term users. Long-term e-cigarette users had a higher cessation rate at 2 years compared with short-term e-cigarette users or non-users (42.4 percent versus 14.2 percent versus 15.6 percent). The dif- ference in cessation rates between long-term users and either short-term or non-users was statistically significant after multivariable adjustment, suggesting that long-term but not short-term e-cigarette use promotes smoking cessation. Shi and colleagues (2016) also conducted a prospective longitudinal population-based study to examine the relationship between e-cigarette use and smoking cessation, but found a different result. A nationally rep- resentative cohort of 2,454 smokers responding to the 2010 CPS-TUS was contacted 1 year later. The analysis found a negative association between ever use of e-cigarettes and quitting smoking for at least 1 month at follow- up. However, the measure of e-cigarette use was limited to ever use. No more detail about the intensity or duration of use, which the Zhuang and colleagues (2016) study suggests may be important factors, was available. Furthermore, the authors point out that only first-­ eneration e-cigarettes g were available to U.S. smokers at the time of the study. These may have been less effective for cessation because they delivered less nicotine to the user than do later-generation devices. SYNTHESIS There is general agreement that the number, size, and quality of studies for judging the effectiveness of e-cigarettes as cessation aids in comparison with cessation aids of proven efficacy are limited, and there- fore there is insufficient evidence to permit a definitive conclusion at this time. Not only are existing studies limited in number, but the random- ized trials provide a limited range of treatment comparisons. Interpreta- tion of relevant observational studies on the topic of the effectiveness of

580 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES e-cigarettes as cessation aids is complicated by the fact that they generally do not account for important covariates that may affect the success of e-cigarettes as cessation aids. These covariates include (1) the e-cigarette product (e.g., type of device, nicotine content and delivery, flavorings or other contents of the e-liquid), (2) pattern of current use (e.g., frequency of use, duration of use), and (3) user characteristics (particularly interest in quitting and prior history of e-cigarette use, but also demographics and smoking history) (Malas et al., 2016). By contrast, some of the more recently published (e.g., since 2016) cohort studies and nationally rep- resentative cross-sectional studies have included one key variable, the frequency of e-cigarette use. Based on this rationale, as described below, the evidence from more recent cohort studies and cross-sectional studies provides the foundation for the committee’s conclusion about the fre- quency of e-cigarette use in relation to likelihood of smoking cessation. Future studies, both observational and experimental, will be strengthened by carefully measuring characteristics of the e-cigarette product, the pat- tern of use, and characteristics of the users. Within the current body of evidence, different study designs have produced conflicting findings. The results of the few RCTs, the study design with the least risk of bias and greatest internal validity, suggest a possible though not definitively positive association with quitting smok- ing (Adriaens et al., 2014; Bullen et al., 2013; Caponnetto et al., 2013) (see Table 17-2). In these trials, the strongest results were observed in the trials that compared the efficacy of a nicotine-containing e-cigarette with a non- nicotine placebo e-cigarette. Two RCTs addressed this narrow question about the marginal benefit of having nicotine in a vaping device. Both tri- als compared a nicotine-containing e-cigarette with an e-cigarette without nicotine (Bullen et al., 2013; Caponnetto et al., 2013). They found consis- tent results that were statistically significant in one of two meta-analyses that pooled data from the two trials (El Dib et al., 2017; Hartmann-Boyce et al., 2016). There are no opposing findings from RCTs. The committee also considered the substantial body of RCT evidence demonstrating the efficacy of nicotine replacement products compared with placebo prod- ucts as smoking cessation aids as evidence that provided plausibility for the role of nicotine in enhancing the likelihood of smoking cessation. The combination of RCT evidence and indirect supportive evidence was judged by the committee to provide moderate evidence that e-cigarettes with nicotine are more effective than e-cigarettes without nicotine for smoking cessation. While scientifically valuable, this evidence does not address a ques- tion that is more relevant to public health: how do e-cigarettes with or without nicotine compare to proven FDA-approved cessation aids or to no specific treatment among smokers who are trying to quit? Only one

SMOKING CESSATION AMONG ADULTS 581 trial has compared an e-cigarette to a nicotine patch (Bullen et al., 2013). No statistically significant difference in quit rates was observed in that trial, and the absolute quit rates were low in all groups. Without replica- tion, this trial by itself provides insufficient evidence at present to support a conclusion of the relative effectiveness of e-cigarettes versus other cessa- tion aids among smokers who are motivated to quit. This is a question of critical public health importance that deserves priority for federal funding agencies. A separate key question for public health impact is whether the availability of e-cigarettes induces more smokers to try to quit, because smokers perceive e-cigarettes to be a more appealing option than FDA- approved cessation aids. An important note is that characteristics of the study design of the few published RCTs may have minimized the potential effectiveness of e-cigarettes as cessation aids. First, participants in two of three trials were not limited to smokers who wanted to quit smoking. One trial specifi- cally recruited smokers not intending to quit (Caponnetto et al., 2013). An e-cigarette may be more effective in helping smokers who are motivated to quit, although this is a hypothesis that requires testing. Second, the existing RCTs used early e-cigarette models with low nicotine content and poor battery life that likely produced insufficient nicotine delivery. Newer-generation e-cigarettes, which deliver higher doses of nicotine to the user, may be more effective than first-generation devices, which are the ones that have largely been studied in clinical trials. Studies with newer e-cigarettes might produce larger effects, although this remains to be demonstrated. Third, the amount of behavioral support (including instruction in proper use of the product) may affect the effectiveness of e-cigarettes, but existing trials have offered low levels of behavioral sup- port, which might have increased cessation rates of both e-cigarettes and other methods tested (Malas et al., 2016). RCTs are superior to observational studies with respect to internal validity, but a strength of observational studies is that they reflect the effectiveness of e-cigarettes as they are being used in real-world settings, rather than how a specific device would perform under controlled or opti- mal conditions. Observational studies reflect how e-cigarettes are actually being used in the population, where they are consumer products sold without specific instructions to aid cessation. The evidence from observa- tional studies is discrepant between studies published through 2015 and those published subsequently. The results of cohort studies have produced mixed results, but the associations in cohort studies published prior to 2016 generally indicate that e-cigarette users are less likely than non-users of combustible tobacco cigarettes to quit smoking. The two systematic reviews that included cohort studies published between 2013 and 2015 in meta-analyses each found a negative association between ­ -cigarette use e

582 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES and cessation, with ORs of 0.74 and 0.72, respectively (El Dib et al., 2017; Kalkhoran and Glantz, 2016). In one case (El Dib et al., 2017), the result was not statistically significant. The disparate results of data from RCTs and cohort studies published prior to 2016 are striking and contribute to the uncertainty about the overall effect of e-cigarettes on cessation. One potential explanation for the discrepancy is a difference between observational studies and RCTs in the measurement of e-cigarette use. As described above, the measurement of e-cigarette exposure in most of the cohort studies is relatively blunt. It is often a dichotomous measure such as “ever use” versus “never use” that cannot account for individual differ- ences in the intensity or frequency of use or in the type of device used. The exposure measured in these earlier cohort studies is likely to have been less frequent or intensive that those in the RCTs. Another important rea- son for the discrepancy is bias in cohort studies due to self-selection. This would occur if the smokers who choose to use e-cigarettes are less likely to succeed because of stronger nicotine dependence, less access to or inter- est in using effective smoking cessation medications, having failed to quit after having exhausted all other smoking cessation aids, or other factors that could bias relative risk estimates of associations with e-cigarette use toward less favorable cessation outcomes. Furthermore, the motivation for e-cigarette use (e.g., to quit smoking or to be a dual user) was usu- ally not measured in the older cohort studies. While a number of cohort studies used multivariable analysis to attempt to adjust for these factors, unmeasured confounding is always a threat to internal validity in obser- vational studies. Notably, an analogous discrepancy exists between the results of RCTs and cohort studies regarding the effectiveness of nico- tine replacement products, but because these products were consistently shown to be efficacious in numerous RCTs the efficacy of these products is well established (Fiore et al., 2008; Stead et al., 2012; USPSTF, 2015). Observational data may largely reflect dual or intermittent use of e-cigarettes. This pattern may not contribute to cessation success any more than does poor adherence to FDA-approved cessation medications. Most cohort and cross-sectional studies published through 2015 have not char- acterized patterns of use sufficiently to allow stratified analysis by this or similar factors. Further complicating the interpretation of observational studies is the fact that real-world use of e-cigarettes changed during the period of time when the studies were conducted because e-cigarette have been evolving as consumer products. The committee thus gave greater weight to more recently published data from both prospective cohort and cross-sectional studies that measured frequency of e-cigarette use. With respect to prospective cohort studies, a population-based prospective lon- gitudinal study found persistent e-cigarette use to be associated with ces- sation while short-term use was not (Zhuang et al., 2016). Other prospec-

SMOKING CESSATION AMONG ADULTS 583 tive longitudinal studies report that daily or very frequent e-cigarette use may be associated with cessation while intermittent use may not (Biener and Hargraves, 2015; Brose et al., 2015; Delnevo et al., 2016; Hitchman et al., 2015; Levy et al., 2017; Malas et al., 2016). Furthermore, several recent cross-sectional studies using nationally representative population-based samples of adults measured exposure frequency in even finer detail (e.g., number of days of use in a defined time period). Four of five studies analyzing U.S. population samples found an association between more frequent e-cigarette use and smoking cessation. The importance of the measurement limitations in the older studies is highlighted by the fact that even within these U.S. cross-sectional studies, when the measures of “ever use” or “intermittent use” of e-cigarettes were considered, several of the studies showed an inverse relationship between these measures of e-cigarette use and cessation. The committee judged the results from more recent observational studies to be biologically plausible, as these findings are conceptually consistent with the large body of evidence that smokers trying to quit benefit from adequate nicotine replacement to reduce nicotine withdrawal symptoms. More frequent use of an e-cigarette (or a licensed short-acting nicotine replacement product) should deliver more nicotine. Furthermore, substantial evidence exists to associate higher cessation rates with bet- ter adherence to FDA-approved cessation aids among smokers who are attempting to quit. Based on this biological plausibility and the strong, consistent body of evidence from higher-quality studies published more recently that over- come measurement limitations of studies published in the past, the com- mittee concluded that there was moderate evidence that more frequent use of e-cigarettes is associated with quitting smoking. Observational studies are inherently limited for causal inferences due to the potential for selection bias and unmeasured confounding. The committee gave greater weight to the evidence from RCTs but acknowledged the over- all evidence from observational studies in describing the strength of its overall conclusion on the effectiveness of e-cigarettes as a cessation aid. In combination with the limited evidence from RCTs, this body of obser- vational evidence also contributed to the committee’s judgment that the total body of evidence that e-cigarettes may be an effective smoking ces- sation aid was limited. Future cohort studies will be most useful if they measure more detailed information about e-cigarette use. Factors likely to be important include the type of e-cigarette product (first-generation versus second- and later-generation devices), the frequency of use (daily/regularly or not), the method of use (complete switch to e-cigarettes versus dual use), and the goal of use (to quit smoking versus primarily to reduce number of

584 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES combustible tobacco cigarettes smoked or otherwise reduce harm without quitting). For both randomized trials and observational studies, critical modifiers of the association of e-cigarette use and smoking cessation may exist, such that certain patterns of use or types of e-cigarettes may be more effective as cessation aids than others. CONCLUSIONS Conclusion 17-1. Overall, there is limited evidence that e-cigarettes may be effective aids to promote smoking cessation. Conclusion 17-2. There is moderate evidence from randomized con- trolled trials that e-cigarettes with nicotine are more effective than e-cigarettes without nicotine for smoking cessation. Conclusion 17-3. There is insufficient evidence from randomized con- trolled trials about the effectiveness of e-cigarettes as cessation aids com- pared with no treatment or to Food and Drug Administration–approved smoking cessation treatments. Conclusion 17-4. While the overall evidence from observational trials is mixed, there is moderate evidence from observational studies that more frequent use of e-cigarettes is associated with an increased likeli- hood of cessation. REFERENCES Adriaens, K., D. Van Gucht, P. Declerck, and F. Baeyens. 2014. Effectiveness of the electronic cigarette: An eight-week Flemish study with six-month follow-up on smoking reduc- tion, craving and experienced benefits and complaints. International Journal of Environ- mental Research & Public Health 11(11):11220–11248. Beard, E., J. Brown, A. McNeill, S. Michie, and R. West. 2015. Has growth in electronic cigarette use by smokers been responsible for the decline in use of licensed nicotine products? Findings from repeated cross-sectional surveys. Thorax 70(10):974–978. Beard, E., R. West, S. Michie, and J. Brown. 2016. Association between electronic cigarette use and changes in quit attempts, success of quit attempts, use of smoking cessation pharmacotherapy, and use of stop smoking services in England: Time series analysis of population trends. BMJ 354:i4645. https://doi.org/10.1136/bmj.i4645 (accessed Febru- ary 9, 2018. Biener, L., and J. L. Hargraves. 2015. A longitudinal study of electronic cigarette use among a population-based sample of adult smokers: Association with smoking cessation and motivation to quit. Nicotine & Tobacco Research 17(2):127–133. Britton, J. 2016. Electronic cigarettes and smoking cessation in England. BMJ 354:i4819. https://doi.org/10.1136/bmj.i4819 (accessed February 9, 2018).

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588 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES Zhuang, Y. L., S. E. Cummins, J. Y. Sun, and S. H. Zhu. 2016. Long-term e-cigarette use and smoking cessation: A longitudinal study with U.S. population. Tobacco Control 25:i90–i95. http://dx.doi.org/10.1136/tobaccocontrol-2016-053096 (accessed February 7, 2018).

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Millions of Americans use e-cigarettes. Despite their popularity, little is known about their health effects. Some suggest that e-cigarettes likely confer lower risk compared to combustible tobacco cigarettes, because they do not expose users to toxicants produced through combustion. Proponents of e-cigarette use also tout the potential benefits of e-cigarettes as devices that could help combustible tobacco cigarette smokers to quit and thereby reduce tobacco-related health risks. Others are concerned about the exposure to potentially toxic substances contained in e-cigarette emissions, especially in individuals who have never used tobacco products such as youth and young adults. Given their relatively recent introduction, there has been little time for a scientific body of evidence to develop on the health effects of e-cigarettes.

Public Health Consequences of E-Cigarettes reviews and critically assesses the state of the emerging evidence about e-cigarettes and health. This report makes recommendations for the improvement of this research and highlights gaps that are a priority for future research.

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