Research paper Tob Control: first published as 10.1136/tobaccocontrol-2018-054726 on 18 January 2019. Downloaded from Electronic in : a tool for harm reduction or a gateway to tobacco? Xiaoqiu Liu,1 Alessandra Lugo,1 Enrico Davoli,1 Giuseppe Gorini,2 Roberta Pacifici,3 Esteve Fernández,4 Silvano Gallus1

1Department of Environmental Abstract as a tool.8 Indeed, the safety of Health Sciences, Istituto di Introduction More than a decade after electronic e- use, particularly its long-term effects, Ricerche Farmacologiche Mario remains unclear9 10: while these e-cigarettes emit Negri IRCCS, Milano, Italy cigarettes (e-cigarette) hit the European market, we are 2Oncological Network, still debating whether they may help or hinder tobacco less toxicants and carcinogens than conventional Prevention and Research control. It is therefore useful to explore the potential net cigarettes, they are still measurable and vary widely Institute (ISPRO), Florence, Italy with individual puffing topography and puff dura- 3 effect of e-cigarette use in the general population. National Centre on Addiction Methods We annually conduct a face-to-face survey tion,11 and from study to study.12 13 Although some and Doping, Istituto Superiore di Sanità, Rome, Italy on smoking in Italy on a representative sample of the studies showed that e-cigarettes may help smokers 4Institut Català d’Oncologia general population aged 15 years or over (52.4 million). cut down or stop smoking conventional ciga- (ICO)-Institut d’Investigació A total of 15 406 subjects were interviewed in 2014– rettes,14–16 others found e-cigarettes even stop cessa- Biomèdica de Bellvitge 2018. We investigated the consequences of using tion or give low cessation rates, similar to those of (IDIBELL), School of Medicine, 10 17–19 Universitat de Barcelona, e-cigarettes on behaviour among ever smokers who have tried to quit with no aid. L’Hospitalet de Llobregat, and regular e-cigarette users. There is also concern that e-cigarettes may under- Barcelona, Spain Results In all, 5.7% of our sample reported ever mine efforts to ‘denormalise’ smoking.20 Finally, e-cigarette use. Multivariate analyses showed more use non-smokers trying e-cigarettes can succumb to Correspondence to by men, ex-smokers and current smokers. E-cigarette nicotine addiction, particularly young people.1 21 22 Dr Silvano Gallus, Department use decreased with age and increased with education To get a better picture of the potential net benefit of Environmental Health Sciences, Istituto di Ricerche and calendar year. Only 1.1% of subjects were regular of e-cigarette use in reducing tobacco consumption Farmacologiche Mario Negri e-cigarette users. This prevalence rose from 0.4% in at a population level, we analysed data from our IRCCS , Milano 20156, Italy; 2014–2015 to 1.8% in 2016–2017 and was 1.3% in annual population-based surveys conducted in Italy silvano.​ ​gallus@marionegri.​ ​it 2018. Among 522 ever users, 13.2% stopped smoking from 2014 to 2018, where a specific section was copyright. after trying e-cigarettes and 22.2% started smoking devoted to e-cigarette use. Received 7 September 2018 Revised 10 December 2018 or relapsed after using e-cigarettes. The corresponding Accepted 20 December 2018 estimates among regular users were 24.7% and 28.0%, respectively. Methods Conclusions Among Italian e-cigarette users, those Surveys were conducted by DOXA, the Italian (re)starting smoking after using e-cigarettes outnumber branch of the Worldwide Independent Network/ those who stop smoking after using e-cigarettes. From Gallup International Association, in collaboration a public health point of view, e-cigarettes may have an with the Italian National Institute of Health and http://tobaccocontrol.bmj.com/ unfavourable net effect. Consequently, if we are not the Mario Negri Institute for Pharmacological able to prevent sales of e-cigarettes to non-smokers, this Research. Each year, the survey is based on around product will more likely stimulate smoking tobacco than 3000 subjects, representative of the general Italian reduce harm. population aged 15 years and over (52.4 million inhabitants in 2018), in terms of sex, age, area of residence and socioeconomic characteristics.23 For the present analysis, the sample comprised 15 406 Introduction individuals aged 15 years or more (7393 men and The electronic cigarette (e-cigarette) is a battery-pow- 8013 women), enrolled in the survey conducted in ered device that heats a liquid containing propylene 2014–2018. glycol, glycerin and/or water with flavours, to Participants were selected by a representative generate an inhalable aerosol containing nicotine multistage sampling. The first stage involved the on October 1, 2021 by guest. Protected or not. E-cigarettes were marketed in most high-in- selection of municipalities in all the 20 Italian come countries around 2010, and its popularity and regions, based on the region and the size of the use soon spread widely.1 Some public and private municipality. We selected 116 municipalities in organisations, including Public Health England, 2014, 110 in 2015, 2016 and 2017 and 119 in © Author(s) (or their have endorsed e-cigarette use, on the basis of the 2018 as representative of the regions sampled. In employer(s)) 2019. No widely accepted standpoint that they could be bene- the second stage, an adequate number of electoral commercial re-use. See rights and permissions. Published ficial for heavy smokers who are not able to quit with wards was randomly extracted in each municipality, 2 3 by BMJ. standard support. This endorsement, conflicting so that the more or less affluent areas of the munic- with the conclusions of the WHO4 and the US ipality were represented in the right proportions. In To cite: Liu X, Lugo A, National Academies of Sciences, Engineering, and the third stage, individuals were randomly sampled Davoli E, et al. Tob Control 5 Epub ahead of print: [please Medicine, has provoked much debate and concern from electoral rolls, within strata defined by sex 6–8 include Day Month Year]. over the spread and use of e-cigarettes. and age. Adolescents aged 15–17 years, who were doi:10.1136/ The debate is mainly due to uncertainty about the not included in the electoral lists, were randomly tobaccocontrol-2018-054726 harmful effects of e-cigarettes and their effectiveness selected by a ‘quota’ method based on the sex and

Liu X, et al. Tob Control 2019;0:1–5. doi:10.1136/tobaccocontrol-2018-054726 1 Research paper Tob Control: first published as 10.1136/tobaccocontrol-2018-054726 on 18 January 2019. Downloaded from age proportions among them. A statistical weight was generated number of conventional cigarettes per day; (7) I quit smoking; for each subject to ensure the representativeness of the Italian (8) I did not smoke conventional cigarettes before and I do not population aged 15 years or more. smoke now’. Almost all e-cigarette users (97%) provided a valid Ad hoc trained interviewers conducted the survey using response to this question. In 2017–2018, a single-choice ques- a structured questionnaire in a computer-assisted personal tion to current e-cigarette users only investigated the type of interview. Besides general information on sociodemographic e-cigarette used (with or without nicotine). characteristics, smoking status (never smoker, ex-smoker and Descriptive statistics were used for the main results, including current smoker) and other tobacco-related data were collected. prevalence and the corresponding 95% confidence interval Ever smokers (current smokers and ex-smokers) were partici- (CI) by categorical variables. In view of the small numbers, we pants who had smoked 100 or more cigarettes in their lifetime. grouped the survey year as 2014–2015, 2016–2017 and 2018. Ex-smokers were participants who had quit smoking for at least Statistical weights were used to reassure the representativeness 1 year, and current smokers were individuals smoking at the time of our sample in terms of age, sex, area of residence and socio- of the interview or having stopped for less than 1 year. Partici- economic characteristics. Odds ratios (OR) and the 95% CIs for pants were asked about their use of e-cigarettes, using the ques- ever—and regular—e-cigarette use were calculated using multi- tion: ‘Do you use electronic cigarettes or other electronic devices variate logistic regression models, adjusting for sex, age, level for vaping (disposable or prefilled or refillable cartridges with of education, smoking status, area of residence and survey year. liquid), even only occasionally?’ (1) Yes, occasionally; (2) Yes, A sensitivity analysis limited to data from 2017 and 2018 was usually; (3) I used it in the past; (4) No. We define herewith as done to explore whether the answers on the consequence of occasional e-cigarette users reporting the first answer, regular e-cigarette use differed between current and past users. Another users the second answer, past users the third answer, current users sensitivity analysis was done on nicotine-containing e-cigarette first and second answers combined, and ever users first, second users, that is, current users in 2014–2015, 2017–2018, to assess and third answers combined. Occasional and regular e-cigarette the consequence of their use of e-cigarettes on tobacco smoking. users (and past e-cigarette users in 2017 and 2018) were further All analyses were done with SAS V.9.4 statistical package. investigated about the consequences of e-cigarette use on their tobacco smoking habits with the following question: ‘Which of the following best describes the consequence of using electronic Results cigarettes on your current cigarette smoking consumption? (1) I The distribution of 15 406 aged 15 years or more started smoking conventional cigarettes (I did not smoke before, according to their use of e-cigarettes is shown in table 1. Only and now I smoke); (2) I re-started smoking conventional ciga- 1.1% of Italian adults (95% CI: 1.0% to 1.3%) reported regular rettes (I was an ex-smoker, and now I relapsed); (3) I haven’t e-cigarette use, 1.1% (95% CI: 0.9% to 1.2%) occasional use copyright. changed my smoking habits (I smoke the same amount of conven- and 3.5% (95% CI: 3.2% to 3.8%) past use (table 1). Among tional cigarettes as before); (4) I slightly reduced the number of regular and occasional users, 62% were dual users (ie, current conventional cigarettes per day; (5) I substantially reduced the smokers and e-cigarette users): 81% in 2014–2015, 53% in number of conventional cigarettes per day; (6) I increased the 2016–2017 and 66% in 2018. Ever (ie, occasional, regular or

Table 1 Prevalence (per cent) of occasional, regular and past use of electronic cigarettes in a total sample of 15 406 Italians aged at least 15 years,

overall and according to selected characteristics (Italy, 2014–2018) http://tobaccocontrol.bmj.com/ Electronic cigarette use (%) n Never use Past use Occasional use Regular use Total (number) 100.0 (15 406) 94.3 (14 528) 3.5 (533) 1.1 (165) 1.1 (178) Sex Men 7393 92.9 4.3 1.2 1.5 Women 8013 95.6 2.7 1.0 0.8 Age (years) 15–24 1751 93.7 3.8 1.7 0.8 25–44 4786 92.6 4.4 1.4 1.6

45–64 5034 93.4 4.2 1.1 1.4 on October 1, 2021 by guest. Protected ≥65 3835 97.9 1.2 0.4 0.4 Level of education Low 5569 96.1 2.6 0.7 0.6 Intermediate 7370 92.6 4.5 1.4 1.5 High 2467 95.1 2.6 1.2 1.0 Smoking status Never smoker 10 046 98.6 0.6 0.3 0.4 Current smoker 3395 82.2 12.0 3.5 2.4 Ex-smoker 1965 93.2 3.2 0.8 2.8 Survey year 2014–2015 6098 95.3 3.4 0.9 0.4 2016–2017 6086 93.1 3.8 1.3 1.8 2018 3222 94.9 3.0 0.8 1.3

2 Liu X, et al. Tob Control 2019;0:1–5. doi:10.1136/tobaccocontrol-2018-054726 Research paper Tob Control: first published as 10.1136/tobaccocontrol-2018-054726 on 18 January 2019. Downloaded from

Table 2 Self-reported consequences of electronic cigarette use on the consumption of combustible cigarettes among 522 ever users and 182 regular users of electronic cigarettes (Italy, 2014–2018) Ever users Regular users n* % (95% CI) n* % (95% CI) Total 522 100.0 182 100.0 Detrimental change Started smoking (from never to current smoker) 54 10.3 (7.7 to 13.0) 32 17.6 (12.1 to 23.1) Restarted smoking (from ex-smoker to current smoker) † 62 11.9 (9.1 to 14.7) 19 10.4 (6.0 to 14.9) No change in smoking status Increased smoking intensity 6 1.2 (0.0 to 2.1) 3 1.7 (0.0 to 3.5) Did not change smoking intensity 163 31.2 (27.3 to 35.2) 18 9.9 (5.6 to 14.2) Did not smoke before and do not smoke now 29 5.6 (3.6 to 7.5) 8 4.4 (1.4 to 7.4) Slightly reduced daily smoking intensity 97 18.6 (15.3 to 21.9) 25 13.7 (8.7 to 18.7) Substantially reduced daily smoking intensity 42 8.1 (5.7 to 10.4) 32 17.6 (12.1 to 23.1) Beneficial change Quit smoking (from current to ex-smoker) 69 13.2 (10.3 to 16.1) 45 24.7 (18.5 to 31.0) *Number of e-cigarette users who provided information on consequences of e-cigarette use on their smoking behaviours (unweighted numbers). This study includes 891 ever users (143 in 2014, 164 in 2015, 262 in 2016, 174 in 2017 and 148 in 2018). The question on the consequence of e-cigarette use was not put to ex-users in 2014–2016 (n=355), while in 2017–2018 it was asked also to ex-users. There are nine occasional users and five regular users who did not answer this question. Numbers do not match those in table 1 because statistical weight was not considered in the table. †This option was available only in the 2016–2018 surveys. past) e-cigarette users were 5.7% with fewer women (4.4%) smoking were more frequent among regular/occasional e-ciga- than men (7.1%; multivariate OR: 0.80; 95% CI: 0.68 to 0.91), rette users (20.0%) than past users (8.9%, only). inversely related to age (p for trend <0.001) and directly related Among younger subjects (under 35 years), 7.1% were ever to education (p for trend 0.021). Compared with never cigarette e-cigarette users. Among these, 5.5% reported having stopped smokers (1.4%), ever e-cigarette use was more frequent among smoking and 16.4% had (re)started smoking as a consequence current smokers (17.8%; multivariate OR: 14.3; 95% CI: 11.8 of their e-cigarette experience. Among the 86 current users copyright. to 17.3) and ex-smokers (6.8%; OR: 5.80; 95% CI: 4.51 to reporting in 2017 and 2018 that they used nicotine-containing 7.45). The prevalence of ever e-cigarette use rose from 4.7% e-cigarettes, 24 (27.9%) started/restarted smoking and 14 in 2014–2015, to 6.9% in 2016–2017 (OR: 1.52; 95% CI: (16.3%) quit smoking (data not shown). 1.29 to 1.78) and was 5.2% in 2018 (OR: 1.01; 95% CI: 0.82 to 1.23). Fewer women than men were regular e-cigarette users Discussion (OR: 0.66; 95% CI: 0.49 to 0.91) and the rate decreased with The prevalence of regular e-cigarette use in Italy is still relatively increasing age (p for trend 0.008). No specific pattern was low, but it rose significantly from 0.4% in 2014–2015 to 1.3% found for level of education (p for trend 0.121). Compared with in 2018. We explicitly asked ever users about the consequence http://tobaccocontrol.bmj.com/ never smokers, regular e-cigarette users were more frequent of e-cigarette use on their smoking status. Among ever, regular, among current smokers (OR: 4.87; 95% CI: 3.33 to 7.12) and young e-cigarette users and subjects vaping nicotine-containing ex-smokers (OR: 7.23; 95% CI: 4.75 to 11.00). Compared with e-cigarettes, the number of those (re)starting smoking due to 2014–2015 (0.4%), Italians were more frequently regular e-cig- e-cigarette use systematically exceeded those quitting smoking arette users in 2016–2017 (1.8%; OR: 4.70; 95% CI: 3.01 to with e-cigarette use. This indicates that only a small proportion 7.33) and in 2018 (1.3%; OR: 3.10; 95% CI: 1.87 to 5.15; p for of ever e-cigarette users in Italy potentially benefit from these trend <0.001). e-cigarettes (only 13% quit smoking), and e-cigarette use seems Among the 522 ever users (including 182 regular users), 13.2% to act as a gateway to smoking tobacco in a larger proportion (95% CI: 10.3% to 16.1%; n=69) reported having stopped (22%). smoking, therefore changing their smoking status from current Our findings are in broad agreement with those by Soneji to ex-smoker; 64.6% (95% CI: 60.5% to 68.7%; n=337) did and colleagues,24 who, using a Monte Carlo simulation model on October 1, 2021 by guest. Protected not substantially change their smoking behaviour (including 139 applied to data from different national surveys from the USA, who cut down the numbers of cigarettes smoked per day); and concluded that e-cigarette use causes more population-level 22.2% (95% CI: 18.7% to 25.8%; n=116) reported they had harm than benefit.24 started smoking or relapsed as a consequence of e-cigarette use, A large proportion of e-cigarette users (27%) reported having therefore changing their smoking status from non-smoker (ie, (slightly or substantially) reduced their smoking intensity. This, never or ex-smokers) to current smoker (table 2). The corre- however, cannot be considered an achievement from a public sponding proportions among regular users were 24.7% (95% health perspective, given the growing evidence that (1) dual users CI: 18.5% to 31.0%; n=45) who stopped smoking, 47.3% are more likely to transition to exclusive combustible use than to (95% CI: 40.0% to 54.5%; n=86) who did not substantially remain in their dual-use category25 and (2) there is no safe level change their smoking behaviour and 28.0% (95% CI: 21.5% of smoking for cardiovascular disease and overall mortality.26 to 34.5%; n=51) who started smoking or relapsed. Sensitivity Among participants who were current smokers at the time analysis using data from 2017 and 2018 showed that the rates of starting e-cigarette use, only 17% stopped smoking. This of e-cigarette users (re)starting smoking were similar among hardly supports e-cigarette as an effective tool for stopping current (22.0%) and past users (21.4%), while those quitting smoking, in agreement with other evidence.10 27–29 In a previous

Liu X, et al. Tob Control 2019;0:1–5. doi:10.1136/tobaccocontrol-2018-054726 3 Research paper Tob Control: first published as 10.1136/tobaccocontrol-2018-054726 on 18 January 2019. Downloaded from meta-analysis, success in quitting smoking was 28% less in those the survey collected self-reported data, which is likely to suffer who used e-cigarettes than in those who did not use them.10 The recall bias and imprecise responses. To reduce these limitations most recent and comprehensive review gave conflicting results. as far as possible, we explicitly explained the purpose of the The only two randomised controlled trials suggested a possible questions, clearly asking ever e-cigarette users how their use increase in smoking cessation using e-cigarettes with nicotine had affected their smoking habits and providing all the mutually compared with e-cigarettes with no nicotine, but cohort studies exclusive responses. suggested possibly lower rates of quitting using e-cigarettes than Another limitation is that the question on the consequences of with other smoking cessation methods.29 e-cigarette use on their smoking habits was not put to past e-cig- We can confirm that most of the smokers who had started arette users in 2014–2016. However, this may, if anything, have e-cigarette use (more than 80%) continued to smoke tobacco.1 19 led to underestimation of quitting smoking as the consequence of Several studies showed that many smokers transition to dual e-cigarette use. In a sensitivity analysis limited to data from 2017 use, vaping in order to have nicotine intake in places where they and 2018, the number of e-cigarette users (re)starting smoking cannot smoke combustible cigarettes, or so as to bother other were similar among current and past users (around 22%), while people less.30–33 those quitting smoking were more frequent among regular/occa- Pharmacological support for smoking cessation in Italy sional e-cigarette users (20%) than past users (only 9%). Thus, includes nicotine patches, chewing gums and nasal/oral sprays, including past users in 2014–2016 may well have lowered the approved by the Italian Medicines Agency after proof of safety percentage of subjects quitting smoking with e-cigarette use. and efficacy through the publication of clinical trials. These Our classification of e-cigarette users as never, past, occasional products can only be purchased in pharmacies and are promoted and regular did not allow us to record the intensity of use (eg, only to smokers. In contrast, e-cigarettes were marketed without daily use, number of puffs per day), so we could not identify any official approval and are available to anyone, including never intensive e-cigarette use, which has been shown to be directly smokers. Indeed, we found that 1.3% of never smokers had tried related to quitting smoking.45 Our study is also limited by the e-cigarettes, and 0.4% were regular e-cigarette users. Findings sample size, focusing on e-cigarette users only. For this reason, have been similar in the USA, where 4.1% of adult never smokers we merged data from the annual surveys conducted over the last had tried e-cigarettes.34 In agreement with the USA results,35 we 5 years. also found that 16% of ever (and 22% of regular) e-cigarette In conclusion, the number of regular e-cigarette users users had never smoked before using e-cigarettes. The potential increased in Italy from 2014 to 2018. Our data indicate that risk of nicotine addiction among never smokers cannot be over- around 680 000 Italians regularly use e-cigarettes today. Among looked, since the majority of never smokers trying e-cigarettes them, 1 70 000 stopped smoking after using e-cigarettes, while started smoking afterwards. 1 90 000 (re)started smoking conventional cigarettes with e-cig- copyright. The environment is hard put to explain these arette use. transitions. In fact, in Italy over the period there was only a Given the limitations inherent to the cross-sectional study marginal improvement in selective tobacco regulations,36 mainly design and the fact that recall and social desirability biases could aimed at children and which did not affect tobacco prices, not be ruled out in self-reported data, our main findings need adopted in 2016.23 In the meantime, e-cigarettes enjoy 50% to be confirmed by longitudinal studies. Nevertheless, they do lower tax than conventional cigarettes. Although in 2017, excise suggest that, from a public health point of view, e-cigarette taxes were introduced for e-cigarettes, the fiscal benefit for this commerce in Italy has had an unfavourable net effect. Conse- product results in a substantially lower price as compared with quently, if we are not able to regulate the sales, taxation, adver- cigarette tobacco. There are no national regulations against tising and places of use, this product is more likely to act as an http://tobaccocontrol.bmj.com/ e-cigarette use in public places, except in schools,37 and the incentive for smoking rather than a strategy for reducing harm. social desirability of e-cigarette is neutral. A large prospective study conducted in the UK recently What this paper adds confirmed findings from a meta-analysis on adolescents and 38 young adults, showing that baseline ever use of e-cigarettes was ►► The popularity and use of electronic cigarettes (e-cigarette) strongly associated with subsequent starting and escalation of worldwide has substantially spread in recent years. 39 conventional cigarette use among teenagers. Our data too show ►► The scientific community is still debating whether e-cigarettes 16% of young e-cigarette users started smoking as a consequence help or hinder tobacco control. The debate is mainly caused of their e-cigarette use. by the uncertainty on their effectiveness as a tool for smoking In the current tobacco market, there are also heated tobacco cessation. on October 1, 2021 by guest. Protected products (HTPs) that heat disposable tobacco sticks, without ►► We found that in Italy the number of e-cigarette users (re) reaching combustion, to generate a sort of ‘cold smoke’ starting smoking after using e-cigarettes exceeded that of containing nicotine.40 Independent toxicological studies showed users quitting smoking by using these e-cigarettes. that these HTPs release relatively high nicotine levels—similar ►► The spread of e-cigarettes may have an unfavourable net to those released by conventional cigarettes—and non-negli- effect from the public health point of view. gible amounts of harmful substances, including various carcin- ogens.41–43 However, given the belief that they are less harmful, hence the fiscal and regulatory favours, HTP rapidly spread Acknowledgements The authors wish to thank J.D. Baggott for editorial assistance. after 2016 in the Italian tobacco market.40 44 This growth may be responsible, at least partially, for the lower number of Italian Contributors SG had the original idea for the study; RP provided the survey data; XL, AL, SG and RP gave substantial contribution to conception and design of e-cigarette consumers in 2018 compared with 2016–2017. data; AL and XL conducted the data analysis; XL and SG drafted the manuscript; all Our study is limited by its cross-sectional design, which meant authors provided substantial contribution to the interpretation of data and critically we could not observe the time sequence of the causal effects of revised the manuscript; all authors approved the final version of the manuscript. e-cigarette use on smoking cessation. Therefore, the findings Funding The surveys were conducted with the contribution of the Italian Ministry need to be confirmed by large longitudinal studies. In addition, of Health. The work of AL was supported by a fellowship from the Italian Association

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