Impact of electronic cigarette and heated tobacco product on conventional smoking: an Italian prospective cohort study conducted during the COVID-19 pandemic

Silvano Gallus; Chiara Stival; Martin McKee; Giulia Carreras; Giuseppe Gorini; Anna Odone; Piet A van den Brandt; Roberta Pacifici; Alessandra Lugo

doi:10.1136/tc-2022-057368

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Impact of electronic cigarette and heated tobacco product on conventional smoking: an Italian prospective cohort study conducted during the COVID-19 pandemic

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No uncertainty exists around the failure of novel products as harm reduction strategies in Italy
Silvano Gallus, Alessandra Lugo, Giuseppe Gorini, Roberta Pacifici and Martin McKee
Published on: 20 February 2024
Inappropriate study design cannot predict smoking initiation and relapse with e-cigarette and heated tobacco product use
Venera Tomaselli, Pasquale Caponnetto
Published on: 20 February 2024

Published on: 20 February 2024
No uncertainty exists around the failure of novel products as harm reduction strategies in Italy
- Silvano Gallus, Head, Laboratory of Lifestyle Epidemiology Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
- Other Contributors:
  Alessandra Lugo, Senior Researcher
  
  Giuseppe Gorini, Senior Epidemiologist
  
  Roberta Pacifici, Head, National Centre on Addiction and Doping
  
  Martin McKee, Professor of European Public Health
NOT PEER REVIEWED
We welcome discussion of our research even when it comes from those whose view on accepting tobacco industry funding is very different from ours. Tomaselli and Caponnetto, from the Center of Excellence for the acceleration of HArm Reduction (CoEHAR),[1] a group funded by the Foundation for a Smoke-Free World (FSFW), an organisation established by Philip Morris International (PMI) with funding of US$1 billion that promotes electronic cigarettes (e-cigarette) and heated tobacco products (HTP),[2] take issue with our finding [3] that these products increase smoking initiation and relapse and reduce quitting. [4]
First, we are puzzled by their main criticism. Of course we agree that smokers who have failed to quit, ex-smokers prone to relapse, and never smokers prone to engage in addictive behaviours could be overrepresented among the baseline e-cigarette or HTP users in our study.[4] But this does not undermine our main conclusions. Even if we were to assume that either none or all novel product users in our cohort were more prone to addiction, our results would still be incompatible with the argument, which underpins the work of FSFW, that these products can reduce smoking conventional cigarettes when used as consumer products.
Second, we hope that they agree with us that we should consider the totality of evidence on a topic as it is rare for a single study to provide a definitive answer, and especially given the record of the tobacco ind...
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NOT PEER REVIEWED
We welcome discussion of our research even when it comes from those whose view on accepting tobacco industry funding is very different from ours. Tomaselli and Caponnetto, from the Center of Excellence for the acceleration of HArm Reduction (CoEHAR),[1] a group funded by the Foundation for a Smoke-Free World (FSFW), an organisation established by Philip Morris International (PMI) with funding of US$1 billion that promotes electronic cigarettes (e-cigarette) and heated tobacco products (HTP),[2] take issue with our finding [3] that these products increase smoking initiation and relapse and reduce quitting. [4]
First, we are puzzled by their main criticism. Of course we agree that smokers who have failed to quit, ex-smokers prone to relapse, and never smokers prone to engage in addictive behaviours could be overrepresented among the baseline e-cigarette or HTP users in our study.[4] But this does not undermine our main conclusions. Even if we were to assume that either none or all novel product users in our cohort were more prone to addiction, our results would still be incompatible with the argument, which underpins the work of FSFW, that these products can reduce smoking conventional cigarettes when used as consumer products.
Second, we hope that they agree with us that we should consider the totality of evidence on a topic as it is rare for a single study to provide a definitive answer, and especially given the record of the tobacco industry in cherry picking those bits that support their case.[5] Their concern about motivation of users was addressed in the US PATH cohort study. This rejected the hypothesis that e-cigarettes as consumer products are effective quit aids even when being used for this purpose, rather than as a recreational product.[6] It compared recent quitters using e-cigarettes during their last quit attempts with those using any pharmaceutical aid, finding that smokers who reported using e-cigarettes in their most recent quit attempt were less likely to successfully quit, and that subjects who switched to e-cigarettes reported higher relapse rates than attempters who did not use e-cigarettes to quit.[6] Similarly, a meta-analysis of 20 observational studies found that, when restricting the analyses to participants who wanted to quit, the odds ratio (OR) of smoking cessation for users of e-cigarettes as compared to non-users was 0.85 (95% confidence interval: 0.68-1.06).[7] Although we did not report it in our paper,[3] we did collect information on quit attempts over the past month among current smokers in our study: all four e-cigarette users and four HTP users who made any quit attempt continued smoking at follow-up.
Tomaselli and Caponnetto also express concern around the fact that we considered current product user, a classification that includes both occasional and daily users. Although we had collected the information on occasional vs. daily use of these products, several models to estimate relative risk (RR) did not converge when these were analysed separately, while combining them generated more stable and robust RR estimates.[3] Table 1 (available online at: http://www.epideuro.eu/wp-content/uploads/2022/12/Table1.pdf) shows OR estimates also considering occasional and daily users separately. The association between HTP regular use and relapse did not reach statistical significance. This is almost certainly because of the small number, eight, of ex-smokers who were regular HTP users. This does not change the key message of our study: the use (both occasional and regular) of e-cigarettes and HTPs predicts smoking initiation and relapse, and appear to reduce smoking cessation rates.
Tomaselli and Caponnetto point to the last Cochrane Review of randomized controlled trials (RCT) comparing e-cigarettes with nicotine replacement therapy (NRT) for smoking cessation.[8] However, this has almost no relevance to our findings. We do not dispute that any form of nicotine delivery can aid cessation when part of a structured and time-limited therapeutic package supported by behavioural interventions. This is entirely different from their use as a consumer product. However, as they mention this review, we feel obliged to raise our concerns on its findings, including: i) the extremely low success rate (e-cigarettes fail in 90% of cases)[8]: ii) no RCT compares e-cigarettes with standard care in clinical settings (i.e., varenicline or bupropion or cytisine), by far more effective in smoking cessation according to other Cochrane Library reviews;[8, 9] iii) e-cigarettes are heterogeneous products so those used in RCTs cannot be considered representative of all products; and iv) more than 80% of those quitting through e-cigarette continue its use after treatment,[8] increasing the risk of relapse, as outlined in our study.[3] More importantly, our study concurs with the totality of the scientific literature that, when used as a consumer product, e-cigarettes are not effective in increasing smoking cessation.[7]
To study the individual trajectories of conventional cigarette smoking in the general population (including non-smokers) outside the clinical setting, interventional studies are clearly not an option. Hence, we are forced to rely on observational studies, with prospective cohort studies best able to reduce risk of bias and increase reliability and generalizability. To our knowledge, our study is the first cohort designed so far involving the general population, at least in Europe. It supports findings from other Italian cross-sectional studies[10] and analyses of trends of the prevalence of conventional cigarette smoking (for the first time substantially increasing after seven decades of continuous decrease) and sales of conventional cigarettes (for the first time no more decreasing after two decades of substantial fall).[11]
Our assessment of the totality of the evidence, including our findings, persuades us that these products represent a threat to tobacco control and we remain unconvinced by the arguments by those associated with CoEHAR whose commentaries challenge the accumulating evidence opposing novel nicotine-containing products undertaken by researchers without conflicts of interests.[12]

References
1. Tobacco Tactics. Centre of Excellence for the Acceleration of Harm Reduction (CoEHAR) (available online at: https://tobaccotactics.org/wiki/coehar/; last access 13 December 2022). 2022.
2. van der Eijk Y, Bero LA, Malone RE. Philip Morris International-funded 'Foundation for a Smoke-Free World': analysing its claims of independence. Tob Control 2019; 28: 712-718.
3. Gallus S, Stival C, McKee M et al. Impact of electronic cigarette and heated tobacco product on conventional smoking: an Italian prospective cohort study conducted during the COVID-19 pandemic. Tob Control 2022.
4. Tomaselli V, Caponnetto P. Inappropriate study design cannot predict smoking initiation and relapse with e-cigarette and heated tobacco product use. Tob Control 2022.
5. Diethelm P, McKee M. Denialism: what is it and how should scientists respond? Eur J Public Health 2009; 19: 2-4.
6. Chen R, Pierce JP, Leas EC et al. Effectiveness of e-cigarettes as aids for smoking cessation: evidence from the PATH Study cohort, 2017-2019. Tob Control 2022.
7. Wang RJ, Bhadriraju S, Glantz SA. E-Cigarette Use and Adult Cigarette Smoking Cessation: A Meta-Analysis. Am J Public Health 2021; 111: 230-246.
8. Hartmann-Boyce J, Lindson N, Butler AR et al. Electronic cigarettes for smoking cessation. Cochrane Database Syst Rev 2022; 11: CD010216.
9. Howes S, Hartmann-Boyce J, Livingstone-Banks J et al. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2020; 4: CD000031.
10. Liu X, Lugo A, Davoli E et al. Electronic cigarettes in Italy: a tool for harm reduction or a gateway to smoking tobacco? Tob Control 2020; 29: 148-152.
11. Gallus S, Borroni E, Odone A et al. The Role of Novel (Tobacco) Products on Tobacco Control in Italy. Int J Environ Res Public Health 2021; 18.
12. Polosa R, Farsalinos K. A tale of flawed e-cigarette research undetected by defective peer review process. Intern Emerg Med 2022.
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Conflict of Interest:
None declared.
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Published on: 20 February 2024
Inappropriate study design cannot predict smoking initiation and relapse with e-cigarette and heated tobacco product use
- Venera Tomaselli, Associated Professor 1Department of Political and Social Sciences, University of Catania, Italy 2Center of Excellence for the Acceleration of Harm Re
- Other Contributors:
  Pasquale Caponnetto, Researcher
NOT PEER REVIEWED
The study by Gallus et al. [1] sought to establish whether electronic cigarettes (ECs) and heated
tobacco products (HTPs) reduce or increase the probability of smoking in a cohort of Italian
participants and concluded that both EC and HTP use predict smoking initiation and relapse
among respondents. We would like to raise some concerns about the interpretation of the study
findings. The study suffers from a potentially crucial bias of the outcome being present at baseline, as
compared non-users with people who were already using products at baseline. Specifically,
smokers who were using ECs or HTPs at baseline may already represent failed attempts to quit at
baseline. Additionally, ex-smokers using these products may have already been in a trajectory to
relapse to smoking at, or even long before, baseline, and may in fact have initiated such product
use in order to avoid relapse. Still, this group may represent ex-smokers who were at higher risk
for relapsing at baseline compared to ex-smokers who did not use these products. Similarly,
never smokers who use novel nicotine products may represent individuals prone to the
engagement of an inhalational habit. Therefore, they would be more likely to initiate smoking.
The situation is very similar to assessing if people who drink beer at baseline are more likely to
drink whiskey at follow up compared to non-drinkers of bee...
Show More

NOT PEER REVIEWED
The study by Gallus et al. [1] sought to establish whether electronic cigarettes (ECs) and heated
tobacco products (HTPs) reduce or increase the probability of smoking in a cohort of Italian
participants and concluded that both EC and HTP use predict smoking initiation and relapse
among respondents. We would like to raise some concerns about the interpretation of the study
findings. The study suffers from a potentially crucial bias of the outcome being present at baseline, as
compared non-users with people who were already using products at baseline. Specifically,
smokers who were using ECs or HTPs at baseline may already represent failed attempts to quit at
baseline. Additionally, ex-smokers using these products may have already been in a trajectory to
relapse to smoking at, or even long before, baseline, and may in fact have initiated such product
use in order to avoid relapse. Still, this group may represent ex-smokers who were at higher risk
for relapsing at baseline compared to ex-smokers who did not use these products. Similarly,
never smokers who use novel nicotine products may represent individuals prone to the
engagement of an inhalational habit. Therefore, they would be more likely to initiate smoking.
The situation is very similar to assessing if people who drink beer at baseline are more likely to
drink whiskey at follow up compared to non-drinkers of beer. People who want to use alcohol
and are using alcohol at baseline, would be much more likely to use stronger liquor at follow up
compared to those who do not use alcohol. This represents a typical case of the common liability
model of addressing risk behaviors, which has been frequently misinterpreted as a “gateway”
theory. Moreover, the study design does not allow for any assessment of the motivations to use these
products. It is unclear if and how many participants were using nicotine products in an attempt to
quit (for smokers) or an attempt to prevent relapse (for ex-smokers) instead of simply
experimenting out of curiosity. Notably, while the study examined daily use through the
questionnaire, results were presented only for current users, a classification that includes both
occasional and daily users. Studies have shown that classifying daily and occasional users in the
same group can often be misleading (2-5), since frequency of use is an indirect indicator of
motivation for use (6), but also a determinant of their success as smoking substitutes (7). The study also suffers from the unpredictability of conducting surveys during COVID-19
lockdowns. Of note, there is convincing evidence that the coronavirus outbreak has had a
negative impact, inducing or exacerbating addictive behaviors as coping mechanisms. It is
possible that smokers preferred smoking – rather than alternatives – depending on their level of
distress (8,9).
Last but not least, the latest Cochrane Review finds high certainty evidence that nicotine e-cigarettes
are more effective than traditional nicotine-replacement therapy (NRT) in helping people quit
smoking (10). In conclusion, methodological issues of the study design makes it inappropriate to address the
research question.

1. Gallus S, Stival C, McKee M, Carreras G, Gorini G, Odone A, van den Brandt PA,
Pacifici R, Lugo A. Impact of electronic cigarette and heated tobacco product on
conventional smoking: an Italian prospective cohort study conducted during the COVID19 pandemic. Tob Control. 2022 Oct 7:tobaccocontrol-2022-057368. doi: 10.1136/tc2022-057368.
2. Hitchman SC, Brose LS, Brown J, Robson D, McNeill A. Associations Between ECigarette Type, Frequency of Use, and Quitting Smoking: Findings From a Longitudinal
Online Panel Survey in Great Britain. Nicotine Tob Res 2015;17:1187-94.
3. Farsalinos, K. E.; Poulas, K.; Voudris, V.; & Le Houezec, J. Prevalence and correlates of
current daily use of electronic cigarettes in the European Union: analysis of the 2014
Eurobarometer survey. 2017, Internal and emergency medicine, 12(6), 757–763.
https://doi.org/10.1007/s11739-017-1643-7
4. Farsalinos, K. E.; & Barbouni, A. Association between electronic cigarette use and
smoking cessation in the European Union in 2017: analysis of a representative sample of
13 057 Europeans from 28 countries. 2021, Tobacco control, 30(1), 71–76.
https://doi.org/10.1136/tobaccocontrol-2019-055190
5. Farsalinos, K. E.; Polosa, R.; Cibella, F.; & Niaura, R. Is e-cigarette use associated with
coronary heart disease and myocardial infarction? Insights from the 2016 and 2017
National Health Interview Surveys. 2019, Therapeutic advances in chronic disease, 10,
2040622319877741. https://doi.org/10.1177/2040622319877741.
6. Amato MS, Boyle RG, Levy D. How to define e-cigarette prevalence? Finding clues in
the use frequency distribution. Tob Control. 2016 Apr;25(e1):e24-9. doi:
10.1136/tobaccocontrol-2015-052236
7. Harlow AF, Stokes AC, Brooks DR, Benjamin EJ, Leventhal AM, McConnell RS,
Barrington-Trimis JL, Ross CS. Prospective association between e-cigarette use
frequency patterns and cigarette smoking abstinence among adult cigarette smokers in the
United States. Addiction. 2022 Dec;117(12):3129-3139. doi: 10.1111/add.16009.
8. Avena NM; Simkus J; Lewandowski A; Gold MS; Potenza MN. Substance Use
Disorders and Behavioral Addictions During the COVID-19 Pandemic and COVID-19-
Related Restrictions. Front Psychiatry. 2021;12:653674.
HTTPS://doi.org/10.3389/fpsyt.2021.653674
9. Caponnetto, P.; Inguscio, L.; Saitta, C.; Maglia, M.; Benfatto, F.; & Polosa, R. Smoking
behavior and psychological dynamics during COVID-19 social distancing and stay-athome policies: A survey. 2020, Health Psychology Research, 8(1).
https://doi.org/10.4081/hpr.2020.9124
10. Hartmann-Boyce J; Lindson N; Butler AR; McRobbie H; Bullen C; Begh R; Theodoulou
A; Notley C; Rigotti NA; Turner T; Fanshawe TR; Hajek P. Electronic cigarettes for
smoking cessation. 2022, Cochrane Database of Systematic Reviews 2022, Issue 11. Art.
No.: CD010216. DOI: 10.1002/14651858.CD010216.pub7.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010216.pub7/...
s
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Conflict of Interest:
VT and PC has been affiliated to the CoEHAR since December 2019 in a
pro bono role. PC is coauthor of a protocol paper supported by an Investigator-Initiated Study
award program established by Philip Morris International in
2017.
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