THIS IS A PRE-PRINT PARTIAL VERSION
Full article may be find in:
Nicotine & Tobacco Research, nty047,https://doi.org/10.1093/ntr/nty047
Nicotine & Tobacco Research (2018). DOI: 10.1093/ntr/nty047.
Nicotine & Tobacco Research, nty175, https://doi.org/10.1093/ntr/nty175
E-Cigarettes May Support Smokers With High
Smoking-Related Risk Awareness to Stop
Smoking in the Short Run: Preliminary
Results by Randomized Controlled Trial
Marianna Masiero Claudio Lucchiari Ketti Mazzocco Giulia VeronesiPatrick
Maisonneuve Costantino Jemos Emanuela Omodeo Salè Stefania SpinaRaffaella
Bertolotti Gabriella Pravettoni
Method: The main focus of this article is on a secondary outcome of the study, that is,
the assessment of effectiveness and safety of e-cigarettes in achieving smoking cessation
in a group of chronic smokers voluntarily involved in long-term lung cancer screening.
Participants were randomized into three arms with a 1:1:1 ratio: e-cigarettes (arm 1),
placebo (arm 2), and control (arm 3). All subjects also received a low intensity
Results: Two hundred ten smokers were randomized (70 to nicotine e-cigarettes, 70 to
nicotine-free placebo e-cigarettes, and 70 to control groups). About 25% of participants
who followed a cessation program based on the use of e-cigarettes (arms 1 and 2) were
abstinent after 3 months. Conversely, only about 10% of smokers in arm 3 stopped. A
Kruskal–Wallis test showed significant differences in daily cigarettes smoking across the
three arms (K-W = 6.277, p = .043). In particular, participants in arm 1 reported a higher
reduction rate (M = −11.6441, SD = 7.574) than participants in arm 2 (M =
−10.7636, SD = 8.156) and arm 3 (M = −9.1379, SD = 8.8127).
The primary outcome of this trial was the assessment of the impact of a 3-month e-
cigarettes program to reduce smoking-related respiratory symptoms (dry cough, breath
shortness, mouth irritation, and phlegm) as a consequence of reduced tobacco cigarette
consumption. The secondary outcomes included the assessment of the success rate of
smoking cessation attempts and daily smoking reduction in the three arms, and the
monitoring of safety and toxicity during the study in arms 1 and 2. The present work
illustrates data at 3 months, where the primary outcome was not measured yet. So, we
focused here on smoking stopping, smoking reduction, and safety issues.
We hypothesized that e-cigarette filled with nicotine liquid (arm 1) would be more
effective than nicotine-free e-cigarette (arm 2) and the control group (arm 3) for smoking
reduction and would have no greater risk of side-effects.
A sample size of 210 participants was chosen to assess smoking reduction. Starting with
the expected intrinsic motivation of participants, the study aimed to have at least 80%
retention at 6 months and 70% at 12 months. Considering these figures, we expected to
maintain a statistical power to detect a reduction of 5 cigarettes/day in our smokers
(being the cigarettes per day mean about 20 in the COSMOS population). Thus, using a
two-sided two-sample t-test with a significance level (alpha) of 0.05, a sample size of 49
participants per arm we expected to achieve 80% power to detect a mean reduction of 5
cigarettes/day between any of the two experimental arms and the control arm, assuming
a mean consumption of 20 cigarettes/day in the control arm and common standard
deviation within group of 8.7.
At the baseline, the levels of anxiety and depression were not significantly different
between the three groups. Generally, participants reported normal values, indicating the
absence of clinical depression. Likewise, no differences among groups were found in the
physical and psychological domains based on the LCQ scores. Some common e-
cigarette side effects were reported.
At month 3, we collected complete data about 170 participants. No statistical differences
in the number of missing data were present between arms (χ2(2) = .835, p = .659).
Participants in Arm 1 and Arm 2 had a similar compliance in the use of e-cigarettes. In
fact, considering the number of empty flacons they gave back at the end of the study we
dind’t find any significant difference, though the placebo group used on average less
liquid (Arm 1 M = 10.9 empty flacons; Arm 2 M = 9.8 empty flacons).
Across study arms, 20% of participants (N = 34) stopped smoking at month 3. The
percentage was significantly higher in the nicotine (N = 15; 25.4%) and nicotine-free (N
= 13; 23.4%) e-cigarette groups than in the control group (N = 6; 10.34%) (χ2(2) =
4.899, p = .044).
Next, we compared reduction of cigarette consumption in participants who had used e-
cigarettes (Arm 1 and Arm 2) and those who only received counseling (Arm 3). The
Mann-Whitney U test reported significant differences between conditions (e-cigarettes
vs. control) at month 1 (U = 2.508, p < .010) and at month 3 (U = 2.130, p < .022). The
use of the electronic device actually helped participants reduce daily cigarettes. At
month 3, also the reduction rate showed interesting results. Participants in Arm 3
reported smoking an average of 10.034 cigarettes/day, while participants in Arm 1 and
Arm 2 showed a lower consumption (7.671 and 9.091, respectively). However, while the
difference between Arm 1 and Arm 3 was statistically significant, differences between
Arms 1 and 2 and between Arms 2 and 3 were not.
Considering the mean difference in cigarette consumption between the baseline and
month 3, the Kruskal-Wallis H test for 3 independent samples showed a significant
difference among Arms 1, 2, and 3 (see table 2): Participants in Arm 1 reported a higher
reduction rate (M = -11.644, SD = 7.574) than participants in Arm 2 (M = -10.763, SD =
8.156) and Arm 3 (M = -9.138, SD = 8.8127).
Table 2 here
However, excluding from the reduction analysis the participants who discontinued
smoking, we failed to find any statistical difference, even though in Arm 1 we found the
highest reduction (M = - 9.164 in Arm1; M = -8.262 in Arm2; M = -7.875 in Arm3).
Considering respiratory symptoms, a significant reduction in all conditions was found,
probably due to the decreased number of daily cigarettes smoked by most participants,
independent of study arms. In particular, about 21.5% of participants reported a decrease
in coughing, about 18.50% reported less catarrh, and about 14.5% reported an
improvement in breathing.
Focusing on e-cigarettes tolerability, our participants reported few side effects (see table
3). In particular, at month 1 the most relevant complain was “burning throat”. It was
reported by about 23% of participants using liquid containing nicotine (while only about
4% of participant reported the same complain using nicotine-free liquid). However, at
month 3 we observed a drastic decrease of the symptom. Cough was also reported at
month 1 by about 10% of participants, both using nicotine and nicotine-free liquid. Also
in this case, the symptom decreased during time.
In this study, we tested the efficacy of e-cigarettes as cessation treatment in a sample of
chronic smokers involved in a screening program. Our main result is that the use of e-
cigarettes helped participant stop smoking since about one-quarter of participants who
followed a cessation program based on e-cigarettes (both with and without nicotine) and
a low-intensity counseling were abstinent after three months. Conversely, about 10% of
smokers stopped following a program based only on a low-intensity counseling.
Furthermore, e-cigarettes increased the reduction rate in participants who continued
smoking. In fact, although all participants reported a significant reduction of daily
cigarette consumption compared to the baseline, the use of e-cigarettes (including those
without nicotine) allowed smokers achieving a better result. The few side effects
reported, which were also reported in other studies,36-39 were well managed by
participants and showed no increase during the treatment. Consequently, our findings
confirm the efficacy as well as the safety of e-cigarettes in a short-term period.
Although participants in Arm 1 generally achieved better results, the placebo condition
was effectively as well, in some case leading to comparable outcomes. This result has
not been described before and provides suggestions for potentially fruitful new lines of
Future studies should analyze costs and benefits related to the use of nicotine-free e-
cigarettes in high-risk patients who smoke. In particular, the efficacy of combining
clinical counseling and nicotine-free e-cigarettes for high-risk patients should be
discussed. In our view, it could have pivotal implications in clinical practice. We believe
that nicotine-free e-cigarettes might be a first-line choice, particularly for subjects who
have severe diseases (for example, those with heart problems) and cannot use nicotine or
receive other medical treatments. However, the lack of differences between nicotine and
nicotine-free device effects on smoking might also be linked to the low dosage of
nicotine we adopted. In fact, using a device working at 10 W with an 8 mg/mL nicotine
concentration we obtained quite a low dosage (less than 0.1 mg per puff) with respect to
the nicotine normally assumed daily by a chronic smoker40. This may explain why
results in Arm 1 (nicotine e-cigarettes) and Arm 2 (nicotine-free e-cigarettes) are so
similar. Increasing nicotine concentration probably may enlarge this difference, although
we need targeted research to establish which protocol may optimize the risk/benefits
In conclusion, taking into consideration the perspective of personalized medicine, e-
cigarettes based protocols associated with new ICT-driven models of self-management
may be implemented to support people to better handle behavioral changes and side
effects.41-45 This is true for ready-to-quit smokers (such as our participants) but could
also be advantageous for less motivated smokers engaged in clinical settings.
Limits of the Study
The number of initial dropouts, i.e., participants who explicitly declared the willingness
not to continue within the first month (1 participant in Arm 1, 2 in Arm 2, and 6 in Arm
3) was particularly high in in the control group. It might suggest that motivation to
participate to the study was related to the possibility of using the e-cigarettes rather than
an actual willingness to stop smoking. During the study we had some missing data
(12.4% at month 1; 21.9% at month 2; 18.1% at month 3) that limit our results.
Monthly, we monitored the use of e-cigarettes during the counseling calls and the
follow-up to manage potential problems. However, we didn’t assess systemically any
quantitative measure about the actual use. For this reason, only qualitative considerations
can be done about the different use of e-cigarettes between subjects in Arm 1 and Arm 2.
Furthermore, the number of smoked cigarettes was recorded as participants’ self-reports,
which might have led to a measurement bias. The impossibility of assessing carbon
monoxide in an expired breath at month 3 because of the study design cannot
disambiguate the aforementioned possible explanation. However, if present, this effect
was constant in all 3 arms, thus not affecting the exhibited effects. Finally, this paper
focused on a secondary outcome, since the primary one was supposed to be assessed at
Clinicaltrials.gov NCT02422914; https://clinicaltrials.gov/ct2/show/NCT02422914
This study was supported by a grant from Fondazione Umberto Veronesi (FUV).
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