Efficacy of Electronic Cigarettes for Smoking Cessation: A Systematic Review and Meta-Analysis

Abstract

Objective:

to synthesize evidence about the efficacy of electronic cigarettes versus Nicotine Replacement Therapy and placebo to quit smoking.

Data sources:

We searched for clinical trials with no publication date restriction until December 2019. The search included CENTRAL, MEDLINE, PsycINFO, Science Direct, Center for reviews and dissemination and HTA database and Trip database, clinical trials registries, gray literature and examined the references of relevant articles.

Inclusion and exclusion criteria:

Two review authors independently checked the titles and abstracts then the full text of initial hits. Main outcomes were sustained continuous abstinence rate, 7-day point prevalence abstinence rate, sustained reduction of 50% or greater in baseline cigarette consumption and adverse effects.

Data extraction and synthesis:

Two review authors independently extracted data and assessed risk of bias using the Cochrane RoB 2 tool. We conducted a random-effects model through the Mantel-Haenszel method.

Results:

We retrieved 12 trials involving 9863 participants. CO- validated 1-month continuous abstinence rate improved by 33% in the e-cigarettes group (range 6-66%, moderate evidence). We are uncertain if e-cigarettess influence continuous abstinence rate at 3-, 6- and 12 months as well as sustained reduction of 50% or greater in baseline cigarette consumption at different follow-up periods. One study of 884 participants displayed improved 12-month 7-day point abstinence by 46% (range 17%-82%). E-cigarettes may increase or do not affect the proportion of serious adverse effect at 6 and 12 months follow up.

Conclusion:

Very low certainty evidence supported e-cigarettess to help quit smoking in the short term. There is not enough evidence to determine if e-cigarettess are a safe and efficacious means of smoking cessation in the long term (12+ months).

Keywords

smoking cessation smoking cessation agents smoking reduction tobacco use cessation devices nicotine chewing gum smoke free policy

Introduction

Smoking is a major public health threat and widely recognized as one cause of premature morbidity and mortality. The 2025 target set under the WHO Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020 illustrated that countries should achieve a 30% reduction in tobacco use prevalence using 2010 level as baseline. This corresponds to a maximum total tobacco use prevalence rate of 19.1% for the total population aged 15 years and older. ¹ However, the estimated tobacco uses in 2015, about a quarter (24.9%) of the global population used some form of tobacco. Assuming that current efforts in tobacco control are maintained in all countries, the rate is projected to decline further to around a fifth (20.9%) of the global population by 2025 which is still higher than 2025 target. The estimated prevalence of tobacco smoking is 19.8% in 2015 and projected prevalence is 17.1% in 2025. ¹ Tobacco epidemic According to recent estimates for assessment of smoking prevalence and attributable disease burden in 195 countries and territories 1990–2015, 11·5% of global deaths (6·4 million [95% Uncertainty Interval 5·7–7·0 million]) were attributable to smoking worldwide.² This corresponds to 4.7% (1·2–8·5%) increase in smoking-attributable deaths since 2005 and justifies smoking as the second-leading risk factor for attributable mortality among both sexes in both 2005 and 2015. More than 3-quarters of deaths were males. In 2015, Smoking was ranked among the fifth leading etiological factor to Disability Adjusted Life Years (DALYs) in the same Countries and Territories.² The consequences of tobacco smoking extend beyond the negative effect on individual and population health. The World Health Organization (WHO) estimates that globally, smoking causes over US$500 billion in economic damage each year.³ The total productivity losses caused by smoking each year in the US have been estimated at $151 billion USD. ⁴

Currently, smoking cessation involves behavioral support together with pharmacological interventions. A novel approach is smoking cessation competitions which encourage individuals or groups to win a prize following successful cessation, either through direct competition or by entering a lottery or raffle. However, they have not been shown to enhance long-term cessation rates with very low certainty evidence.⁵ Also, a recent review concluded moderate certainty evidence that neither reduction-to-quit nor abrupt quitting interventions result in superior long-term quit rates when compared with one another.⁶ Pharmacotherapy involves Nicotine Replacement Therapy (NRT) of different forms and E-cigarettess. NRT demonstrated efficacy and The U.S. Food and Drug Administration (FDA) has approved NRT products as well as bupropion and varenicline a smoking cessation aid. In the United States, NRT is available over the counter or by prescription as patches, gum, and lozenges, and by prescription only as a nasal spray and oral inhaler. ⁷ Many meta-analyses reveal that each of these medications is effective. ^8,9 High certainty evidence was recently released based on many participants and well-conducted large number of studies. It concluded that combination NRT works better than a single form of NRT with no difference in efficacy between different forms of NRT.¹⁰

A meta-analysis in 2015 including 1,242 participants showed the use of e-cigarettess was significantly associated with smoking cessation with a pooled Effect Size of 0.20 (95%CI 0.11-0.28).¹¹ The latest evidence from a Cochrane review in 2016 concluded low certainty evidence for effectiveness and safety of e-cigarettess compared to placebo or NRT to quit smoking.¹²

E-cigarettess are widely used as a smoking cessation intervention in the UK. A randomized clinical trial and health technology assessment (HTA) were recently published in 2019 to compare E-cigarettess with nicotine replacement therapy within the UK Stop Smoking Services (SSS).^13,14 Sustained biochemically validated 1-year quit rate with NRT was 10% compared to a quit rate of 18% (risk ratio 1.83, 95% confidence interval 1.30 to 2.59; p < 0.001) in the e-cigarettes arm with reported less cough and phlegm at 1 year in the e-cigarettes group.

However, reported limitations of this HTA is the comparison of e-cigarettess with combined rather than a single form of NRT. As mentioned previously, NRT combinations are more effective than a single NRT. Another concern was a larger proportion of participants in the NRT arm switched to e-cigarettess than from the e-cigarettes arm switched to NRT.¹³

Recent correspondence to the New England Journal of Medicine reported increases in the prevalence of nicotine vaping to approximately 1.3 million additional adolescents who vaped in 2018, as compared with 2017. This corresponds to a percent change increase in prevalence of Vaped nicotine of 2.6, 7.9 and 10% from 2017 to 2018 among 8th-, 10th- and 12th- grade students respectively. ¹⁵ Another report illustrated trends in Adolescent’s vaping and significant increases in 30-day nicotine vaping at each of the 3 students grade levels (12th-, 10th-, and 8th-grade students) from 2018 to 2019 so that vaping prevalence was doubled in each of the 3 grades from 2017 to 2019.^15,16 Consequently, the US Centers for Disease Control and Prevention (CDC) announced a multistate US outbreak of lung injury associated with e-cigarettes use has affected about one thousand people and caused 18 deaths.¹⁷ The majority (80%) of affected patients were younger than 35 years.¹⁸ Lung biopsy for 17 patients with a history of vaping proved histopathological findings suggesting of patterns of acute lung injury and represented a form of airway-centered chemical pneumonitis from one or more inhaled toxic substances (possibly vitamin E acetate in e-cigarettes liquid).^18,19

To our knowledge, no updated systematic review was conducted yet to conclude about the certainty of evidence for adopting e-cigarettess as smoking cessation intervention despite enough debate. We aim to synthesize available evidence to assess the efficacy as well as safety of e-cigarettess versus different forms of NRT and placebo to quit smoking.

Methods

A protocol for this systematic review and meta-analysis was preregistered with PROSPERO (registration number: CRD42020155314).

Criteria for Considering Studies for This Review

Types of studies and PICO (population, intervention, comparison and outcome)

We restricted type of studies by including only clinical trials which are the best design for interventions.²⁰ Outcomes derived from clinical trials are initially rated as high-quality evidence by Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the certainty of evidence per each outcome. No publication date restriction. Only studies written in English were included. Our review involved current smokers regardless of degree or duration of smoking and whether they were motivated to quit smoking. Participants whether adults or adolescents of both sexes were eligible for inclusion in our review. We included interventions using e-cigarettess as a tool for stopping the use of all forms of nicotine delivery. Outcome measures are:

Sustained abstinence rate at different follow-up periods. Abstinence is defined as i.e. a self-report of smoking no more than 5 cigarettes at least for 2 weeks post target quit date (TQD) and confirmed by bio-markers verification through CO reading of either ≤7ppm or ≤10ppm. follow-up in expired breath. We involved only studies using objectively measured biomarkers rather than self-reported information only on smoking behavior.

Reduction in smoking (as measured by the number of cigarettes per day and sustained reduction of 50% or greater in baseline cigarette consumption).

Seven-day point prevalence at different follow-up period as defined as reporting of smoking not a single puff in the previous 7 days.

Adverse effects (e.g. Respiratory, neurological and any other symptoms) of different severities.

Data Sources for Identification of Studies

Electronic searches

We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via PubMed), PsycINFO, Science Direct, Center for reviews and dissemination and HTA database and Trip database.

Searching for other resources

We also searched clinical trials registries: the US National Library of Medicine’s trial registry (clinicalTrial.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) portal. We searched gray literature including Dissertations (ProQuest Dissertations and Theses), Web of Science Thomson Reuters: Conference Proceedings Citation Index, and unpublished manuscripts, examined the references of relevant articles, hand searched topic-specific journals (by Impact Factor) and contacted authors for incomplete data.

Detailed search strategies, Boolean operations, different search techniques, filters and limits are documented in detail in Online Appendix (1).

Data Collection and Analysis

Selection of studies

Two review authors independently checked the titles and abstracts of studies identified by comprehensive search for relevance. The full text of potentially eligible studies was obtained and further assessed for inclusion. Irrelevant studies by full text assessment were excluded (See table of excluded studies with reasons in Online Appendix 2). Any discrepancy was resolved by consensus and discussion with a third author.

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Flow chart illustrated the identification, screening, and inclusion of relevant articles. PRISMA focuses on ways to ensure the transparent and complete reporting of systematic reviews and meta-analysis (Figure 1).

Figure 1.

PRISMA flow diagram.

Data extraction and management

Two review authors abstracted information from studies independently. Any discrepancies were resolved by consensus and discussion with a third independent author. In case of multiple reports per study, we first linked multiple sources by trial registration numbers and authors’ names then, we retrieved and extracted only one report which contained the most useful information for the review. Characteristics of included studies table contained the following data: Authors, study design, location and settings, sample size, patient characteristics, degree and duration of smoking, Nicotine dependence using the Fagerstrom Test of Cigarette Dependence, different follow-up periods, main outcome measures and numerical data for outcome measures (See supplemental data extraction table). For some studies where the analysis was conducted as an intention to treat and per-protocol, we extracted outcomes based on intention to treat to avoid potential bias.

Assessment of risk of bias in included studies

Each eligible study was evaluated by 2 independent authors to determine the study quality. We assessed risk of bias for each study using the revised Cochrane Risk of Bias tool (ROB 2).²¹ Hence, we were able to distinguish between studies which appeared to give a reliable estimate concerning the review question and those studies where there appears to be a strong possibility that bias has been introduced. Any disagreements were discussed with involving of a third author until consensus was reached (Online Appendix 3).

Measures of treatment effect

We calculated the risk ratio (RR) for all categorical outcomes using different follow-up data reported. RR is ((number of events in intervention condition/ N intervention denominator) / (number of events in control condition/ N control denominator)) with respective 95% confidence interval (CI).

Unit of analysis issues

None of the included studies was clustered randomized trials. Participants were the unit of randomization in all studies. In one study where multiple comparisons involved 5 approaches to smoking cessation,²² we retrieved only relevant comparisons related to our review scope to avoid bias. We combined NRT and placebo groups into one combined comparison to avoid double counting of participants in E-cigarettess arm in multi-arm studies.

Dealing with missing data

The analysis was an intention to treat in almost all of the studies.^{14,22

-28} One study reported lost follow up at an early stage of allocation rather than after randomization²⁹ and one study reported that percent of patients lost to follow up are similar in all arms of the study.³⁰

Assessment of heterogeneity

We anticipated clinical diversity due to different follow-up periods as well as different patients’ characteristics. We assessed statistical heterogeneity by Cochrane Q test and by calculating the I² statistic; we considered a value greater than 50% as evidence of substantial heterogeneity.²¹

Assessment of reporting biases

We examined reporting bias by funnel plot and Egger’s regression intercept test.

Data Synthesis

We pooled data from individual studies by random-effects model through the Mantel-Haenszel method using Sidik-Jonkman estimator for tau^{^} ² and Hartung-Knapp-Sidik-Jonkman (HKSJ) adjustment to produce more robust estimates of variance (tau ²). We performed analysis by R software using “devtools,” “dmetar,” “tidyverse,” “meta,” “metaphor” packages.³¹

Subgroup analysis and investigation of heterogeneity

First, we conducted subgroup analysis for different outcomes by type of controls whether NRT or placebo. This step was very important before deciding to combine both arms into one group. Then, we further assessed the impact of different follow-up periods on different outcomes. We planned to conduct sub-group analysis by sex, age groups, severity, and duration of smoking. However, results of individual studies were not stratified by sex to allow for data abstraction per sub-group. Reported duration and severity of smoking are nearly similar in included studies where participants were all adults. So, we did not perform subgroup analysis by these parameters as planned.

Sensitivity analysis

We performed a sensitivity analysis to assess the robustness of pooled estimates for all outcomes after restriction to only studies with low risk of bias.²⁰

Summary of findings table

We created a summary of findings table to conclude about quality of evidence for abstinence outcome based on GRADE approach using GRADEpro software. We assessed 5 domains of study limitations, inconsistency of effect, imprecision, indirectness and publication bias.³²

Results

Description of Studies

Results of the search

Our search retrieved 2518 initial records identified through electronic databases CENTRAL, MEDLINE PubMed and PsycINFO searching. We identified additional 2964 records through ProQuest dissertation, Clinical Trials Registries, Centre for reviews and dissemination and Health Technology Assessment database, Science Direct, Thomson Reuters: Conference Proceedings Citation Index and Gray literature (open gray) (Online Appendix 1). We removed 809 duplicate records. We excluded 4582 records by title and abstract screening and out of 91 full-text articles assessed, 56 were excluded with reasons (Online Appendix 2), 23 ongoing trials and 12 studies were finally included in quantitative as well as qualitative synthesis (See PRISMA flow diagram for searching, Figure 1).

Included studies

We included 12 clinical trials involving 9863 participants.^{4,22

-30,33,34} Mean age for each trial ranged from 28-53 years old. Male predominance ranged from 30 to 100%. The average number of cigarettes smoked ranged from 13 to 21 cigarettes per day. Nicotine dependence using the Fagerstrom test of cigarette dependence was less than 5 in 3 studies,^14,24,29 more than 5 in 6 studies^{23,26
-28,33,34} and not reported in 3 studies. Nine of included studies reported participants attempts to quit smoking while it’s unclear in 3 studies.^24,28,34 Biochemical validation by carbon monoxide reading in exhaled breath was done in all included studies (Supplemental data extraction table).

Risk of bias assessment results

Figures 2, 3 summarizes risk of bias from all included studies. Four studies were judged as a low risk of bias overall 5 domains of RoB 2 tool^4,24,26,29 and the rest 8 studies were judged as unclear risk of bias. Random sequence generation was done by a computer-generated randomization sequence in 8 studies^{4,23,24,26

-29,33} or randomly permuted blocks of different sizes in 2 studies^25,34 while unclear in 2 studies.^22,30 For allocation concealment domain, we judged 6 studies as unclear risk^{22,23,28,30,33,34} and 6 studies as low risk of bias.^4,24

-27,29 For blinding of participants, personnel and outcome measurement, all studies except one had low risk of bias. We rated attrition as low also in all studies except one.³³ Seven trials had a registered protocol where all primary and secondary outcomes were pre-specified and judged as low risk of bias^{4,22
-24,26,29,30} (for details, see Online Appendix 3).

Figure 2.

Risk of bias summary.

Figure 3.

Traffic light plot for risk of bias in each domain for each study.

Effects of e-cigarettess

Please, see the summary of findings table (1) for the effect of all outcomes with a conclusion about the certainty of evidence per outcome.

Sustained abstinence

CO- validated continuous abstinence rate did not differ significantly between comparison groups whether NRT or placebo (Q = 0.19, p = 0.662) along different follow up periods. Biochemically validated 1-month continuous abstinence rate was borderline significant in the e-cigarettes group than control (5 studies, 32.6 vs 23.1%, N = 1970, RR 1.335, 95 % CI 1.068: 1.667). However, 3- month and 6-month abstinence rate didn’t differ significantly between E-cigarettess and control groups (3 Studies, 12.1 vs 12.8%, N = 1099, RR 1.52, 95% CI 0.348; 6.701) and (7studies, N = 5435, 10.2 vs 6.6%, RR 1.347, 95%CI 0.953; 1.903) respectively (Figure 4). E-cigarettess didn’t significantly improve 12-month abstinence than the control group (2 studies, N = 1184, RR 2.52, 95 % CI 0.00; 1444.26), but we didn’t display this in the forest plot due to very wide confidence interval (95 % CI 0.00; 1444.26). Sensitivity analysis by re-analysis of only low risk of bias studies showed a consistent statistically significant difference between E-cigarettess and control group for 1-month abstinence rate (3 studies, 35 vs 23.6%, N = 1571, RR 1.43, 95 % CI 1.03; 1.99). Also, 3-month (2 studies, 19.4 vs 14.8%, N = 799, RR 1.19, 95 % CI 0.07; 19.70) and 6-month CO-validated continuous abstinence rate (3 studies, 23.9 vs 17.2%, N = 1683, RR 1.19, 95 % CI 0.53; 2.67) didn’t differ significantly between both arms. Surprisingly, sustained abstinence rate significantly improved among e-cigarettess group by 81% for 12-month follow-up with precise 95% confidence interval (1 study, 18 vs 9%, N = 884, RR 1.83, 95 % CI 1.30; 2.58) (Figure 5).

Figure 4.

Biochemically-validated continuous abstinence rate by follow-up periods.

Figure 5.

Sensitivity analysis for biochemically-validated continuous abstinence rate by follow-up periods among low RoB studies.

Sustained reduction

Sustained reduction of 50% or greater in baseline cigarette consumption was assessed in 5 studies across 1,2,3,6, and 12 months. Proportion of participants with sustained reduction didn’t differ significantly between E-cigarettes arm and control arm either NRT or Placebo at 1 month (3 studies, 50.9 vs 33.2%, N = 955, RR 1.29, 95 % CI 0.59; 2.82), at 2 month (2 studies, 26.4 vs 21.9%, N = 330, RR 1.27, 95 % CI 0.08; 19.41), 3 Month(3 studies, 43.2 vs 25.3%, N = 1067, RR 1.36, 95 % CI 0.66; 2.79), at 6 month (5 studies, 27.1 vs 13.4%, N = 1981, RR 1.38, 95 % CI 0.90; 2.11) or at 12 month (1 study, 14.5 vs 12%, N = 300, RR 1.21, 95 % CI 0.64; 2.27) (Figure 6). Sensitivity analysis revealed a consistent insignificant difference between E-cigarettess and control groups among the low risk of bias studies at 1, 2, 3- and 6-months follow-up (Figure 7).

Figure 6.

Sustained reduction of 50% or greater in baseline cigarette consumption by follow-up periods.

Figure 7.

Sensitivity analysis for sustained reduction of 50% or greater in baseline cigarette consumption by follow-up periods among low RoB studies.

Seven-day point prevalence abstinence

Five studies assessed this outcome at 1,3,4,6 and 12-month follow-up. We detected insignificant difference between E-cigarettess and control group regarding 7-day point abstinence at 1 month (3 studies, 37.4 vs 23.7%, N = 2166, RR 1.59, 95 % CI 0.84; 2.98), at 3 month (3 studies, 31.6 vs 23%, N = 1424, RR 1.31, 95 % CI 0.56; 3.06), at 4 month (1 study, 6.5 vs 4.5%, N = 68, RR 1.43, 95 % CI 0.16; 13.02) or at 6 month (4 studies, 27.1 vs 21.1%, N = 2308, RR 1.30, 95 % CI 0.71; 2.38) (Figure 8). However, only one study of 884 participants displayed improved point abstinence by 46% (improvement range 17-82%) in E-cigarettess group relative to control at 12 month (1study, 32.7 vs 22.3%, N = 884, RR 1.46, 95 % CI 1.17; 1.82). Sensitivity analysis by low RoB studies turned insignificant effect to a statistically significant difference in point abstinence between 2 groups at 1 month (2 studies, 35.9 vs 24.6%, N = 1541 , RR 1.40, 95 % CI 1.33; 1.48) while maintained significant effect of E-cigarettess at 12 month (Figure 9).

Figure 8.

Seven-day point prevalence abstinence rate by follow-up.

Figure 9.

Sensitivity analysis for 7-day point prevalence abstinence rate by follow-up among low RoB studies.

Adverse effects

Four studies assessed adverse effects at 6-month follow-up and 2 studies at 12-month follow-up. While insignificant difference was detected between E-cigarettess and control groups in the proportion of serious adverse effects at 6- and 12-month follow-up (Figure 10), sensitivity analysis revealed that serious adverse effects in low RoB studies significantly increased in E-cigarettess by 81% than the control group at 6 month (1 study, 9.3 vs 5.1%, N = 657, RR 1.81, 95 % CI 1.03; 3.19) Figure 11, while still didn’t differ significantly between both groups at 12-month follow-up (1 study, 6 vs 5%, N = 884, RR 1.21, 95 % CI 0.70; 2.08). A study reported non-serious adverse effects such as shortness of breath, wheezing, cough and Phlegm at 12-month follow-up.⁴ Serious adverse events were defined by one study according to International Classification of Diseases 10th edition Australian Modification codes as death, life-threatening, led to hospitalisation or otherwise medically important [i.e., that might not be immediately life but might jeopardise the participant or might require medical or surgical intervention to prevent one of the other outcomes]. ²³ In addition, Bullen et al study considered persistent or significant disability or incapacity and congenital abnormality as serious adverse events. ²⁶

Figure 10.

Adverse effect at 6-month follow-up.

Figure 11.

Sensitivity analysis for adverse effect at 6-month follow-up among low RoB studies.

Nature of non-serious adverse effects reported at 6 months was dry mouth, mouth irritation, breath shortness, throat irritation, headache in 3 studies.^26,27,29

We generated a funnel plot to investigate the likelihood of reporting bias (Figure 12). The figure does not provide evidence of publication bias, but as the number of studies included is low, this should be interpreted with caution.

Figure 12.

Funnel plot for assessment of reporting bias based on sustained abstinence rate.

Discussion

Tobacco smoking is one of the risk factors for non-communicable diseases (NCDs) and still a leading cause of preventable illness and death worldwide. Smoking cessation interventions are vital to interrupt the extrapolated positive trend of tobacco-related deaths.³⁵ Aforementioned Cochrane Review comparing NRT to control demonstrated high-quality evidence of all forms of NRT (gum, transdermal patch, nasal spray, inhalator and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking.³⁶ The last Cochrane review proved low-quality evidence for the efficacy of E-cigarettess for smoking cessation due to the small number of included clinical trials with small number of participants per study.¹² As new clinical trials emerged with contradictory findings, this comprehensive meta-analysis aims to summarize the evidence to help regulatory authorities, policymakers and health care professionals whether to use e-cigarettess as a stop smoking option.

Summary of Main Results

Our review involved 12 studies of 9863 participants. Biochemically-validated continuous abstinence rate was significantly higher in E-cigarettess group than the control group at one-month follow-up (Moderate certainty evidence) but not significantly higher at 3-, 6- or 12- month follow-up (Very low and low certainty evidence respectively). Only one low risk of bias study showed improved 1-year sustained abstinence rate in the e-cigarettess group.⁴ Sustained reduction of 50% or greater in baseline cigarette consumption was assessed in 5 studies across 1,2,3,6 and 12 months and concluded also an insignificant difference between both treatment arms (Very low certainty evidence). Seven-day point prevalence abstinence was also assessed at 1,3,4,6 (Very low certainty evidence) and 12-month follow-up (Moderate certainty evidence) and sensitivity analysis of low RoB studies proved significantly larger proportion of continuous abstinence in E-cigarettess arm at 1- and 12-month follow-up only. This short-term positive effect of E-cigarettess could be attributed to participants’ compliance early in treatment then few regularly use e-cigarettess for quitting smoking. This argument is supported by findings from a study conducted to assess smoking cessation among smokers who plan to quit after a hospitalization. It showed that few contributors used E-cigarettess regularly after 3-month use.³⁷

However, given only 2 studies assessed the effect of e-cigarettes at 12-month follow-up, the available evidence is not supporting long term efficacy of E-cigarettess. Sensitivity analysis of low RoB study, significantly larger proportion of patients who experienced serious adverse effects after E-cigarettes use compared to control group at 6-month,²⁶ while insignificant difference existed between the 2 groups at 1 year.

Agreement and Disagreement With Other Reviews

The last published Cochrane review about the efficacy of E-cigarettes demonstrated low certainty evidence from 2 trials that ECs help smokers to stop smoking compared with placebo ECs.¹² An earlier Cochrane review’s findings supported the same results.³⁸ Our findings differed from that of another review included RCTs as well as cohort and cross-sectional studies.¹¹ it elucidated that Nicotine filled e-cigarettess were more effective for cessation than those without nicotine (pooled Risk Ratio 2.29, 95%CI 1.05-4.97). This difference from our review could be attributed to small no of included clinical trials (only 2) with a smaller sample size of 975 relative to 9 studies with 9292 participants for abstinence outcome in our review. However, the forest plot of this published review showed consistent insignificant study estimates from included trials.¹¹ Another systematic review of 38 studies and 20 studies with control groups (15 cohort studies, 3 cross-sectional studies, and 2 clinical trials) were included in a meta-analysis.³⁹ Odds of quitting cigarettes were 28% lower in those who used e-cigarettess compared with those who did not use e-cigarettess. Authors of this review concluded that e-cigarettess should not be recommended for quitting smoking. A recent report was released by U.S Department of Health and Human Services, Public Health Service, Office of the Surgeon General supports our findings. It concluded that it is difficult to generalize about efficacy for cessation based on clinical trials involving e-cigarettes, and there is presently inadequate evidence to conclude that e-cigarettess, in general, increase smoking cessation. ⁴⁰

Overall Completeness and Applicability of Review

We included only studies where abstinence was not only self-reported but rather biochemically verified by exhaled breath carbon monoxide measurement. Before deciding to combine comparison whether NRT or placebo into one control group, we conducted subgroup analysis by type of comparison per each outcome and illustrated no significant difference between subgroups. We conducted broad and comprehensive search till December 2019 not to miss any relevant research and initially identified over 2500 records. We restricted study design to only randomized clinical trials to minimize any potential bias. However, this limited the number of possibly eligible cohort studies. We followed the Methodological Expectations of Cochrane Intervention Reviews (MECIR) while conducting and reporting our review.

Limitations

A potential limitation was restricting to the English language only studies, so we may miss studies if published in a language other than English. Also, with small number of included studies, absence of evidence of publication bias should be interpreted with caution

The Certainty of the Evidence

The quality of evidence for most of the outcomes derived from included studies was rated as very low quality. This is attributed mainly to serious risk of bias of studies contributed to some outcomes, serious statistical heterogeneity and serious or very serious imprecision of pooled relative risk estimates with wide Confidence intervals that cross the appreciable benefit or clinically important harm. We downgraded RoB by one level only if the study was given a large weight to the pooled estimate, otherwise, we did not downgrade the level of evidence for unclear RoB domain.

Conclusion

There is low certainty evidence that e-cigarettess improve short term (1-month) continuous abstinence rate. We are uncertain whether improvement involves 12-month long-term follow up period given very serious imprecise results from only 2 clinical trials. So, long term efficacy of E-cigarettess is still unknown. We are uncertain if e-cigarettess compared to control whether NRT or placebo influence 7-day point prevalence abstinence rate at 1,3 and 6-month follow up. Moderate certainty evidence suggest that e-cigarettess are likely to improve 7-day point abstinence rate at 1-year as evidenced from only one clinical trial. There is very low certainty evidence of effect of e-cigarettess compared to control whether NRT or placebo on sustained reduction of 50% or greater in baseline cigarette consumption at different follow-up periods. The proportion of serious adverse effect at 6 and 12 months follow up may not differ between e-cigarettess and control groups. Further well-conducted clinical trials are urgently needed to assess the long-term efficacy and safety of e-cigarettess. There is not enough evidence to determine if e-cigarettess are a safe and efficacious means of smoking cessation in the long term (12+ months). Given small number of well conducted clinical trials, the evidence is suggestive but not sufficient to infer that the use of e-cigarettess is associated with increased smoking cessation. Consequently, it is difficult to generalize about efficacy for cessation based on clinical trials involving a E-cigarettess. Policymakers should not suggest e-cigarettess as a smoking cessation aid especially unless new evidence emerges.

So What?

Smoking is a central public health problem. The scope of the burden of disease and death that cigarette smoking imposes on the public’s health is extensive. Nicotine Replacement therapy was approved as smoking cessation tool by the U.S. Food and Drug Administration. No updated systematic review to conclude about the certainty of evidence for adopting E-Cigarettes as smoking cessation intervention despite enough debate. Very low certainty evidence supported e-cigarettes to help quit smoking in the short term. Further clinical trials are needed to assess the long-term efficacy and safety of E-cigarettes and ongoing trials are urgently needed to help concluding about the efficacy of E-cigarettes for smoking cessation.

Supplemental Material

Supplemental Material, sj-pdf-1-ahp-10.1177_0890117120980289 - Efficacy of Electronic Cigarettes for Smoking Cessation: A Systematic Review and Meta-Analysis

Supplemental Material, sj-pdf-1-ahp-10.1177_0890117120980289 for Efficacy of Electronic Cigarettes for Smoking Cessation: A Systematic Review and Meta-Analysis by Shorouk Ibrahim, Mohamed Habiballah and Iman El Sayed in American Journal of Health Promotion

Supplemental Material

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Supplemental Material, sj-pdf-2-ahp-10.1177_0890117120980289 for Efficacy of Electronic Cigarettes for Smoking Cessation: A Systematic Review and Meta-Analysis by Shorouk Ibrahim, Mohamed Habiballah and Iman El Sayed in American Journal of Health Promotion

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Supplemental Material, sj-pdf-3-ahp-10.1177_0890117120980289 - Efficacy of Electronic Cigarettes for Smoking Cessation: A Systematic Review and Meta-Analysis

Supplemental Material, sj-pdf-3-ahp-10.1177_0890117120980289 for Efficacy of Electronic Cigarettes for Smoking Cessation: A Systematic Review and Meta-Analysis by Shorouk Ibrahim, Mohamed Habiballah and Iman El Sayed in American Journal of Health Promotion

Supplemental Material

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Supplemental Material, sj-pdf-4-ahp-10.1177_0890117120980289 for Efficacy of Electronic Cigarettes for Smoking Cessation: A Systematic Review and Meta-Analysis by Shorouk Ibrahim, Mohamed Habiballah and Iman El Sayed in American Journal of Health Promotion

Footnotes

Authors’ Note

Shorouk Ibrahim: Topic selection, question formulation, searching the literature, screening, risk of bias assessment, and writing review report. Mohamed Habiballah: Searching the literature, screening, data extraction, interpretation of findings and writing review report. Iman El Sayed: Topic selection, searching the literature, screening, risk of bias assessment, data extraction, statistical analysis, evidence synthesis by creating summary of finding tables and report writing. A protocol for this systematic review and meta-analysis was preregistered with PROSPERO (registration number: CRD42020155314).

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Mohamed Habiballah

Iman El Sayed

Supplemental Material

Supplemental material for this article is available online.

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