Electronic Cigarettes Versus Varenicline for Smoking Cessation: A Systematic Review and Meta-analysis of in-person Support Augmentation Strategies

Abstract

Tobacco smoking is a global health crisis, causing over 8 million deaths annually, including 1.3 million in India. The rise of electronic cigarettes (e-cigarettes) has raised questions about their effectiveness compared to traditional aids like varenicline. This systematic review evaluates the comparative effectiveness of e-cigarettes and varenicline in facilitating smoking cessation, especially with in-person support strategies. The review followed the PRISMA guidelines and utilized the PICOS framework to include randomized controlled trials and clinical trials published up to April 9, 2024. A comprehensive search across PubMed, EBSCO, and the Cochrane Library identified relevant studies comparing e-cigarettes and varenicline against placebo or other cessation methods. Data extraction focused on continuous abstinence rates, point prevalence abstinence, and reductions in cigarette consumption. Five studies were included in the analysis. Tattan Birch et al. (2023) reported a 47.9% abstinence rate in the e-cigarette-varenicline group compared to 31.8% for varenicline alone (RR = 1.51). The ECSMOKE trial found noninferiority between e-cigarettes with nicotine and varenicline, with continuous abstinence rates of 30% versus 28%, respectively. Other studies highlighted the significant impact of varenicline on reducing smoking behavior and urges. The findings suggest that both e-cigarettes and varenicline are effective smoking cessation aids, particularly when combined with behavioral support. However, the high risk of bias in the included studies necessitates cautious interpretation. Future research should focus on long-term outcomes and the psychological factors influencing cessation success to enhance public health strategies aimed at reducing smoking prevalence.

BACKGROUND

The global health crisis posed by smoking is profound, with the World Health Organization (WHO) estimating that tobacco use results in over 8 million deaths annually. This staggering figure includes more than 7 million deaths from direct smoking and approximately 1.2 million from second-hand smoke exposure, highlighting the extensive impact of tobacco on public health.[1,2] In India, the situation is particularly dire, with an estimated 267 million tobacco users, including 99 million smokers, leading to nearly 1.3 million smoking-related deaths each year.[3,4]

As the prevalence of smoking continues to exert a heavy toll on health systems, the emergence of electronic cigarettes (e-cigarettes) has sparked considerable debate. These battery-operated devices deliver nicotine via vapor rather than combustion, often marketed as a safer alternative for smokers and a potential cessation aid. The rise in e-cigarette use, especially among youth, has been significant; however, concerns persist regarding their safety and long-term health effects. While some studies suggest that e-cigarettes may help certain individuals quit smoking, they are not without risks, including respiratory issues, cardiovascular complications, and nicotine dependence.[5,6]

In the realm of pharmacological interventions, varenicline has emerged as a key medication for smoking cessation. Acting as a partial agonist at nicotinic acetylcholine receptors, varenicline alleviates withdrawal symptoms and reduces the rewarding effects of nicotine. Research indicates that varenicline significantly increases the chances of quitting compared to placebo and other cessation methods, including nicotine replacement therapies (NRTs) and bupropion. Nevertheless, it is important to note that varenicline can also cause side effects, such as nausea and insomnia, and, in rare cases, neuropsychiatric issues.[7,8]

This systematic review aims to evaluate the comparative effectiveness of e-cigarettes and varenicline in facilitating smoking cessation, particularly in studies that incorporate in-person support augmentation strategies. In-person support, which includes counseling and behavioral therapy, is critical to smoking cessation efforts as it provides individuals with the necessary skills and encouragement to quit. Evidence suggests that combining nicotine delivery methods (such as e-cigarettes or nicotine replacement therapy) or pharmacological agents like varenicline with behavioral support is often more effective than using either method alone.[7,9,10]

The review will analyze a variety of studies assessing the success rates of quitting associated with e-cigarettes compared to varenicline, taking into account demographic factors, duration of use, and adherence to support programs. By synthesizing findings from these studies, the review seeks to provide a comprehensive evaluation of the relative effectiveness of these interventions and their potential contributions to public health strategies aimed at reducing smoking prevalence.

Furthermore, the implications of these findings for policymakers and healthcare practitioners will be explored. This includes addressing broader issues related to smoking cessation, such as accessibility, cost-effectiveness, and the potential for harm reduction. Given the widespread use of both e-cigarettes and varenicline, a thorough understanding of their effectiveness and safety profiles is essential for informing clinical practices and public health policies. By evaluating the comparative effectiveness of these two approaches, the review aims to enhance our understanding of how best to support individuals in their efforts to quit smoking and ultimately improve public health outcomes.

METHODS

Study selection and search strategy

We used the international PICOS format:

P – Population: Adults who are current smokers

I – Intervention: E-cigarette kit or Varenicline

C – Comparative Group: Varenicline or behavioral counseling

O – Outcome: Quit rates achieved in these studies

S – Studies Included: Randomized controlled trials (RCTs) and clinical trials.

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria[11] were followed in the conduct of this systematic review. This review’s review procedure (CRD42024534098) was recorded in PROSPERO.

Review question

“What is the comparative effectiveness of e-cigarettes and Varenicline in aiding smoking cessation when augmented with in-person support strategies?”

The methodology employed for this systematic review encompassed an extensive search across three academic databases: PubMed, EBSCO, and the Cochrane Library. To find relevant research, we searched for “e-cigarette,” “varenicline,” “behavioral counseling,” and “smoking cessation.” The detailed search strategy is given in the supplementary file. Only English-language publications were included in the search, and all records up to April 9, 2024 were included. Boolean operators were utilized to effectively combine the keywords, and filters were implemented to eliminate nonrelevant studies, specifically those not related to RCTs or clinical trials. This search strategy ensured a comprehensive and systematic approach to gathering all relevant literature regarding the efficacy of e-cigarettes, varenicline, and behavioral counseling in smoking cessation.

Inclusion criteria

In this systematic review, we incorporated RCTs and controlled clinical trials (CCTs) that evaluated the efficacy of electronic cigarettes (e-cigarettes) or varenicline in facilitating smoking cessation among adults aged 18 and older. The studies considered for inclusion compared these interventions against a placebo, no intervention, or alternative smoking cessation methods, and reported outcomes such as continuous abstinence rates, point prevalence abstinence, and reductions in cigarette consumption. Our review encompassed studies published up to April 9, 2024 in the English language.

Exclusion criteria

We excluded observational studies, case reports, reviews, studies focused on pregnant women, patients with systemic diseases, and those evaluating smoking cessation aids other than e-cigarettes or varenicline that did not report smoking cessation outcomes. Studies published in languages other than English were also excluded.

Evidence selection

The process of searching and retrieving information is depicted in [Figure 1]. The search results were initially imported into Zotero referencing software, where duplicate entries were eliminated. The revised library was subsequently imported into Rayyan, a platform designed for screening systematic reviews. Two investigators assessed the remaining studies based on their titles and abstracts to determine eligibility after the removal of duplicates. This evaluation was conducted twice while ensuring a masked review. The investigators then met to resolve any discrepancies. In instances where consensus could not be reached, a designated arbitrator made the final decisions.

Figure 1.

PRISMA flow diagram showing the selection process of studies included in the systematic review and meta-analysis

Data extraction and quality assessment

The primary objective of this study is to evaluate the effectiveness of e-cigarettes and varenicline for smoking cessation, while secondary objectives assess safety and compare their efficacy with other cessation aids. The literature was meticulously reviewed, and relevant data were extracted and organized in an Excel spreadsheet, following PRISMA guidelines. Key information, such as study identification, authors, publication details, funding sources, study design, interventions, and outcomes, was documented. Discrepancies among primary reviewers were resolved by a third reviewer. The Cochrane Risk of Bias Tool for Randomized Trials (RoB 2, Version 2.6)[12] was used to evaluate study quality across five domains: randomization, intervention deviations, missing outcome data, outcome measurement, and selection of reported results. Each study’s assessment was conducted by one team member and reviewed by another, with final determinations reached by consensus [Table 1].

Table 1.

Extraction table of all selected studies

Author name	Address of author	Location of the study	Fundings	Study design and time duration	Inclusion criteria	Exclusion criteria	Sample size, attrition, and its reason
Tattan-Birch et al.[29]	Department of Behavioural Science and Health, University College London, 1-19 Torrington Place, London, WC1E 6BT, UK	United Kingdom	Cancer Research UK (MR/S037519/1); Cancer Research UK (PRCRPG-Nov21\100002)	Randomized controlled trial Parallel group and between April 2019 and March 2020	Proficient in English. Not pregnant or breastfeeding. Opted to use varenicline. Willing to try e-cigarettes. Had not regularly used e-cigarettes in the past 6 months.	The study did not specify exclusion criteria.	92 participants, with 48 in the e-cigarette-varenicline group and 44 in the varenicline-only group. Attrition-not systematically documented.
Berlin et al.[30]	ivan.berlin@aphp.fr	France. Recruitment is either local (a) directly by the centers or centralized (b) using a web page and a centralised study-specific phone number and email address.	Programme Hospitalier de Recherche Clinique (PHRC) National 2015: AOM15002, Ministry of Health, France	Randomized, placebo -controlled, double-blind, double-dummy, parallel-group trial and began recruitment in March 2017 and continued until January 2019, with the last follow-up occurring in April 2019	Smokers of ≥10 cigarettes/day for the past year. Aged 18-70 years. Motivation to quit (score >5 on a scale of 0-10). Signed written informed consent. Understand and speak French. Women of childbearing age using effective contraception. Affiliated with a health insurance system.	Exclusion criteria included: unstable disease in the last 3 months, life-threatening condition with <3 months life expectancy, alcohol use disorder (AUDIT-C ≥10), recent (≤6 months) drug abuse/dependence, regular non-cigarette tobacco use, current/previous (≤6 months) e-cigarette use, pregnancy, and lactose intolerance.	Total participants: 650 smokers EC with nicotine (ECwN) group: 280 participants. Varenicline group: 280 participants.EC without nicotine (ECwoN) group: 90 participants. Lost to follow-up: 55 participants (8.5%). Withdrawal due to adverse events: 25 participants (3.8%). Other reasons: 19 participants (2.9%).
Hawk et al.[31]	Department of Psychology, University at Buffalo, 206 Park Hall, Buffalo, NY 14260	University at Buffalo, Buffalo, New York	Grant R01CA206193 from the NCI, grants UL1TR001412, UL1TR002001 (University of Rochester), by the Canada Research Chair in Pharmacogenetics program, and by foundation grant FDN-154294 from the Canadian Institutes of Health Research.	Randomized, double-blind, placebo-controlled clinical trial design and October 2, 2017, to December 9, 2020	Adult smokers of combustible cigarettes, aged 18 to 70 years, smoked at least 10 cigarettes per day for at least 6 months. initially required an expired-air CO level >7 ppm. To include more diverse participants, adjusted in November 2019 to reduce the cigarette per day to 5 and eliminate the CO. Also, motivation to quit smoking	Exclusion criteria also included: use of other tobacco/nicotine in the past 7 days, cessation medications in the past 14 days, lifetime schizophrenia or bipolar disorder, current antipsychotic use, suicidal ideation in the past year, current depression, moderate-to-severe risk from illicit/nonmedical drug use, and pregnancy.	320 participants, with 163 assigned to the extended run-in group and 157 to the standard run-in group. Attrition- By week 28, dropouts totalled 36 (standard) and 39 (extended), mainly from missed visits or voluntary withdrawal.
Ashare et al.[32]	University of Pennsylvania, Center for Interdisciplinary Research on Nicotine Addiction,	University of Pennsylvania Perelman School of Medicine in Philadelphia, PA, USA	Global Research Award for Nicotine Dependence (GRAND) from Pfizer (GA30523L) and the National Institutes of	Double-blind, placebo-controlled crossover design and October 2012 to December 2012	Participants were aged 21-65, smoked ≥10 cigarettes/day for the past 5 years, and had an intention to quit smoking in the next 6 months.	Exclusion criteria: Nicotine dependence treatment, menthol smoking, CO >10 ppm, substance/alcohol abuse, major psychiatric illness,	41 were determined eligible and expressed interest in participating in the study. Attrition- Of 29 participants,
	3535 Market St, Suite 4100, Philadelphia, PA 19104, USA		Health: R01 CA120594, R01 CA130961, P30 ES013508, and P50 CA143187.			recent psychotropic use, serious medical conditions, and pregnancy.	23 (80%) returned for follow-up, and 17 completed all visits; losses were due to missed follow-ups.
Eisenberg et al.[33]	MPH, Divisions of Cardiology and Clinical Epidemiology, Jewish General Hospital/McGill University, 3755 Côte Sainte-Catherine Rd, Ste H-421.1, Montréal, Québec, Canada H3T 1E2	17 Canadian sites, including Montréal, Hamilton, Ottawa, Sherbrooke, Thornhill, Québec City, Toronto, and Winnipeg	Canadian Institutes of Health Research (CIHR; funding reference No. 133727 and 155969). Both nicotine e-cigarettes and non-nicotine e-cigarettes were purchased from NJOY Inc (Scottsdale, Arizona).	Randomized clinical trial and November 2016 to September 2019	Participants to be 18 years or older, smoke an average of 10 or more cigarettes per day, and have a moderate or strong desire to quit smoking, as indicated by a score of 5 or higher on the Motivation to Stop Scale.	Exclusion criteria: recent cessation therapy (<30 days), e-cigarette use (<60 days or ≥7 days), bipolar/psychosis/schizophrenia, current or recent (<1 year) cancer, prognosis <1-year, recent cardiac event (<1 month), or non-cigarette tobacco/marijuana use.	376 participants, which was 77% of the initially targeted 486 participants. Of 376 participants, 299 (80%) provided smoking data at 12 weeks and 278 (74%) at 24 weeks, with losses due to follow-up or withdrawal.
Author name	Intervention group and dosing		Control group and dosing	Result of intervention group	Result of control group	Primary outcomes	Secondary outcomes
Tattan-Birch et al.[29]	Participants in the intervention group (e-cigarette-varenicline group) received a standard 12-week course of varenicline, starting approximately 2 weeks prior to their target quit date. They were advised to take one 0.5 mg pill daily for the first 3 days, then two 0.5 mg pills daily for days 4 to 7, and finally two 1 mg pills daily for the remaining 11 weeks. Additionally, they were given an e-cigarette starter kit prior to their quit date.		Participants in the control group (varenicline-only group) were prescribed the standard 12-week course of varenicline, starting approximately 2 weeks prior to their target quit date. They were advised to take one 0.5 mg pill daily for the first 3 days, then two 0.5 mg pills daily for days 4 to 7, and finally two 1 mg pills daily for the remaining 11 weeks.	The mean age of the intervention group (e-cigarette-varenicline group) was 43.8 years with a standard deviation (SD) of 12.1 years.47.9% (23 out of 48 participants) achieved 9-to-12-week abstinence from cigarette smoking.	The mean age of the control group (varenicline-only group) was 44.0 years with a standard deviation (SD) of 14.2 years.31.8% (14 out of 44 participants) achieved 9-to-12-week abstinence.	9-to-12-week abstinence: Self-reported non-smoking between weeks 9 and 12 post quit date, confirmed by CO-reading <10 ppm.	2-to-4-week abstinence: Similar to primary, but measured at weeks 2-4. Length of continuous abstinence: Number of weeks abstinent before relapse. Attendance: Participation in stop smoking services. Adherence: Compliance with varenicline and e-cigarette use.
Berlin et al.[30]	EC with Nicotine (ECwN) Group: Nicotine Concentration: 12 mg/mL		EC without Nicotine (ECwoN) Group: Nicotine Concentration: 0 mg/mL	The Continuous Abstinence Rate (CAR) from weeks 9 to 12 was 14.4%, indicating a significant proportion of participants achieved abstinence. Additionally, there was a notable reduction in cigarette consumption, with the average daily intake decreasing from	Continuous Abstinence Rate (CAR) from weeks 9 to 12 of 9.3%. This indicates a lower success rate in achieving smoking abstinence compared to the intervention group with nicotine.	The Continuous Smoking Abstinence Rate (CAR) during the last four weeks (weeks 9-12) of the treatment period, defined as the self-report of no smoking during the previous two weeks and expired air CO ≤8 ppm.	The safety profile of electronic cigarettes with nicotine compared to placebo and varenicline, point prevalence abstinence (7-day abstinence at several visits with expired air CO ≤8 ppm), time to relapse, CAR confirmed by urinary anabasine concentration ≤3 ng/mL,
			20.4 cigarettes at baseline to 2.6 cigarettes by the end of the study.		Additionally, there was a decrease in daily cigarette consumption from 19.4 cigarettes at baseline to 6.6 cigarettes by the end of the study.	At week 10 (visit 4) and week 12 (visit 5) after the target quit date (TQD), participants’ abstinence was confirmed by these measures.	change in cigarettes/day consumption.
Hawk et al.[31]	Received varenicline, during the first week, participants took a 0.5 mg tablet once daily for the first 3 days, then twice daily (morning and evening) for the remainder of the week. In weeks 2 and 3, participants were given 1.0 mg tablets to be taken twice daily.		Placebo designed to look identical to the varenicline tablets. During the first week, participants took a 0.5 mg placebo tablet once daily for the first 3 days, then twice daily for the remainder of the week. For weeks 2 and 3, participants were given 1.0 mg placebo tablets to be taken twice daily.	Continuous abstinence at the end of treatment (EOT) was achieved by 64 out of 163 participants (39.3%).	Continuous abstinence at the end of treatment (EOT) was achieved by 57 out of 157 participants (36.3%).	The primary outcome was cotinine-verified self-reported continuous abstinence from smoking during the last 4 weeks of treatment (weeks 12-15), also known as the end of treatment (EOT).	The secondary outcomes included bio verified continuous abstinence at the 6-month follow-up and the percentage reduction in self-reported smoking rate during the prequit period (week 1 vs. week 4).
Ashare et al.[32]	The intervention group received varenicline with a dosing regimen as follows: 0.5 mg orally once daily for Days 1-3, 0.5 mg orally twice daily for Days 4-7, and 1.0 mg orally twice daily for Days 8-21.		The control group in the study received a placebo, which followed the same dosing schedule as the varenicline group: 0.5 mg orally once daily for Days 1-3, 0.5 mg orally twice daily for Days 4-7, and 1.0 mg orally twice daily for Days 8–21.	Cigarette consumption, decreasing from 16.1 cigarettes per day at baseline to 12.8 by the end of the study. This represents a 23% reduction. Additionally, there was a decrease in daily smoking behavior, measured as the product of cigarettes per day and total puff volume, from 9375.4 to 6564.4.	Exhibited a slight and nonsignificant reduction in cigarette consumption, with a mean difference of 1.7 cigarettes per day. The reduction was not statistically significant, with the number of cigarettes per day decreasing from 15.8 to 14.2.	The primary outcome was the reduction in cigarette consumption, measured as the number of cigarettes smoked per day.	The secondary outcomes included measures such as total puff volume, daily smoking behavior (product of cigarettes per day and total puff volume), and cravings assessed using the Questionnaire of Smoking Urges (QSU).
Eisenberg et al.[33]	(1) nicotine e-cigarettes plus individual counselling, (2) non-nicotine e-cigarettes plus individual counselling. the nicotine e-cigarettes plus counseling group were provided with		Individual counseling alone, without e-cigarettes.	18.8% achieving point prevalence abstinence at 12 weeks compared to 9.9% in the counselling alone group.	At the 12-week mark, 9.9% of participants in the counseling alone group achieved point prevalence abstinence.	The primary outcome was pointing prevalence smoking abstinence at 12 weeks,	Point prevalence abstinence at other follow-ups, continuous abstinence, daily cigarette
	12 weeks of e-cigarettes containing 15 mg of nicotine per mL and received individualized counseling.		The group that received non-nicotine e-cigarettes plus counseling also showed a higher abstinence rate of 17.0%.	Additionally, there was a lesser reduction in daily cigarette consumption among participants in the counseling alone group compared to those who received e-cigarettes plus counseling.	defined as self-reported abstinence in the past 7 days with exhaled carbon monoxide levels of 10 ppm or less.	consumption changes from baseline, serious adverse events (SAEs), adverse events (AEs), dropouts due to AEs, and treatment adherence.

Statistical analysis and outcome measure

In this meta-analysis, data from the included studies were aggregated to determine the overall effect size using Comprehensive Meta-Analysis Version 4 (Borenstein et al., 2022).[13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28] The primary outcome measure was the risk ratio (RR), which facilitated pooled effect calculations and established a 95% confidence interval. Additionally, odds ratios (OR) were used to enhance understanding of the intervention’s impact. Statistical heterogeneity was assessed using the I² test, and a random-effects model was applied to account for variability among studies. This approach allows for inferences about a broader population, ensuring findings are not overly influenced by any single study, and provides a robust estimate of the intervention’s impact while considering study heterogeneity and pooled accuracy.

RESULTS

A total of 205 records were identified (PubMed = 97, Cochrane Library = 105, EBSCO = 3). After removing 8 duplicates and 29 records without full-text access, 168 records remained for screening. During screening, 58 records were excluded, leaving 110 reports for retrieval. Of these, 72 reports could not be retrieved, and the remaining 38 reports were assessed for eligibility. Of the 38 reports evaluated for eligibility, 33 were excluded. The main reasons for exclusion were populations not matching healthy patients (n = 24), outcomes not matching the expected criteria (n = 4), and populations not meeting the inclusion criteria (n = 5). Ultimately, five studies were included, with a comprehensive summary presented in Figure 1. The review examined the effectiveness of e-cigarettes and varenicline in smoking cessation, providing valuable insights into their comparative efficacy in promoting smoking abstinence and influencing participant behavior.

Several studies have evaluated the effectiveness of e-cigarettes and varenicline for smoking cessation. Tattan Birch et al.[29] reported that combining e-cigarettes with varenicline improved abstinence compared to varenicline alone. After 9-12 weeks, 47.9% of participants in the combined group achieved abstinence versus 31.8% in the varenicline-only group (RR 1.51, 95% CI: 0.91-2.64). Including self-reported quits, rates increased to 52.1% versus 34.1% (RR 1.53, 95% CI: 0.95-2.60), with a 43% lower relapse rate (HR 0.57). The ECSMOKE trial by Berlin et al.[30] compared nicotine-containing e-cigarettes, varenicline, and non-nicotine e-cigarettes in 600 participants. Continuous abstinence from weeks 9 to 12 was higher for nicotine e-cigarettes (30%) than for non-nicotine e-cigarettes (15%) and similar to varenicline (28%), with slightly fewer adverse events in the nicotine e-cigarette group. Hawk et al.[31] investigated extending prequit varenicline treatment but found no significant differences in abstinence at the end of treatment (39.3% vs. 36.3%, OR 1.13, 95% CI: 0.72-1.78) or by gender. Ashare et al.[32] found that varenicline reduced daily cigarette consumption and urges, with high adherence and minor nausea in a few participants. Eisenberg et al.[33] reported that nicotine e-cigarettes plus counseling led to 38% abstinence at 12 weeks, compared to 29% for non-nicotine e-cigarettes and 10% for counseling alone. Overall, these studies suggest nicotine e-cigarettes, particularly when combined with varenicline or counseling, can improve cessation, while extending varenicline alone offers no additional benefit.

Overall, the risk of bias was high across the studies, as shown in Figure 2, which uses the RoB2 tool for assessment. The quality of evidence varied among studies. Tattan-Birch et al.[29] displayed low risk in randomization (D1) and missing outcome data (D3) but had concerns in deviations from intended interventions (D2) and high risks in outcome measurement (D4) and selection of reported results (D5), leading to an overall high risk of bias. Berlin et al.[30] showed low risk in D1, D2, and D3 but high risk in D4 and D5, resulting in a high-risk judgment. Both Ashare et al.[32] and Hawk et al.[31] rated high due to significant issues in D5. Eisenberg et al.[33] also exhibited high risk, particularly in outcome measurement and result selection. This overall high risk of bias indicates that, despite some robust methodologies, the limitations warrant cautious interpretation of the systematic review’s findings.

Figure 2.

Risk of bias assessment of included studies, evaluated across key methodological domains

A meta-analysis of the five included studies using a random-effects model estimated a mean effect size (odds ratio) of 2.287 (95% CI: 1.151-4.544, P = 0.018), indicating that interventions involving e-cigarettes and/or varenicline roughly doubled the odds of smoking cessation compared to controls [Figure 3]. Significant heterogeneity was observed (I² =76%), suggesting that differences in study design, population characteristics, intervention types, and outcome measurements contributed to variability in effect sizes. This analysis was conducted using Comprehensive Meta-Analysis Version 4 (Borenstein et al.,[15]) and followed methodologies from various sources.[13,14,15,16,17,18,19,20,21,22,23,24,25,26,27] Despite this heterogeneity, assessment of publication bias using Egger’s test and Begg and Mazumdar’s rank correlation indicated no strong evidence of selective reporting, increasing confidence in the observed effect. Funnel plots illustrating precision versus Log odds ratio and standard error versus Log odds ratio are shown in Figures 4 and 5. These findings, while requiring cautious interpretation due to methodological limitations and high risk of bias in several studies, collectively support the potential role of e-cigarettes, particularly when combined with varenicline or counseling, as effective tools in smoking cessation. The results provide valuable guidance for both clinical decision-making and public health strategies aimed at reducing tobacco use, highlighting the importance of integrating behavioral and pharmacological interventions to improve cessation outcomes.

Figure 3.

Forest plot showing pooled effect estimates with 95% confidence intervals from included studies

Figure 4.

Contour-enhanced funnel plot of included studies, plotting log odds ratio against study precision (1/SE) to assess publication bias

Figure 5.

Funnel plot assessing publication bias among the included studies (plot of log odds ratio against standard error)

DISCUSSION

This systematic review synthesized evidence from five randomized controlled trials examining the effectiveness of e-cigarettes, varenicline, or their combination in supporting smoking cessation. The pooled evidence suggests that interventions integrating pharmacotherapy with alternative nicotine delivery devices such as e-cigarettes, alongside behavioral support, are associated with higher quit rates compared with single-modality approaches. These findings resonate with broader literature demonstrating that multicomponent strategies—particularly those combining pharmacological and behavioral elements—are more effective in achieving sustained abstinence.

The pragmatic trial by Tattan-Birch et al.[29] showed participants using e-cigarettes in addition to varenicline achieved greater short-term abstinence compared to varenicline alone. Similarly, the ECSMOKE trial[30] conducted in France reported that nicotine-containing e-cigarettes achieved continuous abstinence rates comparable to varenicline and superior to non-nicotine e-cigarettes, highlighting their potential role as an adjunct in cessation. Eisenberg et al.[33] in Canada also observed that e-cigarettes combined with counseling significantly improved cessation outcomes compared to counseling alone, underlining the importance of behavioral support as a cornerstone of treatment. In contrast, trials evaluating varenicline alone, such as those by Hawk et al.[31] and Ashare et al.,[32] confirmed its efficacy but underscored the persistence of relapse when alternative nicotine substitutes or behavioral reinforcements are absent.

Evidence from meta-analyses further strengthens these observations. A network meta-analysis by Thomas et al.[34] demonstrated that varenicline, NRT combinations, and e-cigarettes all improved cessation rates compared with placebo, with the greatest benefits observed when counseling was integrated. More recent systematic reviews have also shown that nicotine e-cigarettes are more effective than non-nicotine e-cigarettes or counseling alone in achieving point prevalence abstinence. These findings support the dual utility of e-cigarettes—not only as nicotine delivery systems but also as behavioral substitutes that replicate the sensory and habitual aspects of smoking, thereby reducing cravings and withdrawal symptoms.[35,36]

From a cessation perspective, evidence suggests that e-cigarettes may serve as a useful adjunct for individuals who struggle to quit with pharmacotherapy alone. Nevertheless, uncertainties remain regarding their long-term safety, the risk of dual use alongside combustible tobacco, and the need for robust regulatory frameworks. In India, e-cigarettes were first introduced in the early 2010s, but their availability was short-lived. The rationale behind the Government of India’s decision to enact the Prohibition of Electronic Cigarettes Act, 2019, was rooted in concerns that these products could encourage nicotine initiation among youth, increase the risk of dependence, and normalize smoking behavior. Furthermore, the limited scientific evidence on their long-term health effects and the possibility of dual use with conventional tobacco were viewed as barriers to cessation rather than supports. Based on these risks and the precautionary principle, a comprehensive ban was imposed on the production, import, sale, and advertisement of e-cigarettes.[37,38] Unlike countries such as the UK, France, and Canada, where e-cigarettes are regulated and evaluated within public health frameworks, their use as cessation tools in India is not legally permitted. Consequently, the translational application of international findings is limited, and cessation strategies in the Indian context continue to rely primarily on approved pharmacotherapies, behavioral counseling, and tobacco control policies.[39]

Overall, this review highlights that e-cigarettes, when combined with pharmacological and behavioral strategies, may improve cessation outcomes compared to single interventions. Nevertheless, their role must be interpreted in light of regulatory constraints, population-specific contexts, and the need for longer-term evidence. In India, where e-cigarettes are banned, emphasis should remain on scaling up evidence-based pharmacotherapies such as varenicline and NRT, integrating behavioral support, and strengthening public health programs to address the burden of tobacco use.

Successful smoking cessation is influenced by various factors. Lower nicotine dependence, as measured by the Fagerström Test for Nicotine Dependence (FTND), is linked to higher success rates; a cohort study in Taiwan and Korea found a 59.5% cessation rate among those with lower FTND scores.[40] Psychological factors, such as depression, can hinder efforts, underscoring the need for tailored interventions.[40] Thus, smoking cessation programs should utilize motivational interviewing techniques to improve success rates.

Limitations

This review acknowledges several limitations, including variability in study designs, sample sizes, and follow-up durations. The COVID-19 pandemic also impacted participant recruitment and study implementation, as noted in the Tattan-Birch et al.[29] study. Future research should focus on standardized methodologies and extended follow-up periods to assess the long-term efficacy and safety of interventions. Additionally, more studies are needed to investigate the psychological and behavioral aspects of smoking cessation to optimize intervention strategies.

CONCLUSION

The extensive health impacts of smoking underscore the importance of effective cessation strategies. The evidence supporting the efficacy of pharmacological aids like varenicline and nicotine e-cigarettes is robust, with significant improvements in quit rates observed when these interventions are employed. Furthermore, understanding the multifaceted factors that influence cessation success can help tailor interventions to meet the needs of diverse populations. As the public health community continues to combat tobacco use, integrating these insights into cessation programs will be vital for reducing smoking prevalence and improving overall health outcomes.

Supplementary Material

The supplementary material for this article can be found online.

Author’s contribution

The design was a collaborative effort by AS and MW, with both contributing significantly. AS and MW also conducted statistical analysis and were involved in various stages of the study. The manuscript was prepared by AS, MW, and RK collectively. Additionally, AS and RK assisted in study design and interpretation. All authors have reviewed and endorsed the manuscript’s content.

Conflicts of interest

The authors have no conflicts of interest.

Funding Statement

Nil.