Electronic cigarettes for smoking cessation

Jamie Hartmann-Boyce; Hayden McRobbie; Nicola Lindson; Chris Bullen; Rachna Begh; Annika Theodoulou; Caitlin Notley; Nancy A Rigotti; Tari Turner; Ailsa R Butler; Thomas R Fanshawe; Peter Hajek

doi:10.1002/14651858.CD010216.pub4

. 2020 Oct 14;2020(10):CD010216. doi: 10.1002/14651858.CD010216.pub4

Electronic cigarettes for smoking cessation

Jamie Hartmann-Boyce ^1,^✉, Hayden McRobbie ², Nicola Lindson ¹, Chris Bullen ³, Rachna Begh ¹, Annika Theodoulou ¹, Caitlin Notley ⁴, Nancy A Rigotti ⁵, Tari Turner ⁶, Ailsa R Butler ¹, Thomas R Fanshawe ¹, Peter Hajek ⁷

Editor: Cochrane Tobacco Addiction Group

PMCID: PMC8094228 PMID: 33052602

Abstract

Background

Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e‐liquid. People who smoke report using ECs to stop or reduce smoking, but some organisations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This review is an update of a review first published in 2014.

Objectives

To evaluate the effect and safety of using electronic cigarettes (ECs) to help people who smoke achieve long‐term smoking abstinence.

Search methods

We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO for relevant records to January 2020, together with reference‐checking and contact with study authors.

Selection criteria

We included randomized controlled trials (RCTs) and randomized cross‐over trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. To be included, studies had to report abstinence from cigarettes at six months or longer and/or data on adverse events (AEs) or other markers of safety at one week or longer.

Data collection and analysis

We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow‐up, AEs, and serious adverse events (SAEs). Secondary outcomes included changes in carbon monoxide, blood pressure, heart rate, blood oxygen saturation, lung function, and levels of known carcinogens/toxicants. We used a fixed‐effect Mantel‐Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data from these studies in meta‐analyses.

Main results

We include 50 completed studies, representing 12,430 participants, of which 26 are RCTs. Thirty‐five of the 50 included studies are new to this review update. Of the included studies, we rated four (all which contribute to our main comparisons) at low risk of bias overall, 37 at high risk overall (including the 24 non‐randomized studies), and the remainder at unclear risk.

There was moderate‐certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.25 to 2.27; I² = 0%; 3 studies, 1498 participants). In absolute terms, this might translate to an additional four successful quitters per 100 (95% CI 2 to 8). There was low‐certainty evidence (limited by very serious imprecision) of no difference in the rate of adverse events (AEs) (RR 0.98, 95% CI 0.80 to 1.19; I² = 0%; 2 studies, 485 participants). SAEs occurred rarely, with no evidence that their frequency differed between nicotine EC and NRT, but very serious imprecision led to low certainty in this finding (RR 1.37, 95% CI 0.77 to 2.41: I² = n/a; 2 studies, 727 participants).

There was moderate‐certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non‐nicotine EC (RR 1.71, 95% CI 1.00 to 2.92; I² = 0%; 3 studies, 802 participants). In absolute terms, this might again lead to an additional four successful quitters per 100 (95% CI 0 to 12). These trials used EC with relatively low nicotine delivery. There was low‐certainty evidence, limited by very serious imprecision, that there was no difference in the rate of AEs between these groups (RR 1.00, 95% CI 0.73 to 1.36; I² = 0%; 2 studies, 346 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 0.25, 95% CI 0.03 to 2.19; I² = n/a; 4 studies, 494 participants).

Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.50, 95% CI 1.24 to 5.04; I² = 0%; 4 studies, 2312 participants). In absolute terms this represents an increase of six per 100 (95% CI 1 to 14). However, this finding was very low‐certainty, due to issues with imprecision and risk of bias. There was no evidence that the rate of SAEs varied, but some evidence that non‐serious AEs were more common in people randomized to nicotine EC (AEs: RR 1.17, 95% CI 1.04 to 1.31; I² = 28%; 3 studies, 516 participants; SAEs: RR 1.33, 95% CI 0.25 to 6.96; I² = 17%; 5 studies, 842 participants).

Data from non‐randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate over time with continued use. Very few studies reported data on other outcomes or comparisons and hence evidence for these is limited, with confidence intervals often encompassing clinically significant harm and benefit.

Authors' conclusions

There is moderate‐certainty evidence that ECs with nicotine increase quit rates compared to ECs without nicotine and compared to NRT. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the degree of effect, particularly when using modern EC products. Confidence intervals were wide for data on AEs, SAEs and other safety markers. Overall incidence of SAEs was low across all study arms. We did not detect any clear evidence of harm from nicotine EC, but longest follow‐up was two years and the overall number of studies was small.

The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up‐to‐date information for decision‐makers, this review is now a living systematic review. We will run searches monthly from December 2020, with the review updated as relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

Plain language summary

Can electronic cigarettes help people stop smoking, and do they have any unwanted effects when used for this purpose?

What are electronic cigarettes?

Electronic cigarettes (e‐cigarettes) are handheld devices that work by heating a liquid that usually contains nicotine and flavourings. E‐cigarettes allow you to inhale nicotine in a vapour rather than smoke. Because they do not burn tobacco, ECs do not expose users to the same levels of toxins that we know can cause smoking‐related diseases in people who use conventional cigarettes.

Using an e‐cigarette is known as 'vaping'. Many people use e‐cigarettes to help them to stop smoking tobacco.

Why we did this Cochrane Review

Stopping smoking lowers your risk of getting lung cancer and other diseases. But many people find it difficult to quit. We wanted to find out if using e‐cigarettes could help people to stop smoking, and if people using them for this purpose experienced any unwanted effects.

What did we do?

We searched for studies that looked at the use of e‐cigarettes to help people stop smoking.

We looked for randomized controlled trials, in which the treatments people received were decided at random. This type of study usually gives the most reliable evidence about the effects of a treatment. We also looked for studies in which everyone received an e‐cigarette treatment.

We were interested in finding out:

· how many people stopped smoking for at least six months; and · how many people had any unwanted effects.

We included studies that reported on smoking habits for at least six months, or reported on unwanted effects for at least one week.

Search date: We included evidence published up to January 2020.

What we found

We found 50 studies in 12,430 adults who smoked. The studies compared e‑cigarettes with:

· nicotine replacement therapy, such as patches or gum;

· varenicline; · nicotine‐free e‐cigarettes; · behavioural support, such as advice or counselling; or · no support, for stopping smoking.

Some studies also tested using NRT and e‐cigarettes together.

The studies took place in the USA (21 studies), the UK (9), Italy (7), Australia (2), New Zealand (2), Greece (2), and one study each in Belgium, Canada, Poland, South Korea, South Africa, Switzerland and Turkey.

What are the results of our review?

More people probably stop smoking for at least six months using nicotine e‐cigarettes than using nicotine replacement therapy (3 studies; 1498 people), or nicotine‐free e‑cigarettes (3 studies; 802 people).

Nicotine e‐cigarettes may help more people to stop smoking than no support or behavioural support only (4 studies; 2312 people).

For every 100 people using nicotine e‐cigarettes to stop smoking, 10 might successfully stop, compared with only six of 100 people using nicotine‐replacement therapy or nicotine‐free e‐cigarettes, or four of 100 people having no support or behavioural support only.

We are uncertain if there is a difference between how many unwanted effects occur using nicotine e‐cigarettes compared with using nicotine‐free e‐cigarettes, nicotine replacement therapy, no support or behavioural support only. Similar low numbers of unwanted effects, including serious unwanted effects, were reported for all groups.

The unwanted effects reported most often with nicotine e‐cigarettes were throat or mouth irritation, headache, cough and feeling sick. These effects reduced over time as people continued using nicotine e‐cigarettes.

How reliable are these results?

Our results are based on a small number of studies, and in some the measured data varied widely.

We are moderately confident that nicotine e‐cigarettes help more people to stop smoking than nicotine replacement therapy or nicotine‐free e‐cigarettes. However, these results might change if further evidence becomes available.

We are less confident about how nicotine e‐cigarettes compare with no support, or behavioural support, to stop smoking.

Our results for the unwanted effects are likely to change when more evidence becomes available.

Key messages

Nicotine e‐cigarettes probably do help people to stop smoking for at least six months. They probably work better than nicotine replacement therapy and nicotine‑free e‐cigarettes.

They may work better than no support, or behavioural support alone, and they may not be associated with serious unwanted effects.

However, we need more, reliable evidence to be confident about the effects of e‐cigarettes, particularly the effects of newer types of e‐cigarettes that have better nicotine delivery.

Summary of findings

Background

Throughout this review, we discuss (1) conventional cigarettes and; (2) electronic cigarettes, defined as handheld electronic vaping devices that produce aerosol for inhalation formed by heating an e‐liquid. In this review, all mention of smoking, smoking cessation, cigarette use, smoke intake, etc. concern combustible tobacco cigarettes. When the text concerns electronic cigarettes we use the abbreviation 'ECs'. EC users are sometimes described as vapers, and EC use as vaping. We refer to ECs that do not contain nicotine as non‐nicotine ECs; these can also be conceptualized as placebo ECs, but we are using the term non‐nicotine EC, as they can be conceptualized as an intervention in themselves. This review does not address the use of vaping devices to inhale substances other than nicotine, such as cannabis.

Description of the condition

Stopping smoking is associated with large health benefits. Despite most people who smoke wanting to quit, many find it difficult to succeed in the long term. Almost half who try to quit without support will not manage to stop for even a week, and fewer than five per cent remain abstinent at one year after quitting (Hughes 2004).

Behavioural support and medications such as nicotine patches or gum increase the chances of quitting through providing nicotine to help alleviate withdrawal symptoms, but even with this additional support long‐term quit rates remain low (Cahill 2016; Hartmann‐Boyce 2018b; Hartmann‐Boyce 2019). One of the limitations of current treatments is that, despite substituting nicotine delivery, none adequately addresses the sensory, behavioural and social aspects of smoking that ex‐smokers miss when they stop smoking (e.g. holding a cigarette in their hands, taking a puff, enjoyment of smoking, feeling part of a group). ECs may offer a way to overcome this limitation (Notley 2018b).

There is no doubt that people become dependent on tobacco, and find it difficult to stop smoking, primarily because of nicotine and its actions on the brain's reward system (Balfour 2004). However, other factors also contribute to tobacco dependence (Benowitz 2010; Rose 2006). Sensory and behavioural cues provide additional reinforcement of smoking behaviour (Rose 1993; Rose 2000) and over time become almost as rewarding as nicotine. There are several lines of evidence to support this. Firstly, people who smoke appear to have a preference for cigarette smoke compared to other forms of nicotine delivery. This is partly related to the speed of nicotine delivery through smoke inhalation. However, even when nicotine is administered intravenously it does not provide the same level of satisfaction or reward as smoking (Rose 2000; Westman 1996). Secondly, the local sensory effects of smoking (e.g. the ‘scratch’ in the back of the throat) may be important for enjoyment and reward. Numbing the sensations of cigarette smoke by anaesthetizing the upper and lower respiratory tract leads to less enjoyment of smoking (Rose 1985). Conversely, products that mimic the sensory effects of smoking on the mouth and throat (such as citric acid, black pepper, and ascorbic acid) reduce craving and some withdrawal symptoms, at least in the short term (Levin 1993; Rose 1994; Westman 1995). Thirdly, very low nicotine content cigarettes (VLNCs) which have a very low content of nicotine (e.g. 0.08 mg instead of the normal 1 mg) and so have negligible or no central effects, have also been investigated for their role in aiding smoking cessation (Przulj 2013). Despite delivering low levels of nicotine, VLNCs are satisfying over the initial few days of abstinence from nicotine (Donny 2007; Donny 2015; Pickworth 1999; Rose 2000). They also reduce tobacco withdrawal symptoms, including urges to smoke and low mood (Barrett 2010; Donny 2009; McRobbie 2016; Perkins 2010; Rose 2000), and have been shown to improve long‐term continuous abstinence rates in one study (Walker 2012). Social aspects of smoking, such as feeling part of a like‐minded group, or including smoking behaviour as part of one's social identity are also key elements of cigarette smoking that people who smoke report to be key aspects of cigarette dependence (Notley 2018a).

Considering the other factors that contribute to tobacco dependence, there is interest in developing smoking‐cessation products that would not only help relieve the unpleasant effects of nicotine withdrawal but would also act as an effective substitute for smoking behaviour and the rituals and sensations that accompany smoking, without the health risks associated with the inhalation of tobacco smoke. Until recently the only pharmaceutical treatments available that had some of these characteristics were the nicotine inhalator and nicotine oral spray. However, these do not have greater cessation efficacy than the other nicotine replacement therapy (NRT) products (Hajek 1999; Hartmann‐Boyce 2018a). This may in part be due to the considerable effort (e.g. 20 minutes of continuous puffing) needed to provide nicotine blood concentrations consistent with other NRTs (Schneider 2001). Adherence to correct use of the inhalator is low compared to other NRTs (Hajek 1999). It is therefore possible that any advantage of sensorimotor replacement is diminished by low nicotine delivery and limited similarities between inhalator use and sensations of smoking (Bullen 2010). A nicotine inhaler using pressurised air has recently been approved as a smoking cessation aid in the UK. The nicotine delivery is substantially lower than from cigarettes, and also lower than from the nicotine inhalator (Romeu 2020).

Description of the intervention

ECs are electronic vaping devices that are handheld and produce an aerosol formed by heating an e‐liquid, designed for inhalation by the user. The e‐liquid, usually comprising propylene glycol and glycerol, with or without nicotine and flavours, is stored in disposable or refillable cartridges or a reservoir or 'pod'. The commonly‐used term for this aerosol is vapour, which we use throughout the review. In many countries, ECs are marketed as consumer products. Although routes are in place for licensing them as a medicine in some areas, no country yet has a licensed, medicinal EC.

ECs provide sensations similar to smoking a cigarette. They provide taste and throat sensations that are closer to smoking than those provided by the nicotine inhalator (Barbeau 2013). The vapour that looks like tobacco smoke is only visible when the user exhales after drawing on the mouthpiece, not when the device is being held. In qualitative studies users report a sense of shared identity with other users, similar to tobacco smoking identity, and also report pleasure and enjoyment of use, suggesting that ECs may be viewed less as a medical cessation aid but rather as an acceptable alternative to tobacco smoking (Cox 2017; Notley 2018a).

There are many different brands and models of EC available. Variation exists both in the device ('product') and consumable (e‐liquid used). There is a wide variation in the composition of e‐liquids (nicotine content, flavours and other components) (Goniewicz 2012; Goniewicz 2014), with some users choosing to mix their own e‐liquids (Cox 2019b). Initial studies showed that early models of EC delivered very low amounts of nicotine to naïve users (Bullen 2010; Eissenberg 2010; Vansickel 2010). Later studies that have measured nicotine pharmacokinetics in both experienced and naïve EC users have found that some EC users can achieve blood nicotine levels similar to those achieved with smoking, albeit more slowly, and that their ability to do so often improves over time (Hajek 2015b; Vansickel 2012; Vansickel 2013; Yingst 2019a; Yingst 2019b).

Early on in their development, ECs looked like cigarettes and used disposable cartridges. These models were often called 'cig‐a‐likes'. The nicotine delivery from these products was low, and even the modern versions of EC devices that use pre‐filled cartridges, mostly produced by the tobacco industry, for the most part have only low nicotine delivery (Hajek 2017). The later refillable, or 'tank', products have a larger battery and a transparent container that users fill with an e‐liquid of their choice, and usually provide faster and more efficient nicotine delivery, allow a wider choice of flavours and nicotine concentrations, and are typically used by experienced vapers who manage to switch to vaping completely (ASH 2019; Dawkins 2013b; Farsalinos 2014; McNeill 2019). Observational evidence suggests people who smoke are more likely to successfully quit using tank models than with cig‐a‐likes (Chen 2016; Hitchman 2015). EC types are also often grouped by 'generation': first‐generation devices are typically cig‐a‐likes; second‐generation devices are usually tank models, sometimes referred to as 'vape pens'; and third‐generation devices are tank models which, unlike second generation devices, allow users to adjust the power (wattage) level of the product (see NCSCT EC briefing for further information and images of different product types). More recently, smaller 'pod' devices, such as Juul, appeared that use nicotine salt. This nicotine formulation reduces irritant effects and allows the delivery of higher nicotine levels that closely mimic the pharmacokinetic profile of nicotine delivery from cigarettes, despite the low battery power of the device (Hajek 2020). Juul has now become the most popular EC in the USA (Huang 2019). The EU Tobacco Products Directive (European Parliament 2014) does not allow sales of e‐liquids with nicotine content higher than 20 mg/ml, and so the US version of Juul (59 mg/nl nicotine) is not available within the EU (Huang 2019; Talih 2020).

The different device types (cig‐a‐like, refillable and pods using high nicotine content salts) may differ significantly in their efficacy in helping people who smoke to quit, as they differ in delivery of nicotine, the active ingredient. Nicotine itself, when delivered through mechanisms and doses similar to that delivered in traditional NRT, is not considered harmful (Hartmann‐Boyce 2018a). The safety profile of the different types of EC may be similar as they use the same constituents, although within the generic range of EC types, there is some evidence to suggest EC providing less nicotine may pose higher risks. This is because low‐nicotine delivery devices need to be puffed with higher intensity to provide users with the nicotine levels that they seek, and more intensive puffing is accompanied by increased inhalation of potential toxicants (Dawkins 2016; Dawkins 2018; Smets 2019). Throughout this review we refer to a nicotine‐containing EC as ‘nicotine EC’ and to nicotine‐free EC as 'non‐nicotine EC', which can also be considered 'placebo EC'. The 'placebo' comparison is a test just of the nicotine effect and not of the potential sensorimotor or behavioural and social replacement that the EC may provide.

There is no one agreed classification system for EC devices, and product development has moved so quickly that the definitions used within trials of the devices tested may no longer be necessarily fit for purpose. In this review, the definitions used are based on those drawn from the included trials. We currently label three different types of EC as 'cartridges' for devices with disposable cartridges and ‐ typically, but not always ‐ low nicotine delivery (e.g. cig‐a‐likes); refillable ECs for devices that vapers fill with their own choice of e‐liquids; and pods for the small devices that use nicotine salts. We may review this categorization system in future versions of the review as new trials and devices emerge.

Why it is important to do this review

Since ECs appeared on the market in 2006 there has been a steady increase in their use. In the UK the ASH 2019 survey found 19.4% of the adult population have ever tried vaping, but only 7.2% were current vapers. EC use remains slightly more common among men compared with women, although the difference is small. EC use is most prevalent in current (19.9%) and former (11.6%) smokers. Less than one per cent of never‐smokers report regular EC use. Prevalence data from the USA in 2019 showed that 4.4% of adults were current EC users (Du 2020). Data from lower‐income countries suggest similar levels of EC use and awareness (Besaratinia 2019; Jiang 2016; Palipudi 2016).

Particular concern has been raised about the increased use of EC in young people, especially among never‐smokers. Data for 2019 from Canada, England, and the USA show regular use (≥ 20 days in the last 30 days) among 16‐ to 19‐year‐olds to be 5.7%, 2.7% and 6.7%, respectively. There appear to be some regional differences in the change in the prevalence of EC use. For example, in North America the rates of regular EC use among 16‐ to 19‐year‐old never‐smokers has significantly increased between 2017 and 2019, compared to England where there has not been any significant change (0.2% to 0.3%) (Hammond 2020). However, as with adults, regular use is greatest among those who are also smoking and lowest among never‐smokers (1.0%, 0.3%, and 1.8% for Canada, England and USA, respectively).

Regulatory approaches being used for ECs currently vary widely, from no regulation to partial and complete bans (McNeill 2019). Within the USA, for example, the Food and Drug Administration (FDA) has classified them as tobacco products and there are a range of laws that include prohibition of EC use indoors, require retailers to have a license to sell, and prohibit sales to minors. Laws prohibiting sales to minors apply nationwide, but other laws vary by state (Du 2020). The European Union includes ECs in their Tobacco Products Directive, except where therapeutic claims are made or in instances where they contain over 20 mg/nl of nicotine, when they will require medicines authorization (European Parliament 2014).

Categorical statements about the toxicity of ECs are not possible because of the large number of devices and liquids available and the frequent addition of new products to the market. In 2019, cases of severe lung injury associated with EC use were reported in the USA, and by February 2020 there were around 2800 hospitalized cases or deaths (CDC 2020). This illness was termed E‐cigarette or Vaping‐Associated Lung Injury (EVALI) and caused concern throughout the world (Hall 2020) and a negative change in people's perception of the risks of EC use compared to smoking (Tattan‐Birch 2020). These cases were somewhat at odds with data from trials and cohort studies, and it was later found that these injuries were related to use of tetrahydrocannabinol (THC)‐containing EC, and in particular THC products adulterated with vitamin E acetate (Blount 2020; Hartnett 2020). Among those brands of nicotine EC that have been tested, levels of toxins have been found to be substantially lower than in cigarettes (Hajek 2014; McNeill 2019). Long‐term effects beyond 12 months are unknown, although based on what is known about liquid and vapour constituents and patterns of use, a report from the UK's Royal College of Physicians has concluded that using an EC is likely to be considerably safer than smoking (RCP 2016). The US National Academies of Sciences, Engineering, and Medicine (NASEM) concluded that ECs are likely to be far less harmful than continuing to smoke cigarettes, with the caveat that the long‐term health effects of e‐cigarette use are not yet known (NASEM 2018).

Despite general acknowledgement that EC use exposes the user to fewer toxicants and at lower levels than smoking cigarettes (McNeill 2019; NASEM 2018; RCP 2016), there remains some hesitancy in making these products available to people who smoke as a harm reduction tool or smoking cessation aid (e.g. McDonald 2020). Lack of quality control measures, possible harms of second‐hand EC vapour inhalation, concerns that the products may be a gateway to smoking initiation or may prolong continued dual‐use of tobacco, concerns that ECs may undermine smoke‐free legislation if used in smoke‐free spaces, concerns about the involvement of the tobacco industry, and concerns that the long‐term effects of EC use on health are not yet known are often cited. However, there are limited data with which to support or refute these concerns, and others suggest that potential benefits outweigh potential disadvantages (Farsalinos 2014; Hajek 2014; McNeill 2019; NASEM 2018; RCP 2016).

People who smoke, healthcare providers and regulators are interested to know if ECs can help smokers quit and if it is safe to use them to do so. In particular, healthcare providers have an urgent need to know what they should recommend for people who want to stop smoking. The largest health gains are achieved from stopping smoking completely, as opposed to reducing cigarette consumption, and as such this review focuses on the effectiveness of ECs in aiding smoking cessation.

This is an update of a review first published in 2014 and last updated in 2016.

Following the publication of the 2020 update of this review, we will maintain it as a living systematic review (Brooker 2019), This means we will be continually running searches and incorporating new evidence into the review. For more information about the living systematic review methods being used, see Appendix 1. A living systematic review approach is appropriate for this review, for three reasons. First, the review addresses an important public health issue; the role of ECs in enabling people who smoke to stop smoking, with potential for substantial ongoing individual and societal benefits if effective. Secondly, there remains uncertainty in the existing evidence; despite searches including the current update (to January 2020) identifying 50 trials for inclusion in the review, more studies are needed to confirm the degree of benefit for different comparisons and product types, and there is considerable uncertainty about adverse events and other markers of safety. Thirdly, we are aware of multiple ongoing trials on this topic that are likely to have an important impact on the conclusions of the review.

Objectives

To evaluate the safety and effect of using electronic cigarettes (ECs) to help people who smoke achieve long‐term smoking abstinence.

Methods

Criteria for considering studies for this review

Types of studies

We include randomized controlled trials (RCTs) and randomized cross‐over trials in which people who smoke are randomized to ECs or to a control condition. RCTs are the best available primary evidence, but the continued paucity of RCTs in this area requires that we also include uncontrolled intervention studies in which all participants are given an EC intervention.

We include studies regardless of their publication status or language of publication.

Types of participants

People defined as currently smoking cigarettes at enrolment into the studies. Participants could be motivated or unmotivated to quit.

Types of interventions

Any type of EC or intervention intended to promote EC use for smoking cessation, including studies which did not measure smoking cessation but provided ECs with the instruction they be used as a complete substitute for cigarette use. ECs may or may not contain nicotine.

Types of comparators

We compare nicotine ECs with non‐nicotine ECs, ECs versus alternative smoking cessation aids, including NRT or no intervention, and ECs added to standard smoking cessation treatment (behavioural or pharmacological or both) with standard treatment alone.

Types of outcome measures

Primary outcomes

Cessation at the longest follow‐up point, at least six months from the start of the intervention, measured on an intention‐to‐treat basis using the strictest definition of abstinence, preferring biochemically‐validated results where reported
Number of participants reporting adverse events or serious adverse events at one week or longer (as defined by study authors)

Secondary outcomes

Changes in the following measures at one week or longer:

Carbon monoxide, as measured through breath or blood
Blood pressure
Heart rate
Blood oxygen saturation
Lung function measures
Known toxins/carcinogens, as measured through blood or urine (toxicant names and abbreviations are listed in Appendix 2)

Studies had to report one of the primary or secondary outcomes above to be eligible for inclusion.

Search methods for identification of studies

Electronic searches

For this update we searched the following databases on 20th January 2020:

Cochrane Tobacco Addiction Group Specialized Register
Cochrane Central Register of Controlled Trials (CENTRAL)
MEDLINE (OVID SP)
Embase (OVID SP)
PsycINFO (OVID SP)

We also searched the clinical trials registries ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP: www.who.int/ictrp/en/). At the time of the search, the Register included the results of searches of the Cochrane Central Register of Controlled trials (CENTRAL), issue 12, 2019; MEDLINE (via OVID) to update 20191127; Embase (via OVID) to week 202005; PsycINFO (via OVID) to update 20200127. See the Tobacco Addiction Group website for full search strategies and a list of other resources searched.

For the first version of the review we also searched CINAHL (EBSCO Host) (2004 to July 2014). We did not search this database from 2016 onwards as it did not contribute additional search results to the first version of the review. The search terms were broad and included e‐cig$ OR elect$ cigar$ OR electronic nicotine. The search for the 2016 update added the terms vape or vaper or vapers or vaping. The 2020 searches added further terms, including the MESH heading 'Electronic Nicotine Delivery Systems' and terms to limit by study design. Our search strategy for MEDLINE (Ovid SP) is listed in Appendix 3. The previously‐used search strategy is shown in Appendix 4. The search date parameters of the original searches were limited to 2004 to the present, due to the fact that ECs were not available before 2004.

Searching other resources

We searched the reference lists of eligible studies found in the literature search and contacted authors of known trials and other published EC studies.

Data collection and analysis

Selection of studies

Two review authors (for this update from: JHB, CN, NL, AT, RB) independently prescreened all titles and abstracts obtained from the search, using a screening checklist, and then independently screened full‐text versions of the potentially relevant papers for inclusion. We resolved any disagreements by discussion or with a third review author.

Data extraction and management

Two review authors (for this update from: JHB, CN, NL, AT, RB, and with support from freelance reviewer KR) extracted data from the included studies using a pre‐piloted data extraction form, and checked them against each other. We resolved any disagreements by discussion or with a third review author. We extracted data on:

Author
Date and place of publication
Study dates
Study design
Inclusion and exclusion criteria
Setting
Summary of study participant characteristics
Summary of intervention and control conditions
Number of participants in each arm
Smoking cessation outcomes
Type of biochemical validation (if any)
Adverse events (AEs), serious adverse events (SAEs), and relevant biomarkers
Assessment time points
Study funding source
Author declarations of interest
Risk of bias in the domains specified below
Additional comments

We adopted a broad focus to detect a variety of adverse events.

One review author then entered the data into Review Manager 2020 software for analyses (JHB), and another checked them (NL).

Assessment of risk of bias in included studies

Two review authors (for this update from: JHB, CN, NL, AT, RB, and with support from freelancer KR) independently assessed the risks of bias for each included study, using the Cochrane 'Risk of bias' Tool v1 (Higgins 2011). This approach uses a domain‐based evaluation that addresses seven different areas: random sequence generation; allocation concealment; blinding of participants and providers; blinding of outcome assessment; incomplete outcome data; selective outcome reporting; and other potential sources of bias. We assigned a grade (low, high, or unclear) for risk of bias for each domain. We resolved disagreements by discussion or by consulting a third review author.

Specific considerations about judgements for individual domains in this review are outlined below:

Random sequence generation/allocation concealment: We rated all non‐randomized studies at high risk in these domains.
Blinding of participants and personnel: We did not evaluate this domain for non‐randomized studies, as we considered it not to be applicable. For randomized studies which did not use blinding, we considered studies to be at low risk in this domain if the intervention was compared to an active control of similar intensity, as we judged performance bias to be unlikely in this circumstance. If studies were unblinded and the comparator group was a minimal‐intervention control or of lower intensity than the intervention group, we considered the study to be at high risk of bias in this domain.
Following standard methods of the Cochrane Tobacco Addiction Review Group, we considered studies to be at low risk of detection bias (blinding of outcome assessment) if our primary outcome was objectively measured or if the intensity of intervention was similar between groups, or both. For studies where cessation was measured, our judgement was based on whether cessation was biochemically verified. For other studies, we judged this domain based on adverse or serious adverse events.
Again following standard methods of the Cochrane Tobacco Addiction Group, we rated studies at high risk of attrition bias if loss to follow‐up was greater than 50% overall or if there was a difference in follow‐up rates of more than 20% between study arms.

We judged studies to be at high risk of bias overall if they were rated at high risk in at least one domain, and at low risk of bias overall if they were judged to be at low risk across all domains evaluated. We judged the remaining studies to be at unclear risk of bias overall.

Measures of treatment effect

We analyzed dichotomous data by calculating the risk ratio (RR). For cessation, we calculated the RR as ((number of events in intervention condition/intervention denominator) / (number of events in control condition/control denominator)) with a 95% confidence interval (CI), using data at the longest follow‐up period reported.

We analyzed continuous data (other measures of tobacco exposure) by comparing the difference between the mean change from baseline to follow‐up in the intervention and comparator groups. For outcomes other than cessation where data were reported at multiple time points, we used data at the longest follow‐up point at which ECs were still being provided.

Unit of analysis issues

In the case of trials with multiple arms, we do not combine data between arms unless this is the way it has been presented by study authors. We note in our analyses where this is the case.

For all but one study, the unit of assignment was the individual. ISRCTN14140672 assigned condition based on homeless shelter; this was a small pilot study with very few events and hence we judged clustering to have very little impact on our overall result. If larger cluster‐randomized trials are eligible in the future, we will assess whether study authors have adjusted for this clustering, and whether this had an impact on the overall result. When clustering appears to have had little impact on the results, we will use unadjusted quit‐rate data; however when clustering does appear to have an impact on results, we will adjust for this using the intraclass correlation (ICC).

For randomized cross‐over trials, we report results at the end of the first assignment period where available and where sufficiently long to meet our inclusion criteria for outcomes. All other outcomes from randomized cross‐over trials are reported narratively. We offer a narrative synthesis of data from non‐randomized studies, and where possible use effect direction plots as described in the Cochrane Handbook (Higgins 2020).

Dealing with missing data

For smoking cessation, we used a conservative approach, as is standard for the Cochrane Tobacco Addiction Group, treating participants with missing data as still smoking. We based the proportion of people affected by adverse events on the number of people available for follow‐up, and not the number randomized. For other outcomes, we use complete‐case data and do not attempt to impute missing values.

Assessment of heterogeneity

We assessed the clinical and methodological diversity between studies to guide our decision as to whether data should be pooled. We were also guided by the degree of statistical heterogeneity, assessed by calculating the I² statistic (Higgins 2003), and considering a value greater than 50% as evidence of substantial heterogeneity. We did not present pooled results where I² values exceeded 75%.

Assessment of reporting biases

Reporting bias is best assessed using funnel plots, where 10 or more RCTs contribute to an outcome. However, there are currently insufficient studies to support this approach.

Data synthesis

We provide a narrative summary of the included studies. Where appropriate, we have pooled data from these studies in meta‐analyses. For dichotomous data, we used a fixed‐effect Mantel‐Haenszel model to calculate the RR with a 95% confidence interval, in accord with the standard methods of the Cochrane Tobacco Addiction Group for cessation studies.

For continuous outcomes, we pooled mean differences (or standardised mean differences for studies using different measures for the same construct), using the inverse variance approach (also with a 95% CI).

Subgroup analysis and investigation of heterogeneity

We had planned to undertake subgroup analyses to investigate differences between studies, such as:

Intensity of behavioural support used;
Type of EC (cartridge; refillable; pod);
Instructions for EC use (e.g. study provision, length of provision, whether participants had a role in product choice);
Type of participants (e.g. experience of EC use).

However, there were too few studies to conduct such analyses. Should further studies become available in future, we will follow this approach. For safety outcomes, we present subgroups by length of follow‐up for descriptive purposes.

In the absence of sufficient data for subgroup analyses on EC type, in the text we specify the type of nicotine EC when reporting pooled results for cessation.

Sensitivity analysis

We conducted sensitivity analyses to detect whether pooled results were sensitive to the removal of studies judged to be at high risk of bias.

Summary of findings and assessment of the certainty of the evidence

Following standard Cochrane methodology, we created 'Summary of findings' tables for our three main comparisons using GRADEpro GDT: nicotine EC versus non‐nicotine EC; nicotine EC versus NRT; and nicotine EC versus behavioural support only/no support. We selected these comparisons a priori as being the most clinically relevant. In the 'Summary of findings' tables, we present data on our primary outcomes (cessation, adverse events, serious adverse events) for these main comparisons. Also following standard Cochrane methodology, we used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of the body of evidence for each outcome, and to draw conclusions about the certainty of evidence within the text of the review.

Results

Description of studies

Results of the search

For this update, our bibliographic database searches identified 951 non‐duplicate records (Figure 1). We found a further three records through screening references in the papers identified through electronic searches. We screened all records and retrieved the full‐text papers of 122 potentially relevant articles. After screening and checking the full‐text of 122 papers, we included 79 records, representing 35 studies new for this update and 20 new ongoing studies (Characteristics of ongoing studies). Secondary study reports, commentaries, and correspondence relating to included studies are linked to studies in the reference section. Figure 2 and Figure 3 present PRISMA flow charts for previous versions of this review.

Study flow diagram for review update 2016

Study flow diagram for original review, 2014

Included studies

In total, we include 50 studies, 35 new included studies and 15 eligible included studies identified in previous versions of the review. Key features of the included studies are summarized below. Further details on each included study can be found in the Characteristics of included studies tables.

Participants

The 50 included studies represented 12,430 participants. Twenty‐one studies were conducted in the USA, nine were conducted in the UK, seven in Italy, two each in Australia, New Zealand, and Greece, and one each in Belgium, Canada, Poland, the Republic of Korea, South Africa, Switzerland, and Turkey. All studies were conducted in adults who smoke. Fifteen studies exclusively recruited participants who were not motivated to quit smoking, and 27 studies exclusively recruited participants motivated to quit; motivation was not specified for the other studies. Fifteen studies recruited from specific population groups; this included five studies which recruited participants based on physical health condition (heart attack, cancer, HIV, periodontitis, awaiting surgery), three studies which recruited participants with serious mental illness, and three studies which recruited participants in treatment or having recently completed treatment for alcohol or other drug use. One study each recruited: people aged 55 or older, young adults, and people accessing homeless centres.

Interventions and comparators

All studies provided nicotine EC, either alone (45 studies) or in conjunction with NRT or varenicline (5 studies). In two studies where nicotine EC was provided on its own, nicotine levels were judged to be so low as to be clinically comparable to non‐nicotine EC (Lee 2019; Van Staden 2013); we include these studies in non‐nicotine EC comparisons. Eight studies compared nicotine EC with non‐nicotine EC, 12 studies compared nicotine EC to behavioural support only or no support, and eight studies compared nicotine EC to NRT. Results from these studies are reported by comparison in Effects of interventions. Further details on the intervention and comparator groups (where applicable) for each study can be found in the Characteristics of included studies tables.

Where reported in the original publications, details on the devices tested can also be found in the Characteristics of included studies tables. Of the studies with sufficient data with which to judge, 25 used cartridge devices (only one of which had high nicotine delivery), 18 used refillable devices, two used both types, and the remainder did not report device type. No studies reported testing used pod systems.

Outcomes

Of the 50 included studies:

20 reported data on abstinence
34 reported data on adverse events
23 reported data on serious adverse events
30 reported data on carbon monoxide
9 reported data on heart rate
10 reported data on blood pressure
2 reported data on blood oxygen saturation
7 reported data on at least one known toxin/carcinogen
4 reported data on at least one measure of lung function

Study types and funding

Twenty‐six studies were RCTs, twelve of which contributed to cessation analyses. Three studies used randomized cross‐over designs, and the remainder were uncontrolled cohort studies. Of the 40 studies which reported funding information, 32 had no EC industry funding or support.

Excluded studies

We list 90 studies excluded at full‐text stage, along with reasons for exclusion, in the Characteristics of excluded studies table. The most common reason for exclusion during this update was follow‐up of less than a week. We excluded nine studies from this update that had been previously included; this is because they did not include any EC intervention (see Differences between protocol and review).

Risk of bias in included studies

Overall, we judged four studies (Bullen 2013; Hajek 2019; Lee 2018; Lee 2019) to be at low risk of bias, nine to be at unclear risk, and the remaining 37 at high risk of bias (note, this includes the 24 non‐randomized studies, which we deemed to be at high risk due to this lack of randomization).

Details of 'Risk of bias' judgements for each domain of each included study can be found in the Characteristics of included studies table. Figure 4 illustrates judgements for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We judged 22 studies to be at high risk of selection bias; for 21, this is because the studies were not randomized. We also rated a pilot cluster‐randomized trial at high risk as randomization was not carried out as intended for pragmatic reasons (ISRCTN14140672). We judged 12 studies to be at low risk of selection bias, and the remainder to be at unclear risk as there was insufficient information with which to judge.

Blinding

Of the 29 studies assessed for these domains, we judged 15 to be at low risk for both performance and detection bias. We rated ten at high risk for performance or detection bias, or both. In these studies, blinding was not used and different levels of support were provided; this alone or in conjunction with the outcome measures being used (subjective rather than objective measures) meant we thought there was a high risk of bias being introduced. We judged the rest to be at unclear risk.

Incomplete outcome data

We judged most studies (36 out of 50) to be at low risk of attrition bias. We rated four studies with substantial loss to follow‐up at high risk of attrition bias, and a further 10 did not provide sufficient data on which to judge, and hence we judged them to be at unclear risk.

Selective reporting

Of the 50 studies, we considered that half were at low risk of reporting bias, as all prespecified/expected outcomes were reported. We rated four at high risk, as data were not presented as specified in the original protocols. We judged the rest to be at unclear risk, due to insufficient information with which to make a judgement.

Other potential sources of bias

We considered Ioakeimidis 2018 to be at high risk of other bias; data were from a conference poster and the associated abstract, and quit rates in the intervention arm differed between the two sources.

Effects of interventions

See: Table 1; Table 2; Table 3

Summary of findings 1. Nicotine EC compared to NRT for smoking cessation.

Nicotine EC compared to NRT for smoking cessation
Patient or population: People who smoke Setting: New Zealand, UK, USA Intervention: Nicotine EC Comparison: NRT
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with NRT	Risk with Nicotine EC
Smoking cessation at 6 months to 1 year Assessed with biochemical validation	Study population		RR 1.69 (1.25 to 2.27)	1498 (3 RCTs)	⊕⊕⊕⊝ MODERATE^a	‐
	6 per 100	10 per 100 (8 to 14)
Adverse events at 4 weeks to 6 months Assessed by self‐report	Study population		RR 0.98 (0.80 to 1.19)	485 (2 RCTs)	⊕⊕⊝⊝ LOW^b	‐
	45 per 100	44 per 100 (36 to 53)
Serious adverse events at 4 weeks to 1 year Assessed via self‐report and medical records	Study population		RR 1.37 (0.77 to 2.41)	727 (2 RCTs)	⊕⊕⊝⊝ LOW^b	‐
	5 per 100	7 per 100 (4 to 13)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). For cessation, the assumed risk in the control group is based on assumed quit rates for NRT assuming receipt of limited behavioural stop‐smoking support (as per Hartmann‐Boyce 2018a). The assumed risk for adverse events and serious adverse events is a weighted mean average of quit rates across control groups in contributing studies.  CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Nicotine EC compared to non‐nicotine EC for smoking cessation
Patient or population: People who smoke cigarettes Setting: Canada, Italy, New Zealand, UK, USA Intervention: Nicotine EC Comparison: Non‐nicotine EC
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with non‐nicotine EC	Risk with Nicotine EC
Smoking cessation at 6‐12 months Assessed with biochemical validation	Study population		RR 1.71 (1.00 to 2.92)	802 (3 RCTs)	⊕⊕⊕⊝ MODERATE^a,b	‐
	6 per 100	10 per 100 (6 to 18)
Adverse events at 1 week to 6 months Assessed via self‐report	Study population		RR 1.00 (0.73 to 1.36)	346 (2 RCTs)	⊕⊕⊝⊝ LOW^c	‐
	35 per 100	35 per 100 (25 to 47)
Serious adverse events at 1 week to 1 year Assessed via self‐report and medical records	Study population		RR 0.25 (0.03 to 2.19)	494 (4 RCTs)	⊕⊕⊝⊝ LOW^c	‐
	2 per 100	0 per 100 (0 to 4)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). For cessation, the assumed risk in the control group is based on receipt of moderate‐intensity behavioural stop‐smoking support. The assumed risk for adverse events and serious adverse events is a weighted mean average of quit rates across control groups in contributing studies.  CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Nicotine EC compared to behavioural support only/no support for smoking cessation
Patient or population: People who smoke Setting: Canada, Italy, UK, USA Intervention: Nicotine EC Comparison: Behavioural support only/no support
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with behavioural support only/no support	Risk with Nicotine EC
Smoking cessation at 6 to 12 months Assessed using biochemical validation	Study population		RR 2.50 (1.24 to 5.04)	2312 (4 RCTs)	⊕⊝⊝⊝ VERY LOW^a,b	‐
	4 per 100	10 per 100 (5 to 20)
Adverse events at 12 weeks to 6 months Assessed via self‐report	Study population		RR 1.17 (1.04 to 1.31)	516 (3 RCTs)	⊕⊝⊝⊝ VERY LOW^a,c	‐
	60 per 100	70 per 100 (62 to 78)
Serious adverse events at 4 weeks to 6 months Assessed via self‐report and medical records	Study population		RR 1.33 (0.25 to 6.96)	842 (5 RCTs)	⊕⊝⊝⊝ VERY LOW^d,e	‐
	1 per 100	1 per 100 (0 to 5)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). For cessation, the assumed risk in the control group is based on receipt of limited stop‐smoking support. The assumed risk for adverse events and serious adverse events is a weighted mean average of quit rates across control groups in contributing studies.  CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Study	Motivated or unmotivated to quit smoking?	% abstinent
Cohort studies		6‐month	12‐month	18‐month	24‐month	Notes
Adriaens 2014^a	Unmotivated to quit	19.6% (10/51)				Data from 8‐month follow‐up
Bell 2017	"Willing to attempt to quit"	26.6% (8/30)
Caponnetto 2013b	Unmotivated to quit		14% (2/14)
Ely 2013^b	Motivated to quit	44% (21/48)
Pacifici 2015	Unmotivated to quit		53% (18/34)
Polosa 2011	Unmotivated to quit	23% (9/40)		15% (6/40)	13% (5/40)
Polosa 2014b	Unmotivated to quit	36% (18/50)
Polosa 2015	Not defined	42% (30/71)	41% (29/71)

Date	Event	Description
4 February 2021	Amended	This is a Living Systematic Review. We run and screen searches monthly. Last search date 1st February 2021. In addition to the studies identified from our December 2020 and January 2021 searches we found one paper linked to a study already included in the review (Lucchiari 2020), and have preliminary results from a study listed as ongoing (Begh 2019). We will incorporate this paper and data into the review as part of a future update.
20 January 2021	Amended	This is a Living Systematic Review. Searches are run and screened monthly. Last search date 4th January 2021. In addition to the studies identified from our December 2020 searches we found four new completed studies, one new ongoing study and one paper linked to a study already included in the review. These studies and papers will be incorporated into the review at the next update. DOIs for the four new included studies are as follows: Ozga‐Hess et al. 2019: 10.1016/j.addbeh.2019.106105; Pulvers et al. 2020: 10.1001/jamanetworkopen.2020.26324; Scheibein 2020: 10.1186/s12954-020-00406-y; Yingst et al. 2020: 10.1080/09540121.2019.1687835
15 December 2020	Amended	This is a Living Systematic Review. Searches are run and screened monthly. Last search date 1st December 2020. Searches found 3 new completed studies, 11 new ongoing studies and 9 papers linked to studies already included in the review. These studies and papers will be incorporated into the review at the next update. DOIs for the three new included studies are as follows: Czoli et al: 10.1093/ntr/nty174;Bonevski et al: 10.1093/ntr/ntaa143;Eisenberg et al: 10.1001/jama.2020.18889.
20 July 2020	New citation required and conclusions have changed	Strength of evidence increased for existing comparisons; new comparisons added
20 July 2020	New search has been performed	New searches run January 2020. 35 new studies added. Living systematic review protocol incorporated
14 December 2016	Amended	Clarification on outcome data from Adriaens ‐ no changes to conclusions
23 June 2016	New search has been performed	Update search run January 2016, 11 new included studies added. Reduction removed as outcome, now covered in Harm Reduction review.
23 June 2016	New citation required but conclusions have not changed	11 new included studies added; no changes to conclusions.

Abbreviation	Name
‐	1‐Hydroxyfluorene
‐	1‐Hydroxyphenanthrene
‐	1‐Hydroxypyrene
2‐HPMA	2‐hydroxypropylmercapturic acid
‐	2‐Hydroxyfluorene
‐	2‐Hydroxyphenanthrene
‐	2‐Naphthol
‐	3‐, 4‐Hydroxyphenanthrenes
3‐HPMA	3‐hydroxypropylmercapturic acid
‐	3‐Hydroxyfluorene
AAMA	N‐acetyl‐S‐(carbamoylethyl)‐L‐cysteine (synonym: 2‐carbamoylethylmercapturic acid)
CEMA/CNEMA	2‐cyanoethylmercapturic acid; referred to as 'acrylonitrile' in Pulvers 2018
‐	Formic acid
HEMA	2‐hydroxyethylmercapturic acid
HMPMA/HPMMA	3‐hydroxy‐1‐methyl propylmercapturic acid
MHBMA	2‐hydroxy‐3‐buten‐1‐ylmercapturic acid
MMA	N‐nitrosodimethyamine
NNAL	4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol
PheT	Phenanthrene tetraol
PMA	phenylmercapturic acid; referred to as 'benzene' in Pulvers 2018
S‐PMA	S‐phenylmercapturic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Smoking cessation	3	1498	Risk Ratio (M‐H, Fixed, 95% CI)	1.69 [1.25, 2.27]
1.2 Adverse events	2	485	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.80, 1.19]
1.2.1 4 weeks	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.31, 1.73]
1.2.2 6 months	1	456	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.81, 1.22]
1.3 Serious adverse events	2	727	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.77, 2.41]
1.3.1 4 weeks	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.2 1 year	1	698	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.77, 2.41]
1.4 Carbon monoxide (ppm)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.4.1 8 weeks	2	136	Mean Difference (IV, Fixed, 95% CI)	‐0.66 [‐1.94, 0.62]
1.5 Heart rate (bpm)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.5.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.6 Systolic blood pressure	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.6.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.7 Blood oxygen saturation	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.7.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.8 3‐HPMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.8.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.9 NNAL (pmol/mg creatinine))	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.9.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.10 2‐HPMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.10.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.11 HMPMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.11.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.12 PheT (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.12.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.13 CEMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.13.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.14 AAMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.14.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.15 FEV1 (ml)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.15.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.16 FEV1/FVC (%)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.16.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Smoking cessation	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2 Serious adverse events	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.2.1 12 weeks	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Smoking cessation	3	802	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [1.00, 2.92]
3.2 Adverse events	2	346	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.73, 1.36]
3.2.1 1 week	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.27, 8.19]
3.2.2 6 months	1	298	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.71, 1.34]
3.3 Serious adverse events	4	494	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.19]
3.3.1 1 week	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.2 4 weeks	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.3 12 weeks	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.19]
3.3.4 1 year	1	117	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.4 Carbon monoxide (ppm)	2	171	Mean Difference (IV, Fixed, 95% CI)	‐2.44 [‐3.91, ‐0.97]
3.4.1 2 weeks	1	25	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐3.00, 2.20]
3.4.2 12 weeks	1	146	Mean Difference (IV, Fixed, 95% CI)	‐3.40 [‐5.18, ‐1.62]
3.5 Heart rate	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.5.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.6 Systolic blood pressure	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.6.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.7 FeNO (ppb)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.7.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.8 FEV1 (l)	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.8.1 12 weeks	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.9 FVC (l)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.9.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.10 FEV1/FVC	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.10.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Smoking cessation	4	2312	Risk Ratio (M‐H, Fixed, 95% CI)	2.50 [1.24, 5.04]
4.2 Adverse events	3	516	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [1.04, 1.31]
4.2.1 12 weeks	1	408	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [1.01, 1.26]
4.2.2 16 weeks	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.67, 2.07]
4.2.3 6 months	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	11.00 [0.64, 190.26]
4.3 Serious adverse events	5	842	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.25, 6.96]
4.3.1 4 weeks	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.3.2 12 weeks	2	657	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.25, 6.96]
4.3.3 16 weeks	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.3.4 6 months	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.4 Carbon monoxide (ppm)	5		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4.1 3 to 4 weeks	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4.2 8 weeks	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4.3 6 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.5 Heart rate (bpm)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.5.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.6 Systolic blood pressure	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.6.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.7 Blood oxygen saturation	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.7.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.8 3‐HPMA (SMD)	2		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.8.1 8 weeks	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.8.2 12 weeks	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.9 NNAL (SMD)	3		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.9.1 3 weeks	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.9.2 8 weeks	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.9.3 12 weeks	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.10 2‐HPMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.10.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.11 HMPMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.11.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.12 PheT (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.12.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.13 CEMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.13.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.14 AAMA (pmol/mg creatinine)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.14.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.15 S‐PMA (nanograms)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.15.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.16 FVC (litres)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.16.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.17 FEV1 (litres)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.17.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.18 FEF 25‐75 (litres/second))	1	387	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.10, 0.30]
4.18.1 12 weeks	1	387	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.10, 0.30]
4.19 PEF 25‐75 (litres/minute)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.19.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Smoking cessation	2	1039	Risk Ratio (M‐H, Fixed, 95% CI)	1.77 [1.07, 2.94]
5.2 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.2.1 12 weeks	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.3 Serious adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.3.1 6 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.4 Carbon monoxide (ppm)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.4.1 8 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.5 FeNO (ppb)	1	30	Mean Difference (IV, Fixed, 95% CI)	‐0.36 [‐7.23, 6.51]
5.5.1 6 months	1	30	Mean Difference (IV, Fixed, 95% CI)	‐0.36 [‐7.23, 6.51]
5.6 FEV1 (%)	1	32	Mean Difference (IV, Fixed, 95% CI)	0.05 [‐0.01, 0.10]
5.6.1 6 months	1	32	Mean Difference (IV, Fixed, 95% CI)	0.05 [‐0.01, 0.10]
5.7 FVC (%)	1	32	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.03, 0.09]
5.7.1 6 months	1	32	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.03, 0.09]

*Study characteristics*
Methods	Design: Pragmatic, uncontrolled, mixed‐methods trial Recruitment: Targeted settings for people with HIV Setting: Community, Brisbane, Australia Study start date: 21 February 2017; Study end date: 26 October 2017
Participants	Total N: 30 Inclusion criteria: Diagnosis of HIV Aged 18 years, or over Smoke ≥ 5 cpd at the time of enrolment into the trial Have been smoking for at least 12 months Willing to attempt to quit tobacco smoking after study enrolment Exclusion criteria: Participating in a smoking‐cessation programme Pregnant or breastfeeding or planning to be during trial period Experienced chest pain, or another cardiovascular event or procedure in the last month Being treated with oxygen therapy Inclusion based on specific population characteristic: People living with HIV 29 participants identified as male, and 1 participant did not identify as male or female; Mean age: 42; Mean cpd: 18 EC use at baseline: 46.7% (n = 14) Never tried; 50% (n = 15) Tried, never used for an extended period; 3.3% (n = 1) Used on a regularly (weekly) basis Willing to attempt to quit
Interventions	EC: Refillable Single‐arm study. Print materials to help quit smoking. Provided booklet with instructions on how to use, store and handle EC; copies of device user manuals. Given Innokin Endura T18® vaporiser kit, Innokin Endura T22® vaporiser kit, 4 spare coils, 1 wall charger, 10 x 10‐mL bottles of Nicophar® 12 mg nicotine e‐liquid. Supplies to last 12 weeks
Outcomes	Weeks 1, 4, 8, 12, 24; Self‐report and semistructured interviews Cessation: 7 days point prevalence at weeks 4, 8, 12 and 24. Continuous abstinence at weeks 12 and 24. No biochemical validation Adverse events Other outcomes: Acceptability and use of trial products; Number of quit attempts
Study funding	"This work was supported by the HIV Foundation Queensland. The funder will play no role in the analysis and interpretation of results. All trial products were purchased and the suppliers have no involvement in the conduct of the trial or the interpretation or reporting of the results."
Author declarations	"No other authors declare conflicts of interest. Mark Boyd has received research grant funding (paid to the institution) from AbbVie, Gilead and Merck and received honoraria for participation in HIV Advisory Boards and for the preparation and delivery of educational materials from AbbVie, Boehringer‐Ingelheim, Bristol Myers Squibb, Gilead, Janssen‐Cilag, Merck and ViiV Healthcare."
Notes	Additional data provided from authors. New for 2020 update
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Uncontrolled study
Allocation concealment (selection bias)	High risk	Uncontrolled study
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “At Week 24, 26 of the 30 participants who enrolled in the study were followed up.” (confirmed by authors)
Selective reporting (reporting bias)	Low risk	Study not published at time of data extraction, but study protocol published

*Study characteristics*
Methods	Design: Prospective cohort Recruitment and setting: Inpatients at a psychiatric institution in Italy Study start date/end date: Not specified
Participants	Total N: 14 Inclusion criteria: Smoked ≥ 20 cpd for at least the past 10 years Diagnosis of schizophrenia Exclusion criteria: Alcohol and illicit drug use Recent myocardial infarction Angina pectoris High blood pressure (BP > 140 mmHg systolic or 90 mmHg diastolic, or both) Diabetes mellitus Severe allergies Poorly‐controlled asthma or other airway diseases Inclusion based on specific population characteristic: Diagnosis of schizophrenia 57% women, mean age 44.6 (SD 12.5), mean pack years smoked 28.8 (SD 12.9) Motivated to quit: Not specified E cigarette use at baseline: Not specified
Interventions	EC: Cig‐a‐like Seen at baseline, given EC ('Categoria' brand) with an initial 4‐week supply of 7.4 mg nicotine cartridges. Instructed to use ad libitum up to 4 cartridges a day. EC cartridges supplied at months 1, 2, and 3 No instruction on cessation or reduction was provided.
Outcomes	Follow‐up at 1, 2, 3, 6 and 12 months where cigarette consumption, CO, AEs and positive and negative symptoms of schizophrenia were measured Sustained reduction of ≥ 50% for at least 30 days at 12 months 30‐day point prevalence CO‐validated abstinence at 12 months Adverse events
Study funding	"We wish to thank Arbi Group Srl (Milano, Italy) for the free supplies of “Categoria” e‐cigarette kits and nicotine cartridges as well as their support. We would also like to thank LIAF (Lega Italiana AntiFumo) for the collaboration."
Author declarations	"Pasquale Caponnetto, Roberta Auditore, Cristina Russo and Giorgio Carlo Cappello declare no conflict of interest. Riccardo Polosa has received lecture fees and research funding from Pfizer and GlaxoSmithKline, manufacturers of stop smoking medications. He has served as a consultant for Pfizer and Arbi Group Srl (Milano, Italy), the distributor of the CategoriaTM e‐cigarette."
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Prospective cohort; no randomization
Allocation concealment (selection bias)	High risk	Not randomized
Incomplete outcome data (attrition bias) All outcomes	Low risk	0/14 lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	Unable to determine prespecified outcomes

*Study characteristics*
Methods	Design: Randomized parallel‐assignment open‐label trial Recruitment: Recruitment from local urban community in southeastern USA, using various media outlets Setting: Community, southeastern USA Study start date: November 2014; Study end date: May 2016
Participants	Total N: 68 N per arm: Control group: 22; ENDS group: 46 (split into 2 non‐randomized groups: BluCig 16 mg: 25; BluCig 24 mg: 21) Inclusion criteria: Age 18+ Current smoker of ≥ 5 cpd for ≥ 1 year No recent history of cardiovascular distress, COPD, cancer (any non‐dermatologic), or uncontrolled diabetes mellitus Neither pregnant nor breastfeeding (verified) Absence of any major current psychiatric impairment, including current alcohol/drug abuse/dependence Current, active use of email At least some concern for health effects of smoking (> none at all on a Likert scale) Not used any ENDS product in the past 6 months Never purchased an ENDS product Exclusion criteria: Use of non‐cigarette tobacco products (e.g. cigarillos) in the last 30 days Current use of any smoking cessation medications Current enrolment in a smoking cessation treatment study Women: 59.7%; Mean age: 42.2; Mean cpd: 15.3; Heaviness of smoking (0 ‐ 6): 2.9 EC use: Control: 9%; ENDS 16 mg group: 4%; ENDS 24mg group: 33% Motivation to quit smoking in next month (0 – 10): Control: 4.0; ENDS 16 mg: 5.0; ENDS 24 mg: 4.4
Interventions	EC: Cig‐a‐like Intervention: At study start, choice of tobacco or menthol flavour Blu Starter Pack EC, with 16 mg/mL nicotine. Midway through study, the manufacturer of Blu altered the product and discontinued availability of the device, replaced with BluPlusþ, with 24 mg/mL nicotine. 3‐week sampling period, given up to 7 cartridges at each of 3 weekly visits. Instructions on usage "kept minimal to preserve naturalistic intent." The study team suggested that ENDS could be used "as you wish, to cut down or quit smoking, help manage smoking restrictions, or both." Control: own brand of cigarettes
Outcomes	Weeks 2, 3, 4, 8, 12 and 16 Carbon monoxide, NNAL Other outcomes: cessation (< 6 months), product evaluation, EMA
Study funding	"Support was provided by NIH R21 DA037407 (to M.J. Carpenter), P01 CA200512 (to K.M. Cummings, M.J. Carpenter, and M.L. Goniewicz), UL1 TR001450, and P30 CA138313. M.L. Goniewicz's laboratory is supported via P30 CA016056. B.W. Heckman is supported via K12 DA031794 and K23 DA041616. T.L. Wagener's effort is partially supported by the Oklahoma Tobacco Research Center, which is funded by the Oklahoma Tobacco Settlement Endowment Trust."
Author declarations	"M.L. Goniewicz is a consultant/advisory board member for Johnson & Johnson. K.M. Cummings reports receiving a commercial research grant from and is a consultant/advisory board member for Pfizer Inc., and has provided expert witness testimony for various plaintiffs in lawsuits involving cigarette manufacturers. No potential conflicts of interest were disclosed by the other authors."
Notes	New for 2020 update. Listed as ongoing study NCT02357173 in 2016 review update. Additional data provided from authors In all, 25 participants (54%) received the Blu Starter Pack (16 mg), and 21 participants (46%) received BluPlusþ (24 mg); no switches were made within participants. Note: this is not included in our analysis of higher v lower as assignment to nicotine dose was not done at random; 24 mg and 16 mg merged in our main analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “Randomization to group was stratified by motivation to quit in the next 30 days (0–6 vs. 7–10 on a VAS scale) but proportioned 2:1 (ENDS:control) to increase precision estimates for e‐cigarette uptake and usage.”
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded and includes non‐active control
Blinding of outcome assessment (detection bias) All outcomes	High risk	CO biochemically verified but abstinence not used as outcome in this review, so rated based on adverse event reporting. Self‐report, no blinding of participants.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Retention rate: Week 4: Control:19/22 (86%); ENDS 16 mg: 23/25 (92%); ENDS 24 mg: 20/21 (95%) Week 16: Control: 16/22 (73%); ENDS 16 mg: 19/25 (76%); ENDS 24 mg: 15/21 (71%)
Selective reporting (reporting bias)	Unclear risk	Not specified
Other bias	Low risk	Midway through the study, the manufacturer of Blu altered the product and discontinued availability of the device, replaced with BluPlusþ, with 24 mg/mL nicotine, again offered in both tobacco and menthol flavourings, and with improved battery duration (4‐watt battery for both devices). In all, 25 participants (54%) received the Blu Starter Pack (16 mg), and 21 participants (46%) received BluPlusþ (24 mg); no switches were made within participants. The change in product (IRB approved) allowed us the unexpected opportunity to assess what impact, if any, the change in product design had on study outcomes. Note that the manufacturer, style of device, and packaging did not change, nor did our messaging to participants. The only difference was the strength of product. Thus, trial outcomes are reported across 3 groups: control versus 16 mg versus 24 mg ENDS. We have not rated this as high risk of bias as our analyses do not compare on nicotine strength and both nicotine arms are combined in our main analysis

*Study characteristics*
Methods	Design: Double‐blind RCT Recruitment: People who smoke were recruited from an outpatient opioid‐maintenance clinic in West Virginia, USA Setting: Outpatient opioid‐maintenance clinic in West Virginia, USA Study start date/Study end date: Not reported
Participants	Total N: 25; N per arm: Placebo (non‐nicotine): 11; Active (18 mg/ml nicotine): 14 Inclusion criteria: ≥18 years of age Report smoking ≥10 cpd for ≥ one year Report a current interest in quitting smoking Exclusion criteria: Reported regular use of any nicotine/tobacco product other than cigarettes, including EC, or were already engaged in attempts to quit smoking Inclusion based on specific population characteristic: People who smoke who were currently receiving a buprenorphine/naloxone combination in sublingual form, and had maintained sobriety from opioids and all other illicit substances for at least 90 consecutive days as verified via urinalysis 73.0% women; mean age 32.5; mean cpd 22; mean FTND 5.8 Motivated to quit: Quit ladder Score (range 1 ‐ 10): 5.6 average
Interventions	EC: Refillable Compared nicotine (18 mg/ml) to non‐nicotine EC. Second‐generation EC consisted of the eGo‐T battery (900mAh, 3.3 V constant output) (Joyetech; Irvine, CA) and the Kanger mini Protank‐II, 1.5 ml Pyrex glass tank with a drip tip and atomizer head coils (KangerTech; China), choice between tobacco (n = 15) and menthol (n = 10) flavoured liquid (2‐week supply). Participants were then trained in EC device operation, including assembly, liquid filling, manual battery operation, and cleaning/storage. Practised puffing on EC in the presence of a team member, and asked questions if needed. Participants instructed to use their ECIG ad libitum every day for 2 weeks
Outcomes	Baseline (day 1), 14 days, 28 days for clinic measures. Data also collected via text‐messages over 2‐week intervention period Withdrawal/side effects: Every evening during the 2‐week intervention period, participants rated a variety of effects possibly experienced as a result of nicotine/tobacco withdrawal and/or use of the ECIG: nausea, dizziness, throat irritation/soreness, cough, dry mouth, headache, shortness of breath, irritability/frustration/anger, craving/urge to smoke, and other. Each item was rated on a continuous scale that ranged from 0 (not at all) to 100 (extremely) Expired air CO Other outcomes: Self‐reported cigarette and EC use; readiness to quit at day 1, 14 and 28
Study funding	Not reported
Author declarations	Not reported
Notes	New for 2020 update
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “Using a mixed factorial, simple randomization, double‐blind study design, participants were assigned to one of two ECIG conditions…” (No further details given)
Allocation concealment (selection bias)	Unclear risk	No details on allocation given.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “double‐blind study design”, no further detail given
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: “double‐blind study design”, no further details given.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “…80.6% completed the two‐week intervention (n=14 active; n=11 placebo), and 70.9% also completed the follow‐up session (n=13 active; n=9 placebo).” Active follow‐up completion rate: 13/14 = 93%; Placebo follow‐up completion rate: 9/11= 82% N.B. 6 participants were disqualified post‐randomization:  Quote: “Of those individuals who were screened for the study, 93.9% were enrolled (n = 18 active; n = 13 placebo); two individuals who were ineligible provided an expired air CO level < 10 ppm. Six of the enrolled participants (n = 4 active and n = 2 placebo; n = 5 tobacco flavor and n = 1 menthol flavor) were disqualified for responding to 7 or fewer days of text messages.”
Selective reporting (reporting bias)	Unclear risk	All measures listed were reported: Self‐reported cigarette use, text message‐based cigarette use, e‐cig use, expired air CO, readiness to quit ladder, withdrawal/side effect; No study protocol or clinical trial record available to confirm all intended outcome measures were reported

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Smoking cessation	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.2 Adverse events	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.2.1 12 weeks	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.3 Serious adverse events	4	930	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.60, 3.31]
6.3.1 5 weeks	1	7	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3.2 12 weeks	2	298	Risk Ratio (M‐H, Fixed, 95% CI)	2.12 [0.48, 9.28]
6.3.3 6 months	1	625	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.39, 3.27]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Serious adverse events	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.1.1 1 year	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.2 Carbon monoxide (ppm)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.2.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.3 Heart rate	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.3.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.4 Systolic blood pressure	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.4.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.5 FeNO (ppb)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.5.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.6 FEV1 (l)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.6.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.7 FVC (l)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.7.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.8 FEV1/FVC	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.8.1 12 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
9.1 Smoking cessation	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.2 Adverse events	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.3 Serious adverse events	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.3.1 6 months	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Smoking cessation	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.2 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.2.1 6 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.3 Serious adverse events	1	132	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.3.1 6 months	1	132	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

*Study characteristics*
Methods	Design: 3‐armed RCT; with all participants then assigned to nicotine EC (treated as cohort in this review) Recruitment: Advertisement on university website, flyers on university campuses, emails to personnel and advertisement in local newspaper Setting: Community and laboratory, Belgium Study start date/end date: Not stated
Participants	Total N: 48 provided data Randomized to: EC1 16; EC2 17; control 17 Inclusion criteria: Smoker for at least 3 years, Smoking at least 10 cpd, not intending to quit in the near future but willing to try a less unhealthy alternative Exclusion criteria: Diabetes; Severe allergies; Asthma or other respiratory diseases; psychiatric problems; Dependence on chemicals other than nicotine; Pregnancy; Breastfeeding; Hypertension; CV disease; Currently using any kind of smoking cessation therapy; prior use of EC 56% women, mean age 44, mean cpd 19, mean FTCD 5.79, all unwilling to quit with no baseline EC use
Interventions	EC: Refillable Intervention: 2 intervention groups (EC1 and EC2) provided with EC and instructed to use EC or smoke ad libitum (EC1 group provided with Joyetech eGO‐C, EC2 group provided with Kanger T2‐CC) and provided guidance on EC use. For both types, provided 30 mL bottles of tobacco‐flavoured e‐liquid (Dekang “Turkish Blend”), containing 18 mg/mL of nicotine. 4 bottles at baseline replenished at 4 weeks, keep any remaining after 8 weeks Control: 6 bottles for 2 months at week 8 (half offered EC1, half offered EC2); no guidance on use
Outcomes	3 lab sessions over 2 months (weeks 1, 4 and 8), plus online questionnaires, further follow‐up at 3 and 6 m after last lab session Cessation: measured but definition not provided, validated with eCO 5 ppm or less Adverse events and biomarkers: eCO, salivary cotinine measured during lab sessions. Also collected craving and withdrawal symptoms via lab sessions, “benefits and complaints”, mood, EC usage
Study funding	"No external funding for this study was obtained. Electronic cigarettes and e‐liquids were purchased at E‐cig4U (`t Rond 10, 4285 DE Woudrichem, The Netherlands; http://www.e‐cig4u.nl/) with balances of previous research funds obtained by Frank Baeyens."
Author declarations	The authors declare no conflict of interest
Notes	Randomization was for short‐term outcomes only Additional data provided from authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomization was performed by using a randomization tool available on the website www.randomizer.org
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Unblinded but as this review only includes data on objective measurements and not cessation judged unlikely to affect outcomes
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Unblinded but as this review only includes data on objective measurements and not cessation judged unlikely to affect outcomes
Incomplete outcome data (attrition bias) All outcomes	Low risk	36 out of 48 completed follow‐up (11/16 in EC1 group, 12/17 in EC2 group, 13/17 in control group)
Selective reporting (reporting bias)	Unclear risk	Outcome reporting somewhat non‐traditional; for example, collecting complaints but not explicitly adverse events, and incidence of AEs not reported. Unable to find prospectively‐registered protocol

*Study characteristics*
Methods	Design: Randomized parallel‐assignment double‐blind trial Recruitment: outpatient pulmonary and primary care clinics, Tobacco Treatment Service, referrals from medical providers Setting: Hospital outpatient and primary care clinics, USA Study start date: October 2014; Study end date: June 2014
Participants	Total N: 40 N per arm: Non‐Nicotine: 20; Nicotine EC: 20 Inclusion criteria: Age 18 years or older Smoking 1 or more cpd Willing to quit smoking Exclusion criteria: Unstable psychiatric or medical conditions requiring hospitalisation within the past 4 months; Acute coronary syndromes or stroke within the past 30 days; History of allergic reactions to adhesives; Women who were pregnant, nursing, or not practicing effective contraception; Current use of an EC for the purpose of stopping tobacco cigarette smoking Women: 52.5%; Mean age: 53 Mean cpd: 17 Mean FTND: 5.9; motivated to quit E cigarette use at baseline: Not reported
Interventions	EC: Refillable Both groups received standard care (8 weeks nicotine patch and counselling) and were randomized to nicotine EC or non‐nicotine EC. EC: eGO style EC (650 mAh battery, EVOD clearomizer, 3.7 V, 1.8 Ω single bottom coil), provided with e‐liquid purchased from an online vape shop (0 mg/ml or 24 mg/ml nicotine strength, 70/30 propylene glycol/vegetable glycerin, tobacco flavour); Instructed to use it as needed as a substitute for tobacco to try to satisfy cravings to smoke. If the patch alone proved adequate to prevent withdrawal and smoking cravings, the participant was advised not to use the EC. Additional EC devices, replacement coils, and liquid were provided as needed for the first 8 weeks of the study
Outcomes	Questionnaires and CO measurements taken at baseline, treatment visits at week 2, 4, 6, 8 and follow‐up at week 24 Cessation: 7‐day point prevalence abstinence, eCO ≤ 6 ppm Adverse events and biomarkers: Side effects were measured although it is unclear whether a questionnaire with prespecified symptoms was used Spirometry and FeNO at baseline and 6‐month follow‐up Other outcomes: Change in reported number of cpd at weeks 8 and 24; Change in per cent predicted FEV1 and FVC from baseline to week 24, and EC use patterns
Study funding	"Funding for this study was provided by the Yale School of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine and the National Heart, Lung, and Blood Institute grant T32HL007778. NHLBI had no role in the study design, collection, analysis, or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication."
Author declarations	"Dr. Toll received a grant from Pfizer for medicine only for a research study, and he receives funding as an expert witness in litigation filed against the tobacco industry. Dr. Chupp received grants from NIH, Genetech, Glaxo Smith Kline, Astra Zeneca/Medimmune and Boston Scientific. He received consulting/speaking fees from Genetech, Astra Zeneca/Medimmune, Mannkind, and Boston Scientific. There are no other conflicts of interest for the remaining authors."
Notes	New for 2020 update. Study listed as ongoing study NCT02498145 in 2016 review update Additional data provided from authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Participants were randomized using a random number generator with 1:1 blocked randomization (block size n= 8).”
Allocation concealment (selection bias)	Unclear risk	Both groups received standard care (nicotine patch and counselling) and were randomized to: nicotine EC or non‐nicotine EC (no further detail given)
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “Treatment assignment was blinded to both the investigators and participants”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	CO biochemically validated
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: “The study had a modest loss to follow‐up (20%) at week 24.” Number lost to follow‐up in each group is not reported in the paper Week 24 retention rate: Nicotine EC group: 19/20 (95%); Non‐nicotine EC group: 13/20 (65%); > 20% difference between groups
Selective reporting (reporting bias)	Low risk	Outcomes reported align with those listed in the clinicaltrials.gov record. (registered 2015; prior to study completion in 2016)

*Study characteristics*
Methods	Design: 3 parallel groups RCT Recruitment: People who smoke recruited from the community, via newspaper advertisements Setting: Research Unit, New Zealand Study start date: 6 September 2011; Study end date: 5 July 2013
Participants	Total N: 657. 289 nicotine EC (NEC), 295 patch, 73 non‐nicotine EC (PEC) Inclusion criteria: 18 years of age or older; Smoked 10 or more cpd over past year; Wanted to stop smoking Exclusion criteria: Pregnant and breastfeeding Using cessation medicines or using other support to quit Heart attack, Stroke, Severe angina in the last 2 weeks, Poorly‐controlled medical disorder, Allergies, Other chemical dependence 62% women, mean age 42, ⅓ NZ Maori, smoking 18 cpd, mean FTND score 5.5 Motivated to quit E cigarette use at baseline: Not specified
Interventions	EC: Cig‐a‐like Randomized to NEC, PATCH or PEC use for 13 weeks (from 1 week prior to TQD) NEC: Elusion brand 16 mg cartridges; sent product via courier PATCH: 21 mg/24‐hour patch; sent voucher to exchange for NRT at pharmacy (dispensing costs covered) PEC: As per EC, but 0 mg cartridges All participants referred to Quitline and received an invitation to access phone‐ or text‐based support. This was accessed by < 10%
Outcomes	Sustained (≤ 5 cigarettes allowed) validated (exhaled breath CO < 10 ppm) abstinence at 6 months ≥ 50% self‐reported reduction in baseline cigarettes at 6 months Participants reporting any adverse events Proportion of AEs that were serious Proportion of unrelated AEs
Study funding	Health Research Council of New Zealand
Author declarations	"We declare that we have received no support from any companies for the submitted work and have no non‐financial interests that might be relevant to the submitted work. ML, via his company Health New Zealand, previously did research funded by Ruyan (an e‐cigarette manufacturer). CB and HM have done research on Ruyan e‐cigarettes funded by Health New Zealand, independently of Ruyan. HM has received honoraria for speaking at research symposia, has received benefits in kind and travel support from, and has provided consultancy to, the manufacturers of smoking cessation drugs. NW has provided consultancy to the manufacturers of smoking cessation drugs, received honoraria for speaking at a research meeting and received benefits in kind and travel support from a manufacturer of smoking cessation drugs. JW has provided consultancy to the manufacturers of smoking cessation medications."
Notes	Accessed support: NEC: 115/289; PATCH: 106/295; PEC: 26/73
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computerized block randomization
Allocation concealment (selection bias)	Low risk	Computerized via study statistician
Blinding of participants and personnel (performance bias) All outcomes	Low risk	NEC and PEC were blind to treatment condition in relation to one another. No blinding for NEC/PEC vs PATCH conditions, but as NEC and PATCH were both active treatments performance bias judged unlikely
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Biochemical validation used
Incomplete outcome data (attrition bias) All outcomes	Low risk	LTFU 22% (all considered to be smoking). Patch group had a higher LTFU and withdrawal than EC (loss to follow‐up 17% NEC, 27% patches, 22% PEC). However, minimal difference in per‐protocol and ITT analyses
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported

*Study characteristics*
Methods	Design: 3‐arm double‐blind randomized controlled trial: EC with 7.2 mg nicotine for 12 weeks; same for 6 weeks followed by 5.2 mg for 6 weeks: EC with no nicotine for 12 weeks Recruitment: Newspaper advertisements Setting: Outpatient clinic, Italy Study start date: April 2010; Study end date:April 2012
Participants	Total N: 300 Inclusion criteria: Smoked at least 10 cpd for past 5 years; Age 18 ‐ 70 In good health Not currently or intending to quit smoking in the next 30 days Exclusion criteria: Symptomatic cardiovascular or respiratory disease Regular psychotropic medicine use Current or past history of alcohol abuse Use of smokeless tobacco or NRT Pregnant or breastfeeding 36% women, mean age 44 (SD 12.5), mean cpd 20 (IQR: 15 ‐ 25) Not currently or intending to quit smoking in the next 30 days E cigarette use at baseline: Not specified
Interventions	EC: Cig‐a‐like EC presented as a healthier alternative to tobacco smoke and could be freely used, ad libitum (up to 4 cartridges a day) for 12 weeks, as a tobacco substitute EC used: 'Categoria' (model 401) with disposable cartridges Grp A: 12 weeks of 7.2 mg capsules ('Original') Grp B: 6 weeks 7.2 mg ('Original'), then 6 weeks 5.4 mg ('Categoria') Grp C: 12 weeks of 0 mg ('Original') Baseline visit and up to 7 follow‐up visits to receive more cartridges, hand‐in diaries, measure CO and vital signs
Outcomes	Abstinence at 12 months (complete self‐reported abstinence from tobacco smoking since previous visit at 6 months, confirmed with CO < 7 ppm at 12 months) ≥ 50% reduction in baseline cigarettes at 12 months Recorded AEs thought to be related to tobacco smoking and EC at baseline and at each study visit (7 follow‐up visits over 12 weeks, plus at 24 and 52 weeks)
Study funding	"This research was supported by a grant‐in‐aid from Lega Italiana AntiFumo. The study sponsor had no involvement in the study design, collection, analysis, and interpretation of data, the writing of the manuscript or the decision to submit the manuscript for publication. RP and PC are currently funded by the University of Catania, Italy. The e‐cigarette supplier had no involvement in the study design, collection, analysis, and interpretation of data, the writing of the manuscript or the decision to submit the manuscript for publication."
Author declarations	"RP has received lecture fees and research funding from Pfizer and GlaxoSmithKline, manufacturers of stop smoking medications. He has served as a consultant for Pfizer and Arbi Group Srl, the distributor of the CategoriaTM e‐Cigarette. The other authors have no relevant conflict of interest to declare in relation to this work."
Notes	Additional data provided from authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, block size 15 (5:5:5 ratio)
Allocation concealment (selection bias)	Low risk	Randomization carried out by pharmacy, who did not have direct contact with the participants
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind. Quote: “Blinding was ensured by the identical external appearance of the cartridges. The hospital pharmacy was in charge of randomization and packaging of the cigarettes”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Biochemical validation used
Incomplete outcome data (attrition bias) All outcomes	Low risk	211 (70.3%) and 183 (61%) attended 6‐ and 12‐month follow‐up (at 12 m, 35% lost in 7.2 group; 37% lost in 5.4 group; 45% lost in no‐nicotine group)
Selective reporting (reporting bias)	Unclear risk	Unclear if original intention was to combine groups A+B or not. In sample size calculation they compared A+B with C, but results are not always reported in this way

*Study characteristics*
Methods	Design: Prospective cohort Recruitment: Letter sent to family practice patients who currently smoked Setting: Single family practice, Colorado USA Study start date: 14 April 2013; Study end date: Not specified
Participants	Letters sent to 640 patients, 48 chose to participate and 44 completed the programme, 4 were lost to follow‐up Inclusion criteria: Want to quit or switch from tobacco cigarettes to ECs Exclusion criteria: None reported Of the 44 participants, 66% women, all non‐Hispanic/white, aged 20 ‐ 75 (30% were age 51 ‐ 60), 57% had a high school education or less Motivated to quit: Want to quit or switch from tobacco cigarettes to ECs E‐cigarette use at baseline: Not specified
Interventions	EC: Cig‐a‐like The 6‐month smoking cessation programme was based on The '5 A's' model and transtheoretical model. Options for treatment were discussed with each participant at the start of the programme. All used an EC, with 16 using bupropion and 2 using varenicline as well Participants were provided with written information on “blu cig” and “smoke tip” ECs, about cost, availability, nicotine dosage options
Outcomes	Phone follow‐ups at 2 weeks, 1 month, 3 months, and 6 months At completion of programme (using ITT) Abstinence from smoking and EC use Abstinence from smoking but not EC use ≥ 50% reduction of baseline cigarette consumption (still using ECs)
Study funding	Not specified
Author declarations	Not specified
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Prospective cohort
Allocation concealment (selection bias)	High risk	Not randomized
Incomplete outcome data (attrition bias) All outcomes	Low risk	4/48 lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	Unable to determine prespecified outcomes
Other bias	Unclear risk	No definition of abstinence provided Not clear if 'completed programme' was at 6 months.

*Study characteristics*
Methods	Design: Prospective, randomized controlled trial with a parallel, nonrandomized preference cohort Recruitment: Participants were recruited from local advertisements, smoking cessation databases, and visits to local businesses, as well as via the Scottish Primary Care Research Network Setting: Single tertiary research centre, UK Study start date: August 2016; Study end date: July 2018
Participants	Total N: 114 in “final evaluable dataset” (145 recruited into the trial) N per arm: Tobacco cigarettes (TC): 40; EC nicotine (16 mg): 37; EC‐Nicotine‐free: 37 Inclusion criteria: People who smoke ≥ 18 years of age who had smoked ≥ 15 cigarettes/day for at least 2 years were free from established CV disease, diabetes, and chronic kidney disease; and were not on medication for those conditions Willing to stop tobacco cigarettes for period of study if required Willing not to use electronic cigarettes if required Able to give informed consent Exclusion criteria: Pregnant or lactating Women of childbearing potential who do not abstain from sex or use effective contraception On current prescribed medication for cardiovascular disease History of cardiovascular disease (excluding hypertension), diabetes, active malignance or chronic renal disease Nut allergy Participation in another clinical trial (other than observational trials and registries) with an investigational product and/or intervention within 30 days before visit 1 65.4% women; mean age 46.9; mean cpd 18.7 Motivated to quit: TC group: No; EC nicotine (16 mg): Yes; EC‐Nicotine‐free: Yes.
Interventions	EC: Cig‐a‐like EC nicotine (16 mg) arm: EC containing 16 mg nicotine (Vapourlites Starter Kit with XR5 16 mg nicotine cartomizer; Vapourlites, Peterlee, United Kingdom) EC‐Nicotine‐free arm: Nicotine‐free EC plus nicotine flavouring (Vapourlites Starter Kit with 0 mg nicotine cartomizer) (non‐randomized) TC arm: continued their usual daily smoking habits and did not use EC for the 4‐week period of the trial
Outcomes	Week 4 Adverse events and biomarkers: BP, heart rate, adverse events Other outcomes measured: Endothelial function, oxidized low‐density lipoprotein, high‐sensitivity C‐reactive protein, tissue plasminogen activator, and platelet activation inhibitor‐1
Study funding	"The VESUVIUS (Vascular Effects of Regular Cigarettes Versus Electronic Cigarette Use) trial was funded by the British Heart Foundation (grant PG/15/64/31681); and supported by Immunoassay Biomarker Core Laboratory, University of Dundee, the Tayside Medical Sciences Centre, and the NHS Tayside Smoking Cessation Service. The funder had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication."
Author declarations	"Dr. Donnan has received research grants from AbbVie, Shire, and Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose."
Notes	New for 2020 update
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Consented participants who were willing to quit smoking were randomized to one of the EC arms in a 1:1 fashion using a centrally controlled web‐based good clinical practices– compliant randomization system to either: 1) EC containing 16 mg nicotine; or 2) nicotine‐free EC plus nicotine flavouring because it was considered by the institutional ethics committee as ethically unacceptable to randomize those who were willing to quit smoking into a smoking arm. Those unwilling to consider quitting smoking continued in the parallel preference TC cohort
Allocation concealment (selection bias)	Low risk	Central randomization
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not specified
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blinded and AE/SAE data are self‐report only. For other outcomes, low risk as objectively measured: Quote: “Patients fasted overnight and measurements were conducted at baseline and 1 month according to the International Brachial Artery Reactivity Task Force guidelines (19) by a single operator (M.H.) blinded to study allocation at a single site.” “Pulse wave velocity and augmentation index were measured at baseline and 1 month by a single operator (M.H.) blinded to study allocation.”
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Number randomized not provided per group. Quote: “A total of 145 patients were recruited into the trial (Figure 1). A final number of 114 patients (40 TC, 37 EC‐nicotine, 37 EC‐nicotine‐free) completed both visits.”
Selective reporting (reporting bias)	Low risk	Clinical trial record lists: Change in FMD; Change in oxidised LDL; Change in PAI‐1; Change in hs‐CRP; Change in Pulse Wave Velocity; Change in tPA; Change in Augmentation Index@75bpm All reported in the paper

PERMALINK

Electronic cigarettes for smoking cessation

Jamie Hartmann-Boyce

Hayden McRobbie

Nicola Lindson

Chris Bullen

Rachna Begh

Annika Theodoulou

Caitlin Notley

Nancy A Rigotti

Tari Turner

Ailsa R Butler

Thomas R Fanshawe

Peter Hajek

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of comparators

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

2.

3.

Included studies

Participants

Interventions and comparators

Outcomes

Study types and funding

Excluded studies

Risk of bias in included studies

4.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings 1. Nicotine EC compared to NRT for smoking cessation.

Summary of findings 2. Nicotine EC compared to non‐nicotine EC for smoking cessation.

Summary of findings 3. Nicotine EC compared to behavioural support only/no support for smoking cessation.

Direct comparisons between nicotine EC and other pharmacotherapies

Cessation

1.1. Analysis.

*Study characteristics*
Methods	Design: Longitudinal within‐subjects observational Recruitment: Advertisements in the media, the internet, posted advertisements in clinics and offices, and by word of mouth Setting: University, Poland Study start date: March 2011; Study end date: June 2011
Participants	Total N: 22 started out and 2 dropped out in the first week due to an adverse event (nausea) and inability to commit to clinic visits. This resulted in analytic sample of 20 Inclusion criteria: 18 or older, current daily cigarette smokers (> 5 cpd within the last 12 months) May have had interest in quitting smoking, in good health (at the clinic screening visit) Able to communicate in Polish Able to use an e‐cigarette safely Exclusion criteria: Diagnosed as having asthma, COPD, hypertension, inhaled allergies, chronic heart disease, or cancer were taking a cardiac medication were pregnant 60% women; mean age 31; mean cpd 16; mean FTND 3.9 Motivated to quit: At the time of screening, 95% of participants (n = 19) reported planning to quit smoking, with 80% (n = 16) reporting that they have made at least 1 quit attempt prior to involvement in the study E cigarette use at baseline: Not reported
Interventions	EC: Cig‐a‐like Pen‐style M201 e‐cigarettes for 2 weeks, with an automatically‐operated battery with an output power of 4.6 Volts (280 mAh) and the heating element resistance of 3.6 – 3.8 Ohms. At baseline, provided with EC (M201 Mild, Poland) with 20 tobacco‐flavoured cartridges a week containing 11.0 ± 1.5 mg of nicotine in a mixture of propylene glycol and vegetable glycerin (50:50). Encouraged to substitute their regular cigarettes with the e‐cigarette for 2 weeks and refrain from smoking
Outcomes	Day 7, Day 14 Adverse events and biomarkers: Biomarkers were metabolites of 13 major carcinogens and toxicants in cigarette smoke: 1 tobacco‐specific nitrosamine (NNK), eight volatile organic compounds (1.3‐butadiene, crotonaldehyde, acrolein, benzene, acrylamide, acrylonitrile, ethylene oxide, and propylene oxide), and 4 polycyclic aromatic hydrocarbons (naphthalene, fluorene, phenanthrene, and pyrene) Questionnaire on ‘health’: At each visit, participants were asked, “In the last week, have you experienced any of the following symptoms?”, while providing a response of “never,” “rarely,” or “often” to the following list of health effects: daytime cough, difficulty concentrating, difficulty breathing during sleep, difficulty sleeping, dizziness, headache, irritability, nausea, nighttime cough, chest pain, phlegm, shortness of breath, tightness in chest, visual disturbances, and wheezing. Responses of “rarely” or “often” were combined to indicate presence of an adverse health effect Expired CO Other outcomes measured: 7 nicotine metabolites (3‐Hydroxycotinine, Cotinine, Cotinine N‐Oxide, Nicotine N‐Oxide, Norcotinine, Nornicotine, Nicotine) Revised Minnesota Nicotine Withdrawal Scale (MNWS‐R) administered to measure ‘withdrawal symptoms’ (0 ‐ 5 rating scale)
Study funding	“This work was supported by the Ministry of Science and Higher Education of Poland (grant number N N404 025638). Instrumentation and analytical chemistry at UCSF was supported by the National Institutes of Health, P30 DA012393 and S10 RR026437. The study sponsor had no involvement in the study design, collection, analysis, and interpretation of data, the writing of the manuscript or the decision to submit the manuscript for publication.”
Author declarations	"MLG was a faculty member of the Medical University of Silesia, Poland during the study. He received a research grant from Pfizer, a pharmaceutical company that markets smoking cessation medications. MLG and NLB have been consultants to pharmaceutical companies that market smoking cessation medications. NLB has been an expert witness in litigation against tobacco companies. The other authors declare no potential conflicts of interest."
Notes	New for 2020 update
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Not randomized
Allocation concealment (selection bias)	High risk	Not randomized
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 dropouts – 1 for nausea, 1 could not complete clinic visits. Analysis based on 20 completers
Selective reporting (reporting bias)	Low risk	All outcomes reported

*Study characteristics*
Methods	Design: Pragmatic, open‐label, single‐centre, 2‐arm randomized controlled trial Recruitment: Withdrawal service in Melbourne, Australia Setting: Substance use disorder treatment setting, and following discharge, community setting, Melbourne, Australia Study start date: 1 August 2017; Study end date: April 2019.
Participants	Total N: 100 N per arm: EC intervention = 50; NRT Control = 50 Inclusion criteria: Aged 18 years or over Tobacco smoker on entering the residential service Have the capacity to consent and able to understand the participant materials and follow the study instructions and procedures (e.g. sufficient English language ability) Exclusion criteria: Have used an END containing nicotine in the past month; Currently pregnant or breast‐feeding (measured by self‐report); Currently enrolled in another study; Scheduled to be transferred to a long‐term rehabilitation unit following discharge from the residential withdrawal unit. Inclusion based on specific population characteristic: Participants were discharged from a smoke‐free alcohol or other drugs (AOD) residential withdrawal service 32% women; mean age 40.9; mean cpd 21 Motivated to quit: Median (SD) = 7.3 (2.4) of 1 to 10 scale with 10 "highly motivated"
Interventions	EC: Refillable. Up to an hours training session, information pack. Innokin Endura T22 starter kit and refill liquid (Nicophar). 4‐week supply of liquid nicotine, with further supplies of liquid nicotine mailed twice at 4‐ week intervals. Dosing schedule of e‐liquid dependent nicotine dependence score: high‐nicotine‐dependence category assigned initial 4‐week e‐liquid supply (total 8 × 10 ml bottles) consisting of: 2 × 10 ml bottles of 18 mg e‐liquid and 6 × 10 ml bottles of 12 mg e‐liquid. The second and third batches = 8 × 10 ml bottles of 12 mg e‐liquid only. Participants scoring in the moderate‐ and low‐dependence categories: three 4‐week supplies of 8 × 10 ml bottles of 12 mg e‐liquid. Participants given 1‐week supply of nicotine patches for use while getting used to the EC. NRT control: Information pack, 12 weeks NRT on the same schedule as for ENDs. 4‐week supply of patches plus a nicotine spray and inhaler, followed by refills including patches plus inhaler, gum and lozenges. Both groups received proactive referral to quitline counselling (call‐back service), which provides calls at pre‐discharge and on days 1, 3, 7, 14 and 28 post‐discharge, with an emphasis on relapse prevention. Counsellors trained on the use of ENDs.
Outcomes	Week 6, 12; self‐report. Adverse events collected Other outcomes measured: Acceptability and feasibility of interventions Treatment adherence Cigarettes smoked per day ‐ Heaviness of Smoking Index Frequency of cravings Minnesota Nicotine Withdrawal Scale (MNWS) 10‐item Kessler Psychological Distress Scale (Kessler‐10) Quitting self‐efficacy, motivation to quit and the Heaviness of Smoking Index were assessed at baseline
Study funding	From published protocol: "The study is supported by a VicHealth Innovation Research Grant (2016–0096). AG is supported by a post‐doctoral fellowship from the Heart Foundation. ALB is supported by an Australian National Health and Medical Research Council (NHMRC) senior research fellowship and a Faculty of Health and Medicine, University of Newcastle Gladys M Brawn senior research fellowship. BB is supported by an Australian NHMRC career development fellowship (GNT1063206) and a Faculty of Health and Medicine, University of Newcastle Gladys M Brawn career development fellowship." From unpublished manuscript: "This study was supported by a VicHealth Innovation Research Grant (2016‐0096)."
Author declarations	From published protocol: "The authors declare that they have no competing interests." From unpublished manuscript: "None to declare."
Notes	New for 2020 update Additional data provided from authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Upon completing the baseline survey, participants were randomised 1:1 to an intervention via a computer‐sequenced 4–6 block randomisation embedded in the tablet device software.”
Allocation concealment (selection bias)	Low risk	Quote:“At the end of the baseline survey, participants will be randomised 1:1 to an intervention via a computer‐sequenced 4–6 block randomisation embedded in the iPad.”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: “Participants were informed of their intervention group by the RA and provided with a training session of up to one hour.” “Due to the nature of the intervention, neither participants nor staff can be blinded to allocation. However, the data safety monitoring committee and the statistician responsible for the data analysis will be blinded.”
Blinding of outcome assessment (detection bias) All outcomes	High risk	No biochemical validation, self‐report data
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “At 6 and 12‐weeks, 63 participants (63%) and 50 participants (50%) were followed up, respectively. While slightly higher retention rates were evidence in the VNP group at 6‐weeks (68% vs 58% in NRT group; p=0.300); there were no differences between groups at 12‐weeks (25 recontacted in both arms; i.e., 50%).”
Selective reporting (reporting bias)	Low risk	Unpublished findings provided by authors report on all outcomes mentioned in the protocol

*Study characteristics*
Methods	Design: Prospective cohort, intervention provided Recruitment: People who smoke attending stop‐smoking service Study start date: March 2014; Study end date: March 2015 Setting: Stop‐smoking service, London, UK
Participants	Total N: 100 (69 of whom accepted offer of EC) Inclusion criteria: All people who smoked joining stop‐smoking service 38% women (those who accepted) 55% women (those who declined), mean age 41, mean cpd 14, all motivated to quit. EC use at baseline not specified but some who declined EC offer had used EC in the past Motivated to quit: Yes E‐cigarette use at baseline: Not specified
Interventions	EC: Cig‐a‐like and refillable EC: offered to all people who smoke joining service; offered choice of ‘cig‐a‐like’ (Gamucci, 1.6% or 2.2% nicotine per ml) product or tank model (EVOD, 1.8%; later replaced with Aspire product due to leakage issues). 69% of those offered received an EC on TQD Medication: Offered stop‐smoking medications including NRT and varenicline as in standard protocol. Of EC users 33% opted to also use NRT, 29% varenicline, 38% nothing Support: weekly, as in standard protocol
Outcomes	Adverse events collected throughout, method for collection unclear Also collected: 4‐week biochemically‐validated abstinence, participant feedback, cost
Study funding	"The pilot study was sponsored by City of London Corporation."
Author declarations	"Peter Hajek received research funds from and provided consultancy to manufacturers of smoking cessation medications. The remaining authors have no conflicts of interest to declare."
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Not randomized
Allocation concealment (selection bias)	High risk	Not randomized
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	26% lost in EC group, dropout rate in EC decliners not reported. Reasons for dropout not stated
Selective reporting (reporting bias)	Unclear risk	Unclear which outcomes authors set out to collect, no protocol available

*Study characteristics*
Methods	Design: Multicentre pragmatic randomized controlled trial to examine the efficacy of e‐cigarettes compared with nicotine replacement therapy Recruitment: participants attending UK stop‐smoking service and via social media Setting: U.K. National Health Service stop‐smoking services Study start date: 1 April 2015; Study end date: 31 March 2018
Participants	Total N: 886 N per arm: EC: 439; NRT: 447 Inclusion criteria: Adults who smoke (aged 18 or over) with no strong preference to use or not to use nicotine replacement or e‐cigarettes, and were currently not using either type of product Able to read/write/understand English Exclusion criteria: Pregnant or breastfeeding Strong preference to use or not use NRT or EC, currently not using either type of product 48% women; median age 41; median cpd 15 ; mean FTND 4.6; 41.5% reported past use of ECs Motivated to quit: Not reported
Interventions	EC: Refillable NRT: Informed of range of NRT products and selected preferred product, encouraged to use combination. Participants free to switch products. Supplies provided for up to 3 months EC: Starter pack (1 Kit, Aspire UK) provided along with 30 ml bottle of Tobacco Royale flavour e‐liquid, concentration 18 mg/ml. Participants showed how to use and asked to purchase future e‐liquid online or from local vape shops and to buy different EC device if the 1 provided did not meet their needs. Enouraged to experiment with e‐liquids of different strengths and flavours. If unable to obtain own supply, provided with further 10‐ml bottle (not proactively offered). Oral and written info on how to operate EC Both arms received multi‐session behavioural support as per UK stop‐smoking service practice (one‐to‐one sessions weekly with local clinicians, exhaled CO monitored for at least 4 wks post‐TQD); signed behavioural contract not to use other therapy for at least 4 weeks
Outcomes	Weeks 4, 26 and 52 Cessation: Sustained and biochemically‐validated CO < 8 ppm Adverse events and biomarkers: “adverse reactions”: presence or absence of nausea, sleep disturbance and throat and mouth irritation, and respiratory symptoms (presence or absence of shortness of breath, wheezing, coughing and phlegm), death Other outcomes measured: Use and ratings of trial products Rating of withdrawal symptoms (weeks 1 ‐ 6) Reduction of cigarette consumption Cost effectiveness
Study funding	“Supported by the National Institute for Health Research (NIHR) Health Technology Assessment Programme (project number, 12/167/135) and by a grant (A16893) from the Cancer Research UK Prevention Trials Unit.”
Author declarations	From ICJME disclosure forms: “Miss Natalie Bisal has nothing to disclose. Dr. Dawkins reports personal fees from Johnson & Johnson, outside the submitted work; Dr. Goniewicz reports personal fees from Johnson and Johnson, outside the submitted work; Dr. Hajek reports grants and personal fees from Pfizer, outside the submitted work; Ms. Li reports grants from NCCHTA, during the conduct of the study; Dr. McRobbie reports grants from NIHR HTA programme, during the conduct of the study; personal fees from Pfizer, personal fees from Johnson & Johnson, outside the submitted work; Dr. Myers Smith has nothing to disclose. Dr. Parrott has nothing to disclose. Dr. Pesola has nothing to disclose. Mrs Anna Phillips‐Waller has nothing to disclose. Dr. Przulj reports grants from Pfizer, outside the submitted work; Dr. Ross has nothing to disclose. Dr. Sasieni has nothing to disclose. Ms. Wu has nothing to disclose."
Notes	New for 2020 update, listed as ongoing study ISRCTN60477608 in 2016 review update Note higher use of allocated product at 12 m in intervention group compared to control group: “Among participants with 1‐year abstinence, 80% (63 of 79) were using e‐cigarettes at 52 weeks in the e‐cigarette group and 9% (4 of 44) were using nicotine replacement in the nicotine‐replacement group.”
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomization took place on the quit date to limit differential dropout. Randomization sequences (1:1 ratio in permuted blocks of 20, stratified according to trial site) were generated with the use of a pseudorandom number generator in Stata software and were embedded into an application that only revealed the next treatment assignment once a participant had been entered into the database.”
Allocation concealment (selection bias)	Low risk	Refer to 'Random sequence generation'.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Not blinded, but as both arms contained active interventions performance bias judged unlikely
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Biochemical validation used
Incomplete outcome data (attrition bias) All outcomes	Low risk	At 12 months: EC Arm: 356/439 NRT Arm: 342/447
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported

*Study characteristics*
Methods	Design: Randomized clinical trial Recruitment: Eligible participants were employees and their spouses at 54 companies that used Vitality wellness programmes Setting: Online resources via workplace setting (54 companies), USA Study start date: First phase of recruitment October 2014, second phase November 2015 (to meet recruitment target); Study end date: 20 April 2017
Participants	Total N: 6006 N per arm: Usual care: 813; Free e‐cigarettes: 1199; Free cessation aids: 1588; Reward incentives plus free cessation aids: 1198; Redeemable deposit plus free cessation aids: 1208. Inclusion criteria: At least 18 years old Reported current smoking on a health risk assessment within the previous year Employees and their spouses that used Vitality wellness programmes Exclusion criteria: Participants who express wanting to opt out of this programme will be un‐enrolled and excluded 51.1% women; median age 44; median cpd 10 Ecig use at baseline: 10.7% current use; 23.1% past but not current use; 39.7% never used ECs Motivated to quit: Unselected sample (total sample): 9.2% no plan to quit; 61.6% want to quit later; 27.7% want to quit/need help
Interventions	EC: Cig‐a‐like a) Usual care: Standardized Vitality programme aimed at promoting tobacco cessation. This programme includes existing employee benefits for quitting and the use of text/email messages to encourage tobacco cessation b) as (a), plus free EC: Free NJOY e‐cigarettes (including battery sticks, a USB charger, and up to 20 chambers with 1.0 to 1.5% nicotine per week in participants’ chosen flavours). Use of all products was free until 6 months after the quit date c) as (b) plus access to free NRT, bupropion or varenicline d) as (c) plus incentives across 6 m for testing negative for tobacco use e) as (c) plus provide money at start and lose money from this fund if they do not test negative across 6 m
Outcomes	Months 1, 3, 6 and 12 Cessation: Sustained smoking abstinence for 6 months, biochemical validation (urine cotinine, anabasine and blood carboxyhaemoglobin) Other outcomes measured: Costs
Study funding	"Supported by a grant from the Vitality Institute to the University of Pennsylvania Center for Health Incentives and Behavioral Economics."
Author declarations	"Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Check these and: Dr. Troxel reports other from VAL Health, outside the submitted work. Dr. Volpp reports grants and personal fees from CVS Health, personal fees from VAL Health, grants from Humana, grants from Merck, grants from Weight Watchers, grants from Hawaii Medical Services Association, grants from Oscar Health Insurance, outside the submitted work. All of the other authors state that they have nothing to disclose."
Notes	New for 2020 update. Study listed as ongoing study NCT02328794 in 2016 review update Only arms (a) and (b) included in our analyses.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded and different amounts of support given to each group
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Biochemical validation
Incomplete outcome data (attrition bias) All outcomes	High risk	At 12 months very low numbers completed biochemical validation. Submitted a sample n = CG:1, free e‐cigs;4, free cessation:5, rewards: 14, deposits:16
Selective reporting (reporting bias)	Low risk	Expected outcomes reported and checked with trial registration

*Study characteristics*
Methods	Design: randomized trial Recruitment: Media advertisements Setting: Clinic visits in community, USA Study start date: 25 November 2014; Study end date: 2 December 2018
Participants	Total N: 264 N per arm: Usual brand: 36; AD‐E: 76; CS‐E: 76; CS‐NRT: 76. Inclusion criteria: At least 18 years of age Smoking at least 5 cpd for the past year with a breath CO at least 10 ppm or NicAlert test = level 6 if CO less than 10 ppm In stable physical and mental health Exclusion criteria: A serious quit attempt in the past 3 months Recent (< 3 months) alcohol or drug abuse problems Regular use of other nicotine or tobacco products (e.g. > 9 days per month to minimize confounding effects of these products on biomarker outcomes) Planning to quit smoking in the next 3 months Chronic conditions affecting results of biomarker analyses (e.g., liver disease) Currently using NRT or other cessation medications Pregnant, planning to become pregnant, or breastfeeding 49% women; mean age 45.2; mean cpd 15.2; mean FTND 3.4 E cigarette use at baseline: Not reported Motivated to quit: Initially uninterested
Interventions	EC: Cig‐a‐like, but the only cig‐a‐like product with high nicotine content Usual brand arm: Purchased their own usual brand of cigarettes; at end of clinical trial phase (week 8), offered ECs or NRT for up to 8 weeks, with a choice of product and no specific instructions for use EC AD‐E arm: Use EC whenever you like instead of a cigarette; can smoke as many or as few cigarettes as you want EC CS‐E arm: Complete substitution with e‐cigarettes (i.e. “you will stop smoking cigarettes and use only e‐cigarettes”) The primary e‐cigarette product was Vuse Solo (4.8% nicotine, manufactured by RJ Reynolds, Inc). Initially a choice of Blu cigarettes (cartridge‐based system, marketed previously by Lorillard) and Fin (prefilled tanks system, manufactured by Fin Branding Group) was offered; but because Vuse attained the highest market share during the early phase of the study, switched exclusively to Vuse. Participants could choose 1 of 4 flavours: tobacco, mint, menthol, and berry. Participants were provided 7 cartridges a week with the option of returning to the clinic before their next visit to obtain additional cartridges if needed. All products provided free to the participants. All unused products and used EC cartridges were collected at each visit CS‐NRT arm: Complete substitution with 4 mg nicotine gum or lozenge, with the participant choosing what product they would like to use (i.e. “you will stop smoking cigarettes and use only nicotine gum or lozenge”). The 4 mg was down‐titrated to 2 mg if adverse side effects were experienced. Nicotine gum came in mint, cinnamon, and fruit flavours, while the nicotine lozenge was mint or cherry flavours. All these products were provided free to the participants and unused products were collected at each visit Behavioural support: CS‐E arm and CS‐NRT arm: received brief counselling on how to avoid smoking cigarettes
Outcomes	2‐week baseline period (weeks −1 and 0); Week 1, 2, 3, 4, 6 and 8 Adverse events and biomarkers: Urinary total nicotine equivalents (total nicotine + total cotinine + total 3′‐hydroxycotinine; TNE) Exhaled CO Urinary 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol and its glucuronides (total NNAL, biomarker for NNK) Urinary phenanthrene tetraol (PheT, an indicator of carcinogenic polycyclic aromatic hydrocarbons) Urinary metabolites of VOCs (mercapturic acids)—2‐cyanoethylmercapturic acid (CEMA, biomarker for acrylonitrile), 3‐hydroxypropylmercapturic acid (3‐HPMA, biomarker for acrolein), 3‐hydroxy‐1‐methylpropylmercapturic acid (HMPMA, biomarker for crotonaldehyde/methylvinyl ketone), 2‐hydroxypropylmercapturic acid (2‐HPMA, biomarker for propylene oxide), and N‐acetyl‐S‐(carbamoylethyl)‐L‐cysteine(AAMA, biomarker for acrylamide) A safety check for adverse events was conducted at a week‐20 follow‐up Blood pressure, heart rate and oxygen saturation Other outcomes measured: Cessation (< 6 months)
Study funding	"supported by grants U19CA157345 from the National Cancer Institute (DKH/PS), UL1 TR000062 and UL1 TR002494 from the National Center for Advancing Translational Science of the National Institutes of Health, and T32 DA007097 from the National Institute of Drug Abuse (EM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies"
Author declarations	"RJC is a member of the FDA Tobacco Products Scientific Advisory Committee. PGS serves or has served as an expert witness in tobacco company litigation on behalf of plaintiffs"
Notes	New for 2020 update. AD‐E arm not included in this review Additional data provided from authors.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not blinded and some interventions contained different levels of support
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not blinded but all relevant outcomes for our analyses were objective
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “There was a significant difference in dropout rates across groups following study entry (p = .041), with the highest dropout rates observed in the complete substitution groups, particularly in the NRT group…” AD‐E: Week 1 = 73/76; Week 2 = 73/76; Week 4 = 69/76; Week 6 = 66/76; Week 8 = 65/76 = 85% CS‐E: Week 1 =69/76; Week 2 = 67/76; Week 4 = 66/76; Week 6 = 61/76; Week 8 = 58/76 = 69.7% CS‐NRT: Week 1 =72/76; Week 2 = 65/76; Week 4 = 60/76; Week 6 = 57/76; Week 8 = 53/76 = 69.7% UB: Week 1 = 35/36; Week 2 = 35/36; Week 4 = 33/36; Week 6 = 33/36; Week 8 = 32/36 = 88.8%
Selective reporting (reporting bias)	Low risk	Table in supplementary section describes that heart rate, blood pressure and oxygen levels were measured, but findings not reported in paper; however, provided by authors upon request

*Study characteristics*
Methods	Design: Single‐group assignment – pre‐test post‐test pilot study Recruitment: Participants were referred from community mental health teams within the South London and Maudsley NHS Foundation Trust. Setting: Healthcare setting, UK. Study start date: 24 September 2014; Study end date: 2 May 2017
Participants	Total N: 50 Inclusion criteria: Aged 18–70 years; Daily smoker (unwilling to quit soon); Exhaled CO level of more than five parts per million; An established clinical diagnosis of schizophreniform, schizophrenia, schizoaffective disorder or bipolar disorder, or attending an early detection service in a high‐risk state Exclusion criteria: The use of e‐cigarettes on more than two occasions in the past 30 days; Intention to quit smoking in the next 30 days; Medication use that may reduce smoking (including, bupropion, nicotine replacement therapies, acamprosate, varenicline, baclofen, clonidine, naltrexone, buprenorphine, nortriptyline, disulfiram and anti‐seizure medications) Hospitalisation/change in dose of psychotropic medication(s) in the last 30 days; Unstable physical health in the past 3 months; A previous serious stomach ulcer and/or phaeochromocytoma Severe heartburn, stroke, unstable kidney/liver disease, an uncontrolled overactive thyroid gland in the past 3 months; Individuals who meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) criteria for illicit/alcohol drug dependency; Medical contraindications to nicotine; Asthma Suicidal ideation/suicide attempt in the past month Pregnancy Inclusion based on specific population characteristic: People who smoke tobacco with a psychotic disorder (established clinical diagnosis of schizophreniform, schizophrenia, schizoaffective disorder or bipolar disorder, or attending an early detection service in a high‐risk state) 24% women; mean age 38.96; mean cpd 17.94; mean FTND not reported Motivated to quit: “unwilling to quit soon” E‐cigarette use at baseline: Must not have used e‐cigarettes on more than 2 occasions in the past 30 days
Interventions	EC: Cig‐a‐like Participants provided with free tobacco‐flavoured NJOY traditional bold disposable e‐cigarette (4.5% nicotine) in an "amount equivalent to 150% of their daily tobacco use (as recommended by the manufacturer)" for 6 weeks. Participants were instructed in the use EC; not required to stop smoking tobacco, but were encouraged to replace it with EC as much as possible. Followed up at 4 weeks and encouraged to continue EC use, informed about EC types and where these could be purchased
Outcomes	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 24 Self‐reported and biochemical validation Cessation: Tobacco use, as measured by the Time Line Follow Back. Tobacco cigarette use was also indexed weekly by measuring exhaled CO levels with a Smokerlyzer ED50 CO meter (Bedfont Instruments, UK) Adverse events and biomarkers: Side effects associated with e‐cigarette use – reported weekly Respiratory symptoms: lung capacity (measured by Wright’s Mini Peak‐flow Meter (Clement Clarke International Ltd., UK) at baseline, weeks 6, 10 and 24; Peak flow was obtained 3 times at each assessment Heart rate and blood pressure Occurrence of (serious) adverse events was assessed on a weekly basis In a subsample of participants (N = 8), 3‐hydroxypropylmercapturic acid (3‐HPMA, a measure of the toxicant acrolein) and formic acid were measured at baseline and week 6. These participants were chosen as their tobacco intake had decreased by more than 50% in this period. The measurement of 3‐HPMA and formic acid was also performed by validated LC‐MS/MS assays Other outcomes measured: Urinary cotinine Weight Motivation to Stop Scale (MTSS) Smoking Consequences Questionnaire‐Adult (SCQ‐A) Positive and Negative Syndrome Scale (PANSS) Calgary Depression Scale for Schizophrenia (CDSS)
Study funding	"This work was funded by the Maudsley Charity (grant number 715); and supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London."
Author declarations	"R.P‐I. has received honoraria and speaker support from Lundbeck. L.D. has provided consultancy for the pharmaceutical industry (Johnson & Johnson 2015, 2017) and acted as an expert witness for an e‐cigarette patent infringement case (Porzio, Bromberg & Newman Attorneys at Law, 2015). Between 2011 and 2013, she conducted research for several independent electronic cigarette companies (Totally Wicked, SKYCIGS and E‐Lites) for which the University of East London received funds. The e‐cigarette companies involved had no input into the design, conduct or write up of these projects and she has not received any funds from e‐cigarette companies in the last 4 years. She has no links with, and has not received any funds from, the tobacco industry, although two e‐cigarette companies that she worked with in 2013 were subsequently acquired by the tobacco industry (SKYCIGs and E‐Lites). L.H., T.R., K‐V.S., J.M., A.M. and P.M. have no conflicts of interest."
Notes	Study listed as ongoing study NCT02212041 in the 2016 review update Additional data provided from authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Uncontrolled study
Allocation concealment (selection bias)	High risk	Uncontrolled study
Incomplete outcome data (attrition bias) All outcomes	Low risk	Follow‐up: Week 6: 46/50; Week 10: 42/50; Week 24: 40/50
Selective reporting (reporting bias)	Low risk	Report all outcomes listed on http://clinical trials.gov except NNAL. Authors confirmed that they had intended to test for NNAL but had major issues with the assays

*Study characteristics*
Methods	Design: Pilot RCT Recruitment: Recruited via the Newcastle Dental Hospital and by primary care practitioners working in the north‐east England region Setting: Dental clinical research facility (DCRF), located in the Newcastle Dental Hospital, Newcastle upon Tyne, UK. Study start date: 20 September 2016; Study end date: 31 July 2018
Participants	Total N: 80 N per arm: Intervention group: 40; Control group: 40 Inclusion criteria: Aged over 18 years old; smoker (≥10 cigarettes/day) Willing and able to come to the DCRF for the required study visits Having a minimum of 16 natural teeth (excluding third molars) Being diagnosed with periodontitis Exclusion criteria: Having used an e‐cigarette for more than 2 days in the last 30 days Infectious or systemic diseases that may be unduly affected by participation in this study Haemodynamically unstable Patients taking the medication adenosine (due to drug interaction risk) Lack of capacity to be able to consent to the research project or inability to follow study instructions, or both Participation in a dental research study within the previous 20 days Pregnant by medical history, or nursing Received any non‐surgical periodontal therapy other than a routine scale and polish in the last 6 months Currently undergoing or requiring extensive dental, orthodontic or implant treatment, or treatment for peri‐implantitis Inclusion based on specific population characteristic: Periodontitis 52.5% women; mean age 44.36; mean cpd 17.4; mean FTND 5 Motivated to quit: Not selected on motivation and not reported E‐cigarette use at baseline: Not currently using an e‐cigarette, or not having used 1 for more than 2 days in the last 30 days
Interventions	EC: Refillable All participants given standard stop‐smoking advice (10 ‐ 15 minutes in duration) and offer of referral to stop‐smoking services Intervention: given EC starter kit (Vype eTank clearomizer) and brief training on its use by a dentist. Provided with an approximately 2‐week supply of e‐liquid (20 ml) with a choice of flavour (Blended Tobacco, Crisp Mint, Dark Cherry and Vpure (flavourless)) and nicotine strength (0 mg/ml, 6 mg/ml, 12 mg/ml, 18 mg/ml) and information on where to buy more. EC intervention delivered directly following the standard stop‐smoking advice and was expected to be 10 ‐ 15 minutes in duration Control group: no further intervention
Outcomes	Months 1 and 6; Self‐report and biochemical validation of smoking status Cessation: Rates of continuous eCO‐verified smoking abstinence at 6 months were calculated following the Russell Standard (RS6) Adverse events and biomarkers: expired air CO, adverse events monitored at each study visit Other outcomes measured: Feasibility outcomes Oral health outcomes Smoking behaviour outcomes comprised: self‐reported tobacco and e‐cigarette use, eCO, e‐salivary cotinine (SC), salivary anabasine (SA), FTND and Mood and Physical Symptoms Scale (MPS)
Study funding	"Richard Holliday is funded by a National Institute for Health Research Doctoral Research Fellowship (DRF‐2015‐08‐077). This paper presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care."
Author declarations	"The authors declare that they have no competing interests."
Notes	New for 2020 update.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was performed using a secure password‐protected web‐based system
Allocation concealment (selection bias)	Low risk	Quote: "The randomisation allocation schedule will be generated by a statistician with no other involvement in the study to achieve concealment of allocation."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Nature of study precluded blinding; different levels of support across intervention arms
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Biochemical validation
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition < 50%
Selective reporting (reporting bias)	Low risk	All prespecified outcomes are reported

*Study characteristics*
Methods	Design: (acute phase) Randomized cross‐over assignment (outcomes measured within hours of the intervention and hence do not meet the criteria of 1 week or more); chronic phase: non‐randomized, single‐group assignment Recruitment: Hospital smoking cessation unit Setting: Hospital smoking‐cessation unit, Greece Study start date: 31 January 2017; Study end date: Estimated completion date: December 2021
Participants	Total N: 90 Inclusion criteria: Active conventional cigarette smoker Adults 18 to 60 years Exclusion criteria: Health condition adversely affected by smoking, history or presence of cardiovascular disease Inclusion based on specific population characteristic: No 54% women; mean age 50.2; mean cpd 23.4; mean FTND: Not reported Motivated to quit: Yes – recruited from smoking cessation unit E‐cigarette use at baseline: Not reported
Interventions	EC: not clear E cigarette details: In the chronic phase, all 70 participants were instructed to replace their conventional cigarettes (con‐cig) with an e‐cig containing nicotine (12 mg/dL (e‐cig fluid with nicotine concentration of 12 mg/mL (propylene glycol 74.3%, glycerin 20%, flavouring 4.5%, nicotine 1.2%))) for 1 month
Outcomes	1 month; Self‐report and objective measures Cessation: Self‐report cessation at 1 month. CO measured at 1 month. Cessation data not used as < 6 months Adverse events and biomarkers: Exhaled CO concentration Heart rate; blood pressure Other outcomes measured: Oxidative stress as assessed by malondialdehyde (MDA) plasma concentrations Aortic stiffness as assessed by pulse wave velocity (PWV) and augmentation index (AIX75)
Study funding	This study was supported by a grant from the Hellenic Cardiology Society and Hellenic Society of Lipidiology and Atherosclerosis.
Author declarations	None
Notes	New for 2020 update. Acute phase of trial not relevant for the review as very short‐term outcomes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded and differential levels of support given
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Objective measures used for all outcomes reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	70 participants and 20 controls recruited – no dropout
Selective reporting (reporting bias)	Unclear risk	NCT record states that chronic endothelial integrity, platelet aggregation and high‐shear stress‐dependent platelet function would be assessed but is not reported in this research letter – however study estimated completion date is December 2021, so perhaps data not ready for publication or limited capacity in the research letter – not the primary publication
Other bias	Unclear risk	Few details – written as commentary. Trial registration suggests this is an ongoing study

*Study characteristics*
Methods	Design: Randomized controlled trial Recruitment: Not specified Setting: Hospital, Greece. Study start date/Study end date: Not specified
Participants	Total N: 54 N per arm: Arm 1: 27; Arm 2: 27 Inclusion criteria: ≥10 cpd Motivation to quit Hospitalized with acute coronary syndrome (ACS) 18 or older Exclusion criteria: Prior EC use History of neuropsychiatric disorders Prior varenicline use or use of SC pharmacotherapy at time of ACS Cardiogencic shock or renal impairment Hepatic impairment prior to ACS Excessive alcohol use or current use of marijuana or non‐cigarette tobacco products Inclusion based on specific population characteristic: People who have experienced acute coronary syndrome 65% women; mean age 52; mean cpd 21; mean FTND 5.6 Motivated to quit: Yes E‐cigarette use at baseline: No prior EC use
Interventions	EC: information on whether cig‐a‐like or refillable not provided Both arms given "low intensity counselling" Intervention 1: 12‐week use of EC 12 mg/ml nicotine Intervention 2: 12‐week varenicline
Outcomes	Weeks: 4, 12, 24 Cessation: 7‐day PP at 24 weeks, self‐report Adverse events and biomarkers: Unclear how these were reported. Abstract says no SAEs, poster implies this may have just been CV or neuropsychiatric SAEs. Abstract says nothing about AEs but nausea and sleeping disorders given in table in poster. Implies (S)AEs collected during treatment period only Other outcomes measured: Not specified
Study funding	Not reported
Author declarations	Not reported
Notes	New for 2020 update. Abstract and poster only; limited data available
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Not specified but equal amounts of contact and support between arms so performance bias judged unlikely
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Self‐report only but equal amounts of contact between arms, no reason to suspect differential misreport
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not specified
Selective reporting (reporting bias)	Unclear risk	Abstract/poster only so not able to judge
Other bias	High risk	Abstract and poster only. Two different figures presented for quit rate in EC arm (no difference in those presented in varenicline arm) between abstract and poster. Poster percentage aligns with figure, so using that (16.5%) as opposed to abstract figure (32.5%). Contacted authors but no reply. Calculated n quit based on percentages but unclear what denominators were; EC calculates back to whole number for EC but not for varenicline