Electronic cigarettes for smoking cessation
 

Throughout this review, we discuss (1) conventional cigarettes and (2) electronic cigarettes, defined as hand‐held and producing for inhalation an aerosol formed by heating an e‐liquid using a battery‐powered heating coil. In this review, all mention of smoking, smoking cessation, cigarette use, smoke intake, etc. concerns 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 tobacco 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 one year after quitting ( ). 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 such support, long‐term quit rates remain low ( ; ; ). One of the limitations of current treatments is that, apart from providing nicotine more slowly and at lower levels than smoking, none adequately addresses the sensory, behavioural, and/or 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 these limitations ( ), and have become a popular consumer choice for smoking cessation support where regulations allow ( ). There is no doubt that people become dependent on tobacco, and many find it difficult to stop smoking, primarily because of nicotine and its actions on the brain's reward system ( ). However, developing dependence on tobacco smoking is a complex biopsychosocial process ( ; ). Other tobacco chemicals, such as acetaldehyde and monoamine oxidase (MAO) inhibitors, seem to potentiate the effects of nicotine ( ). In addition, sensory and behavioural cues provide additional reinforcement of smoking behaviour ( ; ) and may 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 ( ; ). 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 ( ). 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 ( ; ; ). Thirdly, very low nicotine content cigarettes (VLNCs), which have 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 ( ). Despite delivering low levels of nicotine, VLNCs are satisfying over the initial few days of abstinence from nicotine ( ; ; ; ). They also reduce tobacco withdrawal symptoms, including urges to smoke and low mood ( ; ; ; ; ), and have been shown to improve long‐term continuous abstinence rates in one study ( ). 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 elements of cigarette smoking that some people who smoke report to be drivers of cigarette use ( ). Considering the other factors that contribute to tobacco dependence, there is interest in developing smoking‐cessation products that not only help relieve the unpleasant effects of nicotine withdrawal, but that also act as effective substitutes for smoking behaviour and the rituals and sensations that accompany smoking, without the health risks associated with the inhalation of tobacco smoke. The only pharmaceutical treatment with some of these characteristics is the nicotine inhalator. However, these do not have greater cessation efficacy than other nicotine replacement therapy (NRT) products ( ; ). 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 NRT products ( ). Adherence to correct use of the inhalator is low compared to other types of NRT ( ). 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 ( ). Description of the intervention ECs are devices that produce, for inhalation, an aerosol formed by heating a solution (an e‐liquid) using a battery‐powered heating coil ( ). 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. ECs are marketed as consumer products. Although routes are in place for licencing them as medicine or medical devices in some areas, no country yet has a licenced 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 ( ). The aerosol, typically referred to as vapour, looks like tobacco smoke, but 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 medical cessation aids but rather as acceptable alternatives to tobacco smoking ( ; ). 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) ( ; ), with some users choosing to mix their own e‐liquids ( ). Initial studies showed that early models of EC delivered very low amounts of nicotine to naïve users ( ; ; ). 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 ( ; ; ; ; ). Early in their development, ECs were designed to look like cigarettes and used disposable cartridges. These models were often called 'cig‐a‐likes'. The nicotine delivery from these products was low ( ). The later refillable, or 'tank', products had 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, allowing a wider choice of flavours and nicotine concentrations, and were typically used by experienced vapers who reportedly managed to switch to vaping completely ( ; ; ; ). More recently, smaller 'pod' devices that use nicotine salt solutions have become available. 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 devices ( ). In qualitative studies, pod devices have been highly rated by users in terms of satisfaction, usability (simple to use), affordability, and availability ( ). The nicotine salts used in pods allow for high nicotine delivery; this may increase the likelihood that adult smokers are able to transition completely from conventional cigarettes ( ). Average nicotine concentrations in EC sold in the United States increased overall during 2013‐2018, for all flavour categories, and for rechargeable ECs ( ). The EU Tobacco Products Directive ( ) does not allow sales of e‐liquids with nicotine content higher than 20 mg/mL, and so the US version of the Juul pod device (59 mg/nl nicotine) is not legally available within the EU ( ; ). Most recently, there has been rapid growth in the use of disposable and single‐use devices ( ; ). These are available in a range of attractive flavours, generally have a high nicotine content, are low cost, and have a closed system that is designed to be disposed of following use. According to , for adults in Great Britain, tank‐style devices are the most popular. For young people, the report shows that disposables are now the most popular type of device. The different device types may differ significantly in their efficacy in helping people who smoke to quit, as they differ in delivery of nicotine. Nicotine itself, when delivered through mechanisms and doses similar to that delivered in traditional NRT, is not considered harmful ( ). The safety profile of the different types of nicotine 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 ( ; ; ). 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 necessarily be 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 people fill with their own choice of e‐liquids; and pods for the small devices with disposable pods that commonly use nicotine salts. To date, there are no trials of disposable devices, so we do not include this category in the current review. 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 Great Britain, only 27% of people who smoke have never tried vaping according to a recent survey ( ). EC use is most prevalent in people who currently (27%) and have previously (15%) smoked ( ). Only 1.1% of adults who have never smoked report currently using ECs ( ). Prevalence data from the USA in 2019 showed that 4.4% of adults were current EC users ( ). Data from lower‐income countries suggest similar levels of EC use and awareness ( ; ; ). Regulatory approaches being used for ECs currently vary widely, from no regulation to partial and complete bans ( ). Within the USA, for example, the Food and Drug Administration (FDA) has classified EC as tobacco products and laws include prohibition of EC use indoors, a requirement for retailers to have a license to sell, and prohibition of sales to minors. Laws prohibiting sales to minors apply nationwide, but other laws vary by state ( ). 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 ( ). 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 and 68 deaths ( ). This illness, which was termed E‐cigarette or Vaping‐Associated Lung Injury (EVALI), caused concern throughout the world ( ) and a negative change in people's perception of the risks of EC use compared to smoking ( ). 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 products adulterated with vitamin E acetate ( ; ). Amongst those brands of nicotine EC that have been tested, levels of toxins have been found to be substantially lower than in cigarettes ( ; ). Long‐term effects beyond 12 months are unclear, 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 ( ). 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 ( ). Despite general acknowledgement that EC use exposes the user to fewer toxicants and at lower levels than smoking cigarettes ( ; ; ; ), in some countries and settings there remains hesitancy in making these products available to people who smoke as a harm‐reduction tool or smoking‐cessation aid (e.g. ). Concerns include that the long‐term effects of EC use on health are not yet known, the possible harms of second‐hand EC vapour inhalation, the lack of quality control measures, and that ECs may undermine smoke‐free legislation if used in smoke‐free spaces ( ). Of concern is also the involvement of the tobacco industry and that ECs may be a gateway to smoking initiation or nicotine dependence amongst nicotine‐naïve users or may prolong continued dual use of tobacco amongst cigarette smokers ( ). A report from the US Preventive Services Taskforce concluded "that the current evidence is insufficient to assess the balance of benefits and harms of electronic cigarettes (e‐cigarettes) for tobacco cessation in adults" ( ). However, others suggest that potential benefits outweigh potential disadvantages ( ; ; ; ; ; ). People who smoke, healthcare providers, and regulators are interested in knowing if ECs can help people to 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 to people to help them 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 complete smoking cessation. This review was first published in 2014, and updated in 2016, 2020, 2021, 2022, and 2024. We published an update to the protocol in 2023 (see ). Following publication of the 2020 update of this review, we are maintaining it as a living systematic review ( ). This means we are continually running searches and incorporating new evidence into the review. For more information about the living systematic review methods being used, see . 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 the potential for substantial ongoing individual and societal benefits, depending on the extent of effectiveness. Secondly, there remains uncertainty in the existing evidence; 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 that are likely to have an important impact on the conclusions of the review. 

Stopping smoking tobacco 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 one year after quitting ( ). 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 such support, long‐term quit rates remain low ( ; ; ). One of the limitations of current treatments is that, apart from providing nicotine more slowly and at lower levels than smoking, none adequately addresses the sensory, behavioural, and/or 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 these limitations ( ), and have become a popular consumer choice for smoking cessation support where regulations allow ( ). There is no doubt that people become dependent on tobacco, and many find it difficult to stop smoking, primarily because of nicotine and its actions on the brain's reward system ( ). However, developing dependence on tobacco smoking is a complex biopsychosocial process ( ; ). Other tobacco chemicals, such as acetaldehyde and monoamine oxidase (MAO) inhibitors, seem to potentiate the effects of nicotine ( ). In addition, sensory and behavioural cues provide additional reinforcement of smoking behaviour ( ; ) and may 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 ( ; ). 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 ( ). 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 ( ; ; ). Thirdly, very low nicotine content cigarettes (VLNCs), which have 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 ( ). Despite delivering low levels of nicotine, VLNCs are satisfying over the initial few days of abstinence from nicotine ( ; ; ; ). They also reduce tobacco withdrawal symptoms, including urges to smoke and low mood ( ; ; ; ; ), and have been shown to improve long‐term continuous abstinence rates in one study ( ). 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 elements of cigarette smoking that some people who smoke report to be drivers of cigarette use ( ). Considering the other factors that contribute to tobacco dependence, there is interest in developing smoking‐cessation products that not only help relieve the unpleasant effects of nicotine withdrawal, but that also act as effective substitutes for smoking behaviour and the rituals and sensations that accompany smoking, without the health risks associated with the inhalation of tobacco smoke. The only pharmaceutical treatment with some of these characteristics is the nicotine inhalator. However, these do not have greater cessation efficacy than other nicotine replacement therapy (NRT) products ( ; ). 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 NRT products ( ). Adherence to correct use of the inhalator is low compared to other types of NRT ( ). 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 ( ). 

ECs are devices that produce, for inhalation, an aerosol formed by heating a solution (an e‐liquid) using a battery‐powered heating coil ( ). 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. ECs are marketed as consumer products. Although routes are in place for licencing them as medicine or medical devices in some areas, no country yet has a licenced 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 ( ). The aerosol, typically referred to as vapour, looks like tobacco smoke, but 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 medical cessation aids but rather as acceptable alternatives to tobacco smoking ( ; ). 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) ( ; ), with some users choosing to mix their own e‐liquids ( ). Initial studies showed that early models of EC delivered very low amounts of nicotine to naïve users ( ; ; ). 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 ( ; ; ; ; ). Early in their development, ECs were designed to look like cigarettes and used disposable cartridges. These models were often called 'cig‐a‐likes'. The nicotine delivery from these products was low ( ). The later refillable, or 'tank', products had 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, allowing a wider choice of flavours and nicotine concentrations, and were typically used by experienced vapers who reportedly managed to switch to vaping completely ( ; ; ; ). More recently, smaller 'pod' devices that use nicotine salt solutions have become available. 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 devices ( ). In qualitative studies, pod devices have been highly rated by users in terms of satisfaction, usability (simple to use), affordability, and availability ( ). The nicotine salts used in pods allow for high nicotine delivery; this may increase the likelihood that adult smokers are able to transition completely from conventional cigarettes ( ). Average nicotine concentrations in EC sold in the United States increased overall during 2013‐2018, for all flavour categories, and for rechargeable ECs ( ). The EU Tobacco Products Directive ( ) does not allow sales of e‐liquids with nicotine content higher than 20 mg/mL, and so the US version of the Juul pod device (59 mg/nl nicotine) is not legally available within the EU ( ; ). Most recently, there has been rapid growth in the use of disposable and single‐use devices ( ; ). These are available in a range of attractive flavours, generally have a high nicotine content, are low cost, and have a closed system that is designed to be disposed of following use. According to , for adults in Great Britain, tank‐style devices are the most popular. For young people, the report shows that disposables are now the most popular type of device. The different device types may differ significantly in their efficacy in helping people who smoke to quit, as they differ in delivery of nicotine. Nicotine itself, when delivered through mechanisms and doses similar to that delivered in traditional NRT, is not considered harmful ( ). The safety profile of the different types of nicotine 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 ( ; ; ). 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 necessarily be 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 people fill with their own choice of e‐liquids; and pods for the small devices with disposable pods that commonly use nicotine salts. To date, there are no trials of disposable devices, so we do not include this category in the current review. We may review this categorization system in future versions of the review as new trials and devices emerge. 

Since ECs appeared on the market in 2006, there has been a steady increase in their use. In Great Britain, only 27% of people who smoke have never tried vaping according to a recent survey ( ). EC use is most prevalent in people who currently (27%) and have previously (15%) smoked ( ). Only 1.1% of adults who have never smoked report currently using ECs ( ). Prevalence data from the USA in 2019 showed that 4.4% of adults were current EC users ( ). Data from lower‐income countries suggest similar levels of EC use and awareness ( ; ; ). Regulatory approaches being used for ECs currently vary widely, from no regulation to partial and complete bans ( ). Within the USA, for example, the Food and Drug Administration (FDA) has classified EC as tobacco products and laws include prohibition of EC use indoors, a requirement for retailers to have a license to sell, and prohibition of sales to minors. Laws prohibiting sales to minors apply nationwide, but other laws vary by state ( ). 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 ( ). 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 and 68 deaths ( ). This illness, which was termed E‐cigarette or Vaping‐Associated Lung Injury (EVALI), caused concern throughout the world ( ) and a negative change in people's perception of the risks of EC use compared to smoking ( ). 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 products adulterated with vitamin E acetate ( ; ). Amongst those brands of nicotine EC that have been tested, levels of toxins have been found to be substantially lower than in cigarettes ( ; ). Long‐term effects beyond 12 months are unclear, 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 ( ). 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 ( ). Despite general acknowledgement that EC use exposes the user to fewer toxicants and at lower levels than smoking cigarettes ( ; ; ; ), in some countries and settings there remains hesitancy in making these products available to people who smoke as a harm‐reduction tool or smoking‐cessation aid (e.g. ). Concerns include that the long‐term effects of EC use on health are not yet known, the possible harms of second‐hand EC vapour inhalation, the lack of quality control measures, and that ECs may undermine smoke‐free legislation if used in smoke‐free spaces ( ). Of concern is also the involvement of the tobacco industry and that ECs may be a gateway to smoking initiation or nicotine dependence amongst nicotine‐naïve users or may prolong continued dual use of tobacco amongst cigarette smokers ( ). A report from the US Preventive Services Taskforce concluded "that the current evidence is insufficient to assess the balance of benefits and harms of electronic cigarettes (e‐cigarettes) for tobacco cessation in adults" ( ). However, others suggest that potential benefits outweigh potential disadvantages ( ; ; ; ; ; ). People who smoke, healthcare providers, and regulators are interested in knowing if ECs can help people to 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 to people to help them 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 complete smoking cessation. This review was first published in 2014, and updated in 2016, 2020, 2021, 2022, and 2024. We published an update to the protocol in 2023 (see ). Following publication of the 2020 update of this review, we are maintaining it as a living systematic review ( ). This means we are continually running searches and incorporating new evidence into the review. For more information about the living systematic review methods being used, see . 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 the potential for substantial ongoing individual and societal benefits, depending on the extent of effectiveness. Secondly, there remains uncertainty in the existing evidence; 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 that are likely to have an important impact on the conclusions of the review. 

To examine the safety, tolerability, and effectiveness of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long‐term smoking abstinence, in comparison to non‐nicotine EC, other smoking cessation treatments, and no treatment. 

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; we also include uncontrolled intervention studies in which all participants are given an EC intervention. These studies have the potential to provide information on harms and longer‐term use. We include studies regardless of their publication status or language of publication. Types of participants Participants are people defined as currently smoking cigarettes at enrolment into the studies. Participants could be motivated or unmotivated to quit. We include studies that recruited pregnant people and include their data in our pairwise meta‐analyses and narrative syntheses; however, we will not include their data in our network meta‐analyses (NMA) (described in our section) as some of the comparisons eligible for inclusion are unlikely to be offered to this population (e.g. varenicline). Should a study meet all other criteria but include only a subset of eligible participants (e.g. a study on people who currently smoke and people who formerly smoked), we would only include data on the subgroup of participants who met our inclusion criteria. If these data were not available, we would include the study if at least 80% of participants met our inclusion criteria and would test the exclusion of the study in a sensitivity analysis. We include participants regardless of age. Types of interventions Any type of EC or intervention intended to promote EC use for smoking cessation, including studies that did not measure smoking cessation but provided ECs with the instruction that they be used as a complete substitute for cigarette use. ECs may or may not contain nicotine. For the purpose of the NMA, we assume that the interventions were jointly randomizable for all participants except those who were pregnant. Types of comparators We compare nicotine ECs with alternative smoking cessation aids, including NRT or no intervention, with ECs without nicotine, and ECs added to standard smoking cessation treatment (behavioural or pharmacological or both) with standard treatment alone. We compare different types of EC (refillable, cartridge, nicotine salt, free‐base), different nicotine doses, and different flavours. 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 any type of adverse event(s) at one week or longer (as defined by study authors) Number of participants reporting any type of serious adverse event(s) at one week or longer (as defined by study authors) Secondary outcomes Number of people still using study product (EC or pharmacotherapy) at longest follow‐up (at least six months). The product could be that provided by the study, or could be the same product type but bought independently by the participant. Changes in the following measures at longest follow‐up (one week or longer): Carbon monoxide (CO), as measured through breath or blood Blood pressure Heart rate Blood oxygen saturation Lung function measures Known toxins/carcinogens, as measured through blood, urine or saliva (toxicant names and abbreviations are listed in ) Studies had to set out to measure one of the primary or secondary outcomes above to be eligible for inclusion. If a study set out to measure an eligible outcome but did not measure and/or report results on this outcome, we would still include this study and flag its missing data in the results section. In addition, we set out to include any measure of an association between withdrawal symptoms and smoking cessation at six months or longer, as long as withdrawal was measured using a validated scale designed explicitly to investigate smoking withdrawal or craving. We added this because British guidelines now specify that efforts should be made to provide EC in a way that will reduce symptoms of withdrawal in people who smoke ( ). However, no studies provided data on this. Search methods for identification of studies Electronic searches Searches are conducted monthly. This update includes results from searches conducted up to 1 February 2024: Cochrane Tobacco Addiction Group Specialized Register (CRS‐Web up to 1 February 2023); Cochrane Central Register of Controlled Trials (CENTRAL; 2024, Issue 1) via CRS‐Web; MEDLINE (OVID SP; 1 January 2004 to 1 February 2024); Embase (OVID SP; 1 January 2004 to 1 February 2024); PsycINFO (OVID SP; 1 January 2004 to 1 February 2024); ClinicalTrials.gov (via CENTRAL; 2024, Issue 1); WHO International Clinical Trials Registry Platform (ICTRP: www.who.int/ictrp/en/ , via CENTRAL; 2024, Issue 1). We did not search the Cochrane Tobacco Addiction Group Specialized Register beyond 1 February 2023 as it ceased to be maintained. At the time of the last search, the Register included the results of searches of MEDLINE (via OVID) to update 20221222; Embase (via OVID) to week 202251; and PsycINFO (via OVID) to update 20221219. 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. All current search strategies are listed in . The previously used search strategy is shown in . 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. We also searched abstracts from the Society for Research on Nicotine and Tobacco (SRNT) Annual Meetings up to 1 February 2024. Data collection and analysis Selection of studies Two review authors (for this update from: ARB, JHB, NL, AT) independently pre‐screened 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 One review author extracted data on study characteristics (ARB), whereas two review authors (for this update: ARB and ADW) independently extracted outcome data, effect modifiers, and the information needed to make risk of bias judgements. We used a pre‐piloted data extraction form, and checked the forms for inconsistencies. We resolved any disagreements by discussion or with a third review author (NL). We extracted data on the following: 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), number of people still using study product, and relevant biomarkers Continued EC use or pharmaceutical intervention (PI) use at longest follow‐up Data investigating the association between withdrawal and smoking cessation 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. There were no papers that required translation ; should there be in the future, we would seek a translator to assist us. For studies that received tobacco or EC industry funding the study name is followed by an asterisk (*). One review author (NL for this update) then entered the data contributing to pairwise network meta‐analysis (NMA) into software for analyses, and another checked them (JHB for this update). Data for the NMA were collated by one author (ARB) and checked by NL and JHB. Assessment of risk of bias in included studies Two review authors (for this update: ARB and ADW) independently assessed the risks of bias for each included study, using the Cochrane risk of bias tool (RoB 1) ( ). We resolved any disagreements by discussion or with a third review author (NL). 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 that 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 the standard methods of the Cochrane Tobacco Addiction 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 the intervention was similar between groups, or both. For studies where cessation was measured, our judgement was based on whether cessation was biochemically verified. Where cessation was not measured, we judged this domain based on adverse or serious adverse events. Again, following the 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, or by comparing absolute data at follow‐up where insufficient data were available on mean change. 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, or their use was encouraged. 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, or there is no evidence of difference between similar trial arms for the outcome of interest. We note in our analyses where this is the case. For all but one study, the unit of assignment was the individual. assigned the condition based on homeless support service; 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 the 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 outcomes from comparative trials that are not reported with sufficient data for meta‐analysis, using effect direction plots as described in the Cochrane Handbook for Systematic Reviews of Interventions, where possible ( ). Dealing with missing data For smoking cessation, we use a conservative approach, as is standard for the Cochrane Tobacco Addiction Group, treating participants with missing data as still smoking. We base 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 about whether data should be pooled. We were also guided by the degree of statistical heterogeneity, assessed by calculating the I 2 statistic ( ), and considering a value greater than 50% as evidence of substantial heterogeneity. We did not present pooled results where I 2 values exceeded 75%. For our NMA, we assessed global inconsistency using scatterplots of residual deviance in the NMA model against residual deviance in the Unrelated Mean Effects (UME) model. The UME model does not assume transitivity of treatment effects, so a smaller deviance in this model in comparison to the main NMA indicates inconsistency within the network. We also used scatterplots of leverage versus deviance to check the general model fit. We assessed local inconsistency using node‐split models for the main analyses of each outcome. We did not formally assess potential participant‐level effect moderators as a way to evaluate transitivity in our NMA, as previous work has shown these to be inconsistently reported in this body of studies ( ; ; ). Assessment of reporting biases Reporting bias can be assessed using funnel plots, where 10 or more RCTs contribute to an outcome. Where studies were included in an analysis but did not contribute data to the pooled effect (as zero events were reported), these were not included in the count of included studies when deciding whether to generate funnel plots. Therefore, there were only two analyses with sufficient studies to support this approach. Had it been appropriate for our NMA, we would have adapted existing methods for assessing publication bias in standard systematic reviews by generating a funnel plot for each of the comparisons of interest and overlaying these plots on top of one another, while aligning the reference lines (representing the overall component effect). This is called a 'comparison adjusted funnel plot'. We would have considered studies distributed asymmetrically as potential evidence of publication bias. However, there were insufficient studies for each comparison to make this approach appropriate. Data synthesis We provide a narrative summary of the included studies. Pairwise meta‐analyses Where appropriate, we have pooled data from RCTs in pairwise meta‐analyses, grouping studies by comparison type and outcome. Data from single‐armed intervention studies are summarized narratively. Where presented per type of AE, rather than for all types together, these data were summarized narratively rather than meta‐analyzed. For dichotomous data, we used a fixed‐effect Mantel‐Haenszel model to calculate the RR with a 95% CI, in accord with the standard methods of the Cochrane Tobacco Addiction Group for cessation studies. For continuous outcomes, we pooled mean differences (or standardized mean differences for studies using different measures for the same construct), using the inverse variance approach (also with a 95% CI). Network meta‐analyses We also carried out three network meta‐analyses (NMA), as these can give further insight into comparative effects by drawing on data from both direct and indirect comparisons. NMA produces estimates of the relative effects between any pair of interventions in the network, usually providing more precise estimates than a single direct estimate ( ). Our three NMAs are as follows: one for each of our three primary outcomes: smoking cessation at six months follow‐up or longer; AEs at one‐week follow‐up or longer; and SAEs at one‐week follow‐up or longer. All NMAs were run using MetaInsight ( ). The models were Bayesian generalized linear models with non‐informative prior distributions on all parameters. Fixed effects were assumed in each case. MCMC simulations were run for 25,000 iterations, with the first 5,000 discarded, on four chains. Convergence was assessed through Gelman plots. Bayesian models were chosen because they are more flexible and have become the most common choice for NMA in recent years. Our NMAs only included RCTs and excluded studies carried out on pregnant people, as specified in the section. Interventions were classified as nodes as per our primary comparisons, but only including nodes where two or more studies contributed data. In addition, NRT was split into combined and single forms because evidence indicates there is a clinically significant difference in smoking cessation outcomes between them ( ). In this update, the following interventions were eligible nodes (further nodes may be added as additional comparisons are added): Nicotine EC Non‐nicotine EC NRT (single form) NRT (combined fast‐acting form and patch) Nicotine EC plus single‐form NRT Non‐nicotine EC plus single‐form NRT Advice to use nicotine e‐cigarettes in a quit attempt (but no e‐cigarettes provided) No e‐cigarettes or pharmacotherapy Studies that provided an additional intervention component, such as behavioural support, were included only if the additional component was matched between intervention arms and comparator arms, as is the case for this review overall. Studies with no outcome events in any study arm were excluded. In contrast, studies with no outcome events in some but not all arms were included. We did not conduct any ranking of interventions in the NMA. Subgroup analysis and investigation of heterogeneity For our pairwise analyses, we had planned to undertake subgroup analyses to investigate differences between studies, such as the following: Intensity of behavioural support used (as this could potentially influence cessation). Type of EC, e.g. cartridge; refillable; pod (as this could potentially influence all outcomes due to different delivery mechanisms). Instructions for EC use, e.g. study provision, length of provision, whether participants had a role in product choice (as this could potentially influence all outcomes, given variation in available devices and e‐liquids). Type of participants (this could potentially influence all outcomes, depending on, e.g. pre‐existing conditions, previous experience with EC). However, there were too few studies to conduct such analyses. Should further studies become available in future, we will follow this approach. For continuous outcomes, we subgroup data based on whether absolute values or change scores were available. For adverse events, we subgroup data 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 For both pairwise and network meta‐analyses, we conducted sensitivity analyses to detect whether pooled results were sensitive to the removal of studies judged to be at high risk of bias overall, and to the removal of studies reporting funding by the tobacco and/or vaping industry. We did this for all outcomes. 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 : 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 at longest follow‐up, at least six months from baseline, and adverse events and serious adverse events at one week or longer, at the longest follow‐up at which participants were still being provided or encouraged to use EC) for these main comparisons, from our pairwise meta‐analyses only. 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 (also based on our pairwise meta‐analyses only), and to draw conclusions about the certainty of evidence within the text of the review. GRADE assessments were carried out by JHB and NL. If, in the future, results from NMA are inconsistent with those from our pairwise analyses, we will consider this as a possible justification for downgrading based on indirectness (as it would signal that direct and indirect evidence are incongruent). We did not conduct certainty assessments for the NMA outcomes, as our primary analyses of interest were the pair‐wise comparisons. 

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; we also include uncontrolled intervention studies in which all participants are given an EC intervention. These studies have the potential to provide information on harms and longer‐term use. We include studies regardless of their publication status or language of publication. Types of participants Participants are people defined as currently smoking cigarettes at enrolment into the studies. Participants could be motivated or unmotivated to quit. We include studies that recruited pregnant people and include their data in our pairwise meta‐analyses and narrative syntheses; however, we will not include their data in our network meta‐analyses (NMA) (described in our section) as some of the comparisons eligible for inclusion are unlikely to be offered to this population (e.g. varenicline). Should a study meet all other criteria but include only a subset of eligible participants (e.g. a study on people who currently smoke and people who formerly smoked), we would only include data on the subgroup of participants who met our inclusion criteria. If these data were not available, we would include the study if at least 80% of participants met our inclusion criteria and would test the exclusion of the study in a sensitivity analysis. We include participants regardless of age. Types of interventions Any type of EC or intervention intended to promote EC use for smoking cessation, including studies that did not measure smoking cessation but provided ECs with the instruction that they be used as a complete substitute for cigarette use. ECs may or may not contain nicotine. For the purpose of the NMA, we assume that the interventions were jointly randomizable for all participants except those who were pregnant. Types of comparators We compare nicotine ECs with alternative smoking cessation aids, including NRT or no intervention, with ECs without nicotine, and ECs added to standard smoking cessation treatment (behavioural or pharmacological or both) with standard treatment alone. We compare different types of EC (refillable, cartridge, nicotine salt, free‐base), different nicotine doses, and different flavours. 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 any type of adverse event(s) at one week or longer (as defined by study authors) Number of participants reporting any type of serious adverse event(s) at one week or longer (as defined by study authors) Secondary outcomes Number of people still using study product (EC or pharmacotherapy) at longest follow‐up (at least six months). The product could be that provided by the study, or could be the same product type but bought independently by the participant. Changes in the following measures at longest follow‐up (one week or longer): Carbon monoxide (CO), as measured through breath or blood Blood pressure Heart rate Blood oxygen saturation Lung function measures Known toxins/carcinogens, as measured through blood, urine or saliva (toxicant names and abbreviations are listed in ) Studies had to set out to measure one of the primary or secondary outcomes above to be eligible for inclusion. If a study set out to measure an eligible outcome but did not measure and/or report results on this outcome, we would still include this study and flag its missing data in the results section. In addition, we set out to include any measure of an association between withdrawal symptoms and smoking cessation at six months or longer, as long as withdrawal was measured using a validated scale designed explicitly to investigate smoking withdrawal or craving. We added this because British guidelines now specify that efforts should be made to provide EC in a way that will reduce symptoms of withdrawal in people who smoke ( ). However, no studies provided data on this. 

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; we also include uncontrolled intervention studies in which all participants are given an EC intervention. These studies have the potential to provide information on harms and longer‐term use. We include studies regardless of their publication status or language of publication. 

Participants are people defined as currently smoking cigarettes at enrolment into the studies. Participants could be motivated or unmotivated to quit. We include studies that recruited pregnant people and include their data in our pairwise meta‐analyses and narrative syntheses; however, we will not include their data in our network meta‐analyses (NMA) (described in our section) as some of the comparisons eligible for inclusion are unlikely to be offered to this population (e.g. varenicline). Should a study meet all other criteria but include only a subset of eligible participants (e.g. a study on people who currently smoke and people who formerly smoked), we would only include data on the subgroup of participants who met our inclusion criteria. If these data were not available, we would include the study if at least 80% of participants met our inclusion criteria and would test the exclusion of the study in a sensitivity analysis. We include participants regardless of age. 

Any type of EC or intervention intended to promote EC use for smoking cessation, including studies that did not measure smoking cessation but provided ECs with the instruction that they be used as a complete substitute for cigarette use. ECs may or may not contain nicotine. For the purpose of the NMA, we assume that the interventions were jointly randomizable for all participants except those who were pregnant. Types of comparators We compare nicotine ECs with alternative smoking cessation aids, including NRT or no intervention, with ECs without nicotine, and ECs added to standard smoking cessation treatment (behavioural or pharmacological or both) with standard treatment alone. We compare different types of EC (refillable, cartridge, nicotine salt, free‐base), different nicotine doses, and different flavours. 

We compare nicotine ECs with alternative smoking cessation aids, including NRT or no intervention, with ECs without nicotine, and ECs added to standard smoking cessation treatment (behavioural or pharmacological or both) with standard treatment alone. We compare different types of EC (refillable, cartridge, nicotine salt, free‐base), different nicotine doses, and different flavours. 

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 any type of adverse event(s) at one week or longer (as defined by study authors) Number of participants reporting any type of serious adverse event(s) at one week or longer (as defined by study authors) Secondary outcomes Number of people still using study product (EC or pharmacotherapy) at longest follow‐up (at least six months). The product could be that provided by the study, or could be the same product type but bought independently by the participant. Changes in the following measures at longest follow‐up (one week or longer): Carbon monoxide (CO), as measured through breath or blood Blood pressure Heart rate Blood oxygen saturation Lung function measures Known toxins/carcinogens, as measured through blood, urine or saliva (toxicant names and abbreviations are listed in ) Studies had to set out to measure one of the primary or secondary outcomes above to be eligible for inclusion. If a study set out to measure an eligible outcome but did not measure and/or report results on this outcome, we would still include this study and flag its missing data in the results section. In addition, we set out to include any measure of an association between withdrawal symptoms and smoking cessation at six months or longer, as long as withdrawal was measured using a validated scale designed explicitly to investigate smoking withdrawal or craving. We added this because British guidelines now specify that efforts should be made to provide EC in a way that will reduce symptoms of withdrawal in people who smoke ( ). However, no studies provided data on this. 

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 any type of adverse event(s) at one week or longer (as defined by study authors) Number of participants reporting any type of serious adverse event(s) at one week or longer (as defined by study authors) 

Number of people still using study product (EC or pharmacotherapy) at longest follow‐up (at least six months). The product could be that provided by the study, or could be the same product type but bought independently by the participant. Changes in the following measures at longest follow‐up (one week or longer): Carbon monoxide (CO), as measured through breath or blood Blood pressure Heart rate Blood oxygen saturation Lung function measures Known toxins/carcinogens, as measured through blood, urine or saliva (toxicant names and abbreviations are listed in ) Studies had to set out to measure one of the primary or secondary outcomes above to be eligible for inclusion. If a study set out to measure an eligible outcome but did not measure and/or report results on this outcome, we would still include this study and flag its missing data in the results section. In addition, we set out to include any measure of an association between withdrawal symptoms and smoking cessation at six months or longer, as long as withdrawal was measured using a validated scale designed explicitly to investigate smoking withdrawal or craving. We added this because British guidelines now specify that efforts should be made to provide EC in a way that will reduce symptoms of withdrawal in people who smoke ( ). However, no studies provided data on this. 

Electronic searches Searches are conducted monthly. This update includes results from searches conducted up to 1 February 2024: Cochrane Tobacco Addiction Group Specialized Register (CRS‐Web up to 1 February 2023); Cochrane Central Register of Controlled Trials (CENTRAL; 2024, Issue 1) via CRS‐Web; MEDLINE (OVID SP; 1 January 2004 to 1 February 2024); Embase (OVID SP; 1 January 2004 to 1 February 2024); PsycINFO (OVID SP; 1 January 2004 to 1 February 2024); ClinicalTrials.gov (via CENTRAL; 2024, Issue 1); WHO International Clinical Trials Registry Platform (ICTRP: www.who.int/ictrp/en/ , via CENTRAL; 2024, Issue 1). We did not search the Cochrane Tobacco Addiction Group Specialized Register beyond 1 February 2023 as it ceased to be maintained. At the time of the last search, the Register included the results of searches of MEDLINE (via OVID) to update 20221222; Embase (via OVID) to week 202251; and PsycINFO (via OVID) to update 20221219. 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. All current search strategies are listed in . The previously used search strategy is shown in . 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. We also searched abstracts from the Society for Research on Nicotine and Tobacco (SRNT) Annual Meetings up to 1 February 2024. 

Searches are conducted monthly. This update includes results from searches conducted up to 1 February 2024: Cochrane Tobacco Addiction Group Specialized Register (CRS‐Web up to 1 February 2023); Cochrane Central Register of Controlled Trials (CENTRAL; 2024, Issue 1) via CRS‐Web; MEDLINE (OVID SP; 1 January 2004 to 1 February 2024); Embase (OVID SP; 1 January 2004 to 1 February 2024); PsycINFO (OVID SP; 1 January 2004 to 1 February 2024); ClinicalTrials.gov (via CENTRAL; 2024, Issue 1); WHO International Clinical Trials Registry Platform (ICTRP: www.who.int/ictrp/en/ , via CENTRAL; 2024, Issue 1). We did not search the Cochrane Tobacco Addiction Group Specialized Register beyond 1 February 2023 as it ceased to be maintained. At the time of the last search, the Register included the results of searches of MEDLINE (via OVID) to update 20221222; Embase (via OVID) to week 202251; and PsycINFO (via OVID) to update 20221219. 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. All current search strategies are listed in . The previously used search strategy is shown in . 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. 

We searched the reference lists of eligible studies found in the literature search and contacted authors of known trials and other published EC studies. We also searched abstracts from the Society for Research on Nicotine and Tobacco (SRNT) Annual Meetings up to 1 February 2024. 

Selection of studies Two review authors (for this update from: ARB, JHB, NL, AT) independently pre‐screened 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 One review author extracted data on study characteristics (ARB), whereas two review authors (for this update: ARB and ADW) independently extracted outcome data, effect modifiers, and the information needed to make risk of bias judgements. We used a pre‐piloted data extraction form, and checked the forms for inconsistencies. We resolved any disagreements by discussion or with a third review author (NL). We extracted data on the following: 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), number of people still using study product, and relevant biomarkers Continued EC use or pharmaceutical intervention (PI) use at longest follow‐up Data investigating the association between withdrawal and smoking cessation 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. There were no papers that required translation ; should there be in the future, we would seek a translator to assist us. For studies that received tobacco or EC industry funding the study name is followed by an asterisk (*). One review author (NL for this update) then entered the data contributing to pairwise network meta‐analysis (NMA) into software for analyses, and another checked them (JHB for this update). Data for the NMA were collated by one author (ARB) and checked by NL and JHB. Assessment of risk of bias in included studies Two review authors (for this update: ARB and ADW) independently assessed the risks of bias for each included study, using the Cochrane risk of bias tool (RoB 1) ( ). We resolved any disagreements by discussion or with a third review author (NL). 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 that 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 the standard methods of the Cochrane Tobacco Addiction 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 the intervention was similar between groups, or both. For studies where cessation was measured, our judgement was based on whether cessation was biochemically verified. Where cessation was not measured, we judged this domain based on adverse or serious adverse events. Again, following the 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, or by comparing absolute data at follow‐up where insufficient data were available on mean change. 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, or their use was encouraged. 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, or there is no evidence of difference between similar trial arms for the outcome of interest. We note in our analyses where this is the case. For all but one study, the unit of assignment was the individual. assigned the condition based on homeless support service; 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 the 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 outcomes from comparative trials that are not reported with sufficient data for meta‐analysis, using effect direction plots as described in the Cochrane Handbook for Systematic Reviews of Interventions, where possible ( ). Dealing with missing data For smoking cessation, we use a conservative approach, as is standard for the Cochrane Tobacco Addiction Group, treating participants with missing data as still smoking. We base 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 about whether data should be pooled. We were also guided by the degree of statistical heterogeneity, assessed by calculating the I 2 statistic ( ), and considering a value greater than 50% as evidence of substantial heterogeneity. We did not present pooled results where I 2 values exceeded 75%. For our NMA, we assessed global inconsistency using scatterplots of residual deviance in the NMA model against residual deviance in the Unrelated Mean Effects (UME) model. The UME model does not assume transitivity of treatment effects, so a smaller deviance in this model in comparison to the main NMA indicates inconsistency within the network. We also used scatterplots of leverage versus deviance to check the general model fit. We assessed local inconsistency using node‐split models for the main analyses of each outcome. We did not formally assess potential participant‐level effect moderators as a way to evaluate transitivity in our NMA, as previous work has shown these to be inconsistently reported in this body of studies ( ; ; ). Assessment of reporting biases Reporting bias can be assessed using funnel plots, where 10 or more RCTs contribute to an outcome. Where studies were included in an analysis but did not contribute data to the pooled effect (as zero events were reported), these were not included in the count of included studies when deciding whether to generate funnel plots. Therefore, there were only two analyses with sufficient studies to support this approach. Had it been appropriate for our NMA, we would have adapted existing methods for assessing publication bias in standard systematic reviews by generating a funnel plot for each of the comparisons of interest and overlaying these plots on top of one another, while aligning the reference lines (representing the overall component effect). This is called a 'comparison adjusted funnel plot'. We would have considered studies distributed asymmetrically as potential evidence of publication bias. However, there were insufficient studies for each comparison to make this approach appropriate. Data synthesis We provide a narrative summary of the included studies. Pairwise meta‐analyses Where appropriate, we have pooled data from RCTs in pairwise meta‐analyses, grouping studies by comparison type and outcome. Data from single‐armed intervention studies are summarized narratively. Where presented per type of AE, rather than for all types together, these data were summarized narratively rather than meta‐analyzed. For dichotomous data, we used a fixed‐effect Mantel‐Haenszel model to calculate the RR with a 95% CI, in accord with the standard methods of the Cochrane Tobacco Addiction Group for cessation studies. For continuous outcomes, we pooled mean differences (or standardized mean differences for studies using different measures for the same construct), using the inverse variance approach (also with a 95% CI). Network meta‐analyses We also carried out three network meta‐analyses (NMA), as these can give further insight into comparative effects by drawing on data from both direct and indirect comparisons. NMA produces estimates of the relative effects between any pair of interventions in the network, usually providing more precise estimates than a single direct estimate ( ). Our three NMAs are as follows: one for each of our three primary outcomes: smoking cessation at six months follow‐up or longer; AEs at one‐week follow‐up or longer; and SAEs at one‐week follow‐up or longer. All NMAs were run using MetaInsight ( ). The models were Bayesian generalized linear models with non‐informative prior distributions on all parameters. Fixed effects were assumed in each case. MCMC simulations were run for 25,000 iterations, with the first 5,000 discarded, on four chains. Convergence was assessed through Gelman plots. Bayesian models were chosen because they are more flexible and have become the most common choice for NMA in recent years. Our NMAs only included RCTs and excluded studies carried out on pregnant people, as specified in the section. Interventions were classified as nodes as per our primary comparisons, but only including nodes where two or more studies contributed data. In addition, NRT was split into combined and single forms because evidence indicates there is a clinically significant difference in smoking cessation outcomes between them ( ). In this update, the following interventions were eligible nodes (further nodes may be added as additional comparisons are added): Nicotine EC Non‐nicotine EC NRT (single form) NRT (combined fast‐acting form and patch) Nicotine EC plus single‐form NRT Non‐nicotine EC plus single‐form NRT Advice to use nicotine e‐cigarettes in a quit attempt (but no e‐cigarettes provided) No e‐cigarettes or pharmacotherapy Studies that provided an additional intervention component, such as behavioural support, were included only if the additional component was matched between intervention arms and comparator arms, as is the case for this review overall. Studies with no outcome events in any study arm were excluded. In contrast, studies with no outcome events in some but not all arms were included. We did not conduct any ranking of interventions in the NMA. Subgroup analysis and investigation of heterogeneity For our pairwise analyses, we had planned to undertake subgroup analyses to investigate differences between studies, such as the following: Intensity of behavioural support used (as this could potentially influence cessation). Type of EC, e.g. cartridge; refillable; pod (as this could potentially influence all outcomes due to different delivery mechanisms). Instructions for EC use, e.g. study provision, length of provision, whether participants had a role in product choice (as this could potentially influence all outcomes, given variation in available devices and e‐liquids). Type of participants (this could potentially influence all outcomes, depending on, e.g. pre‐existing conditions, previous experience with EC). However, there were too few studies to conduct such analyses. Should further studies become available in future, we will follow this approach. For continuous outcomes, we subgroup data based on whether absolute values or change scores were available. For adverse events, we subgroup data 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 For both pairwise and network meta‐analyses, we conducted sensitivity analyses to detect whether pooled results were sensitive to the removal of studies judged to be at high risk of bias overall, and to the removal of studies reporting funding by the tobacco and/or vaping industry. We did this for all outcomes. 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 : 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 at longest follow‐up, at least six months from baseline, and adverse events and serious adverse events at one week or longer, at the longest follow‐up at which participants were still being provided or encouraged to use EC) for these main comparisons, from our pairwise meta‐analyses only. 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 (also based on our pairwise meta‐analyses only), and to draw conclusions about the certainty of evidence within the text of the review. GRADE assessments were carried out by JHB and NL. If, in the future, results from NMA are inconsistent with those from our pairwise analyses, we will consider this as a possible justification for downgrading based on indirectness (as it would signal that direct and indirect evidence are incongruent). We did not conduct certainty assessments for the NMA outcomes, as our primary analyses of interest were the pair‐wise comparisons. 

Two review authors (for this update from: ARB, JHB, NL, AT) independently pre‐screened 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. 

One review author extracted data on study characteristics (ARB), whereas two review authors (for this update: ARB and ADW) independently extracted outcome data, effect modifiers, and the information needed to make risk of bias judgements. We used a pre‐piloted data extraction form, and checked the forms for inconsistencies. We resolved any disagreements by discussion or with a third review author (NL). We extracted data on the following: 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), number of people still using study product, and relevant biomarkers Continued EC use or pharmaceutical intervention (PI) use at longest follow‐up Data investigating the association between withdrawal and smoking cessation 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. There were no papers that required translation ; should there be in the future, we would seek a translator to assist us. For studies that received tobacco or EC industry funding the study name is followed by an asterisk (*). One review author (NL for this update) then entered the data contributing to pairwise network meta‐analysis (NMA) into software for analyses, and another checked them (JHB for this update). Data for the NMA were collated by one author (ARB) and checked by NL and JHB. 

Two review authors (for this update: ARB and ADW) independently assessed the risks of bias for each included study, using the Cochrane risk of bias tool (RoB 1) ( ). We resolved any disagreements by discussion or with a third review author (NL). 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 that 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 the standard methods of the Cochrane Tobacco Addiction 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 the intervention was similar between groups, or both. For studies where cessation was measured, our judgement was based on whether cessation was biochemically verified. Where cessation was not measured, we judged this domain based on adverse or serious adverse events. Again, following the 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. 

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, or by comparing absolute data at follow‐up where insufficient data were available on mean change. 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, or their use was encouraged. 

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, or there is no evidence of difference between similar trial arms for the outcome of interest. We note in our analyses where this is the case. For all but one study, the unit of assignment was the individual. assigned the condition based on homeless support service; 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 the 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 outcomes from comparative trials that are not reported with sufficient data for meta‐analysis, using effect direction plots as described in the Cochrane Handbook for Systematic Reviews of Interventions, where possible ( ). 

For smoking cessation, we use a conservative approach, as is standard for the Cochrane Tobacco Addiction Group, treating participants with missing data as still smoking. We base 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. 

We assessed the clinical and methodological diversity between studies to guide our decision about whether data should be pooled. We were also guided by the degree of statistical heterogeneity, assessed by calculating the I 2 statistic ( ), and considering a value greater than 50% as evidence of substantial heterogeneity. We did not present pooled results where I 2 values exceeded 75%. For our NMA, we assessed global inconsistency using scatterplots of residual deviance in the NMA model against residual deviance in the Unrelated Mean Effects (UME) model. The UME model does not assume transitivity of treatment effects, so a smaller deviance in this model in comparison to the main NMA indicates inconsistency within the network. We also used scatterplots of leverage versus deviance to check the general model fit. We assessed local inconsistency using node‐split models for the main analyses of each outcome. We did not formally assess potential participant‐level effect moderators as a way to evaluate transitivity in our NMA, as previous work has shown these to be inconsistently reported in this body of studies ( ; ; ). 

Reporting bias can be assessed using funnel plots, where 10 or more RCTs contribute to an outcome. Where studies were included in an analysis but did not contribute data to the pooled effect (as zero events were reported), these were not included in the count of included studies when deciding whether to generate funnel plots. Therefore, there were only two analyses with sufficient studies to support this approach. Had it been appropriate for our NMA, we would have adapted existing methods for assessing publication bias in standard systematic reviews by generating a funnel plot for each of the comparisons of interest and overlaying these plots on top of one another, while aligning the reference lines (representing the overall component effect). This is called a 'comparison adjusted funnel plot'. We would have considered studies distributed asymmetrically as potential evidence of publication bias. However, there were insufficient studies for each comparison to make this approach appropriate. 

We provide a narrative summary of the included studies. Pairwise meta‐analyses Where appropriate, we have pooled data from RCTs in pairwise meta‐analyses, grouping studies by comparison type and outcome. Data from single‐armed intervention studies are summarized narratively. Where presented per type of AE, rather than for all types together, these data were summarized narratively rather than meta‐analyzed. For dichotomous data, we used a fixed‐effect Mantel‐Haenszel model to calculate the RR with a 95% CI, in accord with the standard methods of the Cochrane Tobacco Addiction Group for cessation studies. For continuous outcomes, we pooled mean differences (or standardized mean differences for studies using different measures for the same construct), using the inverse variance approach (also with a 95% CI). Network meta‐analyses We also carried out three network meta‐analyses (NMA), as these can give further insight into comparative effects by drawing on data from both direct and indirect comparisons. NMA produces estimates of the relative effects between any pair of interventions in the network, usually providing more precise estimates than a single direct estimate ( ). Our three NMAs are as follows: one for each of our three primary outcomes: smoking cessation at six months follow‐up or longer; AEs at one‐week follow‐up or longer; and SAEs at one‐week follow‐up or longer. All NMAs were run using MetaInsight ( ). The models were Bayesian generalized linear models with non‐informative prior distributions on all parameters. Fixed effects were assumed in each case. MCMC simulations were run for 25,000 iterations, with the first 5,000 discarded, on four chains. Convergence was assessed through Gelman plots. Bayesian models were chosen because they are more flexible and have become the most common choice for NMA in recent years. Our NMAs only included RCTs and excluded studies carried out on pregnant people, as specified in the section. Interventions were classified as nodes as per our primary comparisons, but only including nodes where two or more studies contributed data. In addition, NRT was split into combined and single forms because evidence indicates there is a clinically significant difference in smoking cessation outcomes between them ( ). In this update, the following interventions were eligible nodes (further nodes may be added as additional comparisons are added): Nicotine EC Non‐nicotine EC NRT (single form) NRT (combined fast‐acting form and patch) Nicotine EC plus single‐form NRT Non‐nicotine EC plus single‐form NRT Advice to use nicotine e‐cigarettes in a quit attempt (but no e‐cigarettes provided) No e‐cigarettes or pharmacotherapy Studies that provided an additional intervention component, such as behavioural support, were included only if the additional component was matched between intervention arms and comparator arms, as is the case for this review overall. Studies with no outcome events in any study arm were excluded. In contrast, studies with no outcome events in some but not all arms were included. We did not conduct any ranking of interventions in the NMA. 

Where appropriate, we have pooled data from RCTs in pairwise meta‐analyses, grouping studies by comparison type and outcome. Data from single‐armed intervention studies are summarized narratively. Where presented per type of AE, rather than for all types together, these data were summarized narratively rather than meta‐analyzed. For dichotomous data, we used a fixed‐effect Mantel‐Haenszel model to calculate the RR with a 95% CI, in accord with the standard methods of the Cochrane Tobacco Addiction Group for cessation studies. For continuous outcomes, we pooled mean differences (or standardized mean differences for studies using different measures for the same construct), using the inverse variance approach (also with a 95% CI). 

We also carried out three network meta‐analyses (NMA), as these can give further insight into comparative effects by drawing on data from both direct and indirect comparisons. NMA produces estimates of the relative effects between any pair of interventions in the network, usually providing more precise estimates than a single direct estimate ( ). Our three NMAs are as follows: one for each of our three primary outcomes: smoking cessation at six months follow‐up or longer; AEs at one‐week follow‐up or longer; and SAEs at one‐week follow‐up or longer. All NMAs were run using MetaInsight ( ). The models were Bayesian generalized linear models with non‐informative prior distributions on all parameters. Fixed effects were assumed in each case. MCMC simulations were run for 25,000 iterations, with the first 5,000 discarded, on four chains. Convergence was assessed through Gelman plots. Bayesian models were chosen because they are more flexible and have become the most common choice for NMA in recent years. Our NMAs only included RCTs and excluded studies carried out on pregnant people, as specified in the section. Interventions were classified as nodes as per our primary comparisons, but only including nodes where two or more studies contributed data. In addition, NRT was split into combined and single forms because evidence indicates there is a clinically significant difference in smoking cessation outcomes between them ( ). In this update, the following interventions were eligible nodes (further nodes may be added as additional comparisons are added): Nicotine EC Non‐nicotine EC NRT (single form) NRT (combined fast‐acting form and patch) Nicotine EC plus single‐form NRT Non‐nicotine EC plus single‐form NRT Advice to use nicotine e‐cigarettes in a quit attempt (but no e‐cigarettes provided) No e‐cigarettes or pharmacotherapy Studies that provided an additional intervention component, such as behavioural support, were included only if the additional component was matched between intervention arms and comparator arms, as is the case for this review overall. Studies with no outcome events in any study arm were excluded. In contrast, studies with no outcome events in some but not all arms were included. We did not conduct any ranking of interventions in the NMA. 

For our pairwise analyses, we had planned to undertake subgroup analyses to investigate differences between studies, such as the following: Intensity of behavioural support used (as this could potentially influence cessation). Type of EC, e.g. cartridge; refillable; pod (as this could potentially influence all outcomes due to different delivery mechanisms). Instructions for EC use, e.g. study provision, length of provision, whether participants had a role in product choice (as this could potentially influence all outcomes, given variation in available devices and e‐liquids). Type of participants (this could potentially influence all outcomes, depending on, e.g. pre‐existing conditions, previous experience with EC). However, there were too few studies to conduct such analyses. Should further studies become available in future, we will follow this approach. For continuous outcomes, we subgroup data based on whether absolute values or change scores were available. For adverse events, we subgroup data 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. 

For both pairwise and network meta‐analyses, we conducted sensitivity analyses to detect whether pooled results were sensitive to the removal of studies judged to be at high risk of bias overall, and to the removal of studies reporting funding by the tobacco and/or vaping industry. We did this for all outcomes. 

Following standard Cochrane methodology, we created summary of findings tables for our three main comparisons using : 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 at longest follow‐up, at least six months from baseline, and adverse events and serious adverse events at one week or longer, at the longest follow‐up at which participants were still being provided or encouraged to use EC) for these main comparisons, from our pairwise meta‐analyses only. 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 (also based on our pairwise meta‐analyses only), and to draw conclusions about the certainty of evidence within the text of the review. GRADE assessments were carried out by JHB and NL. If, in the future, results from NMA are inconsistent with those from our pairwise analyses, we will consider this as a possible justification for downgrading based on indirectness (as it would signal that direct and indirect evidence are incongruent). We did not conduct certainty assessments for the NMA outcomes, as our primary analyses of interest were the pair‐wise comparisons. 

Description of studies Results of the search For this update, our bibliographic database searches identified 624 non‐duplicate records (See for PRISMA flow diagram). We screened all records and retrieved the full‐text papers of 34 potentially relevant articles. After screening and checking the full texts, we included 26 records, representing two new studies for this update ( ; ), 11 new articles linked to studies already identified, 11 new ongoing studies, and two records awaiting classification (see ). Secondary study reports, commentaries, and correspondence relating to included studies are linked to studies in the reference section. Included studies In total, we include 90 studies, with two new included studies and 88 studies included in the previous version of this review. Key features of these included studies are summarized below. Further details on each included study can be found in the table. Participants The 90 included studies represented 29,044 participants. Thirty‐nine studies were conducted in the USA, 20 were conducted in the UK, nine in Italy, five in Australia, four in Greece, two each in New Zealand, Switzerland, and Canada, and one each in Belgium, Ireland, the Netherlands, Poland, the Republic of Korea, South Africa, and Turkey. All studies were conducted in adults who smoked. Twenty‐six studies exclusively recruited participants who were not motivated to quit smoking, and 45 studies exclusively recruited participants motivated to quit; motivation was not specified for the other studies. Thirty‐two studies recruited from specific population groups; these included nine studies that recruited participants based on physical health condition (heart attack, cancer, HIV, periodontitis, awaiting surgery, smoking‐related chronic disease), five studies that recruited participants with serious mental illness, four studies that recruited participants on treatment or having recently completed treatment for alcohol or other drug use, and three studies in dual users of EC and conventional cigarettes. Two studies recruited people accessing homeless centres or using supported temporary accommodation, and a further two recruited specifically within socially deprived areas. One study each recruited: people aged 55 or older, young adults, people who self‐identified as African‐American, pregnant women, people who had recently made a failed attempt to quit smoking, black and Latino participants, and people attending the emergency department. Interventions and comparators Three studies recruited dual users of combustible cigarettes and EC at baseline, and instructed them to continue using their own EC devices ( ; ; ). One study recruited users of combustible cigarettes only and provided information on using EC, but did not provide them with EC ( ). The remaining studies all provided some form of nicotine EC. In two studies where nicotine ECs were provided on their own, nicotine levels were judged to be so low as to be clinically comparable to non‐nicotine EC ( ; ); we include these studies in non‐nicotine EC comparisons. Twelve studies compared nicotine EC with non‐nicotine EC, 26 studies compared nicotine EC to behavioural support only or to no support, and 20 studies compared nicotine EC to NRT. Six studies compared high‐ versus low‐nicotine EC devices ( ; ; ; ; ), four studies included comparisons based on flavours ( ; ; ; ), two studies directly compared device types ( ; ), and two studies directly compared a freebase nicotine to a salt‐based nicotine device ( ; ). Results from these studies are reported by comparison in . Further details on the intervention and comparator groups (where applicable) for each study can be found in the table. Where reported in the primary research publications, details of the devices tested can also be found in the table. Of the studies with sufficient data with which to judge, 31 used cartridge devices, 34 used refillable devices, four used both types, 10 used a pod device, and the remainder did not report device type. Outcomes Of the 90 included studies: 40 reported data on abstinence at six months or longer; 64 reported data on adverse events; 46 reported data on serious adverse events; 49 reported data on carbon monoxide; 12 reported data on heart rate; 14 reported data on blood pressure; 4 reported data on blood oxygen saturation; 16 reported data on at least one known toxin/carcinogen; 8 reported data on at least one measure of lung function; 20 reported data on study product use at six months or longer. One study measured safety outcomes but did not report them in the text available at the time of writing (they may be forthcoming); hence, this study currently does not contribute any data to this review ( ). Study types Forty‐nine studies were RCTs, 28 of which contributed to cessation analyses. Eight studies used randomized cross‐over designs, and the remainder were uncontrolled cohort studies. Funding Of the 83 studies that reported funding information, 68 had no tobacco or EC industry funding or support. Below, we detail the industry funding from the 15 studies that report tobacco or EC industry funding or support. An asterisk (*) has been added after the study name for all studies that received tobacco or EC industry funding. Where these studies contributed to meta‐analyses, we tested whether results were sensitive to their inclusion, and took account of this in our results and conclusions. Fifteen of the included studies reported support from the tobacco or vaping industry, or that authors had received tobacco or vaping industry support outside of the study being conducted. Six of these studies received funding from the Lega Italiana AntiFumo ( ; ; ; ; ; ). and also received free “Categoria” EC kits from the Arbi Group Srl (Milano, Italy). received free JUUL EC from the manufacturer, PAX Labs (became JUUL Labs in 2017). Altria Group (formerly, Philip Morris Companies) acquired a 35% stake in JUUL Labs on 20 December 2018; the study was completed before Altria invested in JUUL. thank FlavourArt (Oleggio, NO, Italy; www.flavourart.it ), an EC flavour company. was funded by Philip Morris Product Société Anonyme. was funded by Altria Client Services LLC. Altria is the parent company of Philip Morris USA (producer of Marlboro cigarettes), John Middleton, Inc., U.S. Smokeless Tobacco Company, Inc., and Philip Morris Capital Corporation. was funded by RAI Services Company. The parent company is Reynolds American. Reynolds American manufacture and market a variety of tobacco products, including cigarettes (Newport, Camel, Pall Mall, Kent, Doral, Misty, Capri, and Natural American Spirit brands), EC (Vuse brand), and moist snuff (Grizzly and Kodiak brands). was funded entirely by Fontem US LLC, a subsidiary of Imperial Brands PLC. was funded by NJOY, Inc., Scottsdale, AZ. Funded by the EC/alternative nicotine products industry. was funded by the National Institute on Drug Abuse (NIDA). However, the lead author declared research support from Foundation for a Smoke‐Free World (which has links to the tobacco industry), Philip Morris International, Altria, Embera Neuro Therapeutics, Inc., Otsuka Pharmaceutical, JUUL Labs, consulting with Revive pharmaceuticals, and consulting and patent purchase agreements with Philip Morris International. was funded by eGo e‐cigarette packs by Twisp. was funded and supported by Fontem Ventures B.V. Imperial Brands plc (Imperial Tobacco plc) is the parent company of Fontem Ventures B.V., the manufacturer of the EC prototype used in their study. was funded by Juul Labs, Inc. Excluded studies We list 32 studies excluded at full‐text stage, along with reasons for exclusion, in the table. After the reference being a duplicate, the most common reason for exclusion was that studies did not include outcomes relevant to this review. Risk of bias in included studies Overall, we judged 10 studies to be at low risk of bias ( ; ; ; ; ; ; ; ; ; ), 19 to be at unclear risk, and the remaining 61 at high risk of bias (this includes the non‐randomized studies, which we deemed to be at high risk due to lack of randomization). Details of the risk of bias judgements for each domain of each included study can be found in the table. and illustrate our judgements across the included studies. Allocation We judged 28 studies to be at high risk of selection bias; for the majority of cases, this is because the study was not randomized. We rated a pilot cluster‐randomized trial to be at high risk, as randomization was not carried out as intended for pragmatic reasons ( ). We judged 31 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 In all, we assessed 65 studies for performance bias and detection bias. For performance bias, we rated 31 to be at low risk, 24 at high risk, and 10 at unclear risk. For detection bias, we rated 46 as low risk, 11 as high risk, and eight at unclear risk. 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 that we thought there was a high risk of bias being introduced. We judged the rest to be at unclear risk, or ineligible for this domain due to single‐arm design. Incomplete outcome data We judged most studies (66 out of 90) to be at low risk of attrition bias. We rated 10 studies with substantial loss to follow‐up as being at high risk of attrition bias. The remainder did not provide sufficient data on which to judge, and hence we judged them to be at unclear risk. Selective reporting Of the 90 studies, we considered 46 at low risk of reporting bias, as all prespecified or expected outcomes were reported. We rated 10 as being at high risk, as data were not available as specified in the original protocols (note in some cases these are recent studies, and judgement on these may change as more publications emerge). 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 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. We considered four further studies to be at unclear risk in this domain. Effects of interventions See: ; ; Data on our outcomes of interest are summarized below and in our , , and . Due to the volume of data available, some relevant information is hosted on a companion repository; these data are open‐access and can be found at http://dx.doi.org/10.5287/ora-jnvxbp7qr . They are referred to below as supplemental tables. Forest plots are available through 'analysis' links; for some outcomes, benefit is plotted on the right; for others it is plotted on the left. This is due to direction of effect, e.g. an increase in cessation is a benefit, whereas an increase in a carcinogen is not. Direct comparisons between nicotine EC and other pharmacotherapies Comparisons reported here include nicotine ECs versus NRT, and nicotine ECs versus varenicline. Only randomized controlled trials contributed data. Cessation Pooled data from seven studies (two cartridges, four refillable, one pod), five of which were rated at low risk of bias ( ; ; ; ; ) and two as unclear ( ; ), showed increased quit rates in people randomized to nicotine EC when compared to NRT (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.30 to 1.93; I 2 = 0%; 2544 participants; ). The certainty of evidence is high and has not been downgraded. One study included in this analysis, , was conducted in pregnant women. There was no evidence of a subgroup difference between this study and studies in participants not selected on the basis of pregnancy (P = 0.87, I 2 for subgroup differences = 0%). Follow‐up time was based on end of pregnancy, and our analysis included only those participants with follow‐up of at least six months. Results were not sensitive to the exclusion of the one study that received industry funding ( ); when this study was removed, the point estimate increased to 1.72, but the CIs remained consistent with those from the main analysis. One study, , available as a conference presentation only and considered at high risk of bias due to inconsistencies in the data reported and an unclear definition of abstinence, favoured varenicline for quitting compared to nicotine EC (cartridge) (RR 0.31, 95% CI 0.11 to 0.82; 54 participants; ). Adverse events Pooled data from five studies (four considered at low risk of bias ( ; ; ; ) and one at unclear risk ( )) showed that there is probably no difference in the number of participants reporting adverse events (AEs) between nicotine EC and NRT arms (RR 1.03, 95% CI 0.91 to 1.17; I 2 = 0%; 2052 participants; ). The certainty of evidence is moderate, downgraded one level due to imprecision; the CIs were consistent with benefit and harm. None of the studies contributing data to this analysis received funding from the vaping or tobacco industries. and did not contribute data to this analysis due to the way in which events were recorded. In 's prespecified adverse reactions of interest, nausea was more frequent in the NRT group, throat/mouth irritation was more frequent in the nicotine EC group, and there was little difference in other reactions (see Supplemental Table 1 for more detail). recruited participants with chronic obstructive pulmonary disease (COPD) and reported "a trend towards decreased dyspnoea and COPD symptoms ... in the EC arm compared to the NRT arm", but did not provide further detail. In , reports of sleep disorders were evenly distributed between groups, and nausea was more common in the varenicline arm than in the nicotine EC arm (see Supplemental Table 1 for more detail). Serious adverse events Six studies (five at low risk of bias ( ; ; ; ; ) and one at unclear risk ( )) comparing nicotine ECs with NRT provided data on serious adverse events. In some studies, no events occurred. Pooled results showed that there may be a slight increase in serious adverse events in the nicotine EC arms compared to NRT. There is low certainty of evidence for this outcome, downgraded two levels due to imprecision; there were fewer than 300 events and wide CIs incorporating no difference, as well as clinically significant harm and clinically significant benefit (RR 1.20, 95% CI 0.90 to 1.60; I 2 = 32%; 2761 participants; ). None of the studies contributing data to this analysis received funding from the vaping or tobacco industries. In (conducted in pregnant women), the authors reported no evidence of a difference in birth outcomes overall. However, low birthweight (< 2500 g) was less frequent in the EC than the NRT arm (14.8% versus 9.6%; RR 0.65, 95% CI 0.47 to 0.90). No SAEs occurred in ( ). Carbon monoxide (CO) Pooled data from four studies ( ; ; ; ), none of which received tobacco/vaping industry funding and none of which were considered at high risk of bias, comparing nicotine EC with NRT, found some evidence that CO levels decreased more in those randomized to nicotine EC; however, the CIs incorporated the possibility of no between‐group difference (mean difference (MD) ‐1.81 ppm, 95% CI ‐3.64 to 0.01; I 2 = 0%; 357 participants; ). A fourth, small study ( ; n = 11) was reported as a conference abstract and hence had limited data available. At three weeks, this study showed that both EC and NRT groups had "significantly reduced" CO, but between‐group differences were not reported. Heart rate, blood pressure, and oxygen saturation Pooled data from two studies (166 participants; one study judged to be at unclear risk of bias ( ) and one at low risk ( ), neither in receipt of vaping/tobacco industry funding) showed no clear evidence of a clinically meaningful difference in heart rate (MD 0.53 bpm, 95% CI ‐1.76 to 2.83; I 2 = 0%; ), systolic blood pressure (MD ‐1.62, 95% CI ‐3.59 to 0.36; I 2 = 0%; ), or blood oxygen saturation (MD ‐0.14, 95% CI ‐0.59 to 0.30; I 2 = 0%; ), although confidence intervals were wide. Toxicants Only (unclear risk of bias, no tobacco/vaping industry funding, n = 111) contributed data for these outcomes. For 3‐HPMA, 2‐HPMA, and HMPMA, point estimates favoured EC but CIs included no difference ( ; ; ). There was no evidence of a difference for NNAL (nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐ butanol) but CIs were again wide ( ). For PheT, CEMA, and AAMA ( ; ; ), point estimates favoured NRT but CIs included no difference. Lung function and (no tobacco/vaping industry funding) measured change in FEV1 (forced expiratory volume) and FEV1/FVC (forced vital capacity) (both low risk of bias; n = 81). High statistical heterogeneity (I 2 = 89%) precluded pooling for FEV1 ( ). The point estimate for favoured EC and for favoured NRT; for , the CIs included no difference. There was no evidence of a difference for FEV1/FVC, but there was moderate unexplained statistical heterogeneity and, again, CIs were wide (MD ‐0.16%, 95% CI ‐1.83 to 1.50; I 2 = 51%; ). For PEF (peak expiratory flow) only one study contributed to this analysis ( , n = 55). The point estimate favoured NRT but CIs were wide and included no difference (MD ‐3.00, 95% CI ‐27.09 to 21.09) ( ). Study product use Five studies (one, , with vaping industry funding) reported study product use at six months or longer, but statistical heterogeneity precluded pooling (I 2 = 95%). Whereas and found no difference between the EC and NRT arms, in the other three studies, people in the EC arm were more likely to continue to use the study product (EC) than those in the NRT arm ( ). A companion publication explored long‐term rates in more detail ( ). Nicotine EC versus other tobacco/nicotine products used for stopping combustible tobacco use Currently, the only comparison reported here is nicotine EC compared to heated tobacco. One study ( ; n = 220, tobacco/vaping industry‐funded), considered at high risk of bias due to a lack of blinding alongside strong participant product preferences, reported on AEs, SAEs, expired carbon monoxide (eCO), and VO 2 max as a measure of lung function, heart rate, and blood pressure at 12 weeks follow‐up. The effect estimate demonstrated no clear evidence of a difference in AEs between the nicotine EC and heated tobacco group (RR 0.86, 95% CI 0.68 to 1.10; 220 participants; ). There were no SAEs reported in either arm, so an effect estimate could not be calculated for this outcome ( ). There was no clear evidence of a between‐group difference in eCO levels (MD 1.90, 95% CI ‐0.71 to 4.51; 217 participants; ), or VO 2 max (MD 6.20, 95% CI ‐2.01 to 14.41; 211 participants; ). The following was reported on heart rate and blood pressure and is reported in Supplemental Tables 4 & 5 : “No significant changes in the mean resting heart rate, blood pressure, and BMI during product use were observed between and within study groups.” Nicotine EC alone or versus control Comparisons reported here include nicotine EC versus non‐nicotine EC, and nicotine EC compared to behavioural support only or to no support. In this section, we also reported results from studies in which all participants received nicotine EC (cohort studies and randomized studies that did not differ across arms in EC provision, device generation, or nicotine content). Cessation Randomized controlled trials At six months or longer, quit rates were higher in nicotine EC groups than in comparator groups. Compared to EC without nicotine (placebo EC), pooled results showed nicotine EC probably produced higher quit rates (RR 1.46, 95% CI 1.09 to 1.96; I 2 = 4%; 5 studies of cartridge and 1 study of refillable devices, 1613 participants; ). There is moderate‐certainty evidence that nicotine EC probably increases quit rates compared to non‐nicotine EC. The certainty has been downgraded one level due to imprecision; there are fewer than 300 events overall. This has not been downgraded for risk of bias: removing the one study considered at high risk of bias increased the direction of the effect in favour of nicotine EC. The interpretation of the effect remained the same when we removed the one study at high risk of bias ( ) and when we removed the one study with tobacco/vaping industry funding ( ). The effect may be more pronounced when comparing nicotine EC to behavioural support only or to no support (RR 1.96, 95% CI 1.66 to 2.32; I 2 = 0%; 11 studies (5 refillable, 3 cartridge, 3 pod), 6819 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (the certainty of the evidence was low, downgraded two levels). One of the studies contributing data to this comparison reported tobacco/vaping industry funding ( ). The removal of this study in a sensitivity analysis did not change the interpretation of the effect ( ). (pod device) measured cessation at six months in the intervention group only, using self‐report. As they did not measure cessation at six months in the comparator group, we could not include these data in our meta‐analysis. At six months, 23 (24%) intervention participants were exclusively using EC and 10 (10.4%) reported using neither EC nor combustible cigarettes (making a combined quit rate of 34.4% in the intervention arm at six months). Data from other studies Ten studies provided all participants with nicotine EC and assessed abstinence at six months or longer ( ; 2 refillable, 6 cartridges, 1 pod, 1 not specified). The highest proportion of quitters at six months was observed in (cartridge), in which all participants (n = 48) used EC and 18 used additional pharmacotherapy; 44% of participants were abstinent at six months. The lowest quit rates were seen in , where 14% of participants were abstinent at 12 months, and , where 5% of participants were abstinent at 12 months. In the former, participants were unmotivated to quit smoking and, in the latter, motivation was unclear and participants were recruited from a socially deprived area on the basis of receiving a free nicotine EC. Adverse events Randomized controlled trials Pooled data from five studies (none at high risk of bias, one reporting tobacco/vaping industry funding) showed that there is probably no difference in the number of participants experiencing adverse events when comparing nicotine EC to non‐nicotine EC (RR 1.01, 95% CI 0.91 to 1.11; I 2 = 0%; 840 participants; ); this is moderate‐certainty evidence, downgraded one level due to imprecision (fewer than 300 events overall). Removing the one study linked to industry funding had no effect on the interpretation of the result ( ). When comparing nicotine EC to behavioural support only or to no support, evidence suggests more people in the groups randomized to nicotine EC experience adverse events (RR 1.18, 95% CI 1.10 to 1.27; I 2 = 6%; 6 studies, 2351 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (low‐certainty evidence downgraded two levels due to risk of bias). Interpretation of the outcome was not sensitive to the inclusion of the one study with tobacco/vaping industry support ( ). A further 11 randomized controlled trials provided adverse event or related data for this comparison, but could not be included in the meta‐analysis due to the way in which data were presented (see Supplemental Table 1 ). In the studies comparing nicotine EC to non‐nicotine EC, one found similar event rates across arms ( ), and two reported more events in the nicotine EC arms ( ; ). In a further study comparing nicotine to non‐nicotine EC, events were reported by type, with an increase in some seen in the nicotine group and an increase in others seen in the non‐nicotine group ( ). In the seven studies comparing nicotine EC to behavioural support only or traditional cigarettes, found an increase in sinonasal symptoms in the group receiving nicotine EC compared to behavioural support only, and found that throat irritation, cough, and dry mouth increased in the e‐cigarette group relative to the traditional cigarette group. By contrast, found a reduction in respiratory symptoms in the EC compared to the traditional cigarette group, and found no clear difference in the number of participants reporting dry cough and throat and mouth irritation between the EC arm and the referral information arm. found an increase in throat irritation, palpitations, and dizziness in the EC group, but decreases in cough, headache, nausea, dry mouth, shortness of breath, and stomach pain. did not break down AEs by group but reported that three participants experienced a non‐serious adverse event definitely related to the study product. reported no statistically significant between‐group difference in AEs. Data from other studies Eighteen studies provided all participants with nicotine EC and assessed adverse events at one week or longer and one RCT reported AEs reported in the nicotine EC group only (see Supplemental Table 1 ). In the eight studies that tracked event rates over time, six showed adverse events reducing over time ( ; ; ; ; ; ). showed no change. The most commonly reported adverse events were throat/mouth irritation, headache, cough, and nausea. Serious adverse events Randomized controlled trials Nine studies compared nicotine EC with non‐nicotine EC and reported data on SAEs; in five of these (including one tobacco/vaping industry study, ), no events occurred, so results could not contribute to the meta‐analysis, although they are included in the forest plots for descriptive purposes. In the four studies (three low risk of bias, one unclear) where events occurred, there may be little to no difference between groups, but CIs were wide (RR 1.00, 95% CI 0.56 to 1.79; I 2 = 0%; 1412 participants; ). The evidence was of low certainty; this was downgraded two levels due to imprecision: the confidence intervals encompassed clinically significant harm as well as clinically significant benefit, and there were fewer than 300 events overall. One of these studies had links to industry funding ( ); removing it from the analysis changed the effect estimate to 0.95 but the 95% CI remained wide (0.52 to 1.72) and so the interpretation of the result remained the same. Twelve studies compared nicotine EC with behavioural support only or no support and reported data on SAEs; in five of these, no events occurred. Pooled results from the seven studies in which events occurred showed very uncertain evidence about the difference between arms, but CIs were wide (RR 0.93, 95% CI 0.68 to 1.28; I 2 = 0%; 4561 participants; ). Here the certainty of evidence was very low; this was downgraded two levels due to risk of bias (lack of blinding and differential support between arms, judged to be at high risk of bias). Removing the one study with tobacco/vaping industry support did not affect the interpretation of the results ( ). In a study in people experiencing homelessness ( ), SAEs were not reported, but authors reported that four to seven participants in the usual care arm and five to seven participants in the nicotine EC arm visited Accident & Emergency services at a hospital. The authors reported that these visits were unrelated to study treatment and were assessed to gather data for future economic evaluation. Further detail can be found in Supplemental Table 2 . Data from other studies Nine studies provided all participants with nicotine EC and reported SAEs at a week or longer ( Supplemental Table 2 ). In six of these, authors reported that no SAEs occurred ( ; ; ; ; ; ; ). In (19 participants), one death occurred (no further detail provided). (50 participants) recruited participants from mental health settings; five SAEs were recorded during the study, all of which were psychiatric hospitalizations. None were considered related to study treatment. Carbon monoxide Randomized controlled trials High statistical heterogeneity (I 2 = 80%) precluded pooling CO data from the six trials (n = 677, none considered at high risk of bias) comparing nicotine EC with non‐nicotine EC ( ). Point estimates from four studies (one reporting links to industry funding; ) favoured nicotine EC and from two (one reporting industry funding; ) favoured non‐nicotine EC, but in all cases CIs were consistent with no clinically meaningful difference. Three further randomized studies measured CO levels in those assigned to nicotine EC and those assigned to non‐nicotine EC, but did not present data in a way that could be pooled: did not compare data by group; reported no between‐group differences; and found a slightly higher CO reading in those using nicotine EC, but the clinical and statistical significance of this difference was not clear (see Supplemental Table 3 for more detail). These data were from all study participants based on group randomized, not on subsequent EC or cigarette use. Pooled data from 11 studies comparing nicotine EC to behavioural support alone or to no support resulted in a high I 2 value (89%); thus, pooled results were not presented here (see for individual study data). None of these studies reported tobacco/vaping industry funding. A funnel plot did not show asymmetry ( ). Heterogeneity was primarily driven by magnitude rather than direction of effect, with results in 10 of 11 studies favouring nicotine EC. Three further trials reported data that could not be included in a meta‐analysis. compared nicotine EC to cigarettes and found that CO levels declined in the EC group and remained similar to baseline in the cigarette group. instructed baseline dual users to spend periods only using EC or only using traditional cigarettes; CO measured during sole EC use was lower than baseline and lower than during cigarette‐only periods. Further details can be found in Supplemental Table 3 . Data from other studies Twenty studies provided all participants with nicotine EC and reported data on CO at one week or longer. In the 19 studies that presented change over time, CO declined from baseline, although in CO levels were equivalent to baseline again at 24 weeks, and in a decline was observed in people who quit smoking or reduced cigarette consumption by at least half, but not in those who continued smoking at least half as many cigarettes as they had from baseline. Heart rate Randomized controlled trials One RCT ( , unclear risk of bias, n = 141) provided data on heart rate and compared nicotine EC with non‐nicotine EC; there was no evidence of a clinically significant between‐group difference (MD ‐2.3, 95% CI ‐6.10 to 1.50) ( ). This was comparable with findings from the one RCT ( , unclear risk of bias, n = 90) comparing nicotine EC with no pharmacotherapy, which also found no evidence of a clinically significant difference (MD 1.17, 95% CI ‐4.17 to 6.61) ( ). A further three RCTs provided data on heart rate that could not be used to calculate effect estimates. compared nicotine to non‐nicotine EC and found no difference in heart rate between arms; compared a nicotine EC with a traditional cigarette and reported "no clinically significant changes", and found decreases in both the EC and QuitSmart cigarette substitute groups, with the decrease being slightly greater in the latter group. See Supplemental Table 4 for further information. Data from other studies Six studies in which all participants received a nicotine EC also reported data on heart rate; for five, changes were minimal and directions of effect were mixed, and for (n = 40), the rate reduced by 9 bpm at 12 weeks (see Supplemental Table 4 ). Blood pressure found no evidence of a difference in the change in systolic blood pressure (BP) between nicotine EC and non‐nicotine EC arms (unclear risk of bias, 141 participants, MD 1.2, 95% CI ‐3.99 to 6.39; ). Three studies (two at high risk of bias, one at unclear risk of bias, none reporting tobacco/vaping industry funding) compared nicotine EC to behavioural support only and reported data on systolic blood pressure; there was a small difference favouring the EC arms (MD ‐2.3, 95% CI ‐3.9 to ‐0.7, I 2 = 24%; 298 participants; ). Three further RCTs measured change in blood pressure but presented results in such a way that they could not be pooled. compared nicotine EC and non‐nicotine EC and combined data from both groups; BP declined over time. Compared to a QuitSmart cigarette substitute, found that EC led to a greater reduction in BP. found "no clinically significant changes" when comparing nicotine EC to a conventional cigarette at two weeks. Five studies, which provided nicotine EC to all participants, reported change in blood pressure; results were clinically insignificant except for in which systolic BP reduced by 12 (from 134 to 122) at 12 weeks (see Supplemental Table 5 for further details on all studies reporting this outcome). Oxygen saturation found no evidence of a difference in blood oxygen saturation when comparing nicotine EC to cigarettes (89 participants, MD 0.20, 95% CI ‐0.30 to 0.70; ). , a short‐term pre‐post study, which measured outcomes after two weeks of EC use, found that people who smoked and switched to ECs had significant improvement in blood oxygen saturation (96.2% (standard deviation (SD) 1.8) to 97.5% (SD 1.3); 1.3% increase, 95% CI 0.6 to 2.1; P = 0.002). Toxicants Unless stated otherwise, all randomized controlled trials measuring these outcomes compared nicotine EC with no pharmacotherapy. Two trials measured change in 3‐HPMA (one at high risk of bias). In both, the point estimate favoured the EC arm, but pooling was precluded due to differences in measurement methods ( ). Five further studies, in which all participants were given nicotine EC, measured 3‐HPMA; all found reductions over time ( Supplemental Table 6 ). Five trials measured change in NNAL and provided sufficient data to calculate summary effects (four at high risk of bias; ). Three of the five studies found results favouring nicotine EC, but the final two indicated no difference; statistical heterogeneity was high (I 2 = 96%), so pooled results were not presented. One study comparing nicotine EC to no treatment described their findings narratively and stated that "NNAL decreased more over time in the e‐cigarette group ... the e‐cigarette group had significantly lower NNAL at 4 weeks (estimate = 0.54; SE = 0.23; t = 2.37; P < 0.02), but the group difference was attenuated at 8 weeks (estimate = 0.42; SE = 0.23; t = 1.83; P < 0.07)" ( ). and , which provided all participants with nicotine EC, found a reduction in NNAL over time and , which was a cross‐over trial, found NNAL decreased when using nicotine EC compared to using traditional cigarettes ( Supplemental Table 6 ). An additional two RCTs (one unclear and one low risk of bias; none reporting tobacco/vaping industry funding) compared nicotine EC versus non‐nicotine EC and found no evidence of difference, with wide CIs and moderate statistical heterogeneity (‐0.02 pmol/mg creatinine, 95% CI ‐0.45 to 0.41; I 2 = 54%; 363 participants; ). One trial (n = 90, unclear risk of bias) found non‐statistically significant lower levels of 2‐HPMA, HMPMA, PhET, and AAMA in nicotine EC arms compared to control ( ; ; ; ). A further two studies, in which all participants received nicotine EC, found reductions in 2‐HPMA and AAMA measures over time ( Supplemental Table 6 ). No difference was found in the one trial (n = 90, unclear risk of bias) evaluating CEMA ( ). One trial (n = 384, unclear risk of bias) found reductions in S‐PMA compared to control (MD ‐1371.00 nanograms, 95% CI ‐1995.23 to ‐746.88) ( ); this was consistent with the two studies in which all participants received nicotine EC that measured S‐PMA, where levels declined over time ( Supplemental Table 6 ). Of the 33 remaining measurements in single studies where all participants received a nicotine EC, 28 reduced over time and five increased ( Supplemental Table 6 ). Lung function measured a number of lung function parameters. FeNO increased more in the nicotine EC than the non‐nicotine EC group (MD 2.35, 95% CI 1.78 to 2.92; 90 participants; ). No difference was found between nicotine and non‐nicotine EC for FEV1 or FEV1/FVC ( ; ). In the comparison of nicotine EC to behavioural support only/no support, pooled results from two studies (both high risk of bias, both tobacco/vaping industry funded) found improvements in FEV1 but with moderate statistical heterogeneity and CIs including no difference (standardized mean difference (SMD) 0.15, 95% CI ‐0.01 to 0.31, I 2 = 70%; 714 participants; ). Pooled data from two studies (both high risk of bias, one reporting tobacco/vaping industry funding ( )) showed no difference in FEF (forced expiratory flow) 25‐75, with substantial levels of statistical heterogeneity (MD ‐0.06, 95% CI ‐0.18 to 0.06, I 2 = 73%; 2 studies, 555 participants; ). In a sensitivity analysis removing Walele, the result was still consistent with no difference, though the point estimate was greater in magnitude. Data from one study at high risk of bias showed no difference in PEF (peak expiratory flow 25‐75 (litres/minute)) (387 participants, MD ‐7.10, 95% CI ‐29.14 to 14.94; ). The one study reporting FEV1/FVC (327 participants, MD 1.72, 95% CI 0.74 to 2.70, high risk of bias) favoured nicotine EC ( ) ( ). , which randomized participants to EC or the QuitSmart cigarette substitute, measured change in a number of lung function parameters: direction of effect was mixed across these, with no statistically or clinically significant between‐group differences at 12 weeks ( Supplemental Table 7 ). Two studies, which provided all participants with nicotine EC, measured change in lung function over time: found an increase in peak flow, and found "no significant differences" in airway function ( Supplemental Table 7 ). Study product use Three trials (all low risk), comparing nicotine EC with non‐nicotine EC, reported the number of participants still using EC at six months or longer. Slightly more participants were still using EC in the nicotine EC arms, but CIs were wide and included no difference (RR 1.15, 95% CI 0.94 to 1.41, I 2 = 30%; 874 participants; ). Data on this outcome from single‐arm studies or RCTs where a study product (i.e. EC) was only provided in one arm can be found in a companion publication ( ) and Supplemental Table 8 . Direct comparisons between nicotine EC Note, studies reported in this section are only those where participants were randomized to different nicotine EC conditions. Comparisons based on nicotine dose Six trials provided data comparing different doses of nicotine in EC (although other studies provided a range of doses, these were not randomly assigned). Only one study provided data on abstinence; in (low risk of bias), quit rates were higher in the higher‐dose arm but the 95% CI included no difference (RR 2.50, 95% CI 0.80 to 7.77; 260 participants; ). Three of the four studies that provided data on adverse events and contributed to this comparison provided them in such a way that the studies could not be pooled. reported "no changes over time or differences between condition", and and did not compare AEs by nicotine strength (see Supplemental Table 1 ). found slightly more participants in the lower‐dose group reported AEs; however, 95% CI incorporated the null and also the possibility that more people experienced AEs in the higher‐dose arm (RR 0.90, 95% CI 0.58 to 1.40; 68 participants; ). In , no serious adverse events were reported in either arm; in , there were more events in the higher‐dose arm but CIs were wide (RR 1.51, 95% CI 0.51 to 4.42; 239 participants; ). In , no serious adverse events occurred ( Supplemental Table 2 ). Point estimates favoured higher‐dose EC and CIs excluded no difference for carbon monoxide and FEV1/FVC (MD ‐0.92, 95% CI ‐1.71 to ‐0.13; 348 participants, 3 studies) ( ), (MD 0.91, 95% CI 0.15, 1.67; 90 participants, 1 industry‐funded study) ( ). Interpretation of did not change when excluding the one study with tobacco/vaping industry funding ( ); includes only this study. There were no clear differences between arms for heart rate, blood pressure, other lung function measures, or NNAL ( ; ; ; ; ; ; all include only one study). More participants in the higher‐dose nicotine group were still using EC at six months or longer, but data were from one study and CIs were wide and included no difference (RR 1.27, 95% CI 0.95 to 1.68; 260 participants; ). In (cross‐over, comparing different doses and different devices), exhaled CO and reported nausea did not differ between devices; self‐reported dizziness was low overall but slightly higher in the higher‐dose arm. Further details can be found in Supplemental Table 1 and Supplemental Table 3 . measured a range of toxicants but did not compare these based on nicotine level assignments ( Supplemental Table 6 ). One further study, , also included comparisons based on nicotine levels (1.8% free‐base nicotine, designated by the authors as 'moderate', and 0.3% free‐base nicotine, designated by the authors as 'low'). This was a factorial trial (unpublished at the time of writing) which, in addition to e‐liquid nicotine content, also manipulated cigarette nicotine content and e‐liquid flavour availability. The authors reported no significant main effects for nicotine content on CO or CEMA, and no statistically significant interactions for these conditions. There also appear to have been no differences in the proportions of people experiencing adverse events, but the study terminated early and was likely underpowered to detect differences. Comparisons based on flavour One study randomized participants to different flavour conditions (1. tobacco flavour only; 2. a choice of flavours) and followed up participants for six months or longer ( , n = 566, industry‐funded, high risk of bias). Quit rates were lower in the choice compared to the tobacco arm, but the CIs were wide and incorporated no difference and a clinically significant increase relative to tobacco flavour (choice versus tobacco, RR 0.80, 95% CI 0.54 to 1.16; ). also reported on product use at six months or longer; again, there was no clear evidence of a difference, but the CIs were wide (choice versus tobacco, RR 1.10, 95% CI 0.86 to 1.40; ). One study ( , n = 300, high risk of bias, vaping/tobacco industry funding) randomized participants to different flavours (tobacco versus menthol) and provided SAE data in a way that could have been used to compute risk ratios, although no SAEs occurred in either arm ( ). NNAL and FEV1/FVC were lower in the tobacco flavour group but CIs were wide and included no difference (MD ‐26.10, 95% CI ‐66.73 to 14.53; ; MD ‐0.46, 95% CI ‐1.67 to 0.75; ). There was no evidence of a difference in FEV1 (MD ‐0.67, 95% CI ‐2.34 to 1.00; ). No other outcomes from this paper were eligible for inclusion in our review. , an industry‐funded, randomized, cross‐over trial, tested the effect of 10 different flavours (as well as nicotine strengths and salt versus free‐base nicotine). Only their data on AE and SAE were eligible for inclusion in our review, but analyses were not reported by flavour ( Supplemental Table 1 ; Supplemental Table 2 ). also contributed data to this comparison, with conditions being tobacco flavours only, or tobacco, fruit, dessert, and mint flavours. No significant main effects or interactions were found for flavours on the outcomes relevant to this review, namely CO and CEMA, and no difference was discernable in the occurrence of AEs. However, as noted above, the study terminated early and hence was underpowered to detect differences. More information on flavour choices across the studies in this review can be found in a companion publication ( ). Comparisons based on device type (high risk of bias) is the only study to directly compare device types (cartridge versus refillable). Outcomes eligible for this review were CO and AE. There was no difference between arms for CO, but CIs were wide (MD 0.70, 95% CI ‐4.98 to 6.38; 32 participants; ). The authors reported "no changes over time or differences between condition" for AEs (see Supplemental Table 1 ). Nicotine salt versus free‐base nicotine One study ( , unclear risk of bias, tobacco/vaping industry funding) contributed data to this comparison. Quit rates and study product use were both similar between arms (RR 1.25, 95% CI 0.85 to 1.83, n = 285; ; and RR 1.07, 95% CI 0.82 to 1.41, n = 227; , respectively). As described above, also tested salt versus free‐base nicotine, but did not provide data broken down by these characteristics for our outcomes of interest ( Supplemental Table 1 ; Supplemental Table 2 ). Non‐nicotine EC Although non‐nicotine ECs serve as a 'control group' in our primary analysis, due to their behavioural properties, they can also be considered an intervention in and of themselves. Comparisons included here are: non‐nicotine EC versus NRT; non‐nicotine EC versus behavioural support/not treatment; and non‐nicotine EC as an adjunct to NRT. All contributing data were from randomized controlled trials. None of these studies reported data on change in heart rate, blood pressure, oxygen saturation, toxicants, or lung function. Cessation When comparing non‐nicotine EC to behavioural support only, pooled results from two studies (n = 388; one at high risk of bias, neither reporting tobacco/vaping industry funding) found higher quit rates in participants randomized to non‐nicotine EC, but the confidence interval included the possibility of no difference (RR 1.63, 95% CI 0.81 to 3.25; I 2 = 0%; ). When evaluating non‐nicotine EC as an adjunct to NRT, also found higher quit rates in participants randomized to non‐nicotine EC, although again the confidence interval included no difference (RR 1.67 95% CI 0.50 to 5.53; 624 participants; ). Two studies (n = 314, neither at high risk of bias, neither reporting tobacco/vaping industry funding) compared non‐nicotine EC with NRT ( ; ). The pooled estimate showed no clear evidence of a difference in quit rates between the two interventions (RR 0.99, 95% CI 0.64 to 1.54; I 2 = 36%; ). Adverse events found a higher rate of adverse events in the non‐nicotine EC arm than in behavioural support only, with the confidence interval excluding no difference (RR 1.28, 95% CI 1.13 to 1.44; 248 participants; ). Also comparing non‐nicotine EC to behavioural support, reported that some AEs were lower in the non‐nicotine EC arm, some higher, and others reported at similar rates to the behavioural support arm (overall AE rates were not reported) ( Supplemental Table 1 ). found fewer adverse events in participants receiving non‐nicotine EC + NRT compared to NRT alone, with the confidence interval excluding no difference (RR 0.70, 95% CI 0.53 to 0.91; ). also found that fewer participants receiving non‐nicotine EC reported adverse events than those receiving NRT, with the confidence interval excluding no difference (RR 0.33, 95% CI 0.12 to 0.87; 132 participants; ). Serious adverse events Two studies reported on rates of SAEs when comparing non‐nicotine EC with behavioural support. reported no SAEs in either arm (RR not estimable), whereas found a higher rate of SAEs in the non‐nicotine EC arm than in the behavioural support‐only arm. However, confidence intervals were wide and incorporated clinically significant benefit and clinically significant harm (n = 388; RR 1.19, 95% CI 0.33 to 4.33; ). In , more SAEs occurred in the group randomized to non‐nicotine EC + NRT than in the NRT‐alone group, but the confidence interval included no difference as well as the potential for a clinically significant difference in favour of the intervention (RR 1.69, 95% CI 0.60 to 4.74; ). No SAEs were reported in either arm of (non‐nicotine EC versus NRT) ( ). Carbon monoxide One study investigating the comparison between non‐nicotine EC and NRT reported change in CO between baseline and six‐month follow‐up. The point estimate favoured NRT; however, the CI encompassed both benefit and harm of the intervention (RR 2.00, 95% CI ‐0.50 to 4.50; n = 164; ). Advice to use EC to quit Three studies did not provide EC, but instead provided participants with advice on how to use EC to stop smoking; none reported tobacco/vaping industry funding. and were short‐term studies and contributed data to supplemental tables only. However, (low risk of bias) and (high risk of bias) provided sufficient data from long‐term follow‐up to include them in meta‐analysis. In both cases, people received self‐help smoking cessation interventions with information on how to use EC to quit smoking compared to a smoking cessation intervention without the recommendation to use EC. However, specifically recruited people using both combustible cigarettes and EC (dual users) at baseline and only required participants to be combustible cigarette users at baseline. Pooled quit rates provided no clear evidence of a difference between the two types of intervention provided (RR 1.02, 95% CI 0.88 to 1.19; 2652 participants; ). In more AEs occurred in the group receiving advice to use EC to quit; however, confidence intervals included no difference (RR 1.27, 95% CI 0.72 to 2.26; 52 participants; ). No SAEs were reported, so RRs were not estimable ( ). and also reported on EC use at six‐month follow‐up. Data from suggested higher rates of long‐term EC use in the EC advice arm; however, the 95% CI also encompassed the possibility of lower long‐term EC use in the intervention arm (RR 1.77, 95% CI 0.83 to 3.79; ). reported that 64% in the targeted booklet arm, and 66% in the generic booklet arm were still using EC. The latter data could not be incorporated into a meta‐analysis due to uncertainty about the denominator used to calculate percentages. Combination therapy Nicotine EC and NRT This section covers two comparisons: studies in which all arms received NRT and participants were randomized to nicotine EC or non‐nicotine EC, and studies in which all participants received NRT and one arm was randomized to nicotine EC, in addition. All studies contributing data were randomized controlled trials. No studies in this group reported data on heart rate, blood pressure, oxygen, or toxicants. Cessation Two trials (both at high risk of bias, both testing refillable devices, neither reporting tobacco/vaping industry funding) in which all participants received NRT compared nicotine EC to non‐nicotine EC. The pooled results favoured nicotine EC, with the CI excluding no difference (RR 1.77, 95% CI 1.07 to 2.94; I 2 = 0%; 1039 participants; ). Three studies (two high risk of bias, one unclear risk; two refillable, one cartridge; none reporting tobacco/vaping industry funding) also compared nicotine EC + NRT to NRT alone. Pooling results from all three studies resulted in high statistical heterogeneity, precluding meta‐analysis (I 2 = 83%). This heterogeneity was driven by the study of a cartridge device (RR 1.00, 95% CI 0.64 to 1.55, 1712 participants) ( ); historically, cartridge devices have had poorer nicotine delivery than refillables. Once this study was removed, heterogeneity disappeared (I 2 = 0%), but only two studies remained. In these two studies, pooled results showed more people quit in the refillable nicotine EC + NRT arm than in the NRT alone arm (RR 3.53, 95% CI 1.93 to 6.44; 980 participants; ). In two of these studies, participants in both groups received nicotine patches but, in , participants in the NRT‐only arm also received a short‐acting form of NRT. Adverse events Three trials in which nicotine ECs were compared to non‐nicotine ECs (both with NRT as an adjunct) reported data on AEs. reported results combined across groups but noted "no significant differences by treatment group" ( Supplemental Table 1 ). Pooled data from the other two studies (one reporting tobacco/vaping industry funding; ) also showed no clear evidence of difference (RR 1.11, 95% CI 0.93 to 1.32, I 2 = 0%; 677 participants; ). As expected due to the low statistical heterogeneity, the two contributing study results had similar interpretations and so removing due to industry funding had no impact. The three trials comparing nicotine EC + NRT to NRT alone that contributed data to this outcome were all at high risk of bias; none reported tobacco/vaping industry funding. Pooled results showed no evidence of a difference in AEs between arms, but with moderate statistical heterogeneity (RR 0.96, 95% CI 0.83 to 1.11; I 2 = 64%; 1984 participants; ). A further trial currently has only very limited information available from a conference abstract and trial registry ( ). This study appears to have trial arms that will allow comparison between nicotine EC + NRT and NRT alone. Data on AEs are reported in the trial registry; however, the way this is currently reported makes it hard to incorporate the data into our meta‐analysis; therefore, data available thus far are reported in Supplemental Table 1 . Serious adverse events Pooled data from two studies (one high risk, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine EC with non‐nicotine EC as adjuncts to NRT showed fewer SAEs in the nicotine EC group than in the non‐nicotine EC group, but the CI included no difference (RR 0.66, 95% CI 0.38 to 1.14; I 2 = 0%; 1069 participants; ). Removing the study with industry funding ( ) had no effect on interpretation. Four studies (all high risk of bias; none reporting tobacco/vaping industry funding) provided data on SAEs and compared nicotine EC + NRT to NRT alone. The pooled estimate favoured the NRT‐alone group, but the CI was wide and included no difference (RR 1.26, 95% CI 0.46 to 3.42: I 2 = 0; 2245 participants; ). As noted above, there is currently very limited data available for . SAE data available thus far are reported in Supplemental Table 2 . Carbon monoxide (which compared nicotine EC + NRT, non‐nicotine EC + NRT, and NRT alone) measured change in CO levels but did not report data in a way that could be pooled. CO declined over time, with the greatest reduction seen in the nicotine EC group (see Supplemental Table 3 ). Pooled data from two studies (one high risk of bias, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine and non‐nicotine EC as adjuncts to NRT found a greater reduction in CO in the nicotine EC group, but the CI included no clear evidence of a clinically significant difference (MD ‐2.58 ppm, 95% CI ‐5.21 to 0.05, I 2 = 77%; 70 participants; ) between groups and there was substantial statistical heterogeneity. We have pooled these studies despite the high I 2 as the individual study effects both showed a benefit of nicotine EC with the difference being in the magnitude of effect. Removing the study at high risk of bias ( ) left only , with the following effect estimate: RR ‐9.10, 95% CI ‐15.83 to ‐2.37; whereas removing the study with industry funding ( ) left only , with the following effect estimate (RR ‐1.40, 95% CI ‐4.26 to 1.46). Lung function , which compared nicotine EC to non‐nicotine EC, in which both groups received NRT, found no between‐group differences in FeNO, FEV1, or FVC ( ; ; ); confidence intervals were wide for all outcomes. Study product use In , at six months, 40% of the patches‐only arm (n = 52) were still using patches and, in the patches + nicotine EC group (n = 317), 22% were using patches only, 45% were using EC only, and 11% were using both patch and EC. In the patches + non‐nicotine EC group (n = 308), 29% were still using patches, 36% were using EC only, and 13% were using both patches and EC. In , there was no difference between arms in product use, but only nine participants contributed data (RR 1.25, 95% CI 0.29 to 5.53; ). Nicotine EC and varenicline One study, (high risk of bias, 92 participants), evaluated nicotine EC and varenicline compared to varenicline alone. The study terminated early due to varenicline supply issues (an international recall), and the only data eligible for inclusion in this review related to AEs and SAEs. There was no evidence of a difference in AEs, though CIs were wide (RR 1.18, 95% CI 0.84 to 1.67; 92 participants; ), and no SAEs occurred ( ). Results from network meta‐analyses We used fixed‐effect models for all three outcomes. For the cessation and SAE outcomes there was no indication of heterogeneity or inconsistency. The models fit well. The difference between the mean residual deviance and the number of data points was, at most, 2.2 (see Supplemental Table 9 for comparisons across models). Node‐splitting models raised no concerns over local inconsistency, resulting in P values greater than 0.05. For the AE outcome, there was inconsistency in the treatment effect comparing no e‐cigarettes or pharmacotherapy to non‐nicotine e‐cigarettes, as indicated by a node‐splitting model. Only one trial, , contributed direct evidence to this comparison. In this trial, the percentage of patients experiencing at least one AE was large, at 87%. This was the highest percentage in a very wide range (9% to 87%, mean 44%, standard deviation 24%). Percentages that are close to 100 can result in large effect sizes even when the absolute differences between the treatment groups are comparatively small. We believe that the inconsistency was caused by there being only one trial providing direct evidence, which had a high level of AEs, especially in the non‐nicotine e‐cigarette arm at 93%. Overall, results from NMAs were consistent with those from pairwise analyses. They are summarized below, and further details on all can be found in the relevant figures and supplemental files. The comparator for all odds ratios was the reference treatment: no e‐cigarettes or pharmacotherapy. Cessation See for the network map of the cessation outcome. Point estimates were highest for nicotine EC combined with NRT and non‐nicotine EC combined with NRT, though 95% credibility intervals (CrI) were wide for both nodes and overlapped with those of nicotine EC. Overall, data were consistent with those from pairwise meta‐analyses, showing higher quit rates with nicotine EC than with non‐nicotine EC or NRT. Risk ratios (RRs) and corresponding credibility intervals (CrI) for each node are as follows (and illustrated in ): Nicotine EC: RR 1.95, 95% CrI 1.66 to 2.31 Nicotine EC plus single‐form NRT: RR 4.18, 95% CrI 2.20 to 8.55 Non‐nicotine EC: RR 1.34, 95% CrI 0.99 to 1.80 Non‐nicotine EC plus single‐form NRT: RR 2.35, 95% CrI 1.06 to 5.37 Combined NRT: RR 1.07, 95% CrI 0.73 to 1.54 Single‐form NRT: RR 1.37, 95% CrI 1.04 to 1.80 Advice on using EC: RR 1.02, 95% CrI 0.88 to 1.19 When removing studies at high risk of bias, there were insufficient data to generate a point estimate for non‐nicotine EC combined with NRT. The risk ratio of single‐form NRT against no e‐cigarettes or pharmacotherapy changed from 1.37 to 2.25, and became significant, where it had been borderline‐significant in the main analysis. All other interpretations remained unchanged ( Supplemental Table 10 ). Results were not sensitive to the exclusion of studies with tobacco or vaping industry funding ( Supplemental Table 10 ). Adverse events See for the network map of the AE outcome. As can be seen in , CrIs overlapped for all nodes. All interventions tested showed an increase in AEs (non‐serious) compared to control (no e‐cigarette or pharmaceutical intervention), with CrIs excluding no difference for nicotine ECs, non‐nicotine ECs, and single‐form NRTs. The RRs and corresponding CrI for each node are as follows (and illustrated in ): Nicotine EC: RR 1.19, 95% CrI 1.12 to 1.27 Nicotine EC plus single‐form NRT: RR 1.17, 95% CrI 0.92 to 1.48 Non‐nicotine EC: RR 1.20, 95% CrI 1.11 to 1.30 Non‐nicotine EC plus single‐form NRT: RR 1.02, 95% CrI 0.77 to 1.35 Combined NRT: RR 1.07, 95% CrI 0.87 to 1.31 Single‐form NRT: RR 1.24, 95% CrI 1.03 to 1.50 Sensitivity analyses removing studies at high risk of bias and removing studies with tobacco or vaping industry funding did not affect interpretation of the results ( Supplemental Table 10 ). Serious adverse events See for the network map of the SAE outcome. As illustrated in , CrIs were wide, overlapped, and included the possibility of no difference for all nodes, though point estimates were lowest for NRT. Only the point estimate for non‐nicotine EC combined with NRT was consistent with an increase in SAEs compared to the control condition, but here CrI were very wide and also encompassed a clinically significant reduction in SAEs in those receiving the intervention. The RRs and corresponding CrI for each node are as follows (and illustrated in ): Nicotine EC: RR 0.98, 95% CrI 0.72 to 1.35 Nicotine EC plus single‐form NRT: RR 1.01, 95% CrI 0.30 to 4.12 Non‐nicotine EC: RR 1.01, 95% CrI 0.53 to 1.86 Non‐nicotine EC plus single‐form NRT: RR 1.43, 95% CrI 0.43 to 5.78 Combined NRT: RR 0.64, 95% CrI 0.36 to 1.10 Single‐form NRT: RR 0.71, 95% CrI 0.35 to 1.40 When removing studies at high risk of bias, only nicotine EC, non‐nicotine EC, combined NRT, and single‐form NRT had sufficient data to generate point estimates; these were consistent with those from the main model ( Supplemental Table 10 ). When removing studies with tobacco or vaping industry funding, there was still sufficient data for all nodes to be displayed; results were consistent with those from the main analysis ( Supplemental Table 10 ). 

Results of the search For this update, our bibliographic database searches identified 624 non‐duplicate records (See for PRISMA flow diagram). We screened all records and retrieved the full‐text papers of 34 potentially relevant articles. After screening and checking the full texts, we included 26 records, representing two new studies for this update ( ; ), 11 new articles linked to studies already identified, 11 new ongoing studies, and two records awaiting classification (see ). Secondary study reports, commentaries, and correspondence relating to included studies are linked to studies in the reference section. Included studies In total, we include 90 studies, with two new included studies and 88 studies included in the previous version of this review. Key features of these included studies are summarized below. Further details on each included study can be found in the table. Participants The 90 included studies represented 29,044 participants. Thirty‐nine studies were conducted in the USA, 20 were conducted in the UK, nine in Italy, five in Australia, four in Greece, two each in New Zealand, Switzerland, and Canada, and one each in Belgium, Ireland, the Netherlands, Poland, the Republic of Korea, South Africa, and Turkey. All studies were conducted in adults who smoked. Twenty‐six studies exclusively recruited participants who were not motivated to quit smoking, and 45 studies exclusively recruited participants motivated to quit; motivation was not specified for the other studies. Thirty‐two studies recruited from specific population groups; these included nine studies that recruited participants based on physical health condition (heart attack, cancer, HIV, periodontitis, awaiting surgery, smoking‐related chronic disease), five studies that recruited participants with serious mental illness, four studies that recruited participants on treatment or having recently completed treatment for alcohol or other drug use, and three studies in dual users of EC and conventional cigarettes. Two studies recruited people accessing homeless centres or using supported temporary accommodation, and a further two recruited specifically within socially deprived areas. One study each recruited: people aged 55 or older, young adults, people who self‐identified as African‐American, pregnant women, people who had recently made a failed attempt to quit smoking, black and Latino participants, and people attending the emergency department. Interventions and comparators Three studies recruited dual users of combustible cigarettes and EC at baseline, and instructed them to continue using their own EC devices ( ; ; ). One study recruited users of combustible cigarettes only and provided information on using EC, but did not provide them with EC ( ). The remaining studies all provided some form of nicotine EC. In two studies where nicotine ECs were provided on their own, nicotine levels were judged to be so low as to be clinically comparable to non‐nicotine EC ( ; ); we include these studies in non‐nicotine EC comparisons. Twelve studies compared nicotine EC with non‐nicotine EC, 26 studies compared nicotine EC to behavioural support only or to no support, and 20 studies compared nicotine EC to NRT. Six studies compared high‐ versus low‐nicotine EC devices ( ; ; ; ; ), four studies included comparisons based on flavours ( ; ; ; ), two studies directly compared device types ( ; ), and two studies directly compared a freebase nicotine to a salt‐based nicotine device ( ; ). Results from these studies are reported by comparison in . Further details on the intervention and comparator groups (where applicable) for each study can be found in the table. Where reported in the primary research publications, details of the devices tested can also be found in the table. Of the studies with sufficient data with which to judge, 31 used cartridge devices, 34 used refillable devices, four used both types, 10 used a pod device, and the remainder did not report device type. Outcomes Of the 90 included studies: 40 reported data on abstinence at six months or longer; 64 reported data on adverse events; 46 reported data on serious adverse events; 49 reported data on carbon monoxide; 12 reported data on heart rate; 14 reported data on blood pressure; 4 reported data on blood oxygen saturation; 16 reported data on at least one known toxin/carcinogen; 8 reported data on at least one measure of lung function; 20 reported data on study product use at six months or longer. One study measured safety outcomes but did not report them in the text available at the time of writing (they may be forthcoming); hence, this study currently does not contribute any data to this review ( ). Study types Forty‐nine studies were RCTs, 28 of which contributed to cessation analyses. Eight studies used randomized cross‐over designs, and the remainder were uncontrolled cohort studies. Funding Of the 83 studies that reported funding information, 68 had no tobacco or EC industry funding or support. Below, we detail the industry funding from the 15 studies that report tobacco or EC industry funding or support. An asterisk (*) has been added after the study name for all studies that received tobacco or EC industry funding. Where these studies contributed to meta‐analyses, we tested whether results were sensitive to their inclusion, and took account of this in our results and conclusions. Fifteen of the included studies reported support from the tobacco or vaping industry, or that authors had received tobacco or vaping industry support outside of the study being conducted. Six of these studies received funding from the Lega Italiana AntiFumo ( ; ; ; ; ; ). and also received free “Categoria” EC kits from the Arbi Group Srl (Milano, Italy). received free JUUL EC from the manufacturer, PAX Labs (became JUUL Labs in 2017). Altria Group (formerly, Philip Morris Companies) acquired a 35% stake in JUUL Labs on 20 December 2018; the study was completed before Altria invested in JUUL. thank FlavourArt (Oleggio, NO, Italy; www.flavourart.it ), an EC flavour company. was funded by Philip Morris Product Société Anonyme. was funded by Altria Client Services LLC. Altria is the parent company of Philip Morris USA (producer of Marlboro cigarettes), John Middleton, Inc., U.S. Smokeless Tobacco Company, Inc., and Philip Morris Capital Corporation. was funded by RAI Services Company. The parent company is Reynolds American. Reynolds American manufacture and market a variety of tobacco products, including cigarettes (Newport, Camel, Pall Mall, Kent, Doral, Misty, Capri, and Natural American Spirit brands), EC (Vuse brand), and moist snuff (Grizzly and Kodiak brands). was funded entirely by Fontem US LLC, a subsidiary of Imperial Brands PLC. was funded by NJOY, Inc., Scottsdale, AZ. Funded by the EC/alternative nicotine products industry. was funded by the National Institute on Drug Abuse (NIDA). However, the lead author declared research support from Foundation for a Smoke‐Free World (which has links to the tobacco industry), Philip Morris International, Altria, Embera Neuro Therapeutics, Inc., Otsuka Pharmaceutical, JUUL Labs, consulting with Revive pharmaceuticals, and consulting and patent purchase agreements with Philip Morris International. was funded by eGo e‐cigarette packs by Twisp. was funded and supported by Fontem Ventures B.V. Imperial Brands plc (Imperial Tobacco plc) is the parent company of Fontem Ventures B.V., the manufacturer of the EC prototype used in their study. was funded by Juul Labs, Inc. Excluded studies We list 32 studies excluded at full‐text stage, along with reasons for exclusion, in the table. After the reference being a duplicate, the most common reason for exclusion was that studies did not include outcomes relevant to this review. 

For this update, our bibliographic database searches identified 624 non‐duplicate records (See for PRISMA flow diagram). We screened all records and retrieved the full‐text papers of 34 potentially relevant articles. After screening and checking the full texts, we included 26 records, representing two new studies for this update ( ; ), 11 new articles linked to studies already identified, 11 new ongoing studies, and two records awaiting classification (see ). Secondary study reports, commentaries, and correspondence relating to included studies are linked to studies in the reference section. 

In total, we include 90 studies, with two new included studies and 88 studies included in the previous version of this review. Key features of these included studies are summarized below. Further details on each included study can be found in the table. 

The 90 included studies represented 29,044 participants. Thirty‐nine studies were conducted in the USA, 20 were conducted in the UK, nine in Italy, five in Australia, four in Greece, two each in New Zealand, Switzerland, and Canada, and one each in Belgium, Ireland, the Netherlands, Poland, the Republic of Korea, South Africa, and Turkey. All studies were conducted in adults who smoked. Twenty‐six studies exclusively recruited participants who were not motivated to quit smoking, and 45 studies exclusively recruited participants motivated to quit; motivation was not specified for the other studies. Thirty‐two studies recruited from specific population groups; these included nine studies that recruited participants based on physical health condition (heart attack, cancer, HIV, periodontitis, awaiting surgery, smoking‐related chronic disease), five studies that recruited participants with serious mental illness, four studies that recruited participants on treatment or having recently completed treatment for alcohol or other drug use, and three studies in dual users of EC and conventional cigarettes. Two studies recruited people accessing homeless centres or using supported temporary accommodation, and a further two recruited specifically within socially deprived areas. One study each recruited: people aged 55 or older, young adults, people who self‐identified as African‐American, pregnant women, people who had recently made a failed attempt to quit smoking, black and Latino participants, and people attending the emergency department. 

Three studies recruited dual users of combustible cigarettes and EC at baseline, and instructed them to continue using their own EC devices ( ; ; ). One study recruited users of combustible cigarettes only and provided information on using EC, but did not provide them with EC ( ). The remaining studies all provided some form of nicotine EC. In two studies where nicotine ECs were provided on their own, nicotine levels were judged to be so low as to be clinically comparable to non‐nicotine EC ( ; ); we include these studies in non‐nicotine EC comparisons. Twelve studies compared nicotine EC with non‐nicotine EC, 26 studies compared nicotine EC to behavioural support only or to no support, and 20 studies compared nicotine EC to NRT. Six studies compared high‐ versus low‐nicotine EC devices ( ; ; ; ; ), four studies included comparisons based on flavours ( ; ; ; ), two studies directly compared device types ( ; ), and two studies directly compared a freebase nicotine to a salt‐based nicotine device ( ; ). Results from these studies are reported by comparison in . Further details on the intervention and comparator groups (where applicable) for each study can be found in the table. Where reported in the primary research publications, details of the devices tested can also be found in the table. Of the studies with sufficient data with which to judge, 31 used cartridge devices, 34 used refillable devices, four used both types, 10 used a pod device, and the remainder did not report device type. 

Of the 90 included studies: 40 reported data on abstinence at six months or longer; 64 reported data on adverse events; 46 reported data on serious adverse events; 49 reported data on carbon monoxide; 12 reported data on heart rate; 14 reported data on blood pressure; 4 reported data on blood oxygen saturation; 16 reported data on at least one known toxin/carcinogen; 8 reported data on at least one measure of lung function; 20 reported data on study product use at six months or longer. One study measured safety outcomes but did not report them in the text available at the time of writing (they may be forthcoming); hence, this study currently does not contribute any data to this review ( ). 

Forty‐nine studies were RCTs, 28 of which contributed to cessation analyses. Eight studies used randomized cross‐over designs, and the remainder were uncontrolled cohort studies. 

Of the 83 studies that reported funding information, 68 had no tobacco or EC industry funding or support. Below, we detail the industry funding from the 15 studies that report tobacco or EC industry funding or support. An asterisk (*) has been added after the study name for all studies that received tobacco or EC industry funding. Where these studies contributed to meta‐analyses, we tested whether results were sensitive to their inclusion, and took account of this in our results and conclusions. Fifteen of the included studies reported support from the tobacco or vaping industry, or that authors had received tobacco or vaping industry support outside of the study being conducted. Six of these studies received funding from the Lega Italiana AntiFumo ( ; ; ; ; ; ). and also received free “Categoria” EC kits from the Arbi Group Srl (Milano, Italy). received free JUUL EC from the manufacturer, PAX Labs (became JUUL Labs in 2017). Altria Group (formerly, Philip Morris Companies) acquired a 35% stake in JUUL Labs on 20 December 2018; the study was completed before Altria invested in JUUL. thank FlavourArt (Oleggio, NO, Italy; www.flavourart.it ), an EC flavour company. was funded by Philip Morris Product Société Anonyme. was funded by Altria Client Services LLC. Altria is the parent company of Philip Morris USA (producer of Marlboro cigarettes), John Middleton, Inc., U.S. Smokeless Tobacco Company, Inc., and Philip Morris Capital Corporation. was funded by RAI Services Company. The parent company is Reynolds American. Reynolds American manufacture and market a variety of tobacco products, including cigarettes (Newport, Camel, Pall Mall, Kent, Doral, Misty, Capri, and Natural American Spirit brands), EC (Vuse brand), and moist snuff (Grizzly and Kodiak brands). was funded entirely by Fontem US LLC, a subsidiary of Imperial Brands PLC. was funded by NJOY, Inc., Scottsdale, AZ. Funded by the EC/alternative nicotine products industry. was funded by the National Institute on Drug Abuse (NIDA). However, the lead author declared research support from Foundation for a Smoke‐Free World (which has links to the tobacco industry), Philip Morris International, Altria, Embera Neuro Therapeutics, Inc., Otsuka Pharmaceutical, JUUL Labs, consulting with Revive pharmaceuticals, and consulting and patent purchase agreements with Philip Morris International. was funded by eGo e‐cigarette packs by Twisp. was funded and supported by Fontem Ventures B.V. Imperial Brands plc (Imperial Tobacco plc) is the parent company of Fontem Ventures B.V., the manufacturer of the EC prototype used in their study. was funded by Juul Labs, Inc. 

We list 32 studies excluded at full‐text stage, along with reasons for exclusion, in the table. After the reference being a duplicate, the most common reason for exclusion was that studies did not include outcomes relevant to this review. 

Overall, we judged 10 studies to be at low risk of bias ( ; ; ; ; ; ; ; ; ; ), 19 to be at unclear risk, and the remaining 61 at high risk of bias (this includes the non‐randomized studies, which we deemed to be at high risk due to lack of randomization). Details of the risk of bias judgements for each domain of each included study can be found in the table. and illustrate our judgements across the included studies. Allocation We judged 28 studies to be at high risk of selection bias; for the majority of cases, this is because the study was not randomized. We rated a pilot cluster‐randomized trial to be at high risk, as randomization was not carried out as intended for pragmatic reasons ( ). We judged 31 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 In all, we assessed 65 studies for performance bias and detection bias. For performance bias, we rated 31 to be at low risk, 24 at high risk, and 10 at unclear risk. For detection bias, we rated 46 as low risk, 11 as high risk, and eight at unclear risk. 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 that we thought there was a high risk of bias being introduced. We judged the rest to be at unclear risk, or ineligible for this domain due to single‐arm design. Incomplete outcome data We judged most studies (66 out of 90) to be at low risk of attrition bias. We rated 10 studies with substantial loss to follow‐up as being at high risk of attrition bias. The remainder did not provide sufficient data on which to judge, and hence we judged them to be at unclear risk. Selective reporting Of the 90 studies, we considered 46 at low risk of reporting bias, as all prespecified or expected outcomes were reported. We rated 10 as being at high risk, as data were not available as specified in the original protocols (note in some cases these are recent studies, and judgement on these may change as more publications emerge). 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 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. We considered four further studies to be at unclear risk in this domain. 

We judged 28 studies to be at high risk of selection bias; for the majority of cases, this is because the study was not randomized. We rated a pilot cluster‐randomized trial to be at high risk, as randomization was not carried out as intended for pragmatic reasons ( ). We judged 31 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. 

In all, we assessed 65 studies for performance bias and detection bias. For performance bias, we rated 31 to be at low risk, 24 at high risk, and 10 at unclear risk. For detection bias, we rated 46 as low risk, 11 as high risk, and eight at unclear risk. 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 that we thought there was a high risk of bias being introduced. We judged the rest to be at unclear risk, or ineligible for this domain due to single‐arm design. 

We judged most studies (66 out of 90) to be at low risk of attrition bias. We rated 10 studies with substantial loss to follow‐up as being at high risk of attrition bias. The remainder did not provide sufficient data on which to judge, and hence we judged them to be at unclear risk. 

Of the 90 studies, we considered 46 at low risk of reporting bias, as all prespecified or expected outcomes were reported. We rated 10 as being at high risk, as data were not available as specified in the original protocols (note in some cases these are recent studies, and judgement on these may change as more publications emerge). We judged the rest to be at unclear risk, due to insufficient information with which to make a judgement. 

We considered 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. We considered four further studies to be at unclear risk in this domain. 

See: ; ; Data on our outcomes of interest are summarized below and in our , , and . Due to the volume of data available, some relevant information is hosted on a companion repository; these data are open‐access and can be found at http://dx.doi.org/10.5287/ora-jnvxbp7qr . They are referred to below as supplemental tables. Forest plots are available through 'analysis' links; for some outcomes, benefit is plotted on the right; for others it is plotted on the left. This is due to direction of effect, e.g. an increase in cessation is a benefit, whereas an increase in a carcinogen is not. Direct comparisons between nicotine EC and other pharmacotherapies Comparisons reported here include nicotine ECs versus NRT, and nicotine ECs versus varenicline. Only randomized controlled trials contributed data. Cessation Pooled data from seven studies (two cartridges, four refillable, one pod), five of which were rated at low risk of bias ( ; ; ; ; ) and two as unclear ( ; ), showed increased quit rates in people randomized to nicotine EC when compared to NRT (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.30 to 1.93; I 2 = 0%; 2544 participants; ). The certainty of evidence is high and has not been downgraded. One study included in this analysis, , was conducted in pregnant women. There was no evidence of a subgroup difference between this study and studies in participants not selected on the basis of pregnancy (P = 0.87, I 2 for subgroup differences = 0%). Follow‐up time was based on end of pregnancy, and our analysis included only those participants with follow‐up of at least six months. Results were not sensitive to the exclusion of the one study that received industry funding ( ); when this study was removed, the point estimate increased to 1.72, but the CIs remained consistent with those from the main analysis. One study, , available as a conference presentation only and considered at high risk of bias due to inconsistencies in the data reported and an unclear definition of abstinence, favoured varenicline for quitting compared to nicotine EC (cartridge) (RR 0.31, 95% CI 0.11 to 0.82; 54 participants; ). Adverse events Pooled data from five studies (four considered at low risk of bias ( ; ; ; ) and one at unclear risk ( )) showed that there is probably no difference in the number of participants reporting adverse events (AEs) between nicotine EC and NRT arms (RR 1.03, 95% CI 0.91 to 1.17; I 2 = 0%; 2052 participants; ). The certainty of evidence is moderate, downgraded one level due to imprecision; the CIs were consistent with benefit and harm. None of the studies contributing data to this analysis received funding from the vaping or tobacco industries. and did not contribute data to this analysis due to the way in which events were recorded. In 's prespecified adverse reactions of interest, nausea was more frequent in the NRT group, throat/mouth irritation was more frequent in the nicotine EC group, and there was little difference in other reactions (see Supplemental Table 1 for more detail). recruited participants with chronic obstructive pulmonary disease (COPD) and reported "a trend towards decreased dyspnoea and COPD symptoms ... in the EC arm compared to the NRT arm", but did not provide further detail. In , reports of sleep disorders were evenly distributed between groups, and nausea was more common in the varenicline arm than in the nicotine EC arm (see Supplemental Table 1 for more detail). Serious adverse events Six studies (five at low risk of bias ( ; ; ; ; ) and one at unclear risk ( )) comparing nicotine ECs with NRT provided data on serious adverse events. In some studies, no events occurred. Pooled results showed that there may be a slight increase in serious adverse events in the nicotine EC arms compared to NRT. There is low certainty of evidence for this outcome, downgraded two levels due to imprecision; there were fewer than 300 events and wide CIs incorporating no difference, as well as clinically significant harm and clinically significant benefit (RR 1.20, 95% CI 0.90 to 1.60; I 2 = 32%; 2761 participants; ). None of the studies contributing data to this analysis received funding from the vaping or tobacco industries. In (conducted in pregnant women), the authors reported no evidence of a difference in birth outcomes overall. However, low birthweight (< 2500 g) was less frequent in the EC than the NRT arm (14.8% versus 9.6%; RR 0.65, 95% CI 0.47 to 0.90). No SAEs occurred in ( ). Carbon monoxide (CO) Pooled data from four studies ( ; ; ; ), none of which received tobacco/vaping industry funding and none of which were considered at high risk of bias, comparing nicotine EC with NRT, found some evidence that CO levels decreased more in those randomized to nicotine EC; however, the CIs incorporated the possibility of no between‐group difference (mean difference (MD) ‐1.81 ppm, 95% CI ‐3.64 to 0.01; I 2 = 0%; 357 participants; ). A fourth, small study ( ; n = 11) was reported as a conference abstract and hence had limited data available. At three weeks, this study showed that both EC and NRT groups had "significantly reduced" CO, but between‐group differences were not reported. Heart rate, blood pressure, and oxygen saturation Pooled data from two studies (166 participants; one study judged to be at unclear risk of bias ( ) and one at low risk ( ), neither in receipt of vaping/tobacco industry funding) showed no clear evidence of a clinically meaningful difference in heart rate (MD 0.53 bpm, 95% CI ‐1.76 to 2.83; I 2 = 0%; ), systolic blood pressure (MD ‐1.62, 95% CI ‐3.59 to 0.36; I 2 = 0%; ), or blood oxygen saturation (MD ‐0.14, 95% CI ‐0.59 to 0.30; I 2 = 0%; ), although confidence intervals were wide. Toxicants Only (unclear risk of bias, no tobacco/vaping industry funding, n = 111) contributed data for these outcomes. For 3‐HPMA, 2‐HPMA, and HMPMA, point estimates favoured EC but CIs included no difference ( ; ; ). There was no evidence of a difference for NNAL (nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐ butanol) but CIs were again wide ( ). For PheT, CEMA, and AAMA ( ; ; ), point estimates favoured NRT but CIs included no difference. Lung function and (no tobacco/vaping industry funding) measured change in FEV1 (forced expiratory volume) and FEV1/FVC (forced vital capacity) (both low risk of bias; n = 81). High statistical heterogeneity (I 2 = 89%) precluded pooling for FEV1 ( ). The point estimate for favoured EC and for favoured NRT; for , the CIs included no difference. There was no evidence of a difference for FEV1/FVC, but there was moderate unexplained statistical heterogeneity and, again, CIs were wide (MD ‐0.16%, 95% CI ‐1.83 to 1.50; I 2 = 51%; ). For PEF (peak expiratory flow) only one study contributed to this analysis ( , n = 55). The point estimate favoured NRT but CIs were wide and included no difference (MD ‐3.00, 95% CI ‐27.09 to 21.09) ( ). Study product use Five studies (one, , with vaping industry funding) reported study product use at six months or longer, but statistical heterogeneity precluded pooling (I 2 = 95%). Whereas and found no difference between the EC and NRT arms, in the other three studies, people in the EC arm were more likely to continue to use the study product (EC) than those in the NRT arm ( ). A companion publication explored long‐term rates in more detail ( ). Nicotine EC versus other tobacco/nicotine products used for stopping combustible tobacco use Currently, the only comparison reported here is nicotine EC compared to heated tobacco. One study ( ; n = 220, tobacco/vaping industry‐funded), considered at high risk of bias due to a lack of blinding alongside strong participant product preferences, reported on AEs, SAEs, expired carbon monoxide (eCO), and VO 2 max as a measure of lung function, heart rate, and blood pressure at 12 weeks follow‐up. The effect estimate demonstrated no clear evidence of a difference in AEs between the nicotine EC and heated tobacco group (RR 0.86, 95% CI 0.68 to 1.10; 220 participants; ). There were no SAEs reported in either arm, so an effect estimate could not be calculated for this outcome ( ). There was no clear evidence of a between‐group difference in eCO levels (MD 1.90, 95% CI ‐0.71 to 4.51; 217 participants; ), or VO 2 max (MD 6.20, 95% CI ‐2.01 to 14.41; 211 participants; ). The following was reported on heart rate and blood pressure and is reported in Supplemental Tables 4 & 5 : “No significant changes in the mean resting heart rate, blood pressure, and BMI during product use were observed between and within study groups.” Nicotine EC alone or versus control Comparisons reported here include nicotine EC versus non‐nicotine EC, and nicotine EC compared to behavioural support only or to no support. In this section, we also reported results from studies in which all participants received nicotine EC (cohort studies and randomized studies that did not differ across arms in EC provision, device generation, or nicotine content). Cessation Randomized controlled trials At six months or longer, quit rates were higher in nicotine EC groups than in comparator groups. Compared to EC without nicotine (placebo EC), pooled results showed nicotine EC probably produced higher quit rates (RR 1.46, 95% CI 1.09 to 1.96; I 2 = 4%; 5 studies of cartridge and 1 study of refillable devices, 1613 participants; ). There is moderate‐certainty evidence that nicotine EC probably increases quit rates compared to non‐nicotine EC. The certainty has been downgraded one level due to imprecision; there are fewer than 300 events overall. This has not been downgraded for risk of bias: removing the one study considered at high risk of bias increased the direction of the effect in favour of nicotine EC. The interpretation of the effect remained the same when we removed the one study at high risk of bias ( ) and when we removed the one study with tobacco/vaping industry funding ( ). The effect may be more pronounced when comparing nicotine EC to behavioural support only or to no support (RR 1.96, 95% CI 1.66 to 2.32; I 2 = 0%; 11 studies (5 refillable, 3 cartridge, 3 pod), 6819 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (the certainty of the evidence was low, downgraded two levels). One of the studies contributing data to this comparison reported tobacco/vaping industry funding ( ). The removal of this study in a sensitivity analysis did not change the interpretation of the effect ( ). (pod device) measured cessation at six months in the intervention group only, using self‐report. As they did not measure cessation at six months in the comparator group, we could not include these data in our meta‐analysis. At six months, 23 (24%) intervention participants were exclusively using EC and 10 (10.4%) reported using neither EC nor combustible cigarettes (making a combined quit rate of 34.4% in the intervention arm at six months). Data from other studies Ten studies provided all participants with nicotine EC and assessed abstinence at six months or longer ( ; 2 refillable, 6 cartridges, 1 pod, 1 not specified). The highest proportion of quitters at six months was observed in (cartridge), in which all participants (n = 48) used EC and 18 used additional pharmacotherapy; 44% of participants were abstinent at six months. The lowest quit rates were seen in , where 14% of participants were abstinent at 12 months, and , where 5% of participants were abstinent at 12 months. In the former, participants were unmotivated to quit smoking and, in the latter, motivation was unclear and participants were recruited from a socially deprived area on the basis of receiving a free nicotine EC. Adverse events Randomized controlled trials Pooled data from five studies (none at high risk of bias, one reporting tobacco/vaping industry funding) showed that there is probably no difference in the number of participants experiencing adverse events when comparing nicotine EC to non‐nicotine EC (RR 1.01, 95% CI 0.91 to 1.11; I 2 = 0%; 840 participants; ); this is moderate‐certainty evidence, downgraded one level due to imprecision (fewer than 300 events overall). Removing the one study linked to industry funding had no effect on the interpretation of the result ( ). When comparing nicotine EC to behavioural support only or to no support, evidence suggests more people in the groups randomized to nicotine EC experience adverse events (RR 1.18, 95% CI 1.10 to 1.27; I 2 = 6%; 6 studies, 2351 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (low‐certainty evidence downgraded two levels due to risk of bias). Interpretation of the outcome was not sensitive to the inclusion of the one study with tobacco/vaping industry support ( ). A further 11 randomized controlled trials provided adverse event or related data for this comparison, but could not be included in the meta‐analysis due to the way in which data were presented (see Supplemental Table 1 ). In the studies comparing nicotine EC to non‐nicotine EC, one found similar event rates across arms ( ), and two reported more events in the nicotine EC arms ( ; ). In a further study comparing nicotine to non‐nicotine EC, events were reported by type, with an increase in some seen in the nicotine group and an increase in others seen in the non‐nicotine group ( ). In the seven studies comparing nicotine EC to behavioural support only or traditional cigarettes, found an increase in sinonasal symptoms in the group receiving nicotine EC compared to behavioural support only, and found that throat irritation, cough, and dry mouth increased in the e‐cigarette group relative to the traditional cigarette group. By contrast, found a reduction in respiratory symptoms in the EC compared to the traditional cigarette group, and found no clear difference in the number of participants reporting dry cough and throat and mouth irritation between the EC arm and the referral information arm. found an increase in throat irritation, palpitations, and dizziness in the EC group, but decreases in cough, headache, nausea, dry mouth, shortness of breath, and stomach pain. did not break down AEs by group but reported that three participants experienced a non‐serious adverse event definitely related to the study product. reported no statistically significant between‐group difference in AEs. Data from other studies Eighteen studies provided all participants with nicotine EC and assessed adverse events at one week or longer and one RCT reported AEs reported in the nicotine EC group only (see Supplemental Table 1 ). In the eight studies that tracked event rates over time, six showed adverse events reducing over time ( ; ; ; ; ; ). showed no change. The most commonly reported adverse events were throat/mouth irritation, headache, cough, and nausea. Serious adverse events Randomized controlled trials Nine studies compared nicotine EC with non‐nicotine EC and reported data on SAEs; in five of these (including one tobacco/vaping industry study, ), no events occurred, so results could not contribute to the meta‐analysis, although they are included in the forest plots for descriptive purposes. In the four studies (three low risk of bias, one unclear) where events occurred, there may be little to no difference between groups, but CIs were wide (RR 1.00, 95% CI 0.56 to 1.79; I 2 = 0%; 1412 participants; ). The evidence was of low certainty; this was downgraded two levels due to imprecision: the confidence intervals encompassed clinically significant harm as well as clinically significant benefit, and there were fewer than 300 events overall. One of these studies had links to industry funding ( ); removing it from the analysis changed the effect estimate to 0.95 but the 95% CI remained wide (0.52 to 1.72) and so the interpretation of the result remained the same. Twelve studies compared nicotine EC with behavioural support only or no support and reported data on SAEs; in five of these, no events occurred. Pooled results from the seven studies in which events occurred showed very uncertain evidence about the difference between arms, but CIs were wide (RR 0.93, 95% CI 0.68 to 1.28; I 2 = 0%; 4561 participants; ). Here the certainty of evidence was very low; this was downgraded two levels due to risk of bias (lack of blinding and differential support between arms, judged to be at high risk of bias). Removing the one study with tobacco/vaping industry support did not affect the interpretation of the results ( ). In a study in people experiencing homelessness ( ), SAEs were not reported, but authors reported that four to seven participants in the usual care arm and five to seven participants in the nicotine EC arm visited Accident & Emergency services at a hospital. The authors reported that these visits were unrelated to study treatment and were assessed to gather data for future economic evaluation. Further detail can be found in Supplemental Table 2 . Data from other studies Nine studies provided all participants with nicotine EC and reported SAEs at a week or longer ( Supplemental Table 2 ). In six of these, authors reported that no SAEs occurred ( ; ; ; ; ; ; ). In (19 participants), one death occurred (no further detail provided). (50 participants) recruited participants from mental health settings; five SAEs were recorded during the study, all of which were psychiatric hospitalizations. None were considered related to study treatment. Carbon monoxide Randomized controlled trials High statistical heterogeneity (I 2 = 80%) precluded pooling CO data from the six trials (n = 677, none considered at high risk of bias) comparing nicotine EC with non‐nicotine EC ( ). Point estimates from four studies (one reporting links to industry funding; ) favoured nicotine EC and from two (one reporting industry funding; ) favoured non‐nicotine EC, but in all cases CIs were consistent with no clinically meaningful difference. Three further randomized studies measured CO levels in those assigned to nicotine EC and those assigned to non‐nicotine EC, but did not present data in a way that could be pooled: did not compare data by group; reported no between‐group differences; and found a slightly higher CO reading in those using nicotine EC, but the clinical and statistical significance of this difference was not clear (see Supplemental Table 3 for more detail). These data were from all study participants based on group randomized, not on subsequent EC or cigarette use. Pooled data from 11 studies comparing nicotine EC to behavioural support alone or to no support resulted in a high I 2 value (89%); thus, pooled results were not presented here (see for individual study data). None of these studies reported tobacco/vaping industry funding. A funnel plot did not show asymmetry ( ). Heterogeneity was primarily driven by magnitude rather than direction of effect, with results in 10 of 11 studies favouring nicotine EC. Three further trials reported data that could not be included in a meta‐analysis. compared nicotine EC to cigarettes and found that CO levels declined in the EC group and remained similar to baseline in the cigarette group. instructed baseline dual users to spend periods only using EC or only using traditional cigarettes; CO measured during sole EC use was lower than baseline and lower than during cigarette‐only periods. Further details can be found in Supplemental Table 3 . Data from other studies Twenty studies provided all participants with nicotine EC and reported data on CO at one week or longer. In the 19 studies that presented change over time, CO declined from baseline, although in CO levels were equivalent to baseline again at 24 weeks, and in a decline was observed in people who quit smoking or reduced cigarette consumption by at least half, but not in those who continued smoking at least half as many cigarettes as they had from baseline. Heart rate Randomized controlled trials One RCT ( , unclear risk of bias, n = 141) provided data on heart rate and compared nicotine EC with non‐nicotine EC; there was no evidence of a clinically significant between‐group difference (MD ‐2.3, 95% CI ‐6.10 to 1.50) ( ). This was comparable with findings from the one RCT ( , unclear risk of bias, n = 90) comparing nicotine EC with no pharmacotherapy, which also found no evidence of a clinically significant difference (MD 1.17, 95% CI ‐4.17 to 6.61) ( ). A further three RCTs provided data on heart rate that could not be used to calculate effect estimates. compared nicotine to non‐nicotine EC and found no difference in heart rate between arms; compared a nicotine EC with a traditional cigarette and reported "no clinically significant changes", and found decreases in both the EC and QuitSmart cigarette substitute groups, with the decrease being slightly greater in the latter group. See Supplemental Table 4 for further information. Data from other studies Six studies in which all participants received a nicotine EC also reported data on heart rate; for five, changes were minimal and directions of effect were mixed, and for (n = 40), the rate reduced by 9 bpm at 12 weeks (see Supplemental Table 4 ). Blood pressure found no evidence of a difference in the change in systolic blood pressure (BP) between nicotine EC and non‐nicotine EC arms (unclear risk of bias, 141 participants, MD 1.2, 95% CI ‐3.99 to 6.39; ). Three studies (two at high risk of bias, one at unclear risk of bias, none reporting tobacco/vaping industry funding) compared nicotine EC to behavioural support only and reported data on systolic blood pressure; there was a small difference favouring the EC arms (MD ‐2.3, 95% CI ‐3.9 to ‐0.7, I 2 = 24%; 298 participants; ). Three further RCTs measured change in blood pressure but presented results in such a way that they could not be pooled. compared nicotine EC and non‐nicotine EC and combined data from both groups; BP declined over time. Compared to a QuitSmart cigarette substitute, found that EC led to a greater reduction in BP. found "no clinically significant changes" when comparing nicotine EC to a conventional cigarette at two weeks. Five studies, which provided nicotine EC to all participants, reported change in blood pressure; results were clinically insignificant except for in which systolic BP reduced by 12 (from 134 to 122) at 12 weeks (see Supplemental Table 5 for further details on all studies reporting this outcome). Oxygen saturation found no evidence of a difference in blood oxygen saturation when comparing nicotine EC to cigarettes (89 participants, MD 0.20, 95% CI ‐0.30 to 0.70; ). , a short‐term pre‐post study, which measured outcomes after two weeks of EC use, found that people who smoked and switched to ECs had significant improvement in blood oxygen saturation (96.2% (standard deviation (SD) 1.8) to 97.5% (SD 1.3); 1.3% increase, 95% CI 0.6 to 2.1; P = 0.002). Toxicants Unless stated otherwise, all randomized controlled trials measuring these outcomes compared nicotine EC with no pharmacotherapy. Two trials measured change in 3‐HPMA (one at high risk of bias). In both, the point estimate favoured the EC arm, but pooling was precluded due to differences in measurement methods ( ). Five further studies, in which all participants were given nicotine EC, measured 3‐HPMA; all found reductions over time ( Supplemental Table 6 ). Five trials measured change in NNAL and provided sufficient data to calculate summary effects (four at high risk of bias; ). Three of the five studies found results favouring nicotine EC, but the final two indicated no difference; statistical heterogeneity was high (I 2 = 96%), so pooled results were not presented. One study comparing nicotine EC to no treatment described their findings narratively and stated that "NNAL decreased more over time in the e‐cigarette group ... the e‐cigarette group had significantly lower NNAL at 4 weeks (estimate = 0.54; SE = 0.23; t = 2.37; P < 0.02), but the group difference was attenuated at 8 weeks (estimate = 0.42; SE = 0.23; t = 1.83; P < 0.07)" ( ). and , which provided all participants with nicotine EC, found a reduction in NNAL over time and , which was a cross‐over trial, found NNAL decreased when using nicotine EC compared to using traditional cigarettes ( Supplemental Table 6 ). An additional two RCTs (one unclear and one low risk of bias; none reporting tobacco/vaping industry funding) compared nicotine EC versus non‐nicotine EC and found no evidence of difference, with wide CIs and moderate statistical heterogeneity (‐0.02 pmol/mg creatinine, 95% CI ‐0.45 to 0.41; I 2 = 54%; 363 participants; ). One trial (n = 90, unclear risk of bias) found non‐statistically significant lower levels of 2‐HPMA, HMPMA, PhET, and AAMA in nicotine EC arms compared to control ( ; ; ; ). A further two studies, in which all participants received nicotine EC, found reductions in 2‐HPMA and AAMA measures over time ( Supplemental Table 6 ). No difference was found in the one trial (n = 90, unclear risk of bias) evaluating CEMA ( ). One trial (n = 384, unclear risk of bias) found reductions in S‐PMA compared to control (MD ‐1371.00 nanograms, 95% CI ‐1995.23 to ‐746.88) ( ); this was consistent with the two studies in which all participants received nicotine EC that measured S‐PMA, where levels declined over time ( Supplemental Table 6 ). Of the 33 remaining measurements in single studies where all participants received a nicotine EC, 28 reduced over time and five increased ( Supplemental Table 6 ). Lung function measured a number of lung function parameters. FeNO increased more in the nicotine EC than the non‐nicotine EC group (MD 2.35, 95% CI 1.78 to 2.92; 90 participants; ). No difference was found between nicotine and non‐nicotine EC for FEV1 or FEV1/FVC ( ; ). In the comparison of nicotine EC to behavioural support only/no support, pooled results from two studies (both high risk of bias, both tobacco/vaping industry funded) found improvements in FEV1 but with moderate statistical heterogeneity and CIs including no difference (standardized mean difference (SMD) 0.15, 95% CI ‐0.01 to 0.31, I 2 = 70%; 714 participants; ). Pooled data from two studies (both high risk of bias, one reporting tobacco/vaping industry funding ( )) showed no difference in FEF (forced expiratory flow) 25‐75, with substantial levels of statistical heterogeneity (MD ‐0.06, 95% CI ‐0.18 to 0.06, I 2 = 73%; 2 studies, 555 participants; ). In a sensitivity analysis removing Walele, the result was still consistent with no difference, though the point estimate was greater in magnitude. Data from one study at high risk of bias showed no difference in PEF (peak expiratory flow 25‐75 (litres/minute)) (387 participants, MD ‐7.10, 95% CI ‐29.14 to 14.94; ). The one study reporting FEV1/FVC (327 participants, MD 1.72, 95% CI 0.74 to 2.70, high risk of bias) favoured nicotine EC ( ) ( ). , which randomized participants to EC or the QuitSmart cigarette substitute, measured change in a number of lung function parameters: direction of effect was mixed across these, with no statistically or clinically significant between‐group differences at 12 weeks ( Supplemental Table 7 ). Two studies, which provided all participants with nicotine EC, measured change in lung function over time: found an increase in peak flow, and found "no significant differences" in airway function ( Supplemental Table 7 ). Study product use Three trials (all low risk), comparing nicotine EC with non‐nicotine EC, reported the number of participants still using EC at six months or longer. Slightly more participants were still using EC in the nicotine EC arms, but CIs were wide and included no difference (RR 1.15, 95% CI 0.94 to 1.41, I 2 = 30%; 874 participants; ). Data on this outcome from single‐arm studies or RCTs where a study product (i.e. EC) was only provided in one arm can be found in a companion publication ( ) and Supplemental Table 8 . Direct comparisons between nicotine EC Note, studies reported in this section are only those where participants were randomized to different nicotine EC conditions. Comparisons based on nicotine dose Six trials provided data comparing different doses of nicotine in EC (although other studies provided a range of doses, these were not randomly assigned). Only one study provided data on abstinence; in (low risk of bias), quit rates were higher in the higher‐dose arm but the 95% CI included no difference (RR 2.50, 95% CI 0.80 to 7.77; 260 participants; ). Three of the four studies that provided data on adverse events and contributed to this comparison provided them in such a way that the studies could not be pooled. reported "no changes over time or differences between condition", and and did not compare AEs by nicotine strength (see Supplemental Table 1 ). found slightly more participants in the lower‐dose group reported AEs; however, 95% CI incorporated the null and also the possibility that more people experienced AEs in the higher‐dose arm (RR 0.90, 95% CI 0.58 to 1.40; 68 participants; ). In , no serious adverse events were reported in either arm; in , there were more events in the higher‐dose arm but CIs were wide (RR 1.51, 95% CI 0.51 to 4.42; 239 participants; ). In , no serious adverse events occurred ( Supplemental Table 2 ). Point estimates favoured higher‐dose EC and CIs excluded no difference for carbon monoxide and FEV1/FVC (MD ‐0.92, 95% CI ‐1.71 to ‐0.13; 348 participants, 3 studies) ( ), (MD 0.91, 95% CI 0.15, 1.67; 90 participants, 1 industry‐funded study) ( ). Interpretation of did not change when excluding the one study with tobacco/vaping industry funding ( ); includes only this study. There were no clear differences between arms for heart rate, blood pressure, other lung function measures, or NNAL ( ; ; ; ; ; ; all include only one study). More participants in the higher‐dose nicotine group were still using EC at six months or longer, but data were from one study and CIs were wide and included no difference (RR 1.27, 95% CI 0.95 to 1.68; 260 participants; ). In (cross‐over, comparing different doses and different devices), exhaled CO and reported nausea did not differ between devices; self‐reported dizziness was low overall but slightly higher in the higher‐dose arm. Further details can be found in Supplemental Table 1 and Supplemental Table 3 . measured a range of toxicants but did not compare these based on nicotine level assignments ( Supplemental Table 6 ). One further study, , also included comparisons based on nicotine levels (1.8% free‐base nicotine, designated by the authors as 'moderate', and 0.3% free‐base nicotine, designated by the authors as 'low'). This was a factorial trial (unpublished at the time of writing) which, in addition to e‐liquid nicotine content, also manipulated cigarette nicotine content and e‐liquid flavour availability. The authors reported no significant main effects for nicotine content on CO or CEMA, and no statistically significant interactions for these conditions. There also appear to have been no differences in the proportions of people experiencing adverse events, but the study terminated early and was likely underpowered to detect differences. Comparisons based on flavour One study randomized participants to different flavour conditions (1. tobacco flavour only; 2. a choice of flavours) and followed up participants for six months or longer ( , n = 566, industry‐funded, high risk of bias). Quit rates were lower in the choice compared to the tobacco arm, but the CIs were wide and incorporated no difference and a clinically significant increase relative to tobacco flavour (choice versus tobacco, RR 0.80, 95% CI 0.54 to 1.16; ). also reported on product use at six months or longer; again, there was no clear evidence of a difference, but the CIs were wide (choice versus tobacco, RR 1.10, 95% CI 0.86 to 1.40; ). One study ( , n = 300, high risk of bias, vaping/tobacco industry funding) randomized participants to different flavours (tobacco versus menthol) and provided SAE data in a way that could have been used to compute risk ratios, although no SAEs occurred in either arm ( ). NNAL and FEV1/FVC were lower in the tobacco flavour group but CIs were wide and included no difference (MD ‐26.10, 95% CI ‐66.73 to 14.53; ; MD ‐0.46, 95% CI ‐1.67 to 0.75; ). There was no evidence of a difference in FEV1 (MD ‐0.67, 95% CI ‐2.34 to 1.00; ). No other outcomes from this paper were eligible for inclusion in our review. , an industry‐funded, randomized, cross‐over trial, tested the effect of 10 different flavours (as well as nicotine strengths and salt versus free‐base nicotine). Only their data on AE and SAE were eligible for inclusion in our review, but analyses were not reported by flavour ( Supplemental Table 1 ; Supplemental Table 2 ). also contributed data to this comparison, with conditions being tobacco flavours only, or tobacco, fruit, dessert, and mint flavours. No significant main effects or interactions were found for flavours on the outcomes relevant to this review, namely CO and CEMA, and no difference was discernable in the occurrence of AEs. However, as noted above, the study terminated early and hence was underpowered to detect differences. More information on flavour choices across the studies in this review can be found in a companion publication ( ). Comparisons based on device type (high risk of bias) is the only study to directly compare device types (cartridge versus refillable). Outcomes eligible for this review were CO and AE. There was no difference between arms for CO, but CIs were wide (MD 0.70, 95% CI ‐4.98 to 6.38; 32 participants; ). The authors reported "no changes over time or differences between condition" for AEs (see Supplemental Table 1 ). Nicotine salt versus free‐base nicotine One study ( , unclear risk of bias, tobacco/vaping industry funding) contributed data to this comparison. Quit rates and study product use were both similar between arms (RR 1.25, 95% CI 0.85 to 1.83, n = 285; ; and RR 1.07, 95% CI 0.82 to 1.41, n = 227; , respectively). As described above, also tested salt versus free‐base nicotine, but did not provide data broken down by these characteristics for our outcomes of interest ( Supplemental Table 1 ; Supplemental Table 2 ). Non‐nicotine EC Although non‐nicotine ECs serve as a 'control group' in our primary analysis, due to their behavioural properties, they can also be considered an intervention in and of themselves. Comparisons included here are: non‐nicotine EC versus NRT; non‐nicotine EC versus behavioural support/not treatment; and non‐nicotine EC as an adjunct to NRT. All contributing data were from randomized controlled trials. None of these studies reported data on change in heart rate, blood pressure, oxygen saturation, toxicants, or lung function. Cessation When comparing non‐nicotine EC to behavioural support only, pooled results from two studies (n = 388; one at high risk of bias, neither reporting tobacco/vaping industry funding) found higher quit rates in participants randomized to non‐nicotine EC, but the confidence interval included the possibility of no difference (RR 1.63, 95% CI 0.81 to 3.25; I 2 = 0%; ). When evaluating non‐nicotine EC as an adjunct to NRT, also found higher quit rates in participants randomized to non‐nicotine EC, although again the confidence interval included no difference (RR 1.67 95% CI 0.50 to 5.53; 624 participants; ). Two studies (n = 314, neither at high risk of bias, neither reporting tobacco/vaping industry funding) compared non‐nicotine EC with NRT ( ; ). The pooled estimate showed no clear evidence of a difference in quit rates between the two interventions (RR 0.99, 95% CI 0.64 to 1.54; I 2 = 36%; ). Adverse events found a higher rate of adverse events in the non‐nicotine EC arm than in behavioural support only, with the confidence interval excluding no difference (RR 1.28, 95% CI 1.13 to 1.44; 248 participants; ). Also comparing non‐nicotine EC to behavioural support, reported that some AEs were lower in the non‐nicotine EC arm, some higher, and others reported at similar rates to the behavioural support arm (overall AE rates were not reported) ( Supplemental Table 1 ). found fewer adverse events in participants receiving non‐nicotine EC + NRT compared to NRT alone, with the confidence interval excluding no difference (RR 0.70, 95% CI 0.53 to 0.91; ). also found that fewer participants receiving non‐nicotine EC reported adverse events than those receiving NRT, with the confidence interval excluding no difference (RR 0.33, 95% CI 0.12 to 0.87; 132 participants; ). Serious adverse events Two studies reported on rates of SAEs when comparing non‐nicotine EC with behavioural support. reported no SAEs in either arm (RR not estimable), whereas found a higher rate of SAEs in the non‐nicotine EC arm than in the behavioural support‐only arm. However, confidence intervals were wide and incorporated clinically significant benefit and clinically significant harm (n = 388; RR 1.19, 95% CI 0.33 to 4.33; ). In , more SAEs occurred in the group randomized to non‐nicotine EC + NRT than in the NRT‐alone group, but the confidence interval included no difference as well as the potential for a clinically significant difference in favour of the intervention (RR 1.69, 95% CI 0.60 to 4.74; ). No SAEs were reported in either arm of (non‐nicotine EC versus NRT) ( ). Carbon monoxide One study investigating the comparison between non‐nicotine EC and NRT reported change in CO between baseline and six‐month follow‐up. The point estimate favoured NRT; however, the CI encompassed both benefit and harm of the intervention (RR 2.00, 95% CI ‐0.50 to 4.50; n = 164; ). Advice to use EC to quit Three studies did not provide EC, but instead provided participants with advice on how to use EC to stop smoking; none reported tobacco/vaping industry funding. and were short‐term studies and contributed data to supplemental tables only. However, (low risk of bias) and (high risk of bias) provided sufficient data from long‐term follow‐up to include them in meta‐analysis. In both cases, people received self‐help smoking cessation interventions with information on how to use EC to quit smoking compared to a smoking cessation intervention without the recommendation to use EC. However, specifically recruited people using both combustible cigarettes and EC (dual users) at baseline and only required participants to be combustible cigarette users at baseline. Pooled quit rates provided no clear evidence of a difference between the two types of intervention provided (RR 1.02, 95% CI 0.88 to 1.19; 2652 participants; ). In more AEs occurred in the group receiving advice to use EC to quit; however, confidence intervals included no difference (RR 1.27, 95% CI 0.72 to 2.26; 52 participants; ). No SAEs were reported, so RRs were not estimable ( ). and also reported on EC use at six‐month follow‐up. Data from suggested higher rates of long‐term EC use in the EC advice arm; however, the 95% CI also encompassed the possibility of lower long‐term EC use in the intervention arm (RR 1.77, 95% CI 0.83 to 3.79; ). reported that 64% in the targeted booklet arm, and 66% in the generic booklet arm were still using EC. The latter data could not be incorporated into a meta‐analysis due to uncertainty about the denominator used to calculate percentages. Combination therapy Nicotine EC and NRT This section covers two comparisons: studies in which all arms received NRT and participants were randomized to nicotine EC or non‐nicotine EC, and studies in which all participants received NRT and one arm was randomized to nicotine EC, in addition. All studies contributing data were randomized controlled trials. No studies in this group reported data on heart rate, blood pressure, oxygen, or toxicants. Cessation Two trials (both at high risk of bias, both testing refillable devices, neither reporting tobacco/vaping industry funding) in which all participants received NRT compared nicotine EC to non‐nicotine EC. The pooled results favoured nicotine EC, with the CI excluding no difference (RR 1.77, 95% CI 1.07 to 2.94; I 2 = 0%; 1039 participants; ). Three studies (two high risk of bias, one unclear risk; two refillable, one cartridge; none reporting tobacco/vaping industry funding) also compared nicotine EC + NRT to NRT alone. Pooling results from all three studies resulted in high statistical heterogeneity, precluding meta‐analysis (I 2 = 83%). This heterogeneity was driven by the study of a cartridge device (RR 1.00, 95% CI 0.64 to 1.55, 1712 participants) ( ); historically, cartridge devices have had poorer nicotine delivery than refillables. Once this study was removed, heterogeneity disappeared (I 2 = 0%), but only two studies remained. In these two studies, pooled results showed more people quit in the refillable nicotine EC + NRT arm than in the NRT alone arm (RR 3.53, 95% CI 1.93 to 6.44; 980 participants; ). In two of these studies, participants in both groups received nicotine patches but, in , participants in the NRT‐only arm also received a short‐acting form of NRT. Adverse events Three trials in which nicotine ECs were compared to non‐nicotine ECs (both with NRT as an adjunct) reported data on AEs. reported results combined across groups but noted "no significant differences by treatment group" ( Supplemental Table 1 ). Pooled data from the other two studies (one reporting tobacco/vaping industry funding; ) also showed no clear evidence of difference (RR 1.11, 95% CI 0.93 to 1.32, I 2 = 0%; 677 participants; ). As expected due to the low statistical heterogeneity, the two contributing study results had similar interpretations and so removing due to industry funding had no impact. The three trials comparing nicotine EC + NRT to NRT alone that contributed data to this outcome were all at high risk of bias; none reported tobacco/vaping industry funding. Pooled results showed no evidence of a difference in AEs between arms, but with moderate statistical heterogeneity (RR 0.96, 95% CI 0.83 to 1.11; I 2 = 64%; 1984 participants; ). A further trial currently has only very limited information available from a conference abstract and trial registry ( ). This study appears to have trial arms that will allow comparison between nicotine EC + NRT and NRT alone. Data on AEs are reported in the trial registry; however, the way this is currently reported makes it hard to incorporate the data into our meta‐analysis; therefore, data available thus far are reported in Supplemental Table 1 . Serious adverse events Pooled data from two studies (one high risk, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine EC with non‐nicotine EC as adjuncts to NRT showed fewer SAEs in the nicotine EC group than in the non‐nicotine EC group, but the CI included no difference (RR 0.66, 95% CI 0.38 to 1.14; I 2 = 0%; 1069 participants; ). Removing the study with industry funding ( ) had no effect on interpretation. Four studies (all high risk of bias; none reporting tobacco/vaping industry funding) provided data on SAEs and compared nicotine EC + NRT to NRT alone. The pooled estimate favoured the NRT‐alone group, but the CI was wide and included no difference (RR 1.26, 95% CI 0.46 to 3.42: I 2 = 0; 2245 participants; ). As noted above, there is currently very limited data available for . SAE data available thus far are reported in Supplemental Table 2 . Carbon monoxide (which compared nicotine EC + NRT, non‐nicotine EC + NRT, and NRT alone) measured change in CO levels but did not report data in a way that could be pooled. CO declined over time, with the greatest reduction seen in the nicotine EC group (see Supplemental Table 3 ). Pooled data from two studies (one high risk of bias, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine and non‐nicotine EC as adjuncts to NRT found a greater reduction in CO in the nicotine EC group, but the CI included no clear evidence of a clinically significant difference (MD ‐2.58 ppm, 95% CI ‐5.21 to 0.05, I 2 = 77%; 70 participants; ) between groups and there was substantial statistical heterogeneity. We have pooled these studies despite the high I 2 as the individual study effects both showed a benefit of nicotine EC with the difference being in the magnitude of effect. Removing the study at high risk of bias ( ) left only , with the following effect estimate: RR ‐9.10, 95% CI ‐15.83 to ‐2.37; whereas removing the study with industry funding ( ) left only , with the following effect estimate (RR ‐1.40, 95% CI ‐4.26 to 1.46). Lung function , which compared nicotine EC to non‐nicotine EC, in which both groups received NRT, found no between‐group differences in FeNO, FEV1, or FVC ( ; ; ); confidence intervals were wide for all outcomes. Study product use In , at six months, 40% of the patches‐only arm (n = 52) were still using patches and, in the patches + nicotine EC group (n = 317), 22% were using patches only, 45% were using EC only, and 11% were using both patch and EC. In the patches + non‐nicotine EC group (n = 308), 29% were still using patches, 36% were using EC only, and 13% were using both patches and EC. In , there was no difference between arms in product use, but only nine participants contributed data (RR 1.25, 95% CI 0.29 to 5.53; ). Nicotine EC and varenicline One study, (high risk of bias, 92 participants), evaluated nicotine EC and varenicline compared to varenicline alone. The study terminated early due to varenicline supply issues (an international recall), and the only data eligible for inclusion in this review related to AEs and SAEs. There was no evidence of a difference in AEs, though CIs were wide (RR 1.18, 95% CI 0.84 to 1.67; 92 participants; ), and no SAEs occurred ( ). Results from network meta‐analyses We used fixed‐effect models for all three outcomes. For the cessation and SAE outcomes there was no indication of heterogeneity or inconsistency. The models fit well. The difference between the mean residual deviance and the number of data points was, at most, 2.2 (see Supplemental Table 9 for comparisons across models). Node‐splitting models raised no concerns over local inconsistency, resulting in P values greater than 0.05. For the AE outcome, there was inconsistency in the treatment effect comparing no e‐cigarettes or pharmacotherapy to non‐nicotine e‐cigarettes, as indicated by a node‐splitting model. Only one trial, , contributed direct evidence to this comparison. In this trial, the percentage of patients experiencing at least one AE was large, at 87%. This was the highest percentage in a very wide range (9% to 87%, mean 44%, standard deviation 24%). Percentages that are close to 100 can result in large effect sizes even when the absolute differences between the treatment groups are comparatively small. We believe that the inconsistency was caused by there being only one trial providing direct evidence, which had a high level of AEs, especially in the non‐nicotine e‐cigarette arm at 93%. Overall, results from NMAs were consistent with those from pairwise analyses. They are summarized below, and further details on all can be found in the relevant figures and supplemental files. The comparator for all odds ratios was the reference treatment: no e‐cigarettes or pharmacotherapy. Cessation See for the network map of the cessation outcome. Point estimates were highest for nicotine EC combined with NRT and non‐nicotine EC combined with NRT, though 95% credibility intervals (CrI) were wide for both nodes and overlapped with those of nicotine EC. Overall, data were consistent with those from pairwise meta‐analyses, showing higher quit rates with nicotine EC than with non‐nicotine EC or NRT. Risk ratios (RRs) and corresponding credibility intervals (CrI) for each node are as follows (and illustrated in ): Nicotine EC: RR 1.95, 95% CrI 1.66 to 2.31 Nicotine EC plus single‐form NRT: RR 4.18, 95% CrI 2.20 to 8.55 Non‐nicotine EC: RR 1.34, 95% CrI 0.99 to 1.80 Non‐nicotine EC plus single‐form NRT: RR 2.35, 95% CrI 1.06 to 5.37 Combined NRT: RR 1.07, 95% CrI 0.73 to 1.54 Single‐form NRT: RR 1.37, 95% CrI 1.04 to 1.80 Advice on using EC: RR 1.02, 95% CrI 0.88 to 1.19 When removing studies at high risk of bias, there were insufficient data to generate a point estimate for non‐nicotine EC combined with NRT. The risk ratio of single‐form NRT against no e‐cigarettes or pharmacotherapy changed from 1.37 to 2.25, and became significant, where it had been borderline‐significant in the main analysis. All other interpretations remained unchanged ( Supplemental Table 10 ). Results were not sensitive to the exclusion of studies with tobacco or vaping industry funding ( Supplemental Table 10 ). Adverse events See for the network map of the AE outcome. As can be seen in , CrIs overlapped for all nodes. All interventions tested showed an increase in AEs (non‐serious) compared to control (no e‐cigarette or pharmaceutical intervention), with CrIs excluding no difference for nicotine ECs, non‐nicotine ECs, and single‐form NRTs. The RRs and corresponding CrI for each node are as follows (and illustrated in ): Nicotine EC: RR 1.19, 95% CrI 1.12 to 1.27 Nicotine EC plus single‐form NRT: RR 1.17, 95% CrI 0.92 to 1.48 Non‐nicotine EC: RR 1.20, 95% CrI 1.11 to 1.30 Non‐nicotine EC plus single‐form NRT: RR 1.02, 95% CrI 0.77 to 1.35 Combined NRT: RR 1.07, 95% CrI 0.87 to 1.31 Single‐form NRT: RR 1.24, 95% CrI 1.03 to 1.50 Sensitivity analyses removing studies at high risk of bias and removing studies with tobacco or vaping industry funding did not affect interpretation of the results ( Supplemental Table 10 ). Serious adverse events See for the network map of the SAE outcome. As illustrated in , CrIs were wide, overlapped, and included the possibility of no difference for all nodes, though point estimates were lowest for NRT. Only the point estimate for non‐nicotine EC combined with NRT was consistent with an increase in SAEs compared to the control condition, but here CrI were very wide and also encompassed a clinically significant reduction in SAEs in those receiving the intervention. The RRs and corresponding CrI for each node are as follows (and illustrated in ): Nicotine EC: RR 0.98, 95% CrI 0.72 to 1.35 Nicotine EC plus single‐form NRT: RR 1.01, 95% CrI 0.30 to 4.12 Non‐nicotine EC: RR 1.01, 95% CrI 0.53 to 1.86 Non‐nicotine EC plus single‐form NRT: RR 1.43, 95% CrI 0.43 to 5.78 Combined NRT: RR 0.64, 95% CrI 0.36 to 1.10 Single‐form NRT: RR 0.71, 95% CrI 0.35 to 1.40 When removing studies at high risk of bias, only nicotine EC, non‐nicotine EC, combined NRT, and single‐form NRT had sufficient data to generate point estimates; these were consistent with those from the main model ( Supplemental Table 10 ). When removing studies with tobacco or vaping industry funding, there was still sufficient data for all nodes to be displayed; results were consistent with those from the main analysis ( Supplemental Table 10 ). 

Comparisons reported here include nicotine ECs versus NRT, and nicotine ECs versus varenicline. Only randomized controlled trials contributed data. Cessation Pooled data from seven studies (two cartridges, four refillable, one pod), five of which were rated at low risk of bias ( ; ; ; ; ) and two as unclear ( ; ), showed increased quit rates in people randomized to nicotine EC when compared to NRT (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.30 to 1.93; I 2 = 0%; 2544 participants; ). The certainty of evidence is high and has not been downgraded. One study included in this analysis, , was conducted in pregnant women. There was no evidence of a subgroup difference between this study and studies in participants not selected on the basis of pregnancy (P = 0.87, I 2 for subgroup differences = 0%). Follow‐up time was based on end of pregnancy, and our analysis included only those participants with follow‐up of at least six months. Results were not sensitive to the exclusion of the one study that received industry funding ( ); when this study was removed, the point estimate increased to 1.72, but the CIs remained consistent with those from the main analysis. One study, , available as a conference presentation only and considered at high risk of bias due to inconsistencies in the data reported and an unclear definition of abstinence, favoured varenicline for quitting compared to nicotine EC (cartridge) (RR 0.31, 95% CI 0.11 to 0.82; 54 participants; ). Adverse events Pooled data from five studies (four considered at low risk of bias ( ; ; ; ) and one at unclear risk ( )) showed that there is probably no difference in the number of participants reporting adverse events (AEs) between nicotine EC and NRT arms (RR 1.03, 95% CI 0.91 to 1.17; I 2 = 0%; 2052 participants; ). The certainty of evidence is moderate, downgraded one level due to imprecision; the CIs were consistent with benefit and harm. None of the studies contributing data to this analysis received funding from the vaping or tobacco industries. and did not contribute data to this analysis due to the way in which events were recorded. In 's prespecified adverse reactions of interest, nausea was more frequent in the NRT group, throat/mouth irritation was more frequent in the nicotine EC group, and there was little difference in other reactions (see Supplemental Table 1 for more detail). recruited participants with chronic obstructive pulmonary disease (COPD) and reported "a trend towards decreased dyspnoea and COPD symptoms ... in the EC arm compared to the NRT arm", but did not provide further detail. In , reports of sleep disorders were evenly distributed between groups, and nausea was more common in the varenicline arm than in the nicotine EC arm (see Supplemental Table 1 for more detail). Serious adverse events Six studies (five at low risk of bias ( ; ; ; ; ) and one at unclear risk ( )) comparing nicotine ECs with NRT provided data on serious adverse events. In some studies, no events occurred. Pooled results showed that there may be a slight increase in serious adverse events in the nicotine EC arms compared to NRT. There is low certainty of evidence for this outcome, downgraded two levels due to imprecision; there were fewer than 300 events and wide CIs incorporating no difference, as well as clinically significant harm and clinically significant benefit (RR 1.20, 95% CI 0.90 to 1.60; I 2 = 32%; 2761 participants; ). None of the studies contributing data to this analysis received funding from the vaping or tobacco industries. In (conducted in pregnant women), the authors reported no evidence of a difference in birth outcomes overall. However, low birthweight (< 2500 g) was less frequent in the EC than the NRT arm (14.8% versus 9.6%; RR 0.65, 95% CI 0.47 to 0.90). No SAEs occurred in ( ). Carbon monoxide (CO) Pooled data from four studies ( ; ; ; ), none of which received tobacco/vaping industry funding and none of which were considered at high risk of bias, comparing nicotine EC with NRT, found some evidence that CO levels decreased more in those randomized to nicotine EC; however, the CIs incorporated the possibility of no between‐group difference (mean difference (MD) ‐1.81 ppm, 95% CI ‐3.64 to 0.01; I 2 = 0%; 357 participants; ). A fourth, small study ( ; n = 11) was reported as a conference abstract and hence had limited data available. At three weeks, this study showed that both EC and NRT groups had "significantly reduced" CO, but between‐group differences were not reported. Heart rate, blood pressure, and oxygen saturation Pooled data from two studies (166 participants; one study judged to be at unclear risk of bias ( ) and one at low risk ( ), neither in receipt of vaping/tobacco industry funding) showed no clear evidence of a clinically meaningful difference in heart rate (MD 0.53 bpm, 95% CI ‐1.76 to 2.83; I 2 = 0%; ), systolic blood pressure (MD ‐1.62, 95% CI ‐3.59 to 0.36; I 2 = 0%; ), or blood oxygen saturation (MD ‐0.14, 95% CI ‐0.59 to 0.30; I 2 = 0%; ), although confidence intervals were wide. Toxicants Only (unclear risk of bias, no tobacco/vaping industry funding, n = 111) contributed data for these outcomes. For 3‐HPMA, 2‐HPMA, and HMPMA, point estimates favoured EC but CIs included no difference ( ; ; ). There was no evidence of a difference for NNAL (nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐ butanol) but CIs were again wide ( ). For PheT, CEMA, and AAMA ( ; ; ), point estimates favoured NRT but CIs included no difference. Lung function and (no tobacco/vaping industry funding) measured change in FEV1 (forced expiratory volume) and FEV1/FVC (forced vital capacity) (both low risk of bias; n = 81). High statistical heterogeneity (I 2 = 89%) precluded pooling for FEV1 ( ). The point estimate for favoured EC and for favoured NRT; for , the CIs included no difference. There was no evidence of a difference for FEV1/FVC, but there was moderate unexplained statistical heterogeneity and, again, CIs were wide (MD ‐0.16%, 95% CI ‐1.83 to 1.50; I 2 = 51%; ). For PEF (peak expiratory flow) only one study contributed to this analysis ( , n = 55). The point estimate favoured NRT but CIs were wide and included no difference (MD ‐3.00, 95% CI ‐27.09 to 21.09) ( ). Study product use Five studies (one, , with vaping industry funding) reported study product use at six months or longer, but statistical heterogeneity precluded pooling (I 2 = 95%). Whereas and found no difference between the EC and NRT arms, in the other three studies, people in the EC arm were more likely to continue to use the study product (EC) than those in the NRT arm ( ). A companion publication explored long‐term rates in more detail ( ). 

Pooled data from seven studies (two cartridges, four refillable, one pod), five of which were rated at low risk of bias ( ; ; ; ; ) and two as unclear ( ; ), showed increased quit rates in people randomized to nicotine EC when compared to NRT (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.30 to 1.93; I 2 = 0%; 2544 participants; ). The certainty of evidence is high and has not been downgraded. One study included in this analysis, , was conducted in pregnant women. There was no evidence of a subgroup difference between this study and studies in participants not selected on the basis of pregnancy (P = 0.87, I 2 for subgroup differences = 0%). Follow‐up time was based on end of pregnancy, and our analysis included only those participants with follow‐up of at least six months. Results were not sensitive to the exclusion of the one study that received industry funding ( ); when this study was removed, the point estimate increased to 1.72, but the CIs remained consistent with those from the main analysis. One study, , available as a conference presentation only and considered at high risk of bias due to inconsistencies in the data reported and an unclear definition of abstinence, favoured varenicline for quitting compared to nicotine EC (cartridge) (RR 0.31, 95% CI 0.11 to 0.82; 54 participants; ). 

Pooled data from five studies (four considered at low risk of bias ( ; ; ; ) and one at unclear risk ( )) showed that there is probably no difference in the number of participants reporting adverse events (AEs) between nicotine EC and NRT arms (RR 1.03, 95% CI 0.91 to 1.17; I 2 = 0%; 2052 participants; ). The certainty of evidence is moderate, downgraded one level due to imprecision; the CIs were consistent with benefit and harm. None of the studies contributing data to this analysis received funding from the vaping or tobacco industries. and did not contribute data to this analysis due to the way in which events were recorded. In 's prespecified adverse reactions of interest, nausea was more frequent in the NRT group, throat/mouth irritation was more frequent in the nicotine EC group, and there was little difference in other reactions (see Supplemental Table 1 for more detail). recruited participants with chronic obstructive pulmonary disease (COPD) and reported "a trend towards decreased dyspnoea and COPD symptoms ... in the EC arm compared to the NRT arm", but did not provide further detail. In , reports of sleep disorders were evenly distributed between groups, and nausea was more common in the varenicline arm than in the nicotine EC arm (see Supplemental Table 1 for more detail). 

Six studies (five at low risk of bias ( ; ; ; ; ) and one at unclear risk ( )) comparing nicotine ECs with NRT provided data on serious adverse events. In some studies, no events occurred. Pooled results showed that there may be a slight increase in serious adverse events in the nicotine EC arms compared to NRT. There is low certainty of evidence for this outcome, downgraded two levels due to imprecision; there were fewer than 300 events and wide CIs incorporating no difference, as well as clinically significant harm and clinically significant benefit (RR 1.20, 95% CI 0.90 to 1.60; I 2 = 32%; 2761 participants; ). None of the studies contributing data to this analysis received funding from the vaping or tobacco industries. In (conducted in pregnant women), the authors reported no evidence of a difference in birth outcomes overall. However, low birthweight (< 2500 g) was less frequent in the EC than the NRT arm (14.8% versus 9.6%; RR 0.65, 95% CI 0.47 to 0.90). No SAEs occurred in ( ). 

Pooled data from four studies ( ; ; ; ), none of which received tobacco/vaping industry funding and none of which were considered at high risk of bias, comparing nicotine EC with NRT, found some evidence that CO levels decreased more in those randomized to nicotine EC; however, the CIs incorporated the possibility of no between‐group difference (mean difference (MD) ‐1.81 ppm, 95% CI ‐3.64 to 0.01; I 2 = 0%; 357 participants; ). A fourth, small study ( ; n = 11) was reported as a conference abstract and hence had limited data available. At three weeks, this study showed that both EC and NRT groups had "significantly reduced" CO, but between‐group differences were not reported. 

Pooled data from two studies (166 participants; one study judged to be at unclear risk of bias ( ) and one at low risk ( ), neither in receipt of vaping/tobacco industry funding) showed no clear evidence of a clinically meaningful difference in heart rate (MD 0.53 bpm, 95% CI ‐1.76 to 2.83; I 2 = 0%; ), systolic blood pressure (MD ‐1.62, 95% CI ‐3.59 to 0.36; I 2 = 0%; ), or blood oxygen saturation (MD ‐0.14, 95% CI ‐0.59 to 0.30; I 2 = 0%; ), although confidence intervals were wide. 

Only (unclear risk of bias, no tobacco/vaping industry funding, n = 111) contributed data for these outcomes. For 3‐HPMA, 2‐HPMA, and HMPMA, point estimates favoured EC but CIs included no difference ( ; ; ). There was no evidence of a difference for NNAL (nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐ butanol) but CIs were again wide ( ). For PheT, CEMA, and AAMA ( ; ; ), point estimates favoured NRT but CIs included no difference. 

and (no tobacco/vaping industry funding) measured change in FEV1 (forced expiratory volume) and FEV1/FVC (forced vital capacity) (both low risk of bias; n = 81). High statistical heterogeneity (I 2 = 89%) precluded pooling for FEV1 ( ). The point estimate for favoured EC and for favoured NRT; for , the CIs included no difference. There was no evidence of a difference for FEV1/FVC, but there was moderate unexplained statistical heterogeneity and, again, CIs were wide (MD ‐0.16%, 95% CI ‐1.83 to 1.50; I 2 = 51%; ). For PEF (peak expiratory flow) only one study contributed to this analysis ( , n = 55). The point estimate favoured NRT but CIs were wide and included no difference (MD ‐3.00, 95% CI ‐27.09 to 21.09) ( ). 

Five studies (one, , with vaping industry funding) reported study product use at six months or longer, but statistical heterogeneity precluded pooling (I 2 = 95%). Whereas and found no difference between the EC and NRT arms, in the other three studies, people in the EC arm were more likely to continue to use the study product (EC) than those in the NRT arm ( ). A companion publication explored long‐term rates in more detail ( ). 

Currently, the only comparison reported here is nicotine EC compared to heated tobacco. One study ( ; n = 220, tobacco/vaping industry‐funded), considered at high risk of bias due to a lack of blinding alongside strong participant product preferences, reported on AEs, SAEs, expired carbon monoxide (eCO), and VO 2 max as a measure of lung function, heart rate, and blood pressure at 12 weeks follow‐up. The effect estimate demonstrated no clear evidence of a difference in AEs between the nicotine EC and heated tobacco group (RR 0.86, 95% CI 0.68 to 1.10; 220 participants; ). There were no SAEs reported in either arm, so an effect estimate could not be calculated for this outcome ( ). There was no clear evidence of a between‐group difference in eCO levels (MD 1.90, 95% CI ‐0.71 to 4.51; 217 participants; ), or VO 2 max (MD 6.20, 95% CI ‐2.01 to 14.41; 211 participants; ). The following was reported on heart rate and blood pressure and is reported in Supplemental Tables 4 & 5 : “No significant changes in the mean resting heart rate, blood pressure, and BMI during product use were observed between and within study groups.” 

Comparisons reported here include nicotine EC versus non‐nicotine EC, and nicotine EC compared to behavioural support only or to no support. In this section, we also reported results from studies in which all participants received nicotine EC (cohort studies and randomized studies that did not differ across arms in EC provision, device generation, or nicotine content). Cessation Randomized controlled trials At six months or longer, quit rates were higher in nicotine EC groups than in comparator groups. Compared to EC without nicotine (placebo EC), pooled results showed nicotine EC probably produced higher quit rates (RR 1.46, 95% CI 1.09 to 1.96; I 2 = 4%; 5 studies of cartridge and 1 study of refillable devices, 1613 participants; ). There is moderate‐certainty evidence that nicotine EC probably increases quit rates compared to non‐nicotine EC. The certainty has been downgraded one level due to imprecision; there are fewer than 300 events overall. This has not been downgraded for risk of bias: removing the one study considered at high risk of bias increased the direction of the effect in favour of nicotine EC. The interpretation of the effect remained the same when we removed the one study at high risk of bias ( ) and when we removed the one study with tobacco/vaping industry funding ( ). The effect may be more pronounced when comparing nicotine EC to behavioural support only or to no support (RR 1.96, 95% CI 1.66 to 2.32; I 2 = 0%; 11 studies (5 refillable, 3 cartridge, 3 pod), 6819 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (the certainty of the evidence was low, downgraded two levels). One of the studies contributing data to this comparison reported tobacco/vaping industry funding ( ). The removal of this study in a sensitivity analysis did not change the interpretation of the effect ( ). (pod device) measured cessation at six months in the intervention group only, using self‐report. As they did not measure cessation at six months in the comparator group, we could not include these data in our meta‐analysis. At six months, 23 (24%) intervention participants were exclusively using EC and 10 (10.4%) reported using neither EC nor combustible cigarettes (making a combined quit rate of 34.4% in the intervention arm at six months). Data from other studies Ten studies provided all participants with nicotine EC and assessed abstinence at six months or longer ( ; 2 refillable, 6 cartridges, 1 pod, 1 not specified). The highest proportion of quitters at six months was observed in (cartridge), in which all participants (n = 48) used EC and 18 used additional pharmacotherapy; 44% of participants were abstinent at six months. The lowest quit rates were seen in , where 14% of participants were abstinent at 12 months, and , where 5% of participants were abstinent at 12 months. In the former, participants were unmotivated to quit smoking and, in the latter, motivation was unclear and participants were recruited from a socially deprived area on the basis of receiving a free nicotine EC. Adverse events Randomized controlled trials Pooled data from five studies (none at high risk of bias, one reporting tobacco/vaping industry funding) showed that there is probably no difference in the number of participants experiencing adverse events when comparing nicotine EC to non‐nicotine EC (RR 1.01, 95% CI 0.91 to 1.11; I 2 = 0%; 840 participants; ); this is moderate‐certainty evidence, downgraded one level due to imprecision (fewer than 300 events overall). Removing the one study linked to industry funding had no effect on the interpretation of the result ( ). When comparing nicotine EC to behavioural support only or to no support, evidence suggests more people in the groups randomized to nicotine EC experience adverse events (RR 1.18, 95% CI 1.10 to 1.27; I 2 = 6%; 6 studies, 2351 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (low‐certainty evidence downgraded two levels due to risk of bias). Interpretation of the outcome was not sensitive to the inclusion of the one study with tobacco/vaping industry support ( ). A further 11 randomized controlled trials provided adverse event or related data for this comparison, but could not be included in the meta‐analysis due to the way in which data were presented (see Supplemental Table 1 ). In the studies comparing nicotine EC to non‐nicotine EC, one found similar event rates across arms ( ), and two reported more events in the nicotine EC arms ( ; ). In a further study comparing nicotine to non‐nicotine EC, events were reported by type, with an increase in some seen in the nicotine group and an increase in others seen in the non‐nicotine group ( ). In the seven studies comparing nicotine EC to behavioural support only or traditional cigarettes, found an increase in sinonasal symptoms in the group receiving nicotine EC compared to behavioural support only, and found that throat irritation, cough, and dry mouth increased in the e‐cigarette group relative to the traditional cigarette group. By contrast, found a reduction in respiratory symptoms in the EC compared to the traditional cigarette group, and found no clear difference in the number of participants reporting dry cough and throat and mouth irritation between the EC arm and the referral information arm. found an increase in throat irritation, palpitations, and dizziness in the EC group, but decreases in cough, headache, nausea, dry mouth, shortness of breath, and stomach pain. did not break down AEs by group but reported that three participants experienced a non‐serious adverse event definitely related to the study product. reported no statistically significant between‐group difference in AEs. Data from other studies Eighteen studies provided all participants with nicotine EC and assessed adverse events at one week or longer and one RCT reported AEs reported in the nicotine EC group only (see Supplemental Table 1 ). In the eight studies that tracked event rates over time, six showed adverse events reducing over time ( ; ; ; ; ; ). showed no change. The most commonly reported adverse events were throat/mouth irritation, headache, cough, and nausea. Serious adverse events Randomized controlled trials Nine studies compared nicotine EC with non‐nicotine EC and reported data on SAEs; in five of these (including one tobacco/vaping industry study, ), no events occurred, so results could not contribute to the meta‐analysis, although they are included in the forest plots for descriptive purposes. In the four studies (three low risk of bias, one unclear) where events occurred, there may be little to no difference between groups, but CIs were wide (RR 1.00, 95% CI 0.56 to 1.79; I 2 = 0%; 1412 participants; ). The evidence was of low certainty; this was downgraded two levels due to imprecision: the confidence intervals encompassed clinically significant harm as well as clinically significant benefit, and there were fewer than 300 events overall. One of these studies had links to industry funding ( ); removing it from the analysis changed the effect estimate to 0.95 but the 95% CI remained wide (0.52 to 1.72) and so the interpretation of the result remained the same. Twelve studies compared nicotine EC with behavioural support only or no support and reported data on SAEs; in five of these, no events occurred. Pooled results from the seven studies in which events occurred showed very uncertain evidence about the difference between arms, but CIs were wide (RR 0.93, 95% CI 0.68 to 1.28; I 2 = 0%; 4561 participants; ). Here the certainty of evidence was very low; this was downgraded two levels due to risk of bias (lack of blinding and differential support between arms, judged to be at high risk of bias). Removing the one study with tobacco/vaping industry support did not affect the interpretation of the results ( ). In a study in people experiencing homelessness ( ), SAEs were not reported, but authors reported that four to seven participants in the usual care arm and five to seven participants in the nicotine EC arm visited Accident & Emergency services at a hospital. The authors reported that these visits were unrelated to study treatment and were assessed to gather data for future economic evaluation. Further detail can be found in Supplemental Table 2 . Data from other studies Nine studies provided all participants with nicotine EC and reported SAEs at a week or longer ( Supplemental Table 2 ). In six of these, authors reported that no SAEs occurred ( ; ; ; ; ; ; ). In (19 participants), one death occurred (no further detail provided). (50 participants) recruited participants from mental health settings; five SAEs were recorded during the study, all of which were psychiatric hospitalizations. None were considered related to study treatment. Carbon monoxide Randomized controlled trials High statistical heterogeneity (I 2 = 80%) precluded pooling CO data from the six trials (n = 677, none considered at high risk of bias) comparing nicotine EC with non‐nicotine EC ( ). Point estimates from four studies (one reporting links to industry funding; ) favoured nicotine EC and from two (one reporting industry funding; ) favoured non‐nicotine EC, but in all cases CIs were consistent with no clinically meaningful difference. Three further randomized studies measured CO levels in those assigned to nicotine EC and those assigned to non‐nicotine EC, but did not present data in a way that could be pooled: did not compare data by group; reported no between‐group differences; and found a slightly higher CO reading in those using nicotine EC, but the clinical and statistical significance of this difference was not clear (see Supplemental Table 3 for more detail). These data were from all study participants based on group randomized, not on subsequent EC or cigarette use. Pooled data from 11 studies comparing nicotine EC to behavioural support alone or to no support resulted in a high I 2 value (89%); thus, pooled results were not presented here (see for individual study data). None of these studies reported tobacco/vaping industry funding. A funnel plot did not show asymmetry ( ). Heterogeneity was primarily driven by magnitude rather than direction of effect, with results in 10 of 11 studies favouring nicotine EC. Three further trials reported data that could not be included in a meta‐analysis. compared nicotine EC to cigarettes and found that CO levels declined in the EC group and remained similar to baseline in the cigarette group. instructed baseline dual users to spend periods only using EC or only using traditional cigarettes; CO measured during sole EC use was lower than baseline and lower than during cigarette‐only periods. Further details can be found in Supplemental Table 3 . Data from other studies Twenty studies provided all participants with nicotine EC and reported data on CO at one week or longer. In the 19 studies that presented change over time, CO declined from baseline, although in CO levels were equivalent to baseline again at 24 weeks, and in a decline was observed in people who quit smoking or reduced cigarette consumption by at least half, but not in those who continued smoking at least half as many cigarettes as they had from baseline. Heart rate Randomized controlled trials One RCT ( , unclear risk of bias, n = 141) provided data on heart rate and compared nicotine EC with non‐nicotine EC; there was no evidence of a clinically significant between‐group difference (MD ‐2.3, 95% CI ‐6.10 to 1.50) ( ). This was comparable with findings from the one RCT ( , unclear risk of bias, n = 90) comparing nicotine EC with no pharmacotherapy, which also found no evidence of a clinically significant difference (MD 1.17, 95% CI ‐4.17 to 6.61) ( ). A further three RCTs provided data on heart rate that could not be used to calculate effect estimates. compared nicotine to non‐nicotine EC and found no difference in heart rate between arms; compared a nicotine EC with a traditional cigarette and reported "no clinically significant changes", and found decreases in both the EC and QuitSmart cigarette substitute groups, with the decrease being slightly greater in the latter group. See Supplemental Table 4 for further information. Data from other studies Six studies in which all participants received a nicotine EC also reported data on heart rate; for five, changes were minimal and directions of effect were mixed, and for (n = 40), the rate reduced by 9 bpm at 12 weeks (see Supplemental Table 4 ). Blood pressure found no evidence of a difference in the change in systolic blood pressure (BP) between nicotine EC and non‐nicotine EC arms (unclear risk of bias, 141 participants, MD 1.2, 95% CI ‐3.99 to 6.39; ). Three studies (two at high risk of bias, one at unclear risk of bias, none reporting tobacco/vaping industry funding) compared nicotine EC to behavioural support only and reported data on systolic blood pressure; there was a small difference favouring the EC arms (MD ‐2.3, 95% CI ‐3.9 to ‐0.7, I 2 = 24%; 298 participants; ). Three further RCTs measured change in blood pressure but presented results in such a way that they could not be pooled. compared nicotine EC and non‐nicotine EC and combined data from both groups; BP declined over time. Compared to a QuitSmart cigarette substitute, found that EC led to a greater reduction in BP. found "no clinically significant changes" when comparing nicotine EC to a conventional cigarette at two weeks. Five studies, which provided nicotine EC to all participants, reported change in blood pressure; results were clinically insignificant except for in which systolic BP reduced by 12 (from 134 to 122) at 12 weeks (see Supplemental Table 5 for further details on all studies reporting this outcome). Oxygen saturation found no evidence of a difference in blood oxygen saturation when comparing nicotine EC to cigarettes (89 participants, MD 0.20, 95% CI ‐0.30 to 0.70; ). , a short‐term pre‐post study, which measured outcomes after two weeks of EC use, found that people who smoked and switched to ECs had significant improvement in blood oxygen saturation (96.2% (standard deviation (SD) 1.8) to 97.5% (SD 1.3); 1.3% increase, 95% CI 0.6 to 2.1; P = 0.002). Toxicants Unless stated otherwise, all randomized controlled trials measuring these outcomes compared nicotine EC with no pharmacotherapy. Two trials measured change in 3‐HPMA (one at high risk of bias). In both, the point estimate favoured the EC arm, but pooling was precluded due to differences in measurement methods ( ). Five further studies, in which all participants were given nicotine EC, measured 3‐HPMA; all found reductions over time ( Supplemental Table 6 ). Five trials measured change in NNAL and provided sufficient data to calculate summary effects (four at high risk of bias; ). Three of the five studies found results favouring nicotine EC, but the final two indicated no difference; statistical heterogeneity was high (I 2 = 96%), so pooled results were not presented. One study comparing nicotine EC to no treatment described their findings narratively and stated that "NNAL decreased more over time in the e‐cigarette group ... the e‐cigarette group had significantly lower NNAL at 4 weeks (estimate = 0.54; SE = 0.23; t = 2.37; P < 0.02), but the group difference was attenuated at 8 weeks (estimate = 0.42; SE = 0.23; t = 1.83; P < 0.07)" ( ). and , which provided all participants with nicotine EC, found a reduction in NNAL over time and , which was a cross‐over trial, found NNAL decreased when using nicotine EC compared to using traditional cigarettes ( Supplemental Table 6 ). An additional two RCTs (one unclear and one low risk of bias; none reporting tobacco/vaping industry funding) compared nicotine EC versus non‐nicotine EC and found no evidence of difference, with wide CIs and moderate statistical heterogeneity (‐0.02 pmol/mg creatinine, 95% CI ‐0.45 to 0.41; I 2 = 54%; 363 participants; ). One trial (n = 90, unclear risk of bias) found non‐statistically significant lower levels of 2‐HPMA, HMPMA, PhET, and AAMA in nicotine EC arms compared to control ( ; ; ; ). A further two studies, in which all participants received nicotine EC, found reductions in 2‐HPMA and AAMA measures over time ( Supplemental Table 6 ). No difference was found in the one trial (n = 90, unclear risk of bias) evaluating CEMA ( ). One trial (n = 384, unclear risk of bias) found reductions in S‐PMA compared to control (MD ‐1371.00 nanograms, 95% CI ‐1995.23 to ‐746.88) ( ); this was consistent with the two studies in which all participants received nicotine EC that measured S‐PMA, where levels declined over time ( Supplemental Table 6 ). Of the 33 remaining measurements in single studies where all participants received a nicotine EC, 28 reduced over time and five increased ( Supplemental Table 6 ). Lung function measured a number of lung function parameters. FeNO increased more in the nicotine EC than the non‐nicotine EC group (MD 2.35, 95% CI 1.78 to 2.92; 90 participants; ). No difference was found between nicotine and non‐nicotine EC for FEV1 or FEV1/FVC ( ; ). In the comparison of nicotine EC to behavioural support only/no support, pooled results from two studies (both high risk of bias, both tobacco/vaping industry funded) found improvements in FEV1 but with moderate statistical heterogeneity and CIs including no difference (standardized mean difference (SMD) 0.15, 95% CI ‐0.01 to 0.31, I 2 = 70%; 714 participants; ). Pooled data from two studies (both high risk of bias, one reporting tobacco/vaping industry funding ( )) showed no difference in FEF (forced expiratory flow) 25‐75, with substantial levels of statistical heterogeneity (MD ‐0.06, 95% CI ‐0.18 to 0.06, I 2 = 73%; 2 studies, 555 participants; ). In a sensitivity analysis removing Walele, the result was still consistent with no difference, though the point estimate was greater in magnitude. Data from one study at high risk of bias showed no difference in PEF (peak expiratory flow 25‐75 (litres/minute)) (387 participants, MD ‐7.10, 95% CI ‐29.14 to 14.94; ). The one study reporting FEV1/FVC (327 participants, MD 1.72, 95% CI 0.74 to 2.70, high risk of bias) favoured nicotine EC ( ) ( ). , which randomized participants to EC or the QuitSmart cigarette substitute, measured change in a number of lung function parameters: direction of effect was mixed across these, with no statistically or clinically significant between‐group differences at 12 weeks ( Supplemental Table 7 ). Two studies, which provided all participants with nicotine EC, measured change in lung function over time: found an increase in peak flow, and found "no significant differences" in airway function ( Supplemental Table 7 ). Study product use Three trials (all low risk), comparing nicotine EC with non‐nicotine EC, reported the number of participants still using EC at six months or longer. Slightly more participants were still using EC in the nicotine EC arms, but CIs were wide and included no difference (RR 1.15, 95% CI 0.94 to 1.41, I 2 = 30%; 874 participants; ). Data on this outcome from single‐arm studies or RCTs where a study product (i.e. EC) was only provided in one arm can be found in a companion publication ( ) and Supplemental Table 8 . 

Randomized controlled trials At six months or longer, quit rates were higher in nicotine EC groups than in comparator groups. Compared to EC without nicotine (placebo EC), pooled results showed nicotine EC probably produced higher quit rates (RR 1.46, 95% CI 1.09 to 1.96; I 2 = 4%; 5 studies of cartridge and 1 study of refillable devices, 1613 participants; ). There is moderate‐certainty evidence that nicotine EC probably increases quit rates compared to non‐nicotine EC. The certainty has been downgraded one level due to imprecision; there are fewer than 300 events overall. This has not been downgraded for risk of bias: removing the one study considered at high risk of bias increased the direction of the effect in favour of nicotine EC. The interpretation of the effect remained the same when we removed the one study at high risk of bias ( ) and when we removed the one study with tobacco/vaping industry funding ( ). The effect may be more pronounced when comparing nicotine EC to behavioural support only or to no support (RR 1.96, 95% CI 1.66 to 2.32; I 2 = 0%; 11 studies (5 refillable, 3 cartridge, 3 pod), 6819 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (the certainty of the evidence was low, downgraded two levels). One of the studies contributing data to this comparison reported tobacco/vaping industry funding ( ). The removal of this study in a sensitivity analysis did not change the interpretation of the effect ( ). (pod device) measured cessation at six months in the intervention group only, using self‐report. As they did not measure cessation at six months in the comparator group, we could not include these data in our meta‐analysis. At six months, 23 (24%) intervention participants were exclusively using EC and 10 (10.4%) reported using neither EC nor combustible cigarettes (making a combined quit rate of 34.4% in the intervention arm at six months). Data from other studies Ten studies provided all participants with nicotine EC and assessed abstinence at six months or longer ( ; 2 refillable, 6 cartridges, 1 pod, 1 not specified). The highest proportion of quitters at six months was observed in (cartridge), in which all participants (n = 48) used EC and 18 used additional pharmacotherapy; 44% of participants were abstinent at six months. The lowest quit rates were seen in , where 14% of participants were abstinent at 12 months, and , where 5% of participants were abstinent at 12 months. In the former, participants were unmotivated to quit smoking and, in the latter, motivation was unclear and participants were recruited from a socially deprived area on the basis of receiving a free nicotine EC. 

At six months or longer, quit rates were higher in nicotine EC groups than in comparator groups. Compared to EC without nicotine (placebo EC), pooled results showed nicotine EC probably produced higher quit rates (RR 1.46, 95% CI 1.09 to 1.96; I 2 = 4%; 5 studies of cartridge and 1 study of refillable devices, 1613 participants; ). There is moderate‐certainty evidence that nicotine EC probably increases quit rates compared to non‐nicotine EC. The certainty has been downgraded one level due to imprecision; there are fewer than 300 events overall. This has not been downgraded for risk of bias: removing the one study considered at high risk of bias increased the direction of the effect in favour of nicotine EC. The interpretation of the effect remained the same when we removed the one study at high risk of bias ( ) and when we removed the one study with tobacco/vaping industry funding ( ). The effect may be more pronounced when comparing nicotine EC to behavioural support only or to no support (RR 1.96, 95% CI 1.66 to 2.32; I 2 = 0%; 11 studies (5 refillable, 3 cartridge, 3 pod), 6819 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (the certainty of the evidence was low, downgraded two levels). One of the studies contributing data to this comparison reported tobacco/vaping industry funding ( ). The removal of this study in a sensitivity analysis did not change the interpretation of the effect ( ). (pod device) measured cessation at six months in the intervention group only, using self‐report. As they did not measure cessation at six months in the comparator group, we could not include these data in our meta‐analysis. At six months, 23 (24%) intervention participants were exclusively using EC and 10 (10.4%) reported using neither EC nor combustible cigarettes (making a combined quit rate of 34.4% in the intervention arm at six months). 

Ten studies provided all participants with nicotine EC and assessed abstinence at six months or longer ( ; 2 refillable, 6 cartridges, 1 pod, 1 not specified). The highest proportion of quitters at six months was observed in (cartridge), in which all participants (n = 48) used EC and 18 used additional pharmacotherapy; 44% of participants were abstinent at six months. The lowest quit rates were seen in , where 14% of participants were abstinent at 12 months, and , where 5% of participants were abstinent at 12 months. In the former, participants were unmotivated to quit smoking and, in the latter, motivation was unclear and participants were recruited from a socially deprived area on the basis of receiving a free nicotine EC. 

Randomized controlled trials Pooled data from five studies (none at high risk of bias, one reporting tobacco/vaping industry funding) showed that there is probably no difference in the number of participants experiencing adverse events when comparing nicotine EC to non‐nicotine EC (RR 1.01, 95% CI 0.91 to 1.11; I 2 = 0%; 840 participants; ); this is moderate‐certainty evidence, downgraded one level due to imprecision (fewer than 300 events overall). Removing the one study linked to industry funding had no effect on the interpretation of the result ( ). When comparing nicotine EC to behavioural support only or to no support, evidence suggests more people in the groups randomized to nicotine EC experience adverse events (RR 1.18, 95% CI 1.10 to 1.27; I 2 = 6%; 6 studies, 2351 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (low‐certainty evidence downgraded two levels due to risk of bias). Interpretation of the outcome was not sensitive to the inclusion of the one study with tobacco/vaping industry support ( ). A further 11 randomized controlled trials provided adverse event or related data for this comparison, but could not be included in the meta‐analysis due to the way in which data were presented (see Supplemental Table 1 ). In the studies comparing nicotine EC to non‐nicotine EC, one found similar event rates across arms ( ), and two reported more events in the nicotine EC arms ( ; ). In a further study comparing nicotine to non‐nicotine EC, events were reported by type, with an increase in some seen in the nicotine group and an increase in others seen in the non‐nicotine group ( ). In the seven studies comparing nicotine EC to behavioural support only or traditional cigarettes, found an increase in sinonasal symptoms in the group receiving nicotine EC compared to behavioural support only, and found that throat irritation, cough, and dry mouth increased in the e‐cigarette group relative to the traditional cigarette group. By contrast, found a reduction in respiratory symptoms in the EC compared to the traditional cigarette group, and found no clear difference in the number of participants reporting dry cough and throat and mouth irritation between the EC arm and the referral information arm. found an increase in throat irritation, palpitations, and dizziness in the EC group, but decreases in cough, headache, nausea, dry mouth, shortness of breath, and stomach pain. did not break down AEs by group but reported that three participants experienced a non‐serious adverse event definitely related to the study product. reported no statistically significant between‐group difference in AEs. Data from other studies Eighteen studies provided all participants with nicotine EC and assessed adverse events at one week or longer and one RCT reported AEs reported in the nicotine EC group only (see Supplemental Table 1 ). In the eight studies that tracked event rates over time, six showed adverse events reducing over time ( ; ; ; ; ; ). showed no change. The most commonly reported adverse events were throat/mouth irritation, headache, cough, and nausea. 

Pooled data from five studies (none at high risk of bias, one reporting tobacco/vaping industry funding) showed that there is probably no difference in the number of participants experiencing adverse events when comparing nicotine EC to non‐nicotine EC (RR 1.01, 95% CI 0.91 to 1.11; I 2 = 0%; 840 participants; ); this is moderate‐certainty evidence, downgraded one level due to imprecision (fewer than 300 events overall). Removing the one study linked to industry funding had no effect on the interpretation of the result ( ). When comparing nicotine EC to behavioural support only or to no support, evidence suggests more people in the groups randomized to nicotine EC experience adverse events (RR 1.18, 95% CI 1.10 to 1.27; I 2 = 6%; 6 studies, 2351 participants; ). As this involved unblinded comparisons with unequal levels of support, we judged all data contributing to this outcome to be at high risk of bias (low‐certainty evidence downgraded two levels due to risk of bias). Interpretation of the outcome was not sensitive to the inclusion of the one study with tobacco/vaping industry support ( ). A further 11 randomized controlled trials provided adverse event or related data for this comparison, but could not be included in the meta‐analysis due to the way in which data were presented (see Supplemental Table 1 ). In the studies comparing nicotine EC to non‐nicotine EC, one found similar event rates across arms ( ), and two reported more events in the nicotine EC arms ( ; ). In a further study comparing nicotine to non‐nicotine EC, events were reported by type, with an increase in some seen in the nicotine group and an increase in others seen in the non‐nicotine group ( ). In the seven studies comparing nicotine EC to behavioural support only or traditional cigarettes, found an increase in sinonasal symptoms in the group receiving nicotine EC compared to behavioural support only, and found that throat irritation, cough, and dry mouth increased in the e‐cigarette group relative to the traditional cigarette group. By contrast, found a reduction in respiratory symptoms in the EC compared to the traditional cigarette group, and found no clear difference in the number of participants reporting dry cough and throat and mouth irritation between the EC arm and the referral information arm. found an increase in throat irritation, palpitations, and dizziness in the EC group, but decreases in cough, headache, nausea, dry mouth, shortness of breath, and stomach pain. did not break down AEs by group but reported that three participants experienced a non‐serious adverse event definitely related to the study product. reported no statistically significant between‐group difference in AEs. 

Eighteen studies provided all participants with nicotine EC and assessed adverse events at one week or longer and one RCT reported AEs reported in the nicotine EC group only (see Supplemental Table 1 ). In the eight studies that tracked event rates over time, six showed adverse events reducing over time ( ; ; ; ; ; ). showed no change. The most commonly reported adverse events were throat/mouth irritation, headache, cough, and nausea. 

Randomized controlled trials Nine studies compared nicotine EC with non‐nicotine EC and reported data on SAEs; in five of these (including one tobacco/vaping industry study, ), no events occurred, so results could not contribute to the meta‐analysis, although they are included in the forest plots for descriptive purposes. In the four studies (three low risk of bias, one unclear) where events occurred, there may be little to no difference between groups, but CIs were wide (RR 1.00, 95% CI 0.56 to 1.79; I 2 = 0%; 1412 participants; ). The evidence was of low certainty; this was downgraded two levels due to imprecision: the confidence intervals encompassed clinically significant harm as well as clinically significant benefit, and there were fewer than 300 events overall. One of these studies had links to industry funding ( ); removing it from the analysis changed the effect estimate to 0.95 but the 95% CI remained wide (0.52 to 1.72) and so the interpretation of the result remained the same. Twelve studies compared nicotine EC with behavioural support only or no support and reported data on SAEs; in five of these, no events occurred. Pooled results from the seven studies in which events occurred showed very uncertain evidence about the difference between arms, but CIs were wide (RR 0.93, 95% CI 0.68 to 1.28; I 2 = 0%; 4561 participants; ). Here the certainty of evidence was very low; this was downgraded two levels due to risk of bias (lack of blinding and differential support between arms, judged to be at high risk of bias). Removing the one study with tobacco/vaping industry support did not affect the interpretation of the results ( ). In a study in people experiencing homelessness ( ), SAEs were not reported, but authors reported that four to seven participants in the usual care arm and five to seven participants in the nicotine EC arm visited Accident & Emergency services at a hospital. The authors reported that these visits were unrelated to study treatment and were assessed to gather data for future economic evaluation. Further detail can be found in Supplemental Table 2 . Data from other studies Nine studies provided all participants with nicotine EC and reported SAEs at a week or longer ( Supplemental Table 2 ). In six of these, authors reported that no SAEs occurred ( ; ; ; ; ; ; ). In (19 participants), one death occurred (no further detail provided). (50 participants) recruited participants from mental health settings; five SAEs were recorded during the study, all of which were psychiatric hospitalizations. None were considered related to study treatment. 

Nine studies compared nicotine EC with non‐nicotine EC and reported data on SAEs; in five of these (including one tobacco/vaping industry study, ), no events occurred, so results could not contribute to the meta‐analysis, although they are included in the forest plots for descriptive purposes. In the four studies (three low risk of bias, one unclear) where events occurred, there may be little to no difference between groups, but CIs were wide (RR 1.00, 95% CI 0.56 to 1.79; I 2 = 0%; 1412 participants; ). The evidence was of low certainty; this was downgraded two levels due to imprecision: the confidence intervals encompassed clinically significant harm as well as clinically significant benefit, and there were fewer than 300 events overall. One of these studies had links to industry funding ( ); removing it from the analysis changed the effect estimate to 0.95 but the 95% CI remained wide (0.52 to 1.72) and so the interpretation of the result remained the same. Twelve studies compared nicotine EC with behavioural support only or no support and reported data on SAEs; in five of these, no events occurred. Pooled results from the seven studies in which events occurred showed very uncertain evidence about the difference between arms, but CIs were wide (RR 0.93, 95% CI 0.68 to 1.28; I 2 = 0%; 4561 participants; ). Here the certainty of evidence was very low; this was downgraded two levels due to risk of bias (lack of blinding and differential support between arms, judged to be at high risk of bias). Removing the one study with tobacco/vaping industry support did not affect the interpretation of the results ( ). In a study in people experiencing homelessness ( ), SAEs were not reported, but authors reported that four to seven participants in the usual care arm and five to seven participants in the nicotine EC arm visited Accident & Emergency services at a hospital. The authors reported that these visits were unrelated to study treatment and were assessed to gather data for future economic evaluation. Further detail can be found in Supplemental Table 2 . 

Nine studies provided all participants with nicotine EC and reported SAEs at a week or longer ( Supplemental Table 2 ). In six of these, authors reported that no SAEs occurred ( ; ; ; ; ; ; ). In (19 participants), one death occurred (no further detail provided). (50 participants) recruited participants from mental health settings; five SAEs were recorded during the study, all of which were psychiatric hospitalizations. None were considered related to study treatment. 

Randomized controlled trials High statistical heterogeneity (I 2 = 80%) precluded pooling CO data from the six trials (n = 677, none considered at high risk of bias) comparing nicotine EC with non‐nicotine EC ( ). Point estimates from four studies (one reporting links to industry funding; ) favoured nicotine EC and from two (one reporting industry funding; ) favoured non‐nicotine EC, but in all cases CIs were consistent with no clinically meaningful difference. Three further randomized studies measured CO levels in those assigned to nicotine EC and those assigned to non‐nicotine EC, but did not present data in a way that could be pooled: did not compare data by group; reported no between‐group differences; and found a slightly higher CO reading in those using nicotine EC, but the clinical and statistical significance of this difference was not clear (see Supplemental Table 3 for more detail). These data were from all study participants based on group randomized, not on subsequent EC or cigarette use. Pooled data from 11 studies comparing nicotine EC to behavioural support alone or to no support resulted in a high I 2 value (89%); thus, pooled results were not presented here (see for individual study data). None of these studies reported tobacco/vaping industry funding. A funnel plot did not show asymmetry ( ). Heterogeneity was primarily driven by magnitude rather than direction of effect, with results in 10 of 11 studies favouring nicotine EC. Three further trials reported data that could not be included in a meta‐analysis. compared nicotine EC to cigarettes and found that CO levels declined in the EC group and remained similar to baseline in the cigarette group. instructed baseline dual users to spend periods only using EC or only using traditional cigarettes; CO measured during sole EC use was lower than baseline and lower than during cigarette‐only periods. Further details can be found in Supplemental Table 3 . Data from other studies Twenty studies provided all participants with nicotine EC and reported data on CO at one week or longer. In the 19 studies that presented change over time, CO declined from baseline, although in CO levels were equivalent to baseline again at 24 weeks, and in a decline was observed in people who quit smoking or reduced cigarette consumption by at least half, but not in those who continued smoking at least half as many cigarettes as they had from baseline. 

High statistical heterogeneity (I 2 = 80%) precluded pooling CO data from the six trials (n = 677, none considered at high risk of bias) comparing nicotine EC with non‐nicotine EC ( ). Point estimates from four studies (one reporting links to industry funding; ) favoured nicotine EC and from two (one reporting industry funding; ) favoured non‐nicotine EC, but in all cases CIs were consistent with no clinically meaningful difference. Three further randomized studies measured CO levels in those assigned to nicotine EC and those assigned to non‐nicotine EC, but did not present data in a way that could be pooled: did not compare data by group; reported no between‐group differences; and found a slightly higher CO reading in those using nicotine EC, but the clinical and statistical significance of this difference was not clear (see Supplemental Table 3 for more detail). These data were from all study participants based on group randomized, not on subsequent EC or cigarette use. Pooled data from 11 studies comparing nicotine EC to behavioural support alone or to no support resulted in a high I 2 value (89%); thus, pooled results were not presented here (see for individual study data). None of these studies reported tobacco/vaping industry funding. A funnel plot did not show asymmetry ( ). Heterogeneity was primarily driven by magnitude rather than direction of effect, with results in 10 of 11 studies favouring nicotine EC. Three further trials reported data that could not be included in a meta‐analysis. compared nicotine EC to cigarettes and found that CO levels declined in the EC group and remained similar to baseline in the cigarette group. instructed baseline dual users to spend periods only using EC or only using traditional cigarettes; CO measured during sole EC use was lower than baseline and lower than during cigarette‐only periods. Further details can be found in Supplemental Table 3 . 

Twenty studies provided all participants with nicotine EC and reported data on CO at one week or longer. In the 19 studies that presented change over time, CO declined from baseline, although in CO levels were equivalent to baseline again at 24 weeks, and in a decline was observed in people who quit smoking or reduced cigarette consumption by at least half, but not in those who continued smoking at least half as many cigarettes as they had from baseline. 

Randomized controlled trials One RCT ( , unclear risk of bias, n = 141) provided data on heart rate and compared nicotine EC with non‐nicotine EC; there was no evidence of a clinically significant between‐group difference (MD ‐2.3, 95% CI ‐6.10 to 1.50) ( ). This was comparable with findings from the one RCT ( , unclear risk of bias, n = 90) comparing nicotine EC with no pharmacotherapy, which also found no evidence of a clinically significant difference (MD 1.17, 95% CI ‐4.17 to 6.61) ( ). A further three RCTs provided data on heart rate that could not be used to calculate effect estimates. compared nicotine to non‐nicotine EC and found no difference in heart rate between arms; compared a nicotine EC with a traditional cigarette and reported "no clinically significant changes", and found decreases in both the EC and QuitSmart cigarette substitute groups, with the decrease being slightly greater in the latter group. See Supplemental Table 4 for further information. Data from other studies Six studies in which all participants received a nicotine EC also reported data on heart rate; for five, changes were minimal and directions of effect were mixed, and for (n = 40), the rate reduced by 9 bpm at 12 weeks (see Supplemental Table 4 ). 

One RCT ( , unclear risk of bias, n = 141) provided data on heart rate and compared nicotine EC with non‐nicotine EC; there was no evidence of a clinically significant between‐group difference (MD ‐2.3, 95% CI ‐6.10 to 1.50) ( ). This was comparable with findings from the one RCT ( , unclear risk of bias, n = 90) comparing nicotine EC with no pharmacotherapy, which also found no evidence of a clinically significant difference (MD 1.17, 95% CI ‐4.17 to 6.61) ( ). A further three RCTs provided data on heart rate that could not be used to calculate effect estimates. compared nicotine to non‐nicotine EC and found no difference in heart rate between arms; compared a nicotine EC with a traditional cigarette and reported "no clinically significant changes", and found decreases in both the EC and QuitSmart cigarette substitute groups, with the decrease being slightly greater in the latter group. See Supplemental Table 4 for further information. 

Six studies in which all participants received a nicotine EC also reported data on heart rate; for five, changes were minimal and directions of effect were mixed, and for (n = 40), the rate reduced by 9 bpm at 12 weeks (see Supplemental Table 4 ). 

found no evidence of a difference in the change in systolic blood pressure (BP) between nicotine EC and non‐nicotine EC arms (unclear risk of bias, 141 participants, MD 1.2, 95% CI ‐3.99 to 6.39; ). Three studies (two at high risk of bias, one at unclear risk of bias, none reporting tobacco/vaping industry funding) compared nicotine EC to behavioural support only and reported data on systolic blood pressure; there was a small difference favouring the EC arms (MD ‐2.3, 95% CI ‐3.9 to ‐0.7, I 2 = 24%; 298 participants; ). Three further RCTs measured change in blood pressure but presented results in such a way that they could not be pooled. compared nicotine EC and non‐nicotine EC and combined data from both groups; BP declined over time. Compared to a QuitSmart cigarette substitute, found that EC led to a greater reduction in BP. found "no clinically significant changes" when comparing nicotine EC to a conventional cigarette at two weeks. Five studies, which provided nicotine EC to all participants, reported change in blood pressure; results were clinically insignificant except for in which systolic BP reduced by 12 (from 134 to 122) at 12 weeks (see Supplemental Table 5 for further details on all studies reporting this outcome). 

found no evidence of a difference in blood oxygen saturation when comparing nicotine EC to cigarettes (89 participants, MD 0.20, 95% CI ‐0.30 to 0.70; ). , a short‐term pre‐post study, which measured outcomes after two weeks of EC use, found that people who smoked and switched to ECs had significant improvement in blood oxygen saturation (96.2% (standard deviation (SD) 1.8) to 97.5% (SD 1.3); 1.3% increase, 95% CI 0.6 to 2.1; P = 0.002). 

Unless stated otherwise, all randomized controlled trials measuring these outcomes compared nicotine EC with no pharmacotherapy. Two trials measured change in 3‐HPMA (one at high risk of bias). In both, the point estimate favoured the EC arm, but pooling was precluded due to differences in measurement methods ( ). Five further studies, in which all participants were given nicotine EC, measured 3‐HPMA; all found reductions over time ( Supplemental Table 6 ). Five trials measured change in NNAL and provided sufficient data to calculate summary effects (four at high risk of bias; ). Three of the five studies found results favouring nicotine EC, but the final two indicated no difference; statistical heterogeneity was high (I 2 = 96%), so pooled results were not presented. One study comparing nicotine EC to no treatment described their findings narratively and stated that "NNAL decreased more over time in the e‐cigarette group ... the e‐cigarette group had significantly lower NNAL at 4 weeks (estimate = 0.54; SE = 0.23; t = 2.37; P < 0.02), but the group difference was attenuated at 8 weeks (estimate = 0.42; SE = 0.23; t = 1.83; P < 0.07)" ( ). and , which provided all participants with nicotine EC, found a reduction in NNAL over time and , which was a cross‐over trial, found NNAL decreased when using nicotine EC compared to using traditional cigarettes ( Supplemental Table 6 ). An additional two RCTs (one unclear and one low risk of bias; none reporting tobacco/vaping industry funding) compared nicotine EC versus non‐nicotine EC and found no evidence of difference, with wide CIs and moderate statistical heterogeneity (‐0.02 pmol/mg creatinine, 95% CI ‐0.45 to 0.41; I 2 = 54%; 363 participants; ). One trial (n = 90, unclear risk of bias) found non‐statistically significant lower levels of 2‐HPMA, HMPMA, PhET, and AAMA in nicotine EC arms compared to control ( ; ; ; ). A further two studies, in which all participants received nicotine EC, found reductions in 2‐HPMA and AAMA measures over time ( Supplemental Table 6 ). No difference was found in the one trial (n = 90, unclear risk of bias) evaluating CEMA ( ). One trial (n = 384, unclear risk of bias) found reductions in S‐PMA compared to control (MD ‐1371.00 nanograms, 95% CI ‐1995.23 to ‐746.88) ( ); this was consistent with the two studies in which all participants received nicotine EC that measured S‐PMA, where levels declined over time ( Supplemental Table 6 ). Of the 33 remaining measurements in single studies where all participants received a nicotine EC, 28 reduced over time and five increased ( Supplemental Table 6 ). 

measured a number of lung function parameters. FeNO increased more in the nicotine EC than the non‐nicotine EC group (MD 2.35, 95% CI 1.78 to 2.92; 90 participants; ). No difference was found between nicotine and non‐nicotine EC for FEV1 or FEV1/FVC ( ; ). In the comparison of nicotine EC to behavioural support only/no support, pooled results from two studies (both high risk of bias, both tobacco/vaping industry funded) found improvements in FEV1 but with moderate statistical heterogeneity and CIs including no difference (standardized mean difference (SMD) 0.15, 95% CI ‐0.01 to 0.31, I 2 = 70%; 714 participants; ). Pooled data from two studies (both high risk of bias, one reporting tobacco/vaping industry funding ( )) showed no difference in FEF (forced expiratory flow) 25‐75, with substantial levels of statistical heterogeneity (MD ‐0.06, 95% CI ‐0.18 to 0.06, I 2 = 73%; 2 studies, 555 participants; ). In a sensitivity analysis removing Walele, the result was still consistent with no difference, though the point estimate was greater in magnitude. Data from one study at high risk of bias showed no difference in PEF (peak expiratory flow 25‐75 (litres/minute)) (387 participants, MD ‐7.10, 95% CI ‐29.14 to 14.94; ). The one study reporting FEV1/FVC (327 participants, MD 1.72, 95% CI 0.74 to 2.70, high risk of bias) favoured nicotine EC ( ) ( ). , which randomized participants to EC or the QuitSmart cigarette substitute, measured change in a number of lung function parameters: direction of effect was mixed across these, with no statistically or clinically significant between‐group differences at 12 weeks ( Supplemental Table 7 ). Two studies, which provided all participants with nicotine EC, measured change in lung function over time: found an increase in peak flow, and found "no significant differences" in airway function ( Supplemental Table 7 ). 

Three trials (all low risk), comparing nicotine EC with non‐nicotine EC, reported the number of participants still using EC at six months or longer. Slightly more participants were still using EC in the nicotine EC arms, but CIs were wide and included no difference (RR 1.15, 95% CI 0.94 to 1.41, I 2 = 30%; 874 participants; ). Data on this outcome from single‐arm studies or RCTs where a study product (i.e. EC) was only provided in one arm can be found in a companion publication ( ) and Supplemental Table 8 . 

Note, studies reported in this section are only those where participants were randomized to different nicotine EC conditions. Comparisons based on nicotine dose Six trials provided data comparing different doses of nicotine in EC (although other studies provided a range of doses, these were not randomly assigned). Only one study provided data on abstinence; in (low risk of bias), quit rates were higher in the higher‐dose arm but the 95% CI included no difference (RR 2.50, 95% CI 0.80 to 7.77; 260 participants; ). Three of the four studies that provided data on adverse events and contributed to this comparison provided them in such a way that the studies could not be pooled. reported "no changes over time or differences between condition", and and did not compare AEs by nicotine strength (see Supplemental Table 1 ). found slightly more participants in the lower‐dose group reported AEs; however, 95% CI incorporated the null and also the possibility that more people experienced AEs in the higher‐dose arm (RR 0.90, 95% CI 0.58 to 1.40; 68 participants; ). In , no serious adverse events were reported in either arm; in , there were more events in the higher‐dose arm but CIs were wide (RR 1.51, 95% CI 0.51 to 4.42; 239 participants; ). In , no serious adverse events occurred ( Supplemental Table 2 ). Point estimates favoured higher‐dose EC and CIs excluded no difference for carbon monoxide and FEV1/FVC (MD ‐0.92, 95% CI ‐1.71 to ‐0.13; 348 participants, 3 studies) ( ), (MD 0.91, 95% CI 0.15, 1.67; 90 participants, 1 industry‐funded study) ( ). Interpretation of did not change when excluding the one study with tobacco/vaping industry funding ( ); includes only this study. There were no clear differences between arms for heart rate, blood pressure, other lung function measures, or NNAL ( ; ; ; ; ; ; all include only one study). More participants in the higher‐dose nicotine group were still using EC at six months or longer, but data were from one study and CIs were wide and included no difference (RR 1.27, 95% CI 0.95 to 1.68; 260 participants; ). In (cross‐over, comparing different doses and different devices), exhaled CO and reported nausea did not differ between devices; self‐reported dizziness was low overall but slightly higher in the higher‐dose arm. Further details can be found in Supplemental Table 1 and Supplemental Table 3 . measured a range of toxicants but did not compare these based on nicotine level assignments ( Supplemental Table 6 ). One further study, , also included comparisons based on nicotine levels (1.8% free‐base nicotine, designated by the authors as 'moderate', and 0.3% free‐base nicotine, designated by the authors as 'low'). This was a factorial trial (unpublished at the time of writing) which, in addition to e‐liquid nicotine content, also manipulated cigarette nicotine content and e‐liquid flavour availability. The authors reported no significant main effects for nicotine content on CO or CEMA, and no statistically significant interactions for these conditions. There also appear to have been no differences in the proportions of people experiencing adverse events, but the study terminated early and was likely underpowered to detect differences. Comparisons based on flavour One study randomized participants to different flavour conditions (1. tobacco flavour only; 2. a choice of flavours) and followed up participants for six months or longer ( , n = 566, industry‐funded, high risk of bias). Quit rates were lower in the choice compared to the tobacco arm, but the CIs were wide and incorporated no difference and a clinically significant increase relative to tobacco flavour (choice versus tobacco, RR 0.80, 95% CI 0.54 to 1.16; ). also reported on product use at six months or longer; again, there was no clear evidence of a difference, but the CIs were wide (choice versus tobacco, RR 1.10, 95% CI 0.86 to 1.40; ). One study ( , n = 300, high risk of bias, vaping/tobacco industry funding) randomized participants to different flavours (tobacco versus menthol) and provided SAE data in a way that could have been used to compute risk ratios, although no SAEs occurred in either arm ( ). NNAL and FEV1/FVC were lower in the tobacco flavour group but CIs were wide and included no difference (MD ‐26.10, 95% CI ‐66.73 to 14.53; ; MD ‐0.46, 95% CI ‐1.67 to 0.75; ). There was no evidence of a difference in FEV1 (MD ‐0.67, 95% CI ‐2.34 to 1.00; ). No other outcomes from this paper were eligible for inclusion in our review. , an industry‐funded, randomized, cross‐over trial, tested the effect of 10 different flavours (as well as nicotine strengths and salt versus free‐base nicotine). Only their data on AE and SAE were eligible for inclusion in our review, but analyses were not reported by flavour ( Supplemental Table 1 ; Supplemental Table 2 ). also contributed data to this comparison, with conditions being tobacco flavours only, or tobacco, fruit, dessert, and mint flavours. No significant main effects or interactions were found for flavours on the outcomes relevant to this review, namely CO and CEMA, and no difference was discernable in the occurrence of AEs. However, as noted above, the study terminated early and hence was underpowered to detect differences. More information on flavour choices across the studies in this review can be found in a companion publication ( ). Comparisons based on device type (high risk of bias) is the only study to directly compare device types (cartridge versus refillable). Outcomes eligible for this review were CO and AE. There was no difference between arms for CO, but CIs were wide (MD 0.70, 95% CI ‐4.98 to 6.38; 32 participants; ). The authors reported "no changes over time or differences between condition" for AEs (see Supplemental Table 1 ). Nicotine salt versus free‐base nicotine One study ( , unclear risk of bias, tobacco/vaping industry funding) contributed data to this comparison. Quit rates and study product use were both similar between arms (RR 1.25, 95% CI 0.85 to 1.83, n = 285; ; and RR 1.07, 95% CI 0.82 to 1.41, n = 227; , respectively). As described above, also tested salt versus free‐base nicotine, but did not provide data broken down by these characteristics for our outcomes of interest ( Supplemental Table 1 ; Supplemental Table 2 ). 

Six trials provided data comparing different doses of nicotine in EC (although other studies provided a range of doses, these were not randomly assigned). Only one study provided data on abstinence; in (low risk of bias), quit rates were higher in the higher‐dose arm but the 95% CI included no difference (RR 2.50, 95% CI 0.80 to 7.77; 260 participants; ). Three of the four studies that provided data on adverse events and contributed to this comparison provided them in such a way that the studies could not be pooled. reported "no changes over time or differences between condition", and and did not compare AEs by nicotine strength (see Supplemental Table 1 ). found slightly more participants in the lower‐dose group reported AEs; however, 95% CI incorporated the null and also the possibility that more people experienced AEs in the higher‐dose arm (RR 0.90, 95% CI 0.58 to 1.40; 68 participants; ). In , no serious adverse events were reported in either arm; in , there were more events in the higher‐dose arm but CIs were wide (RR 1.51, 95% CI 0.51 to 4.42; 239 participants; ). In , no serious adverse events occurred ( Supplemental Table 2 ). Point estimates favoured higher‐dose EC and CIs excluded no difference for carbon monoxide and FEV1/FVC (MD ‐0.92, 95% CI ‐1.71 to ‐0.13; 348 participants, 3 studies) ( ), (MD 0.91, 95% CI 0.15, 1.67; 90 participants, 1 industry‐funded study) ( ). Interpretation of did not change when excluding the one study with tobacco/vaping industry funding ( ); includes only this study. There were no clear differences between arms for heart rate, blood pressure, other lung function measures, or NNAL ( ; ; ; ; ; ; all include only one study). More participants in the higher‐dose nicotine group were still using EC at six months or longer, but data were from one study and CIs were wide and included no difference (RR 1.27, 95% CI 0.95 to 1.68; 260 participants; ). In (cross‐over, comparing different doses and different devices), exhaled CO and reported nausea did not differ between devices; self‐reported dizziness was low overall but slightly higher in the higher‐dose arm. Further details can be found in Supplemental Table 1 and Supplemental Table 3 . measured a range of toxicants but did not compare these based on nicotine level assignments ( Supplemental Table 6 ). One further study, , also included comparisons based on nicotine levels (1.8% free‐base nicotine, designated by the authors as 'moderate', and 0.3% free‐base nicotine, designated by the authors as 'low'). This was a factorial trial (unpublished at the time of writing) which, in addition to e‐liquid nicotine content, also manipulated cigarette nicotine content and e‐liquid flavour availability. The authors reported no significant main effects for nicotine content on CO or CEMA, and no statistically significant interactions for these conditions. There also appear to have been no differences in the proportions of people experiencing adverse events, but the study terminated early and was likely underpowered to detect differences. 

One study randomized participants to different flavour conditions (1. tobacco flavour only; 2. a choice of flavours) and followed up participants for six months or longer ( , n = 566, industry‐funded, high risk of bias). Quit rates were lower in the choice compared to the tobacco arm, but the CIs were wide and incorporated no difference and a clinically significant increase relative to tobacco flavour (choice versus tobacco, RR 0.80, 95% CI 0.54 to 1.16; ). also reported on product use at six months or longer; again, there was no clear evidence of a difference, but the CIs were wide (choice versus tobacco, RR 1.10, 95% CI 0.86 to 1.40; ). One study ( , n = 300, high risk of bias, vaping/tobacco industry funding) randomized participants to different flavours (tobacco versus menthol) and provided SAE data in a way that could have been used to compute risk ratios, although no SAEs occurred in either arm ( ). NNAL and FEV1/FVC were lower in the tobacco flavour group but CIs were wide and included no difference (MD ‐26.10, 95% CI ‐66.73 to 14.53; ; MD ‐0.46, 95% CI ‐1.67 to 0.75; ). There was no evidence of a difference in FEV1 (MD ‐0.67, 95% CI ‐2.34 to 1.00; ). No other outcomes from this paper were eligible for inclusion in our review. , an industry‐funded, randomized, cross‐over trial, tested the effect of 10 different flavours (as well as nicotine strengths and salt versus free‐base nicotine). Only their data on AE and SAE were eligible for inclusion in our review, but analyses were not reported by flavour ( Supplemental Table 1 ; Supplemental Table 2 ). also contributed data to this comparison, with conditions being tobacco flavours only, or tobacco, fruit, dessert, and mint flavours. No significant main effects or interactions were found for flavours on the outcomes relevant to this review, namely CO and CEMA, and no difference was discernable in the occurrence of AEs. However, as noted above, the study terminated early and hence was underpowered to detect differences. More information on flavour choices across the studies in this review can be found in a companion publication ( ). 

(high risk of bias) is the only study to directly compare device types (cartridge versus refillable). Outcomes eligible for this review were CO and AE. There was no difference between arms for CO, but CIs were wide (MD 0.70, 95% CI ‐4.98 to 6.38; 32 participants; ). The authors reported "no changes over time or differences between condition" for AEs (see Supplemental Table 1 ). 

One study ( , unclear risk of bias, tobacco/vaping industry funding) contributed data to this comparison. Quit rates and study product use were both similar between arms (RR 1.25, 95% CI 0.85 to 1.83, n = 285; ; and RR 1.07, 95% CI 0.82 to 1.41, n = 227; , respectively). As described above, also tested salt versus free‐base nicotine, but did not provide data broken down by these characteristics for our outcomes of interest ( Supplemental Table 1 ; Supplemental Table 2 ). 

Although non‐nicotine ECs serve as a 'control group' in our primary analysis, due to their behavioural properties, they can also be considered an intervention in and of themselves. Comparisons included here are: non‐nicotine EC versus NRT; non‐nicotine EC versus behavioural support/not treatment; and non‐nicotine EC as an adjunct to NRT. All contributing data were from randomized controlled trials. None of these studies reported data on change in heart rate, blood pressure, oxygen saturation, toxicants, or lung function. Cessation When comparing non‐nicotine EC to behavioural support only, pooled results from two studies (n = 388; one at high risk of bias, neither reporting tobacco/vaping industry funding) found higher quit rates in participants randomized to non‐nicotine EC, but the confidence interval included the possibility of no difference (RR 1.63, 95% CI 0.81 to 3.25; I 2 = 0%; ). When evaluating non‐nicotine EC as an adjunct to NRT, also found higher quit rates in participants randomized to non‐nicotine EC, although again the confidence interval included no difference (RR 1.67 95% CI 0.50 to 5.53; 624 participants; ). Two studies (n = 314, neither at high risk of bias, neither reporting tobacco/vaping industry funding) compared non‐nicotine EC with NRT ( ; ). The pooled estimate showed no clear evidence of a difference in quit rates between the two interventions (RR 0.99, 95% CI 0.64 to 1.54; I 2 = 36%; ). Adverse events found a higher rate of adverse events in the non‐nicotine EC arm than in behavioural support only, with the confidence interval excluding no difference (RR 1.28, 95% CI 1.13 to 1.44; 248 participants; ). Also comparing non‐nicotine EC to behavioural support, reported that some AEs were lower in the non‐nicotine EC arm, some higher, and others reported at similar rates to the behavioural support arm (overall AE rates were not reported) ( Supplemental Table 1 ). found fewer adverse events in participants receiving non‐nicotine EC + NRT compared to NRT alone, with the confidence interval excluding no difference (RR 0.70, 95% CI 0.53 to 0.91; ). also found that fewer participants receiving non‐nicotine EC reported adverse events than those receiving NRT, with the confidence interval excluding no difference (RR 0.33, 95% CI 0.12 to 0.87; 132 participants; ). Serious adverse events Two studies reported on rates of SAEs when comparing non‐nicotine EC with behavioural support. reported no SAEs in either arm (RR not estimable), whereas found a higher rate of SAEs in the non‐nicotine EC arm than in the behavioural support‐only arm. However, confidence intervals were wide and incorporated clinically significant benefit and clinically significant harm (n = 388; RR 1.19, 95% CI 0.33 to 4.33; ). In , more SAEs occurred in the group randomized to non‐nicotine EC + NRT than in the NRT‐alone group, but the confidence interval included no difference as well as the potential for a clinically significant difference in favour of the intervention (RR 1.69, 95% CI 0.60 to 4.74; ). No SAEs were reported in either arm of (non‐nicotine EC versus NRT) ( ). Carbon monoxide One study investigating the comparison between non‐nicotine EC and NRT reported change in CO between baseline and six‐month follow‐up. The point estimate favoured NRT; however, the CI encompassed both benefit and harm of the intervention (RR 2.00, 95% CI ‐0.50 to 4.50; n = 164; ). 

When comparing non‐nicotine EC to behavioural support only, pooled results from two studies (n = 388; one at high risk of bias, neither reporting tobacco/vaping industry funding) found higher quit rates in participants randomized to non‐nicotine EC, but the confidence interval included the possibility of no difference (RR 1.63, 95% CI 0.81 to 3.25; I 2 = 0%; ). When evaluating non‐nicotine EC as an adjunct to NRT, also found higher quit rates in participants randomized to non‐nicotine EC, although again the confidence interval included no difference (RR 1.67 95% CI 0.50 to 5.53; 624 participants; ). Two studies (n = 314, neither at high risk of bias, neither reporting tobacco/vaping industry funding) compared non‐nicotine EC with NRT ( ; ). The pooled estimate showed no clear evidence of a difference in quit rates between the two interventions (RR 0.99, 95% CI 0.64 to 1.54; I 2 = 36%; ). 

found a higher rate of adverse events in the non‐nicotine EC arm than in behavioural support only, with the confidence interval excluding no difference (RR 1.28, 95% CI 1.13 to 1.44; 248 participants; ). Also comparing non‐nicotine EC to behavioural support, reported that some AEs were lower in the non‐nicotine EC arm, some higher, and others reported at similar rates to the behavioural support arm (overall AE rates were not reported) ( Supplemental Table 1 ). found fewer adverse events in participants receiving non‐nicotine EC + NRT compared to NRT alone, with the confidence interval excluding no difference (RR 0.70, 95% CI 0.53 to 0.91; ). also found that fewer participants receiving non‐nicotine EC reported adverse events than those receiving NRT, with the confidence interval excluding no difference (RR 0.33, 95% CI 0.12 to 0.87; 132 participants; ). 

Two studies reported on rates of SAEs when comparing non‐nicotine EC with behavioural support. reported no SAEs in either arm (RR not estimable), whereas found a higher rate of SAEs in the non‐nicotine EC arm than in the behavioural support‐only arm. However, confidence intervals were wide and incorporated clinically significant benefit and clinically significant harm (n = 388; RR 1.19, 95% CI 0.33 to 4.33; ). In , more SAEs occurred in the group randomized to non‐nicotine EC + NRT than in the NRT‐alone group, but the confidence interval included no difference as well as the potential for a clinically significant difference in favour of the intervention (RR 1.69, 95% CI 0.60 to 4.74; ). No SAEs were reported in either arm of (non‐nicotine EC versus NRT) ( ). 

One study investigating the comparison between non‐nicotine EC and NRT reported change in CO between baseline and six‐month follow‐up. The point estimate favoured NRT; however, the CI encompassed both benefit and harm of the intervention (RR 2.00, 95% CI ‐0.50 to 4.50; n = 164; ). 

Three studies did not provide EC, but instead provided participants with advice on how to use EC to stop smoking; none reported tobacco/vaping industry funding. and were short‐term studies and contributed data to supplemental tables only. However, (low risk of bias) and (high risk of bias) provided sufficient data from long‐term follow‐up to include them in meta‐analysis. In both cases, people received self‐help smoking cessation interventions with information on how to use EC to quit smoking compared to a smoking cessation intervention without the recommendation to use EC. However, specifically recruited people using both combustible cigarettes and EC (dual users) at baseline and only required participants to be combustible cigarette users at baseline. Pooled quit rates provided no clear evidence of a difference between the two types of intervention provided (RR 1.02, 95% CI 0.88 to 1.19; 2652 participants; ). In more AEs occurred in the group receiving advice to use EC to quit; however, confidence intervals included no difference (RR 1.27, 95% CI 0.72 to 2.26; 52 participants; ). No SAEs were reported, so RRs were not estimable ( ). and also reported on EC use at six‐month follow‐up. Data from suggested higher rates of long‐term EC use in the EC advice arm; however, the 95% CI also encompassed the possibility of lower long‐term EC use in the intervention arm (RR 1.77, 95% CI 0.83 to 3.79; ). reported that 64% in the targeted booklet arm, and 66% in the generic booklet arm were still using EC. The latter data could not be incorporated into a meta‐analysis due to uncertainty about the denominator used to calculate percentages. 

Nicotine EC and NRT This section covers two comparisons: studies in which all arms received NRT and participants were randomized to nicotine EC or non‐nicotine EC, and studies in which all participants received NRT and one arm was randomized to nicotine EC, in addition. All studies contributing data were randomized controlled trials. No studies in this group reported data on heart rate, blood pressure, oxygen, or toxicants. Cessation Two trials (both at high risk of bias, both testing refillable devices, neither reporting tobacco/vaping industry funding) in which all participants received NRT compared nicotine EC to non‐nicotine EC. The pooled results favoured nicotine EC, with the CI excluding no difference (RR 1.77, 95% CI 1.07 to 2.94; I 2 = 0%; 1039 participants; ). Three studies (two high risk of bias, one unclear risk; two refillable, one cartridge; none reporting tobacco/vaping industry funding) also compared nicotine EC + NRT to NRT alone. Pooling results from all three studies resulted in high statistical heterogeneity, precluding meta‐analysis (I 2 = 83%). This heterogeneity was driven by the study of a cartridge device (RR 1.00, 95% CI 0.64 to 1.55, 1712 participants) ( ); historically, cartridge devices have had poorer nicotine delivery than refillables. Once this study was removed, heterogeneity disappeared (I 2 = 0%), but only two studies remained. In these two studies, pooled results showed more people quit in the refillable nicotine EC + NRT arm than in the NRT alone arm (RR 3.53, 95% CI 1.93 to 6.44; 980 participants; ). In two of these studies, participants in both groups received nicotine patches but, in , participants in the NRT‐only arm also received a short‐acting form of NRT. Adverse events Three trials in which nicotine ECs were compared to non‐nicotine ECs (both with NRT as an adjunct) reported data on AEs. reported results combined across groups but noted "no significant differences by treatment group" ( Supplemental Table 1 ). Pooled data from the other two studies (one reporting tobacco/vaping industry funding; ) also showed no clear evidence of difference (RR 1.11, 95% CI 0.93 to 1.32, I 2 = 0%; 677 participants; ). As expected due to the low statistical heterogeneity, the two contributing study results had similar interpretations and so removing due to industry funding had no impact. The three trials comparing nicotine EC + NRT to NRT alone that contributed data to this outcome were all at high risk of bias; none reported tobacco/vaping industry funding. Pooled results showed no evidence of a difference in AEs between arms, but with moderate statistical heterogeneity (RR 0.96, 95% CI 0.83 to 1.11; I 2 = 64%; 1984 participants; ). A further trial currently has only very limited information available from a conference abstract and trial registry ( ). This study appears to have trial arms that will allow comparison between nicotine EC + NRT and NRT alone. Data on AEs are reported in the trial registry; however, the way this is currently reported makes it hard to incorporate the data into our meta‐analysis; therefore, data available thus far are reported in Supplemental Table 1 . Serious adverse events Pooled data from two studies (one high risk, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine EC with non‐nicotine EC as adjuncts to NRT showed fewer SAEs in the nicotine EC group than in the non‐nicotine EC group, but the CI included no difference (RR 0.66, 95% CI 0.38 to 1.14; I 2 = 0%; 1069 participants; ). Removing the study with industry funding ( ) had no effect on interpretation. Four studies (all high risk of bias; none reporting tobacco/vaping industry funding) provided data on SAEs and compared nicotine EC + NRT to NRT alone. The pooled estimate favoured the NRT‐alone group, but the CI was wide and included no difference (RR 1.26, 95% CI 0.46 to 3.42: I 2 = 0; 2245 participants; ). As noted above, there is currently very limited data available for . SAE data available thus far are reported in Supplemental Table 2 . Carbon monoxide (which compared nicotine EC + NRT, non‐nicotine EC + NRT, and NRT alone) measured change in CO levels but did not report data in a way that could be pooled. CO declined over time, with the greatest reduction seen in the nicotine EC group (see Supplemental Table 3 ). Pooled data from two studies (one high risk of bias, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine and non‐nicotine EC as adjuncts to NRT found a greater reduction in CO in the nicotine EC group, but the CI included no clear evidence of a clinically significant difference (MD ‐2.58 ppm, 95% CI ‐5.21 to 0.05, I 2 = 77%; 70 participants; ) between groups and there was substantial statistical heterogeneity. We have pooled these studies despite the high I 2 as the individual study effects both showed a benefit of nicotine EC with the difference being in the magnitude of effect. Removing the study at high risk of bias ( ) left only , with the following effect estimate: RR ‐9.10, 95% CI ‐15.83 to ‐2.37; whereas removing the study with industry funding ( ) left only , with the following effect estimate (RR ‐1.40, 95% CI ‐4.26 to 1.46). Lung function , which compared nicotine EC to non‐nicotine EC, in which both groups received NRT, found no between‐group differences in FeNO, FEV1, or FVC ( ; ; ); confidence intervals were wide for all outcomes. Study product use In , at six months, 40% of the patches‐only arm (n = 52) were still using patches and, in the patches + nicotine EC group (n = 317), 22% were using patches only, 45% were using EC only, and 11% were using both patch and EC. In the patches + non‐nicotine EC group (n = 308), 29% were still using patches, 36% were using EC only, and 13% were using both patches and EC. In , there was no difference between arms in product use, but only nine participants contributed data (RR 1.25, 95% CI 0.29 to 5.53; ). Nicotine EC and varenicline One study, (high risk of bias, 92 participants), evaluated nicotine EC and varenicline compared to varenicline alone. The study terminated early due to varenicline supply issues (an international recall), and the only data eligible for inclusion in this review related to AEs and SAEs. There was no evidence of a difference in AEs, though CIs were wide (RR 1.18, 95% CI 0.84 to 1.67; 92 participants; ), and no SAEs occurred ( ). 

This section covers two comparisons: studies in which all arms received NRT and participants were randomized to nicotine EC or non‐nicotine EC, and studies in which all participants received NRT and one arm was randomized to nicotine EC, in addition. All studies contributing data were randomized controlled trials. No studies in this group reported data on heart rate, blood pressure, oxygen, or toxicants. Cessation Two trials (both at high risk of bias, both testing refillable devices, neither reporting tobacco/vaping industry funding) in which all participants received NRT compared nicotine EC to non‐nicotine EC. The pooled results favoured nicotine EC, with the CI excluding no difference (RR 1.77, 95% CI 1.07 to 2.94; I 2 = 0%; 1039 participants; ). Three studies (two high risk of bias, one unclear risk; two refillable, one cartridge; none reporting tobacco/vaping industry funding) also compared nicotine EC + NRT to NRT alone. Pooling results from all three studies resulted in high statistical heterogeneity, precluding meta‐analysis (I 2 = 83%). This heterogeneity was driven by the study of a cartridge device (RR 1.00, 95% CI 0.64 to 1.55, 1712 participants) ( ); historically, cartridge devices have had poorer nicotine delivery than refillables. Once this study was removed, heterogeneity disappeared (I 2 = 0%), but only two studies remained. In these two studies, pooled results showed more people quit in the refillable nicotine EC + NRT arm than in the NRT alone arm (RR 3.53, 95% CI 1.93 to 6.44; 980 participants; ). In two of these studies, participants in both groups received nicotine patches but, in , participants in the NRT‐only arm also received a short‐acting form of NRT. Adverse events Three trials in which nicotine ECs were compared to non‐nicotine ECs (both with NRT as an adjunct) reported data on AEs. reported results combined across groups but noted "no significant differences by treatment group" ( Supplemental Table 1 ). Pooled data from the other two studies (one reporting tobacco/vaping industry funding; ) also showed no clear evidence of difference (RR 1.11, 95% CI 0.93 to 1.32, I 2 = 0%; 677 participants; ). As expected due to the low statistical heterogeneity, the two contributing study results had similar interpretations and so removing due to industry funding had no impact. The three trials comparing nicotine EC + NRT to NRT alone that contributed data to this outcome were all at high risk of bias; none reported tobacco/vaping industry funding. Pooled results showed no evidence of a difference in AEs between arms, but with moderate statistical heterogeneity (RR 0.96, 95% CI 0.83 to 1.11; I 2 = 64%; 1984 participants; ). A further trial currently has only very limited information available from a conference abstract and trial registry ( ). This study appears to have trial arms that will allow comparison between nicotine EC + NRT and NRT alone. Data on AEs are reported in the trial registry; however, the way this is currently reported makes it hard to incorporate the data into our meta‐analysis; therefore, data available thus far are reported in Supplemental Table 1 . Serious adverse events Pooled data from two studies (one high risk, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine EC with non‐nicotine EC as adjuncts to NRT showed fewer SAEs in the nicotine EC group than in the non‐nicotine EC group, but the CI included no difference (RR 0.66, 95% CI 0.38 to 1.14; I 2 = 0%; 1069 participants; ). Removing the study with industry funding ( ) had no effect on interpretation. Four studies (all high risk of bias; none reporting tobacco/vaping industry funding) provided data on SAEs and compared nicotine EC + NRT to NRT alone. The pooled estimate favoured the NRT‐alone group, but the CI was wide and included no difference (RR 1.26, 95% CI 0.46 to 3.42: I 2 = 0; 2245 participants; ). As noted above, there is currently very limited data available for . SAE data available thus far are reported in Supplemental Table 2 . Carbon monoxide (which compared nicotine EC + NRT, non‐nicotine EC + NRT, and NRT alone) measured change in CO levels but did not report data in a way that could be pooled. CO declined over time, with the greatest reduction seen in the nicotine EC group (see Supplemental Table 3 ). Pooled data from two studies (one high risk of bias, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine and non‐nicotine EC as adjuncts to NRT found a greater reduction in CO in the nicotine EC group, but the CI included no clear evidence of a clinically significant difference (MD ‐2.58 ppm, 95% CI ‐5.21 to 0.05, I 2 = 77%; 70 participants; ) between groups and there was substantial statistical heterogeneity. We have pooled these studies despite the high I 2 as the individual study effects both showed a benefit of nicotine EC with the difference being in the magnitude of effect. Removing the study at high risk of bias ( ) left only , with the following effect estimate: RR ‐9.10, 95% CI ‐15.83 to ‐2.37; whereas removing the study with industry funding ( ) left only , with the following effect estimate (RR ‐1.40, 95% CI ‐4.26 to 1.46). Lung function , which compared nicotine EC to non‐nicotine EC, in which both groups received NRT, found no between‐group differences in FeNO, FEV1, or FVC ( ; ; ); confidence intervals were wide for all outcomes. Study product use In , at six months, 40% of the patches‐only arm (n = 52) were still using patches and, in the patches + nicotine EC group (n = 317), 22% were using patches only, 45% were using EC only, and 11% were using both patch and EC. In the patches + non‐nicotine EC group (n = 308), 29% were still using patches, 36% were using EC only, and 13% were using both patches and EC. In , there was no difference between arms in product use, but only nine participants contributed data (RR 1.25, 95% CI 0.29 to 5.53; ). 

Two trials (both at high risk of bias, both testing refillable devices, neither reporting tobacco/vaping industry funding) in which all participants received NRT compared nicotine EC to non‐nicotine EC. The pooled results favoured nicotine EC, with the CI excluding no difference (RR 1.77, 95% CI 1.07 to 2.94; I 2 = 0%; 1039 participants; ). Three studies (two high risk of bias, one unclear risk; two refillable, one cartridge; none reporting tobacco/vaping industry funding) also compared nicotine EC + NRT to NRT alone. Pooling results from all three studies resulted in high statistical heterogeneity, precluding meta‐analysis (I 2 = 83%). This heterogeneity was driven by the study of a cartridge device (RR 1.00, 95% CI 0.64 to 1.55, 1712 participants) ( ); historically, cartridge devices have had poorer nicotine delivery than refillables. Once this study was removed, heterogeneity disappeared (I 2 = 0%), but only two studies remained. In these two studies, pooled results showed more people quit in the refillable nicotine EC + NRT arm than in the NRT alone arm (RR 3.53, 95% CI 1.93 to 6.44; 980 participants; ). In two of these studies, participants in both groups received nicotine patches but, in , participants in the NRT‐only arm also received a short‐acting form of NRT. 

Three trials in which nicotine ECs were compared to non‐nicotine ECs (both with NRT as an adjunct) reported data on AEs. reported results combined across groups but noted "no significant differences by treatment group" ( Supplemental Table 1 ). Pooled data from the other two studies (one reporting tobacco/vaping industry funding; ) also showed no clear evidence of difference (RR 1.11, 95% CI 0.93 to 1.32, I 2 = 0%; 677 participants; ). As expected due to the low statistical heterogeneity, the two contributing study results had similar interpretations and so removing due to industry funding had no impact. The three trials comparing nicotine EC + NRT to NRT alone that contributed data to this outcome were all at high risk of bias; none reported tobacco/vaping industry funding. Pooled results showed no evidence of a difference in AEs between arms, but with moderate statistical heterogeneity (RR 0.96, 95% CI 0.83 to 1.11; I 2 = 64%; 1984 participants; ). A further trial currently has only very limited information available from a conference abstract and trial registry ( ). This study appears to have trial arms that will allow comparison between nicotine EC + NRT and NRT alone. Data on AEs are reported in the trial registry; however, the way this is currently reported makes it hard to incorporate the data into our meta‐analysis; therefore, data available thus far are reported in Supplemental Table 1 . 

Pooled data from two studies (one high risk, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine EC with non‐nicotine EC as adjuncts to NRT showed fewer SAEs in the nicotine EC group than in the non‐nicotine EC group, but the CI included no difference (RR 0.66, 95% CI 0.38 to 1.14; I 2 = 0%; 1069 participants; ). Removing the study with industry funding ( ) had no effect on interpretation. Four studies (all high risk of bias; none reporting tobacco/vaping industry funding) provided data on SAEs and compared nicotine EC + NRT to NRT alone. The pooled estimate favoured the NRT‐alone group, but the CI was wide and included no difference (RR 1.26, 95% CI 0.46 to 3.42: I 2 = 0; 2245 participants; ). As noted above, there is currently very limited data available for . SAE data available thus far are reported in Supplemental Table 2 . 

(which compared nicotine EC + NRT, non‐nicotine EC + NRT, and NRT alone) measured change in CO levels but did not report data in a way that could be pooled. CO declined over time, with the greatest reduction seen in the nicotine EC group (see Supplemental Table 3 ). Pooled data from two studies (one high risk of bias, one unclear; one reporting tobacco/vaping industry funding) comparing nicotine and non‐nicotine EC as adjuncts to NRT found a greater reduction in CO in the nicotine EC group, but the CI included no clear evidence of a clinically significant difference (MD ‐2.58 ppm, 95% CI ‐5.21 to 0.05, I 2 = 77%; 70 participants; ) between groups and there was substantial statistical heterogeneity. We have pooled these studies despite the high I 2 as the individual study effects both showed a benefit of nicotine EC with the difference being in the magnitude of effect. Removing the study at high risk of bias ( ) left only , with the following effect estimate: RR ‐9.10, 95% CI ‐15.83 to ‐2.37; whereas removing the study with industry funding ( ) left only , with the following effect estimate (RR ‐1.40, 95% CI ‐4.26 to 1.46). 

, which compared nicotine EC to non‐nicotine EC, in which both groups received NRT, found no between‐group differences in FeNO, FEV1, or FVC ( ; ; ); confidence intervals were wide for all outcomes. 

In , at six months, 40% of the patches‐only arm (n = 52) were still using patches and, in the patches + nicotine EC group (n = 317), 22% were using patches only, 45% were using EC only, and 11% were using both patch and EC. In the patches + non‐nicotine EC group (n = 308), 29% were still using patches, 36% were using EC only, and 13% were using both patches and EC. In , there was no difference between arms in product use, but only nine participants contributed data (RR 1.25, 95% CI 0.29 to 5.53; ). 

One study, (high risk of bias, 92 participants), evaluated nicotine EC and varenicline compared to varenicline alone. The study terminated early due to varenicline supply issues (an international recall), and the only data eligible for inclusion in this review related to AEs and SAEs. There was no evidence of a difference in AEs, though CIs were wide (RR 1.18, 95% CI 0.84 to 1.67; 92 participants; ), and no SAEs occurred ( ). 

We used fixed‐effect models for all three outcomes. For the cessation and SAE outcomes there was no indication of heterogeneity or inconsistency. The models fit well. The difference between the mean residual deviance and the number of data points was, at most, 2.2 (see Supplemental Table 9 for comparisons across models). Node‐splitting models raised no concerns over local inconsistency, resulting in P values greater than 0.05. For the AE outcome, there was inconsistency in the treatment effect comparing no e‐cigarettes or pharmacotherapy to non‐nicotine e‐cigarettes, as indicated by a node‐splitting model. Only one trial, , contributed direct evidence to this comparison. In this trial, the percentage of patients experiencing at least one AE was large, at 87%. This was the highest percentage in a very wide range (9% to 87%, mean 44%, standard deviation 24%). Percentages that are close to 100 can result in large effect sizes even when the absolute differences between the treatment groups are comparatively small. We believe that the inconsistency was caused by there being only one trial providing direct evidence, which had a high level of AEs, especially in the non‐nicotine e‐cigarette arm at 93%. Overall, results from NMAs were consistent with those from pairwise analyses. They are summarized below, and further details on all can be found in the relevant figures and supplemental files. The comparator for all odds ratios was the reference treatment: no e‐cigarettes or pharmacotherapy. Cessation See for the network map of the cessation outcome. Point estimates were highest for nicotine EC combined with NRT and non‐nicotine EC combined with NRT, though 95% credibility intervals (CrI) were wide for both nodes and overlapped with those of nicotine EC. Overall, data were consistent with those from pairwise meta‐analyses, showing higher quit rates with nicotine EC than with non‐nicotine EC or NRT. Risk ratios (RRs) and corresponding credibility intervals (CrI) for each node are as follows (and illustrated in ): Nicotine EC: RR 1.95, 95% CrI 1.66 to 2.31 Nicotine EC plus single‐form NRT: RR 4.18, 95% CrI 2.20 to 8.55 Non‐nicotine EC: RR 1.34, 95% CrI 0.99 to 1.80 Non‐nicotine EC plus single‐form NRT: RR 2.35, 95% CrI 1.06 to 5.37 Combined NRT: RR 1.07, 95% CrI 0.73 to 1.54 Single‐form NRT: RR 1.37, 95% CrI 1.04 to 1.80 Advice on using EC: RR 1.02, 95% CrI 0.88 to 1.19 When removing studies at high risk of bias, there were insufficient data to generate a point estimate for non‐nicotine EC combined with NRT. The risk ratio of single‐form NRT against no e‐cigarettes or pharmacotherapy changed from 1.37 to 2.25, and became significant, where it had been borderline‐significant in the main analysis. All other interpretations remained unchanged ( Supplemental Table 10 ). Results were not sensitive to the exclusion of studies with tobacco or vaping industry funding ( Supplemental Table 10 ). Adverse events See for the network map of the AE outcome. As can be seen in , CrIs overlapped for all nodes. All interventions tested showed an increase in AEs (non‐serious) compared to control (no e‐cigarette or pharmaceutical intervention), with CrIs excluding no difference for nicotine ECs, non‐nicotine ECs, and single‐form NRTs. The RRs and corresponding CrI for each node are as follows (and illustrated in ): Nicotine EC: RR 1.19, 95% CrI 1.12 to 1.27 Nicotine EC plus single‐form NRT: RR 1.17, 95% CrI 0.92 to 1.48 Non‐nicotine EC: RR 1.20, 95% CrI 1.11 to 1.30 Non‐nicotine EC plus single‐form NRT: RR 1.02, 95% CrI 0.77 to 1.35 Combined NRT: RR 1.07, 95% CrI 0.87 to 1.31 Single‐form NRT: RR 1.24, 95% CrI 1.03 to 1.50 Sensitivity analyses removing studies at high risk of bias and removing studies with tobacco or vaping industry funding did not affect interpretation of the results ( Supplemental Table 10 ). Serious adverse events See for the network map of the SAE outcome. As illustrated in , CrIs were wide, overlapped, and included the possibility of no difference for all nodes, though point estimates were lowest for NRT. Only the point estimate for non‐nicotine EC combined with NRT was consistent with an increase in SAEs compared to the control condition, but here CrI were very wide and also encompassed a clinically significant reduction in SAEs in those receiving the intervention. The RRs and corresponding CrI for each node are as follows (and illustrated in ): Nicotine EC: RR 0.98, 95% CrI 0.72 to 1.35 Nicotine EC plus single‐form NRT: RR 1.01, 95% CrI 0.30 to 4.12 Non‐nicotine EC: RR 1.01, 95% CrI 0.53 to 1.86 Non‐nicotine EC plus single‐form NRT: RR 1.43, 95% CrI 0.43 to 5.78 Combined NRT: RR 0.64, 95% CrI 0.36 to 1.10 Single‐form NRT: RR 0.71, 95% CrI 0.35 to 1.40 When removing studies at high risk of bias, only nicotine EC, non‐nicotine EC, combined NRT, and single‐form NRT had sufficient data to generate point estimates; these were consistent with those from the main model ( Supplemental Table 10 ). When removing studies with tobacco or vaping industry funding, there was still sufficient data for all nodes to be displayed; results were consistent with those from the main analysis ( Supplemental Table 10 ). 

See for the network map of the cessation outcome. Point estimates were highest for nicotine EC combined with NRT and non‐nicotine EC combined with NRT, though 95% credibility intervals (CrI) were wide for both nodes and overlapped with those of nicotine EC. Overall, data were consistent with those from pairwise meta‐analyses, showing higher quit rates with nicotine EC than with non‐nicotine EC or NRT. Risk ratios (RRs) and corresponding credibility intervals (CrI) for each node are as follows (and illustrated in ): Nicotine EC: RR 1.95, 95% CrI 1.66 to 2.31 Nicotine EC plus single‐form NRT: RR 4.18, 95% CrI 2.20 to 8.55 Non‐nicotine EC: RR 1.34, 95% CrI 0.99 to 1.80 Non‐nicotine EC plus single‐form NRT: RR 2.35, 95% CrI 1.06 to 5.37 Combined NRT: RR 1.07, 95% CrI 0.73 to 1.54 Single‐form NRT: RR 1.37, 95% CrI 1.04 to 1.80 Advice on using EC: RR 1.02, 95% CrI 0.88 to 1.19 When removing studies at high risk of bias, there were insufficient data to generate a point estimate for non‐nicotine EC combined with NRT. The risk ratio of single‐form NRT against no e‐cigarettes or pharmacotherapy changed from 1.37 to 2.25, and became significant, where it had been borderline‐significant in the main analysis. All other interpretations remained unchanged ( Supplemental Table 10 ). Results were not sensitive to the exclusion of studies with tobacco or vaping industry funding ( Supplemental Table 10 ). 

See for the network map of the AE outcome. As can be seen in , CrIs overlapped for all nodes. All interventions tested showed an increase in AEs (non‐serious) compared to control (no e‐cigarette or pharmaceutical intervention), with CrIs excluding no difference for nicotine ECs, non‐nicotine ECs, and single‐form NRTs. The RRs and corresponding CrI for each node are as follows (and illustrated in ): Nicotine EC: RR 1.19, 95% CrI 1.12 to 1.27 Nicotine EC plus single‐form NRT: RR 1.17, 95% CrI 0.92 to 1.48 Non‐nicotine EC: RR 1.20, 95% CrI 1.11 to 1.30 Non‐nicotine EC plus single‐form NRT: RR 1.02, 95% CrI 0.77 to 1.35 Combined NRT: RR 1.07, 95% CrI 0.87 to 1.31 Single‐form NRT: RR 1.24, 95% CrI 1.03 to 1.50 Sensitivity analyses removing studies at high risk of bias and removing studies with tobacco or vaping industry funding did not affect interpretation of the results ( Supplemental Table 10 ). 

See for the network map of the SAE outcome. As illustrated in , CrIs were wide, overlapped, and included the possibility of no difference for all nodes, though point estimates were lowest for NRT. Only the point estimate for non‐nicotine EC combined with NRT was consistent with an increase in SAEs compared to the control condition, but here CrI were very wide and also encompassed a clinically significant reduction in SAEs in those receiving the intervention. The RRs and corresponding CrI for each node are as follows (and illustrated in ): Nicotine EC: RR 0.98, 95% CrI 0.72 to 1.35 Nicotine EC plus single‐form NRT: RR 1.01, 95% CrI 0.30 to 4.12 Non‐nicotine EC: RR 1.01, 95% CrI 0.53 to 1.86 Non‐nicotine EC plus single‐form NRT: RR 1.43, 95% CrI 0.43 to 5.78 Combined NRT: RR 0.64, 95% CrI 0.36 to 1.10 Single‐form NRT: RR 0.71, 95% CrI 0.35 to 1.40 When removing studies at high risk of bias, only nicotine EC, non‐nicotine EC, combined NRT, and single‐form NRT had sufficient data to generate point estimates; these were consistent with those from the main model ( Supplemental Table 10 ). When removing studies with tobacco or vaping industry funding, there was still sufficient data for all nodes to be displayed; results were consistent with those from the main analysis ( Supplemental Table 10 ). 

Summary of main results This update includes a further two studies published since the last version (January 2024). Our three main comparisons, nicotine EC compared to NRT, nicotine EC compared to non‐nicotine EC, and nicotine EC compared to behavioural support only/no support continue to show increased quit rates in people assigned to nicotine EC arms. This is high‐certainty for the comparison with NRT, moderate‐certainty for the comparison with non‐nicotine EC, and low‐certainty for the comparison with behavioural support only/no support ( ; ; ). In absolute terms, pooled data suggest an additional two to six people for every 100 would quit smoking with nicotine EC compared to NRT, an additional one to seven people for every 100 would quit smoking with nicotine EC compared to non‐nicotine EC, and an additional three to five people for every 100 would quit smoking with nicotine EC compared to behavioural support only or no support for smoking cessation. Most data come from studies of cartridges and refillable devices, although the number of studies investigating pod devices is increasing, with the two new included studies providing pod devices. There remains moderate certainty of no evidence of a difference in rates of adverse events (AEs) with nicotine EC compared to non‐nicotine EC, and moderate certainty of no evidence of a difference in rates of AEs with nicotine EC compared to NRT. Evidence on AEs and serious adverse events (SAEs) was of low to very low certainty across all other comparisons, due to a paucity of data. Many of the studies that measured SAEs reported no such events in either study arm. For nicotine EC compared to non‐nicotine EC, pooled data suggest no evidence of a difference in the number of people experiencing AEs or SAEs. Conversely, data from comparisons between nicotine EC and behavioural support alone or no support suggest an additional 9 people per 100 assigned to nicotine EC may experience AEs, but with no evidence of a difference in SAEs; this evidence was of low and very low certainty, respectively. As with AEs from other smoking cessation treatments (e.g. NRT, ), AEs in these studies typically related to irritation at site (e.g. dry mouth, cough) and resolved over time. No studies in any of the different comparison conditions detected serious harms considered to be related to EC use. Beyond AEs and SAEs, we consider data on a range of safety‐ and health‐related outcomes, including carbon monoxide and other toxins, lung function, blood pressure, pulse, and oxygen levels. Data on all of these outcome measures were limited; for most outcomes within most comparisons, only one or two studies currently contribute data. A companion paper provides more data on the measured toxicants, analyzing studies based on actual use of ECs and combustible cigarettes ( ). Consistent with findings from this review, the companion paper found that most measured toxicants were lower in people exclusively using EC than those exclusively smoking or those both smoking and using EC. Most measured toxicants were lower in people using both EC and smoking compared to smoking only. We also have data from studies testing nicotine EC as adjuncts to other stop‐smoking treatments. Pooled data from two studies in which all participants received NRT showed that nicotine EC led to higher quit rates than non‐nicotine EC, but we judged both studies to be at high risk of bias, meaning the effect remains uncertain. Three studies compare nicotine EC + NRT to NRT alone. Pooling cessation results from all three studies resulted in high statistical heterogeneity, precluding meta‐analysis, but this heterogeneity was driven by the one study of a cartridge device. When restricting the analyses to refillable devices, heterogeneity disappeared (I 2 = 0%), and results showed more people quit in the nicotine EC + NRT arm than in the NRT alone arm. These results should be treated with caution as one of the two studies was judged to be at high risk of bias, but it does suggest that this is an area where further research is warranted. It is well‐established that combining short‐ and long‐acting forms of NRT ('combined NRT') leads to greater success than single‐form NRT ( ) but, of note, one of the studies showing a benefit of nicotine EC in this comparison compared nicotine EC + patch to short‐acting NRT + patch, suggesting that it is not just the 'combined NRT' effect that is driving increased effectiveness. This review also includes data on the proportion of participants still using the study product (EC or pharmacotherapy) at six months or longer. There remains no clear evidence of a between‐group difference for this outcome, which is also now explored further in a companion publication ( ). We also searched for information investigating any association between withdrawal and smoking cessation, but no studies met our inclusion criteria for this outcome. Findings from the exploratory network meta‐analysis were consistent with those from pairwise meta‐analyses. Overall completeness and applicability of evidence This field of research and EC devices themselves continue to evolve rapidly. This is the fourth update conducted as part of our 'living systematic review' approach, with which we will proceed until at least the end of 2025, meaning we can continue to rapidly incorporate new evidence (see ). This is important, as all but two of our analyses currently demonstrate imprecision. This update incorporates data from 2 July 2023 to 1 February 2024. Subsequent monthly searches will keep the evidence in this review current. Although studies predominantly came from the USA and UK, overall this review covers data from 15 countries. Geographical range in studies may be particularly important in this area, due to the marked differences in EC regulation between countries; for example, studies conducted in countries that limit nicotine dose in EC, or allow only certain EC devices to be tested, may observe less pronounced effects on quitting. This review includes studies on some under‐researched populations, including people not motivated to quit smoking, people with substance misuse disorders, people with serious mental health conditions, people living in socially deprived areas and people experiencing homelessness. Quit rates in these groups are traditionally lower, which may make it more difficult to detect the effects of interventions. However, it could be that these groups may particularly stand to benefit from EC if they are effective because, in absolute terms, conventional cessation methods are often not as effective for them. As well as the rapid pace of research in this field, evolutions in EC technology pose a challenge when considering the applicability of our evidence to the present. We had downgraded the certainty of our data in the 2016 update, as the devices tested in the trials were first‐generation 'cig‐a‐like' devices which did not deliver nicotine well, meaning the studies may have yielded more conservative estimates than would be seen with newer models, as newer devices and models have tended towards improved nicotine delivery. Nicotine delivery is also relevant to the comparator NRT arms tested; use of both a shorter‐ and a longer‐acting form of NRT show the highest success, and it is important that, where possible, this be the comparator chosen for such trials ( ). We no longer downgrade the evidence on this basis as studies with newer device types are now included, although there will always be a time lag between current devices and the research evidence available. Within our primary comparisons, none of the analyses of our primary outcomes signified substantial levels of statistical heterogeneity, despite the fact that different devices were used in the included studies. However, this could be because confidence intervals were wide for individual studies, and does not rule out clinically significant differences in effects between EC types. As further data emerge, we hope to be able to formally test for differences in subgroup analyses, and in head‐to‐head comparisons of different device types. As of this 2024 update, we have only three studies of pod devices contributing to our cessation analyses ( ; ; ). No studies tested newer disposable devices, which data show are growing in popularity ( ; ). There also continues to be little evidence on the impact of different devices, flavours, and nicotine delivery profiles when directly compared to one another, although this update includes the first study that both randomized participants to different flavour conditions and measured smoking cessation at a follow‐up of six months or more. A companion paper explores available data on flavours in more detail but is not as up‐to‐date as this review ( ). The AEs described in both the RCT and cohort studies continue to look similar, regardless of the brand of EC used or nicotine content, with placebo and nicotine‐containing ECs showing similar numbers and types of AEs in direct comparisons. They also reflect what is reported in survey data ( ; ). The structure of our analyses follows the standard practice of the Cochrane Tobacco Addiction Group, i.e. evaluating outcomes on an intention‐to‐treat basis, meaning our pooled results represent the effect of offering an EC intervention. This is different from evaluating the per‐protocol effect, or the effect only on those who use the EC to quit smoking entirely, or continue to smoke whilst also using EC. Although pragmatic and hopefully of use to those designing and delivering interventions, we acknowledge that our intention‐to‐treat approach limits the ability to use the data presented here to draw conclusions about biomarkers in subgroups of participants based on subsequent EC use/smoking profiles. A companion publication attempts to address this deficit ( ). Cessation All three comparisons found effect estimates favouring nicotine EC for smoking cessation. For nicotine EC versus NRT, we continue to judge the evidence to be of high certainty, meaning we are very confident that the true effect lies close to the estimate of the effect. For nicotine EC versus non‐nicotine EC, we continue to judge the evidence to be of moderate certainty, meaning we think the true effect is likely to be close to the estimate of effect. For nicotine EC versus behavioural support only/no support, we continue to judge the evidence to be of low certainty, meaning we have limited confidence in the effect estimate. Nicotine EC versus non‐nicotine EC comparisons isolate the effect of nicotine as provided by an EC, and nicotine EC versus NRT comparisons isolate the effect of the sensorimotor elements provided by an EC. Both of these comparisons find a benefit of nicotine EC for smoking cessation. Therefore, it might logically follow that the comparison between nicotine EC and behavioural support only/no support would find a benefit in favour of nicotine EC, since this comparison would capture both pharmacological and sensorimotor mechanisms of effect. This increases our confidence in the effect of nicotine EC when compared to behavioural support alone or to no support. NRT has also been shown to be more effective than behavioural support alone, further supporting the likelihood that nicotine EC would be more effective than behavioural support alone ( ). Adverse and serious adverse events We have moderate certainty of no evidence of a difference in adverse events for nicotine EC compared to NRT as well as for non‐nicotine EC. For all other outcomes in this category, evidence is of low or very low certainty. Imprecision remains a key issue for these outcomes, and particularly for SAEs. None of the analyses signalled serious harm, nor did complementary data from cohort studies but, unlike our cessation analyses, many of the confidence intervals encompassed the possibility of both clinically significant harm and clinically significant benefit. This uncertainty should reduce as more studies become available. Quality of the evidence We consider the certainty of the evidence as it relates to primary outcomes for our three main comparisons: nicotine EC versus NRT; nicotine EC versus non‐nicotine EC; nicotine EC versus behavioural support only/no support ( ; ; ). The certainty of evidence for all other comparisons and outcomes should be considered very low due to a paucity of data and issues with risk of bias. Our summary of findings tables and assessments of certainty are based on the evidence from randomized controlled trials (RCTs). The cohort studies that we include are all deemed to have high risks of bias, which is inherent in the study design. Data presented from these studies need to be interpreted with caution. However, data from cohort studies were reassuringly consistent with data from RCTs. Risk of bias did not impact on the certainty of evidence for comparisons between nicotine and non‐nicotine EC, or between nicotine EC and NRT. For the latter, we judged all seven studies to be at low or unclear risk of bias overall. For the former, removing one study at high risk of bias increased the effect estimate for our efficacy outcome. Risk of bias decreased our certainty in the effect estimates for our nicotine EC versus behavioural support only/no support comparison as, due to the nature of the comparison, blinding was not possible and different levels of support could lead to bias. All but three of our primary outcomes for our main comparisons were downgraded for imprecision, due to wide confidence intervals and few events. Other than the risk of bias and imprecision, we identified no other issues that decreased the certainty of the primary outcomes for our main comparisons. Due to the small number of studies contributing to individual analyses, we were unable to formally test for publication bias in most cases and cannot rule this out. For the comparison nicotine EC versus behavioural/no support, two of our outcomes had more than 10 studies contributing to meta‐analysis and therefore we did generate funnel plots. The funnel plot for the exhaled carbon monoxide outcome did not show any evidence of publication bias ( ). However, the funnel plot for smoking cessation showed evidence of asymmetry ( ), suggesting that smaller studies showing no benefit of nicotine EC may remain unpublished. We carried out a sensitivity analysis removing the two outlying studies (i.e. the smallest studies showing the most marked effects of EC; ; ) and this did not change the interpretation of the pooled result. Therefore, we did not downgrade the certainty of the evidence for publication bias; however, we will continue to monitor this as the evidence is updated. Potential biases in the review process We consider the review process we used to be robust. For outcome assessment, we followed the standard methods used for Cochrane Tobacco Addiction Review Group cessation reviews. Our search strategy included CENTRAL, which incorporates findings from trial registries, and we were able to capture a number of ongoing studies. However, there may be unpublished data that our searches did not uncover. We also considered participants lost to follow‐up as continuing to smoke, which is standard practice in this field. There are concerns that frequently updating meta‐analyses can lead to issues with multiple testing; we followed Cochrane guidance in conducting this living systematic review and hence do not adjust for multiple testing ( ). Six of our review authors are authors of the included studies. These authors were not involved in the decisions about inclusion of their studies, or in risk of bias assessment for these studies; this approach is standard across all Cochrane reviews (regardless of subject area) and has been approved by the Cochrane editorial office as sufficient to avoid bias. Our review includes studies funded by the tobacco/vaping industry ‐ Cochrane guidelines (not tobacco addiction‐specific) mandate that studies be included regardless of funder, in order that the reviews remain transparent and rigorous. As noted throughout the results section, we removed studies with tobacco or vaping industry funding in sensitivity analyses; our conclusions were unchanged when we did this. This means that studies funded by tobacco or vaping industries do not influence our conclusions. We do not receive any funding from tobacco or vaping industries, and maintain a firm stance of independence. Agreements and disagreements with other studies or reviews This Cochrane review aligns with but updates the conclusions of the 2018 US National Academies of Science, Engineering, and Medicine Consensus Study Report, Public Health Consequences of E‐cigarettes ( ) , which reviewed literature published through August 2017 to address the question, “Do e‐cigarettes help smokers quit smoking combustible tobacco cigarettes?”. Focusing on RCTs and existing systematic reviews, it used a prespecified 'Level of Evidence' framework to develop conclusions. The report’s overall conclusion was that there was “limited evidence that e‐cigarettes may be effective aids to promote smoking cessation.” Based on the RCTs available, it concluded that there was “moderate evidence” that e‐cigarettes containing nicotine were more effective for cessation than e‐cigarettes without nicotine, but “insufficient evidence” about the effectiveness of e‐cigarettes compared to no treatment or to FDA‐approved smoking cessation treatments. Our review differs on this latter point, as we find high‐certainty evidence of benefit when comparing nicotine EC with NRT; this is due to the inclusion of studies published after . Reviews from the Office for Health Improvement and Disparities (formerly Public Health England) conclude that, compared to their 2018 review, there is now stronger evidence that nicotine vaping products are effective for smoking cessation ( ; ). conducted a rapid review; while their pooled analysis also suggested that EC increased quit rates compared to NRT or non‐nicotine EC, they judged the evidence to be of low certainty according to GRADE, driven by imprecision and inconsistency. combined studies with NRT comparators and those with non‐nicotine EC comparators in the same analysis and found moderate statistical heterogeneity; we evaluated these two comparisons separately and did not find evidence of statistical heterogeneity. We include more studies than . reviewed evidence on tobacco cessation interventions for the US Preventive Services Task Force ( ). The authors stated that none of their included EC trials suggested higher rates of serious adverse events; this is in line with our analyses. However, they reported that findings across EC trials were inconsistent for effectiveness, with some finding statistically significant evidence of benefit and some finding no statistically significant difference. They did not conduct statistical meta‐analyses and included five trials, all of which are included in our cessation meta‐analyses. None of our cessation meta‐analyses, which include these trials, detected levels of heterogeneity beyond what would be expected from chance alone. reviewed data both from observational studies and from randomized controlled trials; in the trials, e‐cigarettes were associated with increased smoking cessation (as with our review). In observational studies, ECs were not associated with increased smoking cessation. As discussed in , although we included non‐randomized studies in which an EC intervention is provided in this review, we did not include observational studies in which no EC intervention is provided, due to known issues with confounding. , , and also reviewed evidence from randomized controlled trials and found higher quit rates in people assigned to nicotine EC than to NRT or non‐nicotine EC, although noted that evidence was less clear at longer follow‐up when comparing nicotine EC to counselling alone. only compared nicotine EC with NRT; their pooled estimate showed a higher quit rate with nicotine EC (RR 1.42), but 95% CIs were wide and included the possibility of no difference. They included two studies in their comparison that we do not: one which measured cessation at less than six months and hence was not eligible for inclusion in our cessation analysis, and one in which the nicotine level was so low that we have classified the study as assessing non‐nicotine ( ). The latter introduced statistical heterogeneity to their pooled results. We also include additional studies not available at the time of their analyses. Findings are also broadly consistent with those from other recent reviews regarding safety and markers of harm, with some exceptions. focused only on safety; consistent with our review, they found very low‐ to moderate‐certainty evidence of a range of possible adverse effects, with the most frequently reported being cough, dry mouth, shortness of breath, irritation of the mouth and throat, and headache. Consistent with our review, the studies reviewed by showed that, compared to combustible cigarettes, using ECs led to a substantial reduction in biomarkers of toxicant exposure associated with cigarette smoking; and also agree with this finding. reviewed biomarker findings from clinical studies and also concluded that the use of EC could lead to a significant reduction in exposure to harmful substances compared to traditional cigarettes; this is again consistent with findings from our review. A systematic review of 22 studies found that several carcinogens with a known link to bladder cancer were present in the urine of EC users and recommended further study on the urological safety of ECs ( ). systematically reviewed tobacco‐specific nitrosamine exposure between people smoking, vaping, and doing neither. Exposure to all tobacco‐specific nitrosamines was lower amongst people who vaped compared to people who smoked. Levels were higher amongst people who vaped compared to people who neither vaped nor smoked. reviewed blood pressure findings and concluded that EC may result in short‐term elevations, but that more data are needed; our review also lacks sufficient data to draw any conclusions about blood pressure at one week or longer. A scoping review by looked at the pulmonary health effects of EC and found an association between EC use and negative pulmonary symptoms. EC use resulted in worse outcomes than non‐smoking, but resulted in improved outcomes when compared with combustible cigarette use or dual use of combustible cigarettes and EC. The review by found acute and short‐to‐medium exposure to most potential respiratory toxicants from ECs to be significantly lower than combustible cigarettes, with substantial reductions in some biomarkers. For the respiratory toxicants assessed at long‐term exposure, evidence was moderate. found moderate evidence that exposure to most respiratory toxicants from ECs was similar to non‐use of tobacco or nicotine products. focused on the absolute risks of EC; in this review, we are interested in both their absolute and relative risks in comparison to smoking. carried out a systematic review of randomized and observational studies on the association between EC and cardiovascular health and concluded that EC use was associated with a significant increase in cardiovascular haemodynamic measures and biomarkers. A systematic review by on the acute effects of EC on vascular endothelial function included eight RCTs. Evidence from their pooled analyses indicated that acute inhalation of EC led to negative changes in vascular endothelial function. carried out a systematic review of EC and CC on periodontal health; findings suggested that EC use might be considered a healthier alternative to CC concerning periodontal health. However, harmful effects of EC usage on periodontal health were observed. A network meta‐analysis, with searches up‐to‐date until February 2019, used direct and indirect evidence to compare the effectiveness and safety of ECs to placebo, bupropion, NRT, and varenicline ( ). The evidence was imprecise; however, there was evidence of a benefit of ECs with a nicotine level of 15 mg over placebo. The effect estimate also suggested a benefit of ECs with a 10 mg nicotine level, but the credibility interval indicated the possibility of both benefit and harm. Similarly, when EC was compared with individual pharmacotherapies, the direction of effect was in favour of ECs; however, imprecision means further evidence may change the interpretation of the effect. The safety data for ECs was inconclusive. A second network meta‐analysis also suffered from imprecision when comparing EC and NRT, though CIs were consistent with our results ( ). A component network analysis updating this evidence and investigating additional components of the interventions and studies reports findings consistent with our review. Compared to placebo/no treatment, nicotine e‐cigarettes were associated with an approximate doubling of the odds of successfully quitting smoking at six months or longer (OR 2.37, 95% CrI 1.73 to 3.24; 16 RCTs, 3828 participants), placing them in the top three most effective treatments (alongside varenicline and cytisine). Evidence suggested combination NRT may also be as effective, but the point estimate was lower and this evidence was less certain ( ). SAEs were rare and there was no clear evidence of a difference in the proportion of people experiencing SAEs between those randomized to nicotine e‐cigarettes and to no treatment, or to nicotine replacement therapies or nicotine receptor partial agonists. A systematic review by examined the evidence on the role of EC flavours in quit rates and concluded that the evidence was inconclusive, reflecting highly heterogeneous study definitions and methodological limitations, and called for more high‐quality evidence, ideally from RCTs. Reviews of ECs for policymaking (e.g. ) are often broader in scope than our review, which focuses exclusively on their role in supporting smoking cessation in people who smoke. Outside of smoking cessation, there remain unanswered questions about the impact of EC availability and use, including in young people; we are evaluating this in a separate review ( ). 

This update includes a further two studies published since the last version (January 2024). Our three main comparisons, nicotine EC compared to NRT, nicotine EC compared to non‐nicotine EC, and nicotine EC compared to behavioural support only/no support continue to show increased quit rates in people assigned to nicotine EC arms. This is high‐certainty for the comparison with NRT, moderate‐certainty for the comparison with non‐nicotine EC, and low‐certainty for the comparison with behavioural support only/no support ( ; ; ). In absolute terms, pooled data suggest an additional two to six people for every 100 would quit smoking with nicotine EC compared to NRT, an additional one to seven people for every 100 would quit smoking with nicotine EC compared to non‐nicotine EC, and an additional three to five people for every 100 would quit smoking with nicotine EC compared to behavioural support only or no support for smoking cessation. Most data come from studies of cartridges and refillable devices, although the number of studies investigating pod devices is increasing, with the two new included studies providing pod devices. There remains moderate certainty of no evidence of a difference in rates of adverse events (AEs) with nicotine EC compared to non‐nicotine EC, and moderate certainty of no evidence of a difference in rates of AEs with nicotine EC compared to NRT. Evidence on AEs and serious adverse events (SAEs) was of low to very low certainty across all other comparisons, due to a paucity of data. Many of the studies that measured SAEs reported no such events in either study arm. For nicotine EC compared to non‐nicotine EC, pooled data suggest no evidence of a difference in the number of people experiencing AEs or SAEs. Conversely, data from comparisons between nicotine EC and behavioural support alone or no support suggest an additional 9 people per 100 assigned to nicotine EC may experience AEs, but with no evidence of a difference in SAEs; this evidence was of low and very low certainty, respectively. As with AEs from other smoking cessation treatments (e.g. NRT, ), AEs in these studies typically related to irritation at site (e.g. dry mouth, cough) and resolved over time. No studies in any of the different comparison conditions detected serious harms considered to be related to EC use. Beyond AEs and SAEs, we consider data on a range of safety‐ and health‐related outcomes, including carbon monoxide and other toxins, lung function, blood pressure, pulse, and oxygen levels. Data on all of these outcome measures were limited; for most outcomes within most comparisons, only one or two studies currently contribute data. A companion paper provides more data on the measured toxicants, analyzing studies based on actual use of ECs and combustible cigarettes ( ). Consistent with findings from this review, the companion paper found that most measured toxicants were lower in people exclusively using EC than those exclusively smoking or those both smoking and using EC. Most measured toxicants were lower in people using both EC and smoking compared to smoking only. We also have data from studies testing nicotine EC as adjuncts to other stop‐smoking treatments. Pooled data from two studies in which all participants received NRT showed that nicotine EC led to higher quit rates than non‐nicotine EC, but we judged both studies to be at high risk of bias, meaning the effect remains uncertain. Three studies compare nicotine EC + NRT to NRT alone. Pooling cessation results from all three studies resulted in high statistical heterogeneity, precluding meta‐analysis, but this heterogeneity was driven by the one study of a cartridge device. When restricting the analyses to refillable devices, heterogeneity disappeared (I 2 = 0%), and results showed more people quit in the nicotine EC + NRT arm than in the NRT alone arm. These results should be treated with caution as one of the two studies was judged to be at high risk of bias, but it does suggest that this is an area where further research is warranted. It is well‐established that combining short‐ and long‐acting forms of NRT ('combined NRT') leads to greater success than single‐form NRT ( ) but, of note, one of the studies showing a benefit of nicotine EC in this comparison compared nicotine EC + patch to short‐acting NRT + patch, suggesting that it is not just the 'combined NRT' effect that is driving increased effectiveness. This review also includes data on the proportion of participants still using the study product (EC or pharmacotherapy) at six months or longer. There remains no clear evidence of a between‐group difference for this outcome, which is also now explored further in a companion publication ( ). We also searched for information investigating any association between withdrawal and smoking cessation, but no studies met our inclusion criteria for this outcome. Findings from the exploratory network meta‐analysis were consistent with those from pairwise meta‐analyses. 

This field of research and EC devices themselves continue to evolve rapidly. This is the fourth update conducted as part of our 'living systematic review' approach, with which we will proceed until at least the end of 2025, meaning we can continue to rapidly incorporate new evidence (see ). This is important, as all but two of our analyses currently demonstrate imprecision. This update incorporates data from 2 July 2023 to 1 February 2024. Subsequent monthly searches will keep the evidence in this review current. Although studies predominantly came from the USA and UK, overall this review covers data from 15 countries. Geographical range in studies may be particularly important in this area, due to the marked differences in EC regulation between countries; for example, studies conducted in countries that limit nicotine dose in EC, or allow only certain EC devices to be tested, may observe less pronounced effects on quitting. This review includes studies on some under‐researched populations, including people not motivated to quit smoking, people with substance misuse disorders, people with serious mental health conditions, people living in socially deprived areas and people experiencing homelessness. Quit rates in these groups are traditionally lower, which may make it more difficult to detect the effects of interventions. However, it could be that these groups may particularly stand to benefit from EC if they are effective because, in absolute terms, conventional cessation methods are often not as effective for them. As well as the rapid pace of research in this field, evolutions in EC technology pose a challenge when considering the applicability of our evidence to the present. We had downgraded the certainty of our data in the 2016 update, as the devices tested in the trials were first‐generation 'cig‐a‐like' devices which did not deliver nicotine well, meaning the studies may have yielded more conservative estimates than would be seen with newer models, as newer devices and models have tended towards improved nicotine delivery. Nicotine delivery is also relevant to the comparator NRT arms tested; use of both a shorter‐ and a longer‐acting form of NRT show the highest success, and it is important that, where possible, this be the comparator chosen for such trials ( ). We no longer downgrade the evidence on this basis as studies with newer device types are now included, although there will always be a time lag between current devices and the research evidence available. Within our primary comparisons, none of the analyses of our primary outcomes signified substantial levels of statistical heterogeneity, despite the fact that different devices were used in the included studies. However, this could be because confidence intervals were wide for individual studies, and does not rule out clinically significant differences in effects between EC types. As further data emerge, we hope to be able to formally test for differences in subgroup analyses, and in head‐to‐head comparisons of different device types. As of this 2024 update, we have only three studies of pod devices contributing to our cessation analyses ( ; ; ). No studies tested newer disposable devices, which data show are growing in popularity ( ; ). There also continues to be little evidence on the impact of different devices, flavours, and nicotine delivery profiles when directly compared to one another, although this update includes the first study that both randomized participants to different flavour conditions and measured smoking cessation at a follow‐up of six months or more. A companion paper explores available data on flavours in more detail but is not as up‐to‐date as this review ( ). The AEs described in both the RCT and cohort studies continue to look similar, regardless of the brand of EC used or nicotine content, with placebo and nicotine‐containing ECs showing similar numbers and types of AEs in direct comparisons. They also reflect what is reported in survey data ( ; ). The structure of our analyses follows the standard practice of the Cochrane Tobacco Addiction Group, i.e. evaluating outcomes on an intention‐to‐treat basis, meaning our pooled results represent the effect of offering an EC intervention. This is different from evaluating the per‐protocol effect, or the effect only on those who use the EC to quit smoking entirely, or continue to smoke whilst also using EC. Although pragmatic and hopefully of use to those designing and delivering interventions, we acknowledge that our intention‐to‐treat approach limits the ability to use the data presented here to draw conclusions about biomarkers in subgroups of participants based on subsequent EC use/smoking profiles. A companion publication attempts to address this deficit ( ). Cessation All three comparisons found effect estimates favouring nicotine EC for smoking cessation. For nicotine EC versus NRT, we continue to judge the evidence to be of high certainty, meaning we are very confident that the true effect lies close to the estimate of the effect. For nicotine EC versus non‐nicotine EC, we continue to judge the evidence to be of moderate certainty, meaning we think the true effect is likely to be close to the estimate of effect. For nicotine EC versus behavioural support only/no support, we continue to judge the evidence to be of low certainty, meaning we have limited confidence in the effect estimate. Nicotine EC versus non‐nicotine EC comparisons isolate the effect of nicotine as provided by an EC, and nicotine EC versus NRT comparisons isolate the effect of the sensorimotor elements provided by an EC. Both of these comparisons find a benefit of nicotine EC for smoking cessation. Therefore, it might logically follow that the comparison between nicotine EC and behavioural support only/no support would find a benefit in favour of nicotine EC, since this comparison would capture both pharmacological and sensorimotor mechanisms of effect. This increases our confidence in the effect of nicotine EC when compared to behavioural support alone or to no support. NRT has also been shown to be more effective than behavioural support alone, further supporting the likelihood that nicotine EC would be more effective than behavioural support alone ( ). Adverse and serious adverse events We have moderate certainty of no evidence of a difference in adverse events for nicotine EC compared to NRT as well as for non‐nicotine EC. For all other outcomes in this category, evidence is of low or very low certainty. Imprecision remains a key issue for these outcomes, and particularly for SAEs. None of the analyses signalled serious harm, nor did complementary data from cohort studies but, unlike our cessation analyses, many of the confidence intervals encompassed the possibility of both clinically significant harm and clinically significant benefit. This uncertainty should reduce as more studies become available. 

All three comparisons found effect estimates favouring nicotine EC for smoking cessation. For nicotine EC versus NRT, we continue to judge the evidence to be of high certainty, meaning we are very confident that the true effect lies close to the estimate of the effect. For nicotine EC versus non‐nicotine EC, we continue to judge the evidence to be of moderate certainty, meaning we think the true effect is likely to be close to the estimate of effect. For nicotine EC versus behavioural support only/no support, we continue to judge the evidence to be of low certainty, meaning we have limited confidence in the effect estimate. Nicotine EC versus non‐nicotine EC comparisons isolate the effect of nicotine as provided by an EC, and nicotine EC versus NRT comparisons isolate the effect of the sensorimotor elements provided by an EC. Both of these comparisons find a benefit of nicotine EC for smoking cessation. Therefore, it might logically follow that the comparison between nicotine EC and behavioural support only/no support would find a benefit in favour of nicotine EC, since this comparison would capture both pharmacological and sensorimotor mechanisms of effect. This increases our confidence in the effect of nicotine EC when compared to behavioural support alone or to no support. NRT has also been shown to be more effective than behavioural support alone, further supporting the likelihood that nicotine EC would be more effective than behavioural support alone ( ). 

We have moderate certainty of no evidence of a difference in adverse events for nicotine EC compared to NRT as well as for non‐nicotine EC. For all other outcomes in this category, evidence is of low or very low certainty. Imprecision remains a key issue for these outcomes, and particularly for SAEs. None of the analyses signalled serious harm, nor did complementary data from cohort studies but, unlike our cessation analyses, many of the confidence intervals encompassed the possibility of both clinically significant harm and clinically significant benefit. This uncertainty should reduce as more studies become available. 

We consider the certainty of the evidence as it relates to primary outcomes for our three main comparisons: nicotine EC versus NRT; nicotine EC versus non‐nicotine EC; nicotine EC versus behavioural support only/no support ( ; ; ). The certainty of evidence for all other comparisons and outcomes should be considered very low due to a paucity of data and issues with risk of bias. Our summary of findings tables and assessments of certainty are based on the evidence from randomized controlled trials (RCTs). The cohort studies that we include are all deemed to have high risks of bias, which is inherent in the study design. Data presented from these studies need to be interpreted with caution. However, data from cohort studies were reassuringly consistent with data from RCTs. Risk of bias did not impact on the certainty of evidence for comparisons between nicotine and non‐nicotine EC, or between nicotine EC and NRT. For the latter, we judged all seven studies to be at low or unclear risk of bias overall. For the former, removing one study at high risk of bias increased the effect estimate for our efficacy outcome. Risk of bias decreased our certainty in the effect estimates for our nicotine EC versus behavioural support only/no support comparison as, due to the nature of the comparison, blinding was not possible and different levels of support could lead to bias. All but three of our primary outcomes for our main comparisons were downgraded for imprecision, due to wide confidence intervals and few events. Other than the risk of bias and imprecision, we identified no other issues that decreased the certainty of the primary outcomes for our main comparisons. Due to the small number of studies contributing to individual analyses, we were unable to formally test for publication bias in most cases and cannot rule this out. For the comparison nicotine EC versus behavioural/no support, two of our outcomes had more than 10 studies contributing to meta‐analysis and therefore we did generate funnel plots. The funnel plot for the exhaled carbon monoxide outcome did not show any evidence of publication bias ( ). However, the funnel plot for smoking cessation showed evidence of asymmetry ( ), suggesting that smaller studies showing no benefit of nicotine EC may remain unpublished. We carried out a sensitivity analysis removing the two outlying studies (i.e. the smallest studies showing the most marked effects of EC; ; ) and this did not change the interpretation of the pooled result. Therefore, we did not downgrade the certainty of the evidence for publication bias; however, we will continue to monitor this as the evidence is updated. 

We consider the review process we used to be robust. For outcome assessment, we followed the standard methods used for Cochrane Tobacco Addiction Review Group cessation reviews. Our search strategy included CENTRAL, which incorporates findings from trial registries, and we were able to capture a number of ongoing studies. However, there may be unpublished data that our searches did not uncover. We also considered participants lost to follow‐up as continuing to smoke, which is standard practice in this field. There are concerns that frequently updating meta‐analyses can lead to issues with multiple testing; we followed Cochrane guidance in conducting this living systematic review and hence do not adjust for multiple testing ( ). Six of our review authors are authors of the included studies. These authors were not involved in the decisions about inclusion of their studies, or in risk of bias assessment for these studies; this approach is standard across all Cochrane reviews (regardless of subject area) and has been approved by the Cochrane editorial office as sufficient to avoid bias. Our review includes studies funded by the tobacco/vaping industry ‐ Cochrane guidelines (not tobacco addiction‐specific) mandate that studies be included regardless of funder, in order that the reviews remain transparent and rigorous. As noted throughout the results section, we removed studies with tobacco or vaping industry funding in sensitivity analyses; our conclusions were unchanged when we did this. This means that studies funded by tobacco or vaping industries do not influence our conclusions. We do not receive any funding from tobacco or vaping industries, and maintain a firm stance of independence. 

This Cochrane review aligns with but updates the conclusions of the 2018 US National Academies of Science, Engineering, and Medicine Consensus Study Report, Public Health Consequences of E‐cigarettes ( ) , which reviewed literature published through August 2017 to address the question, “Do e‐cigarettes help smokers quit smoking combustible tobacco cigarettes?”. Focusing on RCTs and existing systematic reviews, it used a prespecified 'Level of Evidence' framework to develop conclusions. The report’s overall conclusion was that there was “limited evidence that e‐cigarettes may be effective aids to promote smoking cessation.” Based on the RCTs available, it concluded that there was “moderate evidence” that e‐cigarettes containing nicotine were more effective for cessation than e‐cigarettes without nicotine, but “insufficient evidence” about the effectiveness of e‐cigarettes compared to no treatment or to FDA‐approved smoking cessation treatments. Our review differs on this latter point, as we find high‐certainty evidence of benefit when comparing nicotine EC with NRT; this is due to the inclusion of studies published after . Reviews from the Office for Health Improvement and Disparities (formerly Public Health England) conclude that, compared to their 2018 review, there is now stronger evidence that nicotine vaping products are effective for smoking cessation ( ; ). conducted a rapid review; while their pooled analysis also suggested that EC increased quit rates compared to NRT or non‐nicotine EC, they judged the evidence to be of low certainty according to GRADE, driven by imprecision and inconsistency. combined studies with NRT comparators and those with non‐nicotine EC comparators in the same analysis and found moderate statistical heterogeneity; we evaluated these two comparisons separately and did not find evidence of statistical heterogeneity. We include more studies than . reviewed evidence on tobacco cessation interventions for the US Preventive Services Task Force ( ). The authors stated that none of their included EC trials suggested higher rates of serious adverse events; this is in line with our analyses. However, they reported that findings across EC trials were inconsistent for effectiveness, with some finding statistically significant evidence of benefit and some finding no statistically significant difference. They did not conduct statistical meta‐analyses and included five trials, all of which are included in our cessation meta‐analyses. None of our cessation meta‐analyses, which include these trials, detected levels of heterogeneity beyond what would be expected from chance alone. reviewed data both from observational studies and from randomized controlled trials; in the trials, e‐cigarettes were associated with increased smoking cessation (as with our review). In observational studies, ECs were not associated with increased smoking cessation. As discussed in , although we included non‐randomized studies in which an EC intervention is provided in this review, we did not include observational studies in which no EC intervention is provided, due to known issues with confounding. , , and also reviewed evidence from randomized controlled trials and found higher quit rates in people assigned to nicotine EC than to NRT or non‐nicotine EC, although noted that evidence was less clear at longer follow‐up when comparing nicotine EC to counselling alone. only compared nicotine EC with NRT; their pooled estimate showed a higher quit rate with nicotine EC (RR 1.42), but 95% CIs were wide and included the possibility of no difference. They included two studies in their comparison that we do not: one which measured cessation at less than six months and hence was not eligible for inclusion in our cessation analysis, and one in which the nicotine level was so low that we have classified the study as assessing non‐nicotine ( ). The latter introduced statistical heterogeneity to their pooled results. We also include additional studies not available at the time of their analyses. Findings are also broadly consistent with those from other recent reviews regarding safety and markers of harm, with some exceptions. focused only on safety; consistent with our review, they found very low‐ to moderate‐certainty evidence of a range of possible adverse effects, with the most frequently reported being cough, dry mouth, shortness of breath, irritation of the mouth and throat, and headache. Consistent with our review, the studies reviewed by showed that, compared to combustible cigarettes, using ECs led to a substantial reduction in biomarkers of toxicant exposure associated with cigarette smoking; and also agree with this finding. reviewed biomarker findings from clinical studies and also concluded that the use of EC could lead to a significant reduction in exposure to harmful substances compared to traditional cigarettes; this is again consistent with findings from our review. A systematic review of 22 studies found that several carcinogens with a known link to bladder cancer were present in the urine of EC users and recommended further study on the urological safety of ECs ( ). systematically reviewed tobacco‐specific nitrosamine exposure between people smoking, vaping, and doing neither. Exposure to all tobacco‐specific nitrosamines was lower amongst people who vaped compared to people who smoked. Levels were higher amongst people who vaped compared to people who neither vaped nor smoked. reviewed blood pressure findings and concluded that EC may result in short‐term elevations, but that more data are needed; our review also lacks sufficient data to draw any conclusions about blood pressure at one week or longer. A scoping review by looked at the pulmonary health effects of EC and found an association between EC use and negative pulmonary symptoms. EC use resulted in worse outcomes than non‐smoking, but resulted in improved outcomes when compared with combustible cigarette use or dual use of combustible cigarettes and EC. The review by found acute and short‐to‐medium exposure to most potential respiratory toxicants from ECs to be significantly lower than combustible cigarettes, with substantial reductions in some biomarkers. For the respiratory toxicants assessed at long‐term exposure, evidence was moderate. found moderate evidence that exposure to most respiratory toxicants from ECs was similar to non‐use of tobacco or nicotine products. focused on the absolute risks of EC; in this review, we are interested in both their absolute and relative risks in comparison to smoking. carried out a systematic review of randomized and observational studies on the association between EC and cardiovascular health and concluded that EC use was associated with a significant increase in cardiovascular haemodynamic measures and biomarkers. A systematic review by on the acute effects of EC on vascular endothelial function included eight RCTs. Evidence from their pooled analyses indicated that acute inhalation of EC led to negative changes in vascular endothelial function. carried out a systematic review of EC and CC on periodontal health; findings suggested that EC use might be considered a healthier alternative to CC concerning periodontal health. However, harmful effects of EC usage on periodontal health were observed. A network meta‐analysis, with searches up‐to‐date until February 2019, used direct and indirect evidence to compare the effectiveness and safety of ECs to placebo, bupropion, NRT, and varenicline ( ). The evidence was imprecise; however, there was evidence of a benefit of ECs with a nicotine level of 15 mg over placebo. The effect estimate also suggested a benefit of ECs with a 10 mg nicotine level, but the credibility interval indicated the possibility of both benefit and harm. Similarly, when EC was compared with individual pharmacotherapies, the direction of effect was in favour of ECs; however, imprecision means further evidence may change the interpretation of the effect. The safety data for ECs was inconclusive. A second network meta‐analysis also suffered from imprecision when comparing EC and NRT, though CIs were consistent with our results ( ). A component network analysis updating this evidence and investigating additional components of the interventions and studies reports findings consistent with our review. Compared to placebo/no treatment, nicotine e‐cigarettes were associated with an approximate doubling of the odds of successfully quitting smoking at six months or longer (OR 2.37, 95% CrI 1.73 to 3.24; 16 RCTs, 3828 participants), placing them in the top three most effective treatments (alongside varenicline and cytisine). Evidence suggested combination NRT may also be as effective, but the point estimate was lower and this evidence was less certain ( ). SAEs were rare and there was no clear evidence of a difference in the proportion of people experiencing SAEs between those randomized to nicotine e‐cigarettes and to no treatment, or to nicotine replacement therapies or nicotine receptor partial agonists. A systematic review by examined the evidence on the role of EC flavours in quit rates and concluded that the evidence was inconclusive, reflecting highly heterogeneous study definitions and methodological limitations, and called for more high‐quality evidence, ideally from RCTs. Reviews of ECs for policymaking (e.g. ) are often broader in scope than our review, which focuses exclusively on their role in supporting smoking cessation in people who smoke. Outside of smoking cessation, there remain unanswered questions about the impact of EC availability and use, including in young people; we are evaluating this in a separate review ( ). 

Implications for practice Evidence suggesting that nicotine electronic cigarettes (EC) can aid in smoking cessation is consistent across several comparisons. There is high‐certainty evidence that EC with nicotine increases quit rates at six months or longer compared to nicotine replacement therapy (NRT), and moderate‐certainty evidence (limited by imprecision) that EC with nicotine increases quit rates at six months or longer compared to non‐nicotine EC. There is also low‐certainty evidence (limited by risk of bias) that EC with nicotine may increase quit rates compared to behavioural support alone or to no support. Issues with risk of bias, few studies, and differences between studies preclude strong conclusions regarding the effect of nicotine EC when added to NRT, but the data available suggest a benefit. None of the evidence synthesized provides a clear indication that serious adverse events are increased by EC use. However, more long‐term data are needed, and this conclusion relates specifically to people using EC to quit smoking and not to people who have never smoked. The most commonly reported adverse effects are throat/mouth irritation, headache, cough, and nausea, which tend to dissipate with continued use. In some studies, reduced toxin concentrations and biomarkers of harm were observed in people who smoked and switched to vaping, consistent with reductions seen in people who stopped smoking without EC. Implications for research Further randomized controlled trials of nicotine EC are needed. All studies (including uncontrolled intervention cohort studies) should aim to assess the safety profile of EC for as long as possible (the current review only includes data up to two years), and ideally be powered to detect differences in safety outcomes, particularly serious adverse events. Safety results should be presented in both absolute and relative risk terms (in comparison to the risks of continuing to smoke tobacco). Studies with active comparators (i.e. comparing nicotine EC to frontline smoking cessation pharmacotherapies, particularly those other than NRT) are likely to be of particular use to decision‐makers, as are those testing EC as an adjunct to existing stop‐smoking pharmacotherapies; in particular, those testing combinations of traditional NRTs with e‐cigarettes (e.g. patch plus e‐cigarettes). Studies should offer recent devices with good nicotine delivery to participants to be most representative of what will be on the market at the time results are released. Studies should also monitor and collect data on participants switching use of other devices during trials, and use of different flavours and nicotine strengths. Protocols and statistical analysis plans should be registered in advance and openly available. Further RCTs need to be adequately powered. Further trials of pod and newer disposable devices would be of particular value, as would RCTs providing ECs in a way that would be used in real‐world settings (e.g. taking into account individual preferences for strengths and flavours of e‐liquids and even EC devices, and also allowing for changes in preferences over time). Further studies directly comparing nicotine ECs based on characteristics including nicotine content and delivery, flavour, and device type, and reporting outcomes including cessation at six months or longer, would also be particularly useful. Further reviews, using the best available methods, need to be conducted to evaluate the possible relationships between EC use and availability and youth uptake of EC and conventional cigarettes (such as ), as well as the safety of EC use in people who have never smoked. 

 

Protocol first published: Issue 11, 2012 Review first published: Issue 12, 2014 

