Background Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, but some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of eIicacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This is an update of a review first published in 2014. Objectives To examine the eIectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke achieve long-term smoking abstinence. Search methods We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 February 2021, together with reference-checking and contact with study authors. Selection criteria We included randomized controlled trials (RCTs) and randomized cross-over trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. To be included, studies had to report abstinence from cigarettes at six months or longer and/or data on adverse events (AEs) or other markers of safety at one week or longer. Data collection and analysis We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking aOer at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included changes in carbon monoxide, blood pressure, heart rate, blood oxygen saturation, lung function, and levels of known carcinogens/toxicants. We used a fixed-eIect Mantel-Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean diIerences. Where appropriate, we pooled data from these studies in meta-analyses. Main results We included 56 completed studies, representing 12,804 participants, of which 29 were RCTs. Six of the 56 included studies were new to this review update. Of the included studies, we rated five (all contributing to our main comparisons) at low risk of bias overall, 41 at high risk overall (including the 25 non-randomized studies), and the remainder at unclear risk. There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.25 to 2.27; I2 = 0%; 3 studies, 1498 participants). In absolute terms, this might translate to an additional four successful quitters per 100 (95% CI 2 to 8). There was lowcertainty evidence (limited by very serious imprecision) that the rate of occurrence of AEs was similar) (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs occurred rarely, with no evidence that their frequency diIered between nicotine EC and NRT, but very serious imprecision led to low certainty in this finding (RR 1.37, 95% CI 0.77 to 2.41: I2 = n/a; 2 studies, 727 participants). There was moderate-certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.70, 95% CI 1.03 to 2.81; I2 = 0%; 4 studies, 1057 participants). In absolute terms, this might again lead to an additional four successful quitters per 100 (95% CI 0 to 11). These trials mainly used older EC with relatively low nicotine delivery. There was moderate-certainty evidence of no diIerence in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 3 studies, 601 participants). There was insuIicient evidence to determine whether rates of SAEs diIered between groups, due to very serious imprecision (RR 0.60, 95% CI 0.15 to 2.44; I2 = n/a; 4 studies, 494 participants). Compared to behavioral support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.70, 95% CI 1.39 to 5.26; I2 = 0%; 5 studies, 2561 participants). In absolute terms this represents an increase of seven per 100 (95% CI 2 to 17). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was no evidence that the rate of SAEs diIered, but some evidence that non-serious AEs were more common in people randomized to nicotine EC (AEs: RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants; SAEs: RR 1.17, 95% CI 0.33 to 4.09; I2 = 5%; 6 studies, 1011 participants, very low certainty). Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued use. Very few studies reported data on other outcomes or comparisons and hence evidence for these is limited, with confidence intervals oOen encompassing clinically significant harm and benefit. Authors' conclusions There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to ECs without nicotine and compared to NRT. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the size of eIect, particularly when using modern EC products. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, though evidence indicated no diIerence in AEs between nicotine and non-nicotine ECs. Overall incidence of SAEs was low across all study arms. We did not detect any clear evidence of harm from nicotine EC, but longest follow-up was two years and the overall number of studies was small. The evidence is limited mainly by imprecision due to the small number of RCTs, oOen with low event rates. Further RCTs are underway. To ensure the review continues to provide up-to-date information, this review is now a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.
