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 conducted as part of a living systematic review. Objectives To examine the eIectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke tobacco achieve longterm 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 May 2021, and reference-checked and contacted study authors. We screened abstracts from the Society for Research on Nicotine and Tobacco (SRNT) 2021 Annual Meeting. 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. Studies had to report abstinence from cigarettes at six months or longer or data on safety markers at one week or longer, or both. 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 the proportion of people still using study product (EC or pharmacotherapy) at six or more months aOer randomization or starting EC use, changes in carbon monoxide (CO), blood pressure (BP), heart rate, arterial oxygen saturation, lung function, and levels of carcinogens or toxicants or both. We used a fixed-eIect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean diIerences. Where appropriate, we pooled data in meta-analyses. Main results We included 61 completed studies, representing 16,759 participants, of which 34 were RCTs. Five of the 61 included studies were new to this review update. Of the included studies, we rated seven (all contributingto our main comparisons) at low risk of bias overall, 42 at high risk overall (including all 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) 1.53, 95% confidence interval (CI) 1.21 to 1.93; I-2 = 0%; 4 studies, 1924 participants). In absolute terms, this might translate to an additional three quitters per 100 (95% CI 1 to 6). There was low-certainty 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; I-2 = 0%; 2 studies, 485 participants). SAEs were rare, but there was insuIicient evidence to determine whether rates diIered between groups due to very serious imprecision (RR 1.44, 95% CI 0.94 to 2.19: I-2 = 0; 3 studies, 1183 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 1.94, 95% CI 1.21 to 3.13; I-2 = 0%; 5 studies, 1447 participants). In absolute terms, this might lead to an additional seven quitters per 100 (95% CI 2 to 16). 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; I-2 = 0%; 3 studies, 601 participants). There was insuIicient evidence to determine whether rates of SAEs diIered between groups, due to very serious imprecision (RR 0.95, 95% CI 0.52to 1.72; I-2 = 0; 6 studies, 1033 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.61, 95% CI 1.44 to 4.74; I-2 = 0%; 6 studies, 2886 participants). In absolute terms this represents an additional six quitters per 100 (95% CI 2 to 15). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was some evidence that non-serious AEs were more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I-2 = 41%, low certainty; 4 studies, 765 participants), and again, insuIicient evidence to determine whether rates of SAEs diIered between groups (RR 1.51, 95% CI 0.70 to 3.24; I-2 = 0%; 7 studies, 1303 participants). Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued use. Very few studies reported data on other outcomes or comparisons, hence evidence for these is limited, with CIs oOen encompassing clinically significant harm and benefit. Authors' conclusions There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to NRT and compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the eIect size. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no diIerence in AEs between nicotine and non-nicotine ECs. Overall incidence of SAEs was low across all study arms. We did not detect evidence of harm from nicotine EC, but longest follow-up was two years and the number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, oOen with low event rates, but further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, 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.
