Background: Smoking is a major public health problem and widely recognized as one cause of premature morbidity and mortality. No updated evidence to conclude about the certainty of evidence for adopting E-Cigarettes as smoking cessation intervention despite enough debate. We aim to synthesize available evidence to assess the efficacy as well as safety of E-Cigarettes versus different forms of NRT and placebo to quit smoking. Methods: We comprehensively searched of clinical trials in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via PubMed), PsycINFO, Science Direct, Center for reviews and dissemination and HTA database and Trip database. We also searched and WHO International Clinical Trials Registry Platform (ICTRP) portal. We searched grey literature including Dissertations (ProQuest Dissertations and Theses), Web of Science Thomson Reuters: Conference Proceedings Citation Index, and unpublished manuscripts, examined the references of relevant articles, hand searched topic-specific journals and contacted authors for incomplete data. After data extraction, we assessed the risk of bias using the Cochrane RoB 2 tool. We synthesized data by random-effects model through the Mantel-Haenszel method and R software. We conducted subgroup analysis by length of follow-up and sensitivity analysis by restricting to only studies with low risk of bias. We created a summary of findings table based on GRADE approach. Results: We retrieved 12 clinical trials involving 9863 participants. Four studies were judged as low risk of bias across five domains of RoB 2 tool and the rest were judged as unclear risk of bias. CO- validated one-month continuous abstinence rate was significantly higher in E-cigarettes group than control (5 studies, 32.6 vs 23.1%, N = 1970, RR 1.335, 95 % CI 1.068; 1.667, moderate evidence). However, Three-month and six- month abstinence rate didn't differ significantly between E-cigarettes and control groups (3 Studies, 12.1 vs 12.8%, N=1099, RR 1.52, 95% CI 0.348; 6.701) and (7studies, N = 5435,10.2 vs 6.6%, RR 1.347, 95%CI 0.953; 1.903, very low evidence) respectively. There is very low certainty evidence of effect of E-cigarettes compared to control whether NRT or placebo on sustained reduction of 50% or greater in baseline cigarette consumption at different follow-up periods (1 month, 3 studies, 50.9 vs 33.2%, N = 955, RR 1.29, 95 % CI 0.59; 2.82), (3 Month , 3 studies, 43.2 vs 25.3%, N = 1067, RR 1.36, 95 % CI 0.66; 2.79), (6 month , 5 studies, 27.1 vs 13.4%, N = 1981, RR 1.38, 95 % CI 0.90; 2.11) and at 12 month (1 study, 14.5 vs 12%, N = 300, RR 1.21, 95 % CI 0.64; 2.27). Only one study of 884 participants displayed improved point abstinence by 46% (improvement range 17-82%) in E-cigarettes group relative to control at 12 months (1study, 32.7 vs 22.3%, N = 884, RR 1.46, 95 % CI 1.17; 1.82, moderate evidence). E-cigarettes may increase the proportion of serious adverse effect at 6 month-follow up (1 study, 9.3 vs 5.1%, N = 657, RR 1.81, 95 % CI 1.03; 3.19, low evidence) Conclusion: We are uncertain if E-cigarettes improve continuous abstinence rate at short term (1 month). There is very low certainty evidence of the effect of E-cigarettes compared to control whether NRT or placebo on the sustained reduction of 50% or greater in baseline cigarette consumption as well as 7-day point prevalence abstinence rate at 1-,3-, and 6-month follow-up periods. Long term efficacy of E-cigarettes is unknown, and E-cigarettes may increase or have no effects on the proportion of serious adverse effect at 6 months follow up. The information presented are indeed useful for policy makers , public health practitioners, and to encourage further research. Further clinical trials are needed to assess the long-term efficacy and safety of E-cigarettes and ongoing trials are urgently needed to help concluding about the efficacy of E-cigarettes for smoking cessation. Objective: to synthesize evidence about the efficacy of electronic cigarettes versus Nicotine Replacement Therapy and placebo to quit smoking. Data sources: We searched for clinical trials with no publication date restriction until December 2019. The search included CENTRAL, MEDLINE, PsycINFO, Science Direct, Center for reviews and dissemination and HTA database and Trip database, clinical trials registries, gray literature and examined the references of relevant articles. Inclusion and exclusion criteria: Two review authors independently checked the titles and abstracts then the full text of initial hits. Main outcomes were sustained continuous abstinence rate, 7-day point prevalence abstinence rate, sustained reduction of 50% or greater in baseline cigarette consumption and adverse effects. Data extraction and synthesis: Two review authors independently extracted data and assessed risk of bias using the Cochrane RoB 2 tool. We conducted a random-effects model through the Mantel-Haenszel method. Results: We retrieved 12 trials involving 9863 participants. CO-validated 1-month continuous abstinence rate improved by 33% in the e-cigarettes group (range 6-66%, moderate evidence). We are uncertain if e-cigarettess influence continuous abstinence rate at 3-, 6- and 12 months as well as sustained reduction of 50% or greater in baseline cigarette consumption at different follow-up periods. One study of 884 participants displayed improved 12-month 7-day point abstinence by 46% (range 17%-82%). E-cigarettes may increase or do not affect the proportion of serious adverse effect at 6 and 12 months follow up. Conclusion: Very low certainty evidence supported e-cigarettess to help quit smoking in the short term. There is not enough evidence to determine if e-cigarettess are a safe and efficacious means of smoking cessation in the long term (12+ months).
