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AIM: To determine how varenicline, bupropion, nicotine replacement therapy (NRT) and electronic cigarettes compare with respect to their clinical effectiveness and safety.

METHOD: Systematic reviews and Bayesian network meta-analyses of randomized controlled trials, in any setting, of varenicline, bupropion, NRT and e-cigarettes (in high, standard and low doses, alone or in combination) in adult smokers and smokeless tobacco users with follow-up duration of 24 weeks or greater (effectiveness) or any duration (safety). Nine databases were searched until 19 February 2019. Primary outcomes were sustained tobacco abstinence and serious adverse events (SAEs). We estimated odds ratios (ORs) and treatment rankings and conducted meta-regression to explore covariates.

RESULTS: We identified 363 trials for effectiveness and 355 for safety. Most monotherapies and combination therapies were more effective than placebo at helping participants to achieve sustained abstinence; the most effective of these, estimated with some imprecision, were varenicline standard [OR = 2.83, 95% credible interval (CrI) = 2.34-3.39] and varenicline standard + NRT standard (OR = 5.75, 95% CrI = 2.27-14.88). Estimates were higher in smokers receiving counselling than in those without and in studies with higher baseline nicotine dependence scores than in those with lower scores. Varenicline standard + NRT standard showed a high probability of being ranked best or second-best. For safety, only bupropion at standard dose increased the odds of experiencing SAEs compared with placebo (OR = 1.27, 95% CrI = 1.04-1.58), and we found no evidence of effect modification.

CONCLUSIONS: Most tobacco cessation monotherapies and combination therapies are more effective than placebo at helping participants to achieve sustained abstinence, with varenicline appearing to be most effective based on current evidence. There does not appear to be strong evidence of associations between most tobacco cessation pharmacotherapies and adverse events; however, the data are limited and there is a need for improved reporting of safety data.

Original languageEnglish
Pages (from-to)861-876
Number of pages16
Issue number4
Early online date11 Oct 2021
Publication statusPublished - 8 Mar 2022

Bibliographical note

Funding Information:
K.T. reports grants and other financial support from the National Institute for Health Research (NIHR) for this study. N.W. and M.S. report grants from the National Institute for Health Research during the conduct of the study and Honoraria from the Association of British Pharmaceutical Industry outside the submitted work. D.P. reports grants from the Medical Research Council during the conduct of the study, personal fees from the Association of the British Pharmaceutical Industry and personal fees from UCB outside the submitted work. E.K. reports personal fees from Novartis Pharma and Pfizer outside the submitted work. M.M. reports grants from Pfizer outside the submitted work. J.L.L., E.K. and M.D. were funded by the National Institute for Health Research for the project. The funder of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Funding Information:
The study was funded by the NIHR Health Technology Assessment programme (project number 15/58/18). This publication presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. J.L.L.’s time was also funded by a grant from the Spanish Government (Ministerio de Ciencia e Innovación, project number PID2019‐104033GA‐I00). The authors acknowledge Professor David Gunnell for help with preparing the original project proposal and grant submission, Sarah Dawson and Cath Borwick for help with designing and running search strategies and Olivia Crane and the Public Health Internal Guideline Development team at the National Institute for Health and Care Excellence (NICE) for their collaboration.

Publisher Copyright:
© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Structured keywords

  • HEB


  • adverse events
  • bupropion
  • effectiveness
  • electronic cigarettes
  • network meta-analysis
  • nicotine replacement therapy
  • safety
  • smoking
  • varenicline


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