Title: Pharmacotherapies and electronic cigarettes for smoking cessation: evaluating comparative effectiveness, safety and tolerability using component network meta-analysis
Funder: Department of Health and Social Care

Abstract: Background_x000D_ Tobacco smoking causes many health problems and increases the risk of early death. Quitting smoking can reduce much of this damage and improve mental wellbeing, even after 40 years of smoking. Many people still smoke, and most would like to stop. However, quitting smoking is very difficult and people often need to try several times before they succeed. Treatments can improve the success rate. Some aim to change people’s behaviour through counselling or self-help materials, and others are medications, such as skin patches or tablets. Our previous reviews have shown that the following medicines can help people quit smoking: nicotine replacement therapy (e.g. patch, gum, lozenge), bupropion, nortriptyline, varenicline and cytisine. Our reviews also suggest that electronic cigarettes may help people to quit smoking. However, existing studies and reviews mostly focus on how well each of these treatments work compared with no treatment, rather than compared with each other. What people stopping smoking and doctors prescribing stop smoking medicines want to know is how these medicines compare with one another. Taking medicines for any reason is a trade-off between its benefits and side-effects. Some rare side-effects can be serious enough to require people to go to hospital. Understanding these trade-offs would help people make better decisions on whether to, and which medications or electronic cigarettes to use to support a quit attempt._x000D_ Aim_x000D_ We will examine how stop smoking medicines and electronic cigarettes compare with one another in effectiveness, safety, and likelihood of continuing medication use. We will also look at whether the subtype or dose of medicine, length of treatment, or timing of treatment affects success rates and continuation of medicine use, and whether benefits or side-effects vary across different types of people or depend on the context in which the medication is used, such as with or without the support of a health professional._x000D_ Research methods_x000D_ We will search for studies that test nicotine replacement therapy, bupropion, nortriptyline, varenicline, cytisine or electronic cigarettes in adults who smoke and are trying to quit. To be included, studies must be at least six months long. Two people will decide whether each study should be included in the review and will record key information from the reports of each of these studies. This will include information on the number of people who quit smoking, the number of people who said they had medication side effects, and the number of people who decided to stop taking part in the study because of the medication or electronic cigarette side effects. We will also rate the quality of each study and consider this when explaining our findings. We will analyse the data to compare studies and see if different medications or electronic cigarettes result in different quit rates, side effects and tolerability when compared with each other._x000D_ Sharing findings_x000D_ We will create a plain language summary of our results that we will send to relevant health organisations. We will work with members of the public who smoke or have smoked to explore the best ways to share our findings with the public (e.g. through media briefings), and to ensure that communications are understood by a wide range of audiences (e.g. through clear infographics). We will also publish our results in research papers and present the findings to health professionals and researchers at meetings.

Lay abstract: Research question_x000D_ How comparatively effective, safe and tolerable are different types and combinations of smoking cessation pharmacotherapies and electronic cigarettes for quitting tobacco smoking?_x000D_ Background_x000D_ Tobacco smoking is a leading cause of preventable death and disease, and cessation treatment is extremely cost-effective. A combination of behavioural and pharmacological support boosts smoking quit rates. However, evidence of the most effective, safe and tolerable pharmacological treatments requires updating, and more in-depth investigation, as identified by research prioritisation exercises. Such investigations would identify treatments that deserve an increased focus of efforts and funds on their implementation and promotion worldwide. _x000D_ Aims and objectives_x000D_ To carry out a Cochrane systematic review and component network meta-analyses (cNMAs) investigating the relative effectiveness, safety and tolerability of different smoking cessation pharmacotherapies and electronic cigarettes, both individually and in combination, for helping people to quit tobacco smoking. We will examine whether effects vary by study, participant and intervention characteristics. We will also update three existing Cochrane Reviews of nicotine replacement therapy (NRT), nicotine receptor partial agonists, and antidepressants, for smoking cessation. _x000D_ Methods_x000D_ We will search the Cochrane Tobacco Addiction Group’s specialised register, to identify randomised controlled trials. Eligible trials will test licensed smoking cessation treatments (NRT, varenicline, cytisine, bupropion, nortriptyline) or electronic cigarettes, in adult cigarette smokers attempting to quit, in comparison to no treatment, placebo, or a variation on eligible treatment. Trials must measure smoking cessation at six months follow-up or longer. We will also assess adverse events, serious adverse events and/or withdrawals due to treatment where possible. We will assess eligibility, data extraction and risk of bias in duplicate. We will combine studies in a Bayesian cNMA for each outcome, evaluating components, such as pharmacotherapy type, subtype, dose, plus covariates. We will present results as odds ratios with 95% credibility intervals. We will carry out Cochrane Review updates in-line with their published methods._x000D_ Timelines for delivery_x000D_ Proposed timeline: September 2021 to February 2023. The project will launch with an advisory meeting, with a further meeting mid-way, and one in the final quarter (to inform analyses and dissemination respectively). Following drafting and submission of the primary review protocol, we will search the literature in November 2021, followed by screening, data extraction and update searches. Analyses will begin in June 2022, followed by write-up and submission of all reviews by November 2022, with publication of all reviews by the end of February 2023. _x000D_ Dissemination and impact_x000D_ We will disseminate findings through Cochrane Reviews, a research conference, and a national meeting of health professionals. We will work with the Royal College of Physicians, and members of the public to produce summaries of our findings for clinicians and people who smoke. The findings will provide new evidence on adverse effects, the efficacy of different medication doses and combinations, and how these vary for different populations and co-interventions. It will also inform a further project looking at the optimum combination of behavioural and pharmacological smoking cessation support.

Research activity codes: 6.1 PHARMACEUTICALS;6.3 MEDICAL DEVICES
Health categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;RESPIRATORY;STROKE