Nicotine receptor partial agonists for smoking cessation

Abstract

Background

Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). This is an update of a Cochrane Review first published in 2007.

Objectives

To assess the effectiveness of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.

Search methods

We searched the Cochrane Tobacco Addiction Group's Specialised Register in April 2022 for trials, using relevant terms in the title or abstract, or as keywords. The register is compiled from searches of CENTRAL, MEDLINE, Embase, and PsycINFO.

Selection criteria

We included randomised controlled trials that compared the treatment drug with placebo, another smoking cessation drug, e‐cigarettes, or no medication. We excluded trials that did not report a minimum follow‐up period of six months from baseline.

Data collection and analysis

We followed standard Cochrane methods. Our main outcome was abstinence from smoking at longest follow‐up using the most rigorous definition of abstinence, preferring biochemically validated rates where reported. We pooled risk ratios (RRs), using the Mantel‐Haenszel fixed‐effect model. We also reported the number of people reporting serious adverse events (SAEs).

Main results

We included 75 trials of 45,049 people; 45 were new for this update. We rated 22 at low risk of bias, 18 at high risk, and 35 at unclear risk. We found moderate‐certainty evidence (limited by heterogeneity) that cytisine helps more people to quit smoking than placebo (RR 1.30, 95% confidence interval (CI) 1.15 to 1.47; I2 = 83%; 4 studies, 4623 participants), and no evidence of a difference in the number reporting SAEs (RR 1.04, 95% CI 0.78 to 1.37; I2 = 0%; 3 studies, 3781 participants; low‐certainty evidence). SAE evidence was limited by imprecision. We found no data on neuropsychiatric or cardiac SAEs. We found high‐certainty evidence that varenicline helps more people to quit than placebo (RR 2.32, 95% CI 2.15 to 2.51; I2 = 60%, 41 studies, 17,395 participants), and moderate‐certainty evidence that people taking varenicline are more likely to report SAEs than those not taking it (RR 1.23, 95% CI 1.01 to 1.48; I2 = 0%; 26 studies, 14,356 participants). While point estimates suggested increased risk of cardiac SAEs (RR 1.20, 95% CI 0.79 to 1.84; I2 = 0%; 18 studies, 7151 participants; low‐certainty evidence), and decreased risk of neuropsychiatric SAEs (RR 0.89, 95% CI 0.61 to 1.29; I2 = 0%; 22 studies, 7846 participants; low‐certainty evidence), in both cases evidence was limited by imprecision, and confidence intervals were compatible with both benefit and harm. Pooled results from studies that randomised people to receive cytisine or varenicline showed that more people in the varenicline arm quit smoking (RR 0.83, 95% CI 0.66 to 1.05; I2 = 0%; 2 studies, 2131 participants; moderate‐certainty evidence) and reported SAEs (RR 0.67, 95% CI 0.44 to 1.03; I2 = 45%; 2 studies, 2017 participants; low‐certainty evidence). However, the evidence was limited by imprecision, and confidence intervals incorporated the potential for benefit from either cytisine or varenicline. We found no data on neuropsychiatric or cardiac SAEs. We found high‐certainty evidence that varenicline helps more people to quit than bupropion (RR 1.36, 95% CI 1.25 to 1.49; I2 = 0%; 9 studies, 7560 participants), and no clear evidence of difference in rates of SAEs (RR 0.89, 95% CI 0.61 to 1.31; I2 = 0%; 5 studies, 5317 participants), neuropsychiatric SAEs (RR 1.05, 95% CI 0.16 to 7.04; I2 = 10%; 2 studies, 866 participants), or cardiac SAEs (RR 3.17, 95% CI 0.33 to 30.18; I2 = 0%; 2 studies, 866 participants). Evidence of harms was of low certainty, limited by imprecision. We found high‐certainty evidence that varenicline helps more people to quit than a single form of nicotine replacement therapy (NRT) (RR 1.25, 95% CI 1.14 to 1.37; I2 = 28%; 11 studies, 7572 participants), and low‐certainty evidence, limited by imprecision, of fewer reported SAEs (RR 0.70, 95% CI 0.50 to 0.99; I2 = 24%; 6 studies, 6535 participants). We found no data on neuropsychiatric or cardiac SAEs. We found no clear evidence of a difference in quit rates between varenicline and dual‐form NRT (RR 1.02, 95% CI 0.87 to 1.20; I2 = 0%; 5 studies, 2344 participants; low‐certainty evidence, downgraded because of imprecision). While pooled point estimates suggested increased risk of SAEs (RR 2.15, 95% CI 0.49 to 9.46; I2 = 0%; 4 studies, 1852 participants) and neuropsychiatric SAEs (RR 4.69, 95% CI 0.23 to 96.50; I2 not estimable as events only in 1 study; 2 studies, 764 participants), and reduced risk of cardiac SAEs (RR 0.32, 95% CI 0.01 to 7.88; I2 not estimable as events only in 1 study; 2 studies, 819 participants), in all three cases evidence was of low certainty and confidence intervals were very wide, encompassing both substantial harm and benefit.

Authors' conclusions

Cytisine and varenicline both help more people to quit smoking than placebo or no medication. Varenicline is more effective at helping people to quit smoking than bupropion, or a single form of NRT, and may be as or more effective than dual‐form NRT. People taking varenicline are probably more likely to experience SAEs than those not taking it, and while there may be increased risk of cardiac SAEs and decreased risk of neuropsychiatric SAEs, evidence was compatible with both benefit and harm. Cytisine may lead to fewer people reporting SAEs than varenicline. Based on studies that directly compared cytisine and varenicline, there may be a benefit from varenicline for quitting smoking, however further evidence could strengthen this finding or demonstrate a benefit from cytisine. Future trials should test the effectiveness and safety of cytisine compared with varenicline and other pharmacotherapies, and should also test variations in dose and duration. There is limited benefit to be gained from more trials testing the effect of standard‐dose varenicline compared with placebo for smoking cessation. Further trials on varenicline should test variations in dose and duration, and compare varenicline with e‐cigarettes for smoking cessation.

Summary of findings

Background

Description of the condition

Smoking is the main preventable cause of morbidity and premature death worldwide, killing more than 8 million people each year (WHO 2022). It is also a leading cause of health inequalities (ASH 2019). Quitting tobacco smoking significantly reduces risk of tobacco‐related disease and death (USDHHS 2020). There are a range of interventions available to help people quit smoking, including different kinds of behavioural and pharmacological support, but even with the most effective interventions, long‐term quit rates remain relatively low (Livingstone‐Banks 2022a; Rigotti 2022).

Description of the intervention and how it might work

Nicotine receptor partial agonists are a family of drugs that aim to mitigate the addictiveness of tobacco by binding to the α4β2 nicotinic acetylcholine receptor (the receptor that mediates nicotine dependence through released dopamine). When bound to the receptor, a partial agonist prompts the receptor to release dopamine in the way nicotine would, and prevents nicotine from tobacco from binding to the receptor. This reduces nicotine withdrawal symptoms and reduces the rewarding effects of tobacco. There are two main nicotine receptor partial agonists: varenicline and cytisine. A third drug, dianicline, was developed but unfavourable results led to its withdrawal from further development (Kirchhoff 2009).

Varenicline was developed by Pfizer Inc in 1997 (Coe 2005), and was approved as a prescription‐only aid to smoking cessation in 2006 by the American Food and Drug Administration under the trade name Chantix, and by the European Medicines Evaluation Agency under the trade name Champix. In July 2007 it was approved by the National Institute for Health and Clinical Excellence (NICE) for prescribing by the UK National Health Service (ASH 2006; NICE 2007). In 2021, the World Health Organization added varenicline to its Essential Medicines List (WHO 2021). Post‐marketing surveillance raised subsequent concerns about possible links between varenicline and major health risks, including suicidal ideation and behaviour, depression, and serious adverse cardiovascular events (FDA 2008), which led to an FDA warning label in 2009. This warning was removed in 2016 after a large trial found no evidence to support the concerns (EAGLES 2016). In 2021, Pfizer announced a recall of varenicline because it exceeded acceptable intake limits of a nitrosamine impurity, called N‐nitroso‐varenicline. While this is believed to only be temporary, it has led to shortages at the time of writing.

Cytisine was developed in Bulgaria in the 1960s, and is less widely available than varenicline (Foulds 2004; Tutka 2005; Tutka 2006). Its original manufacturer, Sopharma Pharmaceuticals, developed their phytoproduct from the plant Cytisus Laburnum L. (Golden Rain). Although cytisine is not licensed and available for use as a smoking cessation aid across most countries outside Eastern Europe, it works by the same mechanism as varenicline and it is available for substantially less cost (Tutka 2019; Gotti 2021). An important difference between the treatments is that standard treatment with cytisine lasts 25 days, compared with 12 weeks for varenicline.

Why it is important to do this review

The scale of the impact on health from tobacco worldwide makes it imperative that we continue to develop our understanding of smoking cessation interventions. While the effectiveness of varenicline for smoking cessation is well established, substantial questions remain about different doses and durations of treatment, and what impact they have on how effective varenicline is at helping people to quit smoking.

Varenicline is a front‐line smoking cessation medication in many countries, and its current shortage poses a substantial challenge for tobacco control strategies around the world. Learning more about how effective and safe cytisine is for smoking cessation may inform decisions about whether to licence it in countries that have historically relied on varenicline.

This is an update of a Cochrane Review first published in 2007, and most recently updated in 2016. The previous update found high‐certainty evidence of a benefit from varenicline, but only included a limited number of studies testing cytisine for smoking cessation (Cahill 2016). New evidence comparing cytisine with placebo and with varenicline warranted an update of this review.

Objectives

To assess the effectiveness of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) and cluster‐RCTs. We did not include quasi‐randomised studies, in which the allocation sequence is not truly random, for example, studies where participant date of birth determines participant allocation.

Types of participants

We included studies that recruited adult tobacco smokers. Studies testing nicotine receptor partial agonists to help smokeless tobacco users to quit, or as a relapse prevention intervention among people who are already abstinent from smoking tobacco, are covered in separate Cochrane Reviews (Ebbert 2011a; Livingstone‐Banks 2019; Livingstone‐Banks 2022b).

Types of interventions

Selective nicotine receptor partial agonists, including cytisine, dianicline and varenicline (or any other in this class of drug as they reach Phase 3 trial stage), compared with placebo, no medication, or another smoking cessation pharmacotherapy (including nicotine replacement therapy, bupropion, electronic cigarettes, and other nicotine receptor partial agonists). We also included studies that compared different doses and regimes of eligible treatments. Lobeline is covered in an earlier Cochrane Review (Stead 2003). We only included studies that tested the effect of nicotine receptor partial agonists for smoking cessation and not studies focused on harm reduction, which is covered in a separate Cochrane Review (Lindson‐Hawley 2016).

Types of outcome measures

Primary outcomes

• Abstinence from smoked tobacco at longest follow‐up, at least six months from study baseline. We used the strictest definition of abstinence reported in each study (e.g. prolonged or continuous over point prevalence), and where available, we favoured biochemically validated over self‐reported abstinence. We only included studies that measured abstinence from tobacco smoking at six months or longer from baseline.
• Number of participants who experienced the following adverse events: nausea, insomnia, abnormal dreams, headache, depression, and suicidal ideation
• Number of participants who experienced serious adverse events as defined by the authors of included studies
• Number of participants who experienced neuropsychiatric serious adverse events
• Number of participants who experienced cardiac serious adverse events.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Tobacco Addiction Group's Specialised Register for studies, using relevant terms (e.g. 'cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. This Register has been developed from electronic searching of the Cochrane Central Register of Controlled trials (CENTRAL), MEDLINE, Embase, and PsycINFO, together with handsearching of specialist journals, conference proceedings and reference lists of previous trials and overviews. The most recent search of the Register was on 29 April 2022, and included reports of trials indexed in CENTRAL, 2022, Issue 3; MEDLINE (via OVID) to update 20220405; Embase (via OVID) to week 202214; PsycINFO (via OVID) to update 20220404, all from inception. See the Cochrane Tobacco Addiction Group Website for details of the search strategies for these databases. The search strategy for this specific review is listed in Appendix 1. We did not place any limits on our searches (e.g. by language, year of publication, or publication format).

Searching other resources

Our search of the Cochrane Tobacco Addiction Group Specialised Register also covered ongoing and unpublished trials included in the following databases, as these are indexed in CENTRAL.

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov, searched via CENTRAL); and
• World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch, searched via CENTRAL).

We also checked the reference lists of included studies for potentially eligible trials.

Data collection and analysis

Selection of studies

For this update we screened the search results in two stages using the software Covidence. Two review authors (of JL‐B, AT, AH and NL) independently screened the title and abstract of each study found in our searches. We then reviewed the full text of all potentially eligible reports in duplicate. At each stage, we resolved any disagreement through discussion and if needed by referring to a third review author. We noted the reasons for study exclusion at full‐text stage for our PRISMA diagram illustrating the flow of studies (Liberati 2009).

Data extraction and management

Two review authors (of JL‐B, AT, AH, LH, TRF, and KT) independently extracted the following information about each included study in duplicate, using a prepiloted data extraction form. We resolved disagreement through discussion and if needed by referring to a third review author.

• Country and setting (e.g. primary care, community, hospital outpatient/inpatient)
• Method of recruiting participants
• Definition of smoker used
• Methods of randomisation and allocation, and blinding of study personnel, participants and assessors
• Demographic characteristics of participants (e.g. average age, sex, average cigarettes per day)
• Intervention and control description (dose, provider, duration, number of visits, etc.)
• Outcomes including definition of abstinence used, and biochemical validation of cessation
• Proportion of participants with follow‐up data
• Any adverse events
• Declarations of interest and sources of study funding

Assessment of risk of bias in included studies

We assessed each included study using Cochrane's RoB 1 tool for the following domains of risk (Higgins 2011).

• Random sequence generation (selection bias)
• Allocation concealment (selection bias)
• Blinding of participants and study personnel and blinding/objectivity of outcome assessment (performance bias and detection bias)
• Incomplete outcome data (attrition bias)
• Selective reporting (reporting bias)
• Other potential risks of bias. For this domain, we assessed and reported any forms of bias present in studies that did not fall under one of the above domains. Where no relevant form of other potential bias was found, we left this field blank.

Two review authors (of JL‐B, AT, AH, LH, TRF, and KT) independently judged each study as at low, unclear, or high risk of bias for each domain, justifying judgements using information from the study report. We resolved disagreements in judgements through discussion and by referral to a third review author where needed.

Measures of treatment effect

We present estimates of effects for individual studies using risk ratios (RRs), calculated as ((number of events in intervention condition/intervention denominator)/(number of events in control condition/control denominator)), with a 95% confidence interval (CI). An RR greater than one indicates a higher rate of outcome (either smoking abstinence or adverse events) in the intervention group than in the control group.

Unit of analysis issues

As cluster‐randomised trials are eligible for inclusion in this review, there is the potential for unit of analysis issues. Where required, we adjusted for clustering using an intraclass correlation, either from the study in question or from a similar study. Where studies compared more than one eligible intervention arm with a non‐intervention control, we either pooled intervention arms together (assuming they did not differ in pharmacotherapy given) or added them separately to the meta‐analysis and split the control group data evenly between them, to avoid double‐counting any participants in the analysis.

Dealing with missing data

We conducted our analyses on an intention‐to‐treat basis, including all participants in the study arms to which they were randomised, regardless of whether they received the intervention. We counted participants lost to follow‐up as continuing smoking, which is standard in the field (West 2005). Where study reports lacked the information needed for our analyses, we tried to contact study authors to ask for this information. Attempts to contact study authors are recorded in the Characteristics of included studies tables.

Assessment of heterogeneity

To investigate heterogeneity, we used the I² statistic, given by the formula [(Q ‐ df)/Q] × 100%, where Q is the Chi² statistic and df is its degrees of freedom (Higgins 2003). This describes the percentage of variability in effect estimates that is due to heterogeneity rather than to sampling error (chance). We interpreted the I² result using the following overlapping bands (Deeks 2022):

• 0% to 40%: might not be important
• 30% to 60%: may represent moderate heterogeneity
• 50% to 90%: may represent substantial heterogeneity
• 75% to 100%: considerable heterogeneity

Where we found moderate to substantial heterogeneity, we investigated further using subgroup analyses based on study characteristics decided upon through review author consensus. In the event of considerable unexplained statistical heterogeneity (i.e. I² =75% or over), we evaluated whether it was still appropriate to report a pooled result (Deeks 2022).

Assessment of reporting biases

For the two smoking cessation comparisons with 10 or more studies, we assessed the risk of reporting bias using a funnel plot. Regardless of the number of studies included, we considered the possibility of reporting bias in our discussion.

Data synthesis

We conducted a narrative summary of the included studies and, where more than one study reported an outcome comparing an eligible intervention with placebo, no medication, another eligible intervention, or the same intervention delivered with a different dose or regime, we conducted meta‐analyses to pool data from sufficiently similar studies using a Mantel‐Haenszel fixed‐effect model to calculate pooled RRs with 95% CIs.

Subgroup analysis and investigation of heterogeneity

Where studies compared an intervention pharmacotherapy with either placebo or no medication and there was substantial heterogeneity, we considered subgrouping analyses based on comparator and using the I² statistic to test for difference between subgroups and decide whether to report an overall pooling or by subgroup only.

Sensitivity analysis

We conducted sensitivity analyses testing the effect of removing studies we judged to be at high risk of bias to see if those studies affected the overall result. In analyses where we pooled studies that compared an intervention with either placebo or no medication but did not subgroup, we conducted sensitivity analyses testing removing studies comparing against no medication. In our comparison of varenicline versus placebo we also conducted a further ad hoc sensitivity analysis to explore the high level of heterogeneity, removing studies that used an extended treatment course of 24 or 52 weeks rather than the 12 weeks of the other studies.

Because we were primarily interested in whether there is evidence that varenicline works differently for disease‐specific populations and people in specific subgroups and healthcare settings, we conducted sensitivity analyses, treating studies in these populations and settings as subgroups of the main analyses and using the I² statistic to test for subgroup differences.

Summary of findings and assessment of the certainty of the evidence

Following standard Cochrane methods, we produced summary of findings tables for smoking abstinence at longest follow‐up and all of our serious adverse events outcomes for each comparison of varenicline or cytisine with placebo or another pharmacotherapy (Schünemann 2022). Two review authors (JLB, NL) assessed the certainty of the evidence using the five GRADE considerations (risk of bias, inconsistency, imprecision, indirectness, and publication bias (Schünemann 2013).

Results

Description of studies

Results of the search

Our literature searches for this update found 810 studies (from 885 records). After we removed duplicates, 682 studies remained for title and abstract screening. We ruled out 544 studies at this stage, leaving 138 studies for full‐text screening. From this, we identified 45 new included studies and 20 new ongoing studies, combined with studies from previous updates of this review, this resulted in a total of 75 included studies of 45,049 people and 28 ongoing studies. See Figure 1 for PRISMA diagram detailing study flow (Liberati 2009). For this update, we contacted authors of four studies and received additional results data.

1 Study flow diagram of searches for 2022 update (Figure not reproduced here; see the original article.)

For this update, we excluded 14 previously included studies because they focused on relapse prevention (these studies are covered in a separate review; Livingstone‐Banks 2019), or had previously been included for data on harms but did not fully meet our inclusion criteria.

Included studies

Full details of the included studies are given in the Characteristics of included studies tables.

Cytisine

Eight studies in just under 9000 people investigated cytisine as a smoking cessation drug. Four studies compared cytisine with placebo, two with varenicline, one with nicotine replacement therapy (NRT), and one with no medication. Pastorino 2022 also compared longer with shorter duration cytisine. Studies tested cytisine at a dose of 9 mg per day for 20 to 25 days, except for Pastorino 2022, which gave cytisine for 40 and 84 days in different arms.

Studies were conducted in Australia, Bangladesh and Pakistan, Italy, East Germany, Kyrgyzstan, New Zealand, and Poland. Two studies took place in smoking cessation clinics, and two in the community. Walker 2014 recruited people who contacted a national smoking quitline. Vinnikov 2008 was set in a Kyrgyz mining company, and Dogar 2020 took place in tuberculosis treatment centres. Pastorino 2022 recruited heavy smokers participating in a lung‐screening trial.

Varenicline

Sixty‐eight studies of over 37,000 people tested varenicline for smoking cessation. This excludes two studies that compared varenicline with cytisine, which are described above.

Setting

Twenty‐eight studies were conducted in the USA, four in Canada, three in China, three in Japan, two in France, two in Greece, two in India, two in Turkey, one in Australia, one in Iran, one in Denmark, one in Finland, one in Israel, and one in Spain. Fifteen studies took place internationally, in between two and 15 countries. The studies were conducted in smoking cessation clinics, hospitals, universities and other research centres.

Participants

Participants in the majority of trials were adult smokers, willing to make a quit attempt. Several trials were conducted in clinical subgroups, including hospital inpatients (Carson‐Chahhoud 2020; Hong 2015; Le Mao 2020; Steinberg 2011; Windle 2018; Wong 2012), and disease‐specific patient groups: cardiovascular disease (Rigotti 2010; Windle 2018); chronic obstructive pulmonary disease (Hong 2015; Le Mao 2020; Tashkin 2011; Yang 2016); HIV (Ashare 2019; Mercie 2018); asthma (Westergaard 2015); substance use disorder (Nahvi 2014a; Stein 2013); alcohol dependence (Hurt 2018; O'Malley 2018; Zawertailo 2020); depression (Anthenelli 2013; Cinciripini 2018); and bipolar/schizophrenia, schizoaffective disorder (Chengappa 2014; Williams 2012). EAGLES 2016 enrolled two cohorts of adult smokers with and without histories of psychiatric disorders, including primary affective disorders (70%), anxiety disorders (19%), psychotic disorders (9.5%) and personality disorders (0.6%). Gonzales 2014 recruited people who had previously used varenicline in an unsuccessful quit attempt. De Dios 2012 and Ebbert 2016 tested varenicline in light smokers.

Interventions

Forty‐seven trials used the standard 12‐week regimen of varenicline, routinely titrating the first week up to the recommended daily dose of 1 mg twice a day. Nakamura 2007, Nides 2006 and Oncken 2006 tested 1 mg per day, and Niaura 2008 allowed participants to regulate their own dosage throughout the treatment phase. Ebbert 2015 and Stein 2013 tested a 24‐week regimen, and Williams 2007 tested 52 weeks.

Comparators

Forty‐five studies compared varenicline with placebo and five with no medication. Of the 14 studies that compared varenicline with NRT, 12 randomised participants to receive single‐form NRT and five to a combination of two or more forms of NRT (3 studies tested varenicline against both NRT monotherapy and combination NRT). Ten studies compared varenicline with bupropion.

Seven studies compared standard varenicline with either a lower dose (4 studies) or a longer duration (3 studies).

Outcomes

All studies measured smoking cessation at least six months after study baseline. Follow‐up lengths ranged from six months to two years. Many studies biochemically validated abstinence using either exhaled carbon monoxide, or salivary or urinary cotinine.

Thirty‐eight studies measured adverse events, including nausea, insomnia, abnormal dreams, headache, depression, and suicidal ideation. Twenty‐eight measured serious adverse events, neuropsychiatric serious adverse events and cardiac serious adverse events.

Dianicline

One trial investigated dianicline. It was set in 22 sites across six European countries (Tonstad 2011). Dianicline was administered as a 40 mg tablet twice a day for seven weeks, with brief counselling at each contact. Final follow‐up of the participants was at 26 weeks, with self‐reported abstinence verified by expired carbon monoxide and by plasma cotinine samples.

Study funding

Of the trials included in this review, 35 received funds from pharmaceutical companies with interests in the treatment being tested, 13 received free study medications, and four trials without pharmaceutical support had authors who had received funds for other work. Fifteen studies reported no conflicts, and two did not report study funding or author declarations of interests. This is significant because a recent analysis found that authors of opinion pieces on varenicline who reported financial ties to the pharmaceutical industry (as a conflict of interest or funding source) were more likely to minimise the cardiovascular and psychiatric risk of varenicline compared to those without conflicts of interest or industry funding (odds ratio 4.00, 95% CI 1.32 to 12.16 for cardiovascular risk; odds ratio 8.51, 95% CI 3.79 to 19.11 for psychiatric risk; Fabbri 2022).

Excluded studies

We list 95 potentially eligible but ultimately excluded studies, along with reasons for exclusion, in the Characteristics of excluded studies tables. Common reasons for exclusion were following up with participants for less than six months, not randomising participants, testing an eligible intervention for an ineligible purpose (smoking reduction or alcohol dependence), or testing another intervention as an adjunct to an eligible one.

For this update we excluded 14 studies that were included in the previous version of the review. Evins 2014, Tonstad 2006, Tønnesen 2013, and NCT00828113 recruited already abstinent participants and tested varenicline for relapse prevention, a topic covered in a different Cochrane Review (Livingstone‐Banks 2019). We excluded Hajek 2015 because follow‐up was under six months. Brandon 2011, Ebbert 2011b, Faessel 2009, Fagerström 2010, Garza 2011, Hughes 2011, McClure 2013, Meszaros 2013 and Mitchell 2012 were previously included for data on harms only but did not meet all of our prespecified inclusion criteria.

We did not find sufficient information to include or exclude two studies. These are listed in Characteristics of studies awaiting classification.

Ongoing studies

We found 28 eligible ongoing studies, some with multiple relevant comparisons. Studies that tested varenicline compared it with placebo (11 studies), no medication (two studies), bupropion (one study), NRT (seven studies), e‐cigarettes (one study), and different doses or regimes of varenicline (six studies). Studies that tested cytisine compared it with placebo (two studies), varenicline (two studies), NRT (one study), and e‐cigarettes (one study).

Studies were set in various populations and setting, including HIV (three studies), hospital and perioperative patients (three studies), cardiovascular disease (three studies), substance abuse (two studies), mental health (two studies), and single studies in lung cancer, diabetes, chronic obstructive pulmonary disease, adolescents, and e‐cigarette users who smoke.

Further details of the ongoing studies are given in the Characteristics of ongoing studies tables.

Risk of bias in included studies

Overall, we judged 22 studies to be at low risk of bias (low risk of bias across all domains), 18 at high risk of bias (high risk of bias in at least one domain), and the remaining 35 at unclear risk of bias. Our judgements on the risks of bias of all the included studies are summarised in Figure 2 and Figure 3, and reasons for the judgements are detailed in the Characteristics of included studies tables.

2 Risk of bias summary: review authors' judgements about each risk of bias item for each included study (Figure not reproduced here; see the original article.)

3 Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (Figure not reproduced here; see the original article.)

Allocation

We separately assessed allocation bias resulting from randomisation sequence generation and from allocation concealment. We judged 29 studies to be at unclear risk of allocation bias as a result of insufficient information about randomisation sequence generation. The remaining studies were judged at low risk, with none deemed to be at high risk.

We judged one study to be at high risk of allocation bias as a result of inadequate concealment of randomisation because that study's participant allocation was unblinded. We judged 34 studies to be at unclear risk because there was insufficient information to make a judgement. We judged the remaining studies to be at low risk.

Blinding

We judged 10 studies to be at high risk of performance or detection bias because they were open‐label studies without blinding of participant allocation. We judged 13 studies to be at unclear risk because there was insufficient information to make a judgement. The remaining studies were deemed at low risk.

Incomplete outcome data

We judged five studies to be at high risk of attrition bias, four because of either high levels of attrition or highly differential attrition rates between study arms, and one that did not provide a baseline number of participants, and reported only those followed up at 12 months as a denominator (Benli 2017). We judged 20 studies to be at unclear risk because of insufficient reporting of follow‐up rates for us to make a judgement. The remaining studies were deemed at low risk.

Selective reporting

We judged two studies to be at high risk of reporting bias. In Nakamura 2007, continuous abstinence rates for all participants were reported, but demographics, withdrawal and craving measures, and point‐prevalence abstinence were reported for the nicotine‐dependent subset of participants only. The trial registry entry for Tuisku 2016 planned a 12‐month follow‐up, which was not reported in their results paper. However, it is possible that this may be reported in a subsequent paper. We judged 18 studies to be at unclear risk because there was insufficient information to make a judgement; typically because no protocol or trial registry entry was available. We judged the remaining studies to be at low risk.

Other potential sources of bias

We judged two studies to be at high risk of bias for other reasons. For Ioakeimidis 2018, we found only an abstract and poster, which reported different quit rates in the e‐cigarette arm. Zincir 2013 reported that no participants experienced adverse events, which is unlikely given standard definitions of adverse events.

We judged five studies to be at unclear risk of bias from other sources. In Rose 2013, there was a minor unexplained reporting disparity, with different denominators given for the varenicline arm. Walker 2014 supplied cytisine for free, while NRT users had to pay a nominal charge (NZD 3 for an 8‐week course of each NRT item). Le Mao 2020 reported that their small sample size was because of premature interruption of pharmaceutical funding. Cinciripini 2013 began comparing nortriptyline with bupropion, but after three months nortriptyline was changed to varenicline. In Chengappa 2014, four participants in each arm received bupropion for depression. Three out of 15 varenicline quitters and one out of three placebo quitters were on long‐term bupropion.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8

See summary of findings tables (Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8).

Cytisine versus placebo or no medication

Smoking cessation

We pooled five studies that compared cytisine to either placebo or no medication, subgrouping by comparator type (placebo versus no medication). We found evidence of a substantial subgroup difference (I² = 97.3%; Analysis 1.1) and so present the subgroup effects separately here. Four studies, including 4623 participants, compared standard dose cytisine (9 mg per day) with placebo. More people successfully quit smoking in the cytisine arm (RR 1.30, 95% CI 1.15 to 1.47; moderate‐certainty evidence; Analysis 1.1.1), but there was a high level of heterogeneity (I² = 83%). We present the pooled estimate despite this heterogeneity as all point estimates suggested a benefit from cytisine. Pastorino 2022 compared standard‐dose cytisine with no medication. This three‐arm trial tested different durations of cytisine (40 days and 84 days), so we split the control arm. More people randomised to receive cytisine successfully quit than in the no‐medication arm (RR 4.44, 95% CI 3.06 to 6.46; I² = 0%; 869 participants; Analysis 1.1.2).

1.1 AnalysisComparison 1: Cytisine vs placebo or no medication, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

We were unable to conduct our planned sensitivity analysis removing studies at high risk of bias because we judged all studies comparing with placebo to be at low or unclear risk and the sole study comparing with no medication to be at high risk.

Adverse events

None of the studies in this comparison measured our prespecified adverse events outcomes, so we pooled all non‐serious adverse events. Results from four studies of 4052 participants showed that more people randomised to receive cytisine reported experiencing non‐serious adverse events than those randomised to receive placebo or no medication (RR 1.22, 95% CI 1.07 to 1.39; I² = 0%; Analysis 1.2). However, a sensitivity analysis removing one study comparing cytisine with no medication resulted in a confidence interval that crossed the null (RR 1.19, 95% CI 0.97 to 1.46; I² = 0%; 3 studies, 3183 participants).

1.2 AnalysisComparison 1: Cytisine vs placebo or no medication, Outcome 2: Adverse events (Figure not reproduced here; see the original article.)

Serious adverse events

Results from three studies of 3781 participants comparing cytisine with placebo or no medication showed no evidence of difference in the number who experienced serious adverse events (RR 1.04, 95% CI 0.78 to 1.37; I² = 0%; low‐certainty evidence; Analysis 1.3). A sensitivity analysis removing one study comparing cytisine with no medication did not affect the interpretation of this result (RR 1.15, 95% CI 0.79 to 1.67; I² = 0%; 2 studies, 3012 participants). None of the studies measured neuropsychiatric or cardiac serious adverse events.

1.3 AnalysisComparison 1: Cytisine vs placebo or no medication, Outcome 3: Serious adverse events (Figure not reproduced here; see the original article.)

Cytisine: variations in usage

Pastorino 2022 compared 40 days and 84 days of cytisine, and found that more people successfully quit on the longer treatment, although confidence intervals did cross the null, indicating the potential for no difference in the effects (RR 1.28, 95% CI 0.98 to 1.67; 480 participants; Analysis 2.1).

2.1 AnalysisComparison 2: Cytisine: longer vs shorter duration, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

Cytisine versus varenicline

Smoking cessation

Two studies including 2131 people compared standard‐dose cytisine (9 mg per day) with standard‐dose varenicline (2 mg per day). The point estimate showed more people quitting in the varenicline arm, but confidence intervals indicate imprecision and incorporate the potential for no difference or slight benefit from cytisine (RR 0.83, 95% CI 0.66 to 1.05; I² = 0%; moderate‐certainty evidence; point estimate favours varenicline; Analysis 3.1).

3.1 AnalysisComparison 3: Cytisine vs varenicline, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

Adverse events

Two studies of 2017 participants found that people randomised to receive cytisine were less likely to report experiencing nausea (RR 0.41, 95% CI 0.33 to 0.50; I² = 0%; Analysis 3.2) and abnormal dreams (RR 0.60, 95% CI 0.50 to 0.73; I² = 58%; Analysis 3.3) than those in the varenicline arm.

3.2 AnalysisComparison 3: Cytisine vs varenicline, Outcome 2: Nausea (Figure not reproduced here; see the original article.)

3.3 AnalysisComparison 3: Cytisine vs varenicline, Outcome 3: Abnormal dreams (Figure not reproduced here; see the original article.)

The same two studies of 2017 participants, found no evidence of clear differences between the cytisine and varenicline arms in the number of people experiencing insomnia (RR 0.90, 95% CI 0.73 to 1.10; I² = 68%; Analysis 3.4), headaches (RR 1.02, 95% CI 0.79 to 1.33; I² = 0%; Analysis 3.5), and suicidal ideation (RR 0.33, 95% CI 0.01 to 8.02; I² not estimable as events only in 1 study; Analysis 3.7). However, in all cases confidence intervals indicated imprecision, and the potential for more adverse events when using either treatment.

3.4 AnalysisComparison 3: Cytisine vs varenicline, Outcome 4: Insomnia (Figure not reproduced here; see the original article.)

3.5 AnalysisComparison 3: Cytisine vs varenicline, Outcome 5: Headache (Figure not reproduced here; see the original article.)

3.7 AnalysisComparison 3: Cytisine vs varenicline, Outcome 7: Suicidal ideation (Figure not reproduced here; see the original article.)

One study of 679 participants did not find evidence of a clear difference between cytisine and varenicline arms in the number of people experiencing depression (RR 3.04, 95% CI 0.12 to 74.47; Analysis 3.6); however, this result should also be treated with caution because of substantial imprecision.

3.6 AnalysisComparison 3: Cytisine vs varenicline, Outcome 6: Depression (Figure not reproduced here; see the original article.)

Serious adverse events

Two studies of 2017 participants compared the number of people in cytisine and varenicline arms reporting experiencing serious adverse events. The point estimate showed that fewer people in the cytisine arm reported serious adverse events (RR 0.67, 95% CI 0.44 to 1.03; I² = 45%; low‐certainty evidence; point estimate favours cytisine; Analysis 3.8), but confidence intervals did incorporate the potential for no difference. Neither study measured neuropsychiatric or cardiac serious adverse events.

3.8 AnalysisComparison 3: Cytisine vs varenicline, Outcome 8: SAEs (Figure not reproduced here; see the original article.)

Cytisine versus nicotine replacement therapy

Smoking cessation

Walker 2014 provided participants with cytisine, compared with an eight‐week course of NRT, supplied in the form of vouchers that required redemption by participants. Participants in the cytisine arm also received vouchers for NRT to use after their initial 25‐day course of cytisine, and study authors reported that at week one 26 participants were using NRT obtained through the vouchers; only 19 participants used NRT and cytisine concomitantly. This study found that more people in the cytisine arm successfully quit than in the NRT arm (RR 1.43, 95% CI 1.13 to 1.80; 1310 participants; low‐certainty evidence; Analysis 4.1).

4.1 AnalysisComparison 4: Cytisine vs NRT, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

Adverse events

Nausea was the only one of our adverse event outcomes measured. Walker 2014 reported that, compared with people randomised to receive NRT, those in the cytisine arm were more likely to report experiencing nausea (RR 15.00, 95% CI 3.60 to 62.51; 1310 participants; Analysis 4.2).

4.2 AnalysisComparison 4: Cytisine vs NRT, Outcome 2: Nausea (Figure not reproduced here; see the original article.)

Serious adverse events

Walker 2014 did not find evidence of a difference in the rate of serious adverse events between those randomised to receive cytisine or NRT (RR 1.15, 95% CI 0.76 to 1.75; 1310 participants; very low‐certainty evidence; Analysis 4.3). Walker 2014 did not measure neuropsychiatric or cardiac serious adverse events.

4.3 AnalysisComparison 4: Cytisine vs NRT, Outcome 3: SAEs (Figure not reproduced here; see the original article.)

Varenicline versus placebo or no medication

Smoking cessation

We pooled studies that compared varenicline to either placebo or no medication, subgrouping by comparator type (placebo or no medication). We found evidence of a substantial subgroup difference (I² = 95.8%; Analysis 5.1) and so present the subgroup effects separately here. Forty‐six studies compared standard‐dose varenicline (2 mg per day) with either placebo or no medication. Our meta‐analysis found that more people successfully quit smoking when randomised to receive varenicline compared with placebo (RR 2.32, 95% CI 2.15 to 2.51; I² = 60%, 41 studies, 17,395 participants; high‐certainty evidence; Analysis 5.1.1) or with no medication (RR 1.57, 95% CI 1.37 to 1.80; I² = 95%; 5 studies, 1050 participants; Analysis 5.1.2). Despite the substantial heterogeneity in the latter subgroup we present the pooled estimate as all the individual study point estimates suggested a benefit of varenicline.

5.1 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

A sensitivity analysis removing studies at high risk of bias did not reduce the heterogeneity found in the varenicline versus placebo analysis or the interpretation of the effect. However, removing three studies that used an extended treatment course of 24 or 52 weeks rather than the 12 weeks of the other studies, resulted in a minor impact, reducing the I² statistic to 53%. We were unable to conduct a sensitivity analysis removing high risk of bias studies for the varenicline versus no medication analysis, as we judged all studies to be at high risk.

King 2022 tested varenicline combined with NRT patch against NRT patch with a varenicline placebo. We did not include this study in our analysis, but it showed no clear evidence of a difference in quit rates as a result of adding varenicline (RR 0.94, 95% CI 0.51 to 1.72; 122 participants). However, confidence intervals incorporated the possibilities of both an increased and a decreased quit rate, as well as no difference.

Adverse events

Studies comparing varenicline with placebo or no medication found that people randomised to receive varenicline were more likely to report experiencing nausea (RR 2.61, 95% CI 2.44 to 2.80; I² = 79%; 36 studies, 17,080 participants; Analysis 5.2), insomnia (RR 1.37, 95% CI 1.27 to 1.47; I² = 29%; 35 studies, 16,803 participants; Analysis 5.3), abnormal dreams (RR 1.82, 95% CI 1.67 to 1.97; I² = 70%; 32 studies, 16,211 participants; Analysis 5.4), and headaches (RR 1.11, 95% CI 1.03 to 1.19; I² = 30%; 31 studies, 16,326 participants; Analysis 5.5). Statistical heterogeneity was substantial in our analyses for nausea and abnormal dreams, but we decided to present the pooled estimate because the point estimates of individuals studies were almost entirely in the same direction.

5.2 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 2: Nausea (Figure not reproduced here; see the original article.)

5.3 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 3: Insomnia (Figure not reproduced here; see the original article.)

5.4 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 4: Abnormal dreams (Figure not reproduced here; see the original article.)

5.5 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 5: Headache (Figure not reproduced here; see the original article.)

Studies comparing varenicline with placebo or no medication did not find clear evidence of difference in the numbers of participants who reported experiencing depression (RR 1.05, 95% CI 0.91 to 1.20; I² = 0%; 32 studies, 15,922 participants; Analysis 5.6), and found fewer people reporting suicidal ideation in the varenicline arm (RR 0.69, 95% CI 0.44 to 1.08; I² = 0%; 22 studies, 12,343 participants; Analysis 5.7). However, confidence intervals indicated imprecision, and included the potential for harm as well as no difference.

5.6 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 6: Depression (Figure not reproduced here; see the original article.)

5.7 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 7: Suicidal ideation (Figure not reproduced here; see the original article.)

We conducted sensitivity analyses removing studies comparing varenicline with no medication rather than placebo, but this had no substantial impact on heterogeneity or results.

Serious adverse event

Serious adverse events

Twenty‐six studies of 14,356 participants found that more people randomised to receive varenicline reported experiencing serious adverse events than those randomised to receive placebo or no medication (RR 1.23, 95% CI 1.01 to 1.48; I² = 0%; moderate‐certainty evidence; Analysis 5.8). Absolute rates for serious adverse events were 3.3% and 2.7% in varenicline and control arms respectively. King 2022 tested varenicline combined with NRT patch against NRT patch with a varenicline placebo. We did not include this study in our analysis, but it reported two participants with serious adverse events in the varenicline arm and none in the NRT‐alone arm. A sensitivity analysis removing one study comparing varenicline with no medication had no substantial impact on this result.

5.8 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 8: SAEs (Figure not reproduced here; see the original article.)

Neuropsychiatric serious adverse events

The point estimate from pooling 22 studies of 7846 people showed that fewer people reported experiencing neuropsychiatric serious adverse events in the varenicline arm compared with placebo or no medication (RR 0.89, 95% CI 0.61 to 1.29; I² = 0%; low‐certainty evidence; Analysis 5.9). However confidence intervals demonstrated imprecision, also encompassing the possibility of more neuropsychiatric serious adverse events in the varenicline arm. A sensitivity analysis removing one study comparing varenicline with no medication had no substantial impact on this result.

5.9 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 9: Neuropsychiatric SAEs (not deaths) (Figure not reproduced here; see the original article.)

Cardiac serious adverse events

The point estimate from pooling 18 studies of 7151 people showed that more people reported experiencing cardiac serious adverse events in the varenicline arm compared with placebo or no medication (RR 1.20, 95% CI 0.79 to 1.84; I² = 0%; low‐certainty evidence; Analysis 5.10). However confidence intervals demonstrated imprecision, also encompassing the possibility of no difference or fewer serious adverse events in the varenicline arm. A sensitivity analysis removing one study comparing varenicline with no medication had no substantial impact on this result.

5.10 AnalysisComparison 5: Varenicline 2 mg per day vs placebo or no medication, Outcome 10: Cardiac SAEs, including deaths (Figure not reproduced here; see the original article.)

Varenicline: variations in usage

Low‐dose varenicline versus placebo

Four studies tested varenicline at doses lower than standard (under 2 mg per day). Three studies tested 1 mg per day compared with placebo and still found that more people quit in the varenicline arm (RR 1.87, 95% CI 1.35 to 2.60; 906 participants; Analysis 6.1.1). There was substantial heterogeneity (I² = 71%), however in all cases point estimates favoured varenicline.

6.1 AnalysisComparison 6: Varenicline: variations in usage, Outcome 1: Low‐dose varenicline vs placebo (Figure not reproduced here; see the original article.)

Niaura 2008 allowed participants to choose their own dose of varenicline, ranging between 0.5 mg and 2.0 mg daily, and found more people in the varenicline arm quit than in the placebo arm (RR 2.92, 95% CI 1.57 to 5.41; 320 participants; Analysis 6.1.2).

Higher‐dose varenicline versus lower‐dose varenicline

Four studies compared varenicline at 2 mg per day with 1 mg per day and did not provide clear evidence of a difference in how many people quit (RR 1.12, 95% CI 0.97 to 1.30; 1563 participants; I² = 44%; Analysis 6.2.1); however confidence intervals encompassed potential benefit and a slight disadvantage of the higher dose. Nides 2006 also compared other dosages and also did not find clear evidence of a difference in quit rates among participants randomised to receive 2 mg compared with 0.3 mg per day (RR 1.84 95% CI 0.89 to 3.84; 253 participants; Analysis 6.2.2) or 1 mg compared with 0.3 mg per day (RR 0.71, 95% CI 0.28 to 1.81; 254 participants; Analysis 6.2.3). However, in both cases confidence intervals were wide and may indicate benefit and harm of higher doses.

6.2 AnalysisComparison 6: Varenicline: variations in usage, Outcome 2: Higher‐dose varenicline versus lower‐dose varenicline (Figure not reproduced here; see the original article.)

Longer‐duration varenicline versus standard‐duration varenicline

Three studies tested extended durations of varenicline compared with standard duration of varenicline (12 weeks). We found no clear evidence of a difference as a result of extending varenicline treatment to 24 weeks (RR 0.97, 95% CI 0.77 to 1.23; I² = 17%; 2 studies, 1458 participants; Analysis 6.3.1) or 52 weeks (RR 1.30, 95% CI 0.70 to 2.43; 1 study; 107 participants; Analysis 6.3.2). However, the confidence intervals indicate imprecision and uncertainty in the point estimates.

6.3 AnalysisComparison 6: Varenicline: variations in usage, Outcome 3: Longer vs standard duration varenicline (Figure not reproduced here; see the original article.)

Six weeks versus one week of varenicline preloading

Bohadana 2020 tested varenicline with a preloading period of six weeks before quit date against the standard one week of preloading and found that more people in the six‐week preloading arm quit than in the one‐week arm (RR 5.60, 95% CI 2.24 to 14.02; 242 participants).

Varenicline in specific patient groups

Studies testing varenicline against placebo or no medication in specific patient populations did not find any clear evidence of varenicline working differently in these groups than in the general population.

Analyses found more people successfully quitting in the varenicline arm than in control in studies of people with cardiovascular disease (RR 1.88, 95% CI 1.44 to 2.47; I² = 81%; 2 studies, 1006 participants; Analysis 7.1); schizophrenia, bipolar disorder, or another psychiatric disorder (RR 2.26, 95% CI 1.78 to 2.86; I² = 0%; 3 studies, 2245 participants; Analysis 7.4); depression (RR 2.17, 95% CI 1.45 to 3.24; I² = 0%; 2 studies, 745 participants; Analysis 7.5); HIV (RR 1.96, 95% CI 1.06 to 3.63; I² = 0%; 2 studies, 427 participants; Analysis 7.8); and chronic obstructive pulmonary disease (RR 1.47, 95% CI 1.28 to 1.69; I² = 94%; 4 studies of 860 participants; Analysis 7.2).

7.1 AnalysisComparison 7: Varenicline (vs placebo or no medication) in specific patient groups, Outcome 1: Cardiovascular disease (Figure not reproduced here; see the original article.)

7.4 AnalysisComparison 7: Varenicline (vs placebo or no medication) in specific patient groups, Outcome 4: Schizophrenia/bipolar/psychiatric disorder (Figure not reproduced here; see the original article.)

7.5 AnalysisComparison 7: Varenicline (vs placebo or no medication) in specific patient groups, Outcome 5: Depression (Figure not reproduced here; see the original article.)

7.8 AnalysisComparison 7: Varenicline (vs placebo or no medication) in specific patient groups, Outcome 8: HIV (Figure not reproduced here; see the original article.)

7.2 AnalysisComparison 7: Varenicline (vs placebo or no medication) in specific patient groups, Outcome 2: COPD (Figure not reproduced here; see the original article.)

Treating these trials as a subgroup of the main analysis (Analysis 5.1), testing for subgroup differences showed no evidence that varenicline works differently from in the general population: cardiovascular disease, P = 0.24, I² = 26.2%; psychiatric disorders, P = 0.40, I² = 0%; depression, P = 0.92, I² = 0%; HIV, P = 0.69, I² = 0%). Testing the COPD result for subgroup difference initially showed evidence that varenicline may work differently, with lower effectiveness, in this population (P < 0.00001, I² = 96.8%), however this difference disappeared when we performed a sensitivity analysis removing studies comparing varenicline with no medication rather than placebo (P = 1.00, I² = 0%).

Analyses presented inconclusive evidence for three patient populations: asthma (RR 1.25, 95% CI 0.38 to 4.14; 1 study; 52 participants; Analysis 7.3), substance use disorder (RR 3.72, 95% CI 0.50 to 27.59; I² = 0%; 2 studies, 294 participants; Analysis 7.6), and alcohol dependence (RR 3.01, 95% CI 0.92 to 9.92; I² = 54%; 3 studies, 195 participants; Analysis 7.7). However, point estimates all favoured varenicline, and wide confidence intervals were likely the result of very low numbers of events. Treating the trials as a subgroup of the main analysis (Analysis 5.1) and testing for subgroup differences showed no evidence that varenicline works differently in these populations (asthma: P = 0.76, I² = 0.4%; substance use disorder: P = 0.61, I² = 0%; alcohol dependence: P = 0.70, I² = 0.4%).

7.3 AnalysisComparison 7: Varenicline (vs placebo or no medication) in specific patient groups, Outcome 3: Asthma (Figure not reproduced here; see the original article.)

7.6 AnalysisComparison 7: Varenicline (vs placebo or no medication) in specific patient groups, Outcome 6: Substance use disorder/ methadone‐maintained at 24 weeks (Figure not reproduced here; see the original article.)

7.7 AnalysisComparison 7: Varenicline (vs placebo or no medication) in specific patient groups, Outcome 7: Alcohol‐dependence (Figure not reproduced here; see the original article.)

Varenicline in specific settings or subgroups

Six studies of 1324 participants tested varenicline against placebo or no medication among hospital inpatients and perioperative patients and found that more people successfully quit in the varenicline arm (RR 1.27, 95% CI 1.12 to 1.43; I² = 58%; Analysis 8.1). Treating these trials as a subgroup of the main analysis (Analysis 5.1), which includes studies conducted in both clinical and community settings such as cessation clinics and university campuses, and testing for subgroup differences did show evidence of subgroup difference, with lower effectiveness (P < 0.00001; I² = 98.6%). Heterogeneity remained when we performed a sensitivity analysis removing studies comparing varenicline with no medication rather than placebo (P < 0.00001; I² = 96%).

8.1 AnalysisComparison 8: Varenicline in specific settings/subgroups, Outcome 1: Hospital inpatients/perioperative patients (Figure not reproduced here; see the original article.)

Gonzales 2014 tested varenicline against placebo among people who had previously used varenicline for two weeks or more, at least three months prior to admission to the study, and had not successfully quit but were motivated to try again. This single study found that more people successfully quit in the varenicline arm (RR 6.15, 95% CI 2.98 to 12.70; 494 participants; Analysis 8.2).

8.2 AnalysisComparison 8: Varenicline in specific settings/subgroups, Outcome 2: Smokers with a previous quit attempt on varenicline (Figure not reproduced here; see the original article.)

Two studies of 114 participants tested varenicline against placebo among light smokers and found that more people successfully quit in the varenicline arm (RR 4.16, 95% CI 1.58 to 10.97; I² = 0%; Analysis 8.3). Treating these trials as a subgroup of the main analysis (Analysis 5.1) and testing for subgroup differences showed no evidence that varenicline works differently in this population (P = 0.20, I² = 39.3%).

8.3 AnalysisComparison 8: Varenicline in specific settings/subgroups, Outcome 3: Light or heavy smokers (Figure not reproduced here; see the original article.)

Varenicline versus bupropion

Smoking cessation

Nine studies of 7560 participants compared varenicline with bupropion and found that more people quit smoking when using varenicline (RR 1.36, 95% CI 1.25 to 1.49; I² = 0%; high‐certainty evidence; Analysis 9.1).

9.1 AnalysisComparison 9: Varenicline vs bupropion, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

Johns 2017b randomised 300 participants to receive varenicline, bupropion, or both. They did not provide any useable results data but reported that more people quit in the combined varenicline and bupropion arm compared with the bupropion‐ or varenicline‐alone arms. However, only an abstract was available for this study, and without further information, this result should be treated with caution.

Adverse events

Studies comparing varenicline with bupropion found that people randomised to receive varenicline were more likely to report experiencing nausea (RR 2.46, 95% CI 2.20 to 2.75; I² = 0%; 4 studies, 5808 participants; Analysis 9.2), abnormal dreams (RR 1.56, 95% CI 1.39 to 1.76; I² = 0%; 4 studies, 5808 participants; Analysis 9.4), and headache (RR 1.24, 95% CI 1.06 to 1.45; I² = 13%; 3 studies, 4888 participants; Analysis 9.5). However, people randomised to receive varenicline were less likely to report experiencing insomnia (RR 0.84, 95% CI 0.75 to 0.93; I² = 75%; 6 studies, 6789 participants; Analysis 9.3).

9.2 AnalysisComparison 9: Varenicline vs bupropion, Outcome 2: Nausea (Figure not reproduced here; see the original article.)

9.4 AnalysisComparison 9: Varenicline vs bupropion, Outcome 4: Abnormal dreams (Figure not reproduced here; see the original article.)

9.5 AnalysisComparison 9: Varenicline vs bupropion, Outcome 5: Headache (Figure not reproduced here; see the original article.)

9.3 AnalysisComparison 9: Varenicline vs bupropion, Outcome 3: Insomnia (Figure not reproduced here; see the original article.)

Two studies of 4210 people did not find evidence a difference between those randomised to receive varenicline or bupropion in reported rates of depression (RR 0.90, 95% CI 0.35 to 2.35; I² = 0%; Analysis 9.6) or suicidal ideation (RR 1.99, 95% CI 0.18 to 21.93; I² not estimable as events only in 1 study; Analysis 9.7).

9.6 AnalysisComparison 9: Varenicline vs bupropion, Outcome 6: Depression (Figure not reproduced here; see the original article.)

9.7 AnalysisComparison 9: Varenicline vs bupropion, Outcome 7: Suicidal ideation (Figure not reproduced here; see the original article.)

Serious adverse events

Serious adverse events

Five studies of 5317 people did not find evidence of a clear difference in the number of people reporting experiencing serious adverse events (RR 0.89, 95% CI 0.61 to 1.31; I² = 0%; low‐certainty evidence; Analysis 9.8).

9.8 AnalysisComparison 9: Varenicline vs bupropion, Outcome 8: SAEs (Figure not reproduced here; see the original article.)

Neuropsychiatric serious adverse events

Two studies of 866 people did not find evidence of a clear difference in the number of people reporting experiencing neuropsychiatric serious adverse events (RR 1.05, 95% CI 0.16 to 7.04; I² = 10%; low‐certainty evidence; Analysis 9.9), though confidence intervals were very wide.

9.9 AnalysisComparison 9: Varenicline vs bupropion, Outcome 9: Neuropsychiatric SAEs (not deaths) (Figure not reproduced here; see the original article.)

Cardiac serious adverse events

Two studies of 866 people did not find evidence of a clear difference in the number of people reporting experiencing cardiac serious adverse events (RR 3.17, 95% CI 0.33 to 30.18; I² = 0%; low‐certainty evidence; Analysis 9.10), though confidence intervals were very wide.

9.10 AnalysisComparison 9: Varenicline vs bupropion, Outcome 10: Cardiac SAEs, including deaths (Figure not reproduced here; see the original article.)

Varenicline versus nicotine replacement therapy (NRT) monotherapy

Smoking cessation

Eleven studies of 7572 participants compared varenicline with NRT monotherapy and found that more people quit smoking in the varenicline arm (RR 1.25, 95% CI 1.14 to 1.37; I² = 28%; high‐certainty evidence; Analysis 10.1).

10.1 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

Adverse events

Studies comparing varenicline with NRT monotherapy found that people randomised to receive varenicline were more likely to report experiencing nausea (RR 2.69, 95% CI 2.41 to 3.01; I² = 59%; 6 studies, 6500 participants; Analysis 10.2) and headache (RR 1.14, 95% CI 1.01 to 1.28; I² = 69%; 4 studies, 6287 participants; Analysis 10.5). However, they did not find evidence of a clear difference in the number of people reporting experiencing insomnia (RR 1.08, 95% CI 0.96 to 1.21; I² = 42%; 5 studies, 6319 participants; Analysis 10.3), abnormal dreams (RR 0.93, 95% CI 0.83 to 1.05; I² = 67%; 4 studies, 5803 participants; Analysis 10.4), or depression (RR 0.94, 95% CI 0.76 to 1.16; I² = 0%; 3 studies, 5541 participants; Analysis 10.6). The pooled point estimate from two studies found a higher rate of suicidal ideation among participants in the varenicline arm (RR 5.00, 95% CI 0.87 to 28.77; I² = 0%; 2 studies, 4876 participants; Analysis 10.7), but confidence intervals were very wide and incorporated the potential for no difference or reduced harm. Statistical heterogeneity was substantial in several analyses, but we decided to present the pooled estimate because the point estimates of individuals studies were almost entirely in the same direction in each analysis.

10.2 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 2: Nausea (Figure not reproduced here; see the original article.)

10.5 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 5: Headache (Figure not reproduced here; see the original article.)

10.3 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 3: Insomnia (Figure not reproduced here; see the original article.)

10.4 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 4: Abnormal dreams (Figure not reproduced here; see the original article.)

10.6 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 6: Depression (Figure not reproduced here; see the original article.)

10.7 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 7: Suicidal ideation (Figure not reproduced here; see the original article.)

Serious adverse events

Serious adverse events

Six studies of 6535 people comparing varenicline with NRT monotherapy found that people randomised to receive varenicline were less likely to report experiencing serious adverse events (RR 0.70, 95% CI 0.50 to 0.99; I² = 24%; low‐certainty evidence; Analysis 10.8).

10.8 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 8: SAEs (Figure not reproduced here; see the original article.)

Neuropsychiatric serious adverse events

Only one study measured neuropsychiatric serious adverse events, and reported no events in either arm (Rohsenow 2017; 137 participants).

Cardiac serious adverse events

Only one study measured cardiac serious adverse events, and reported no events in either arm (Rohsenow 2017; 137 participants).

Varenicline versus combination NRT

Smoking cessation

Five studies of 2344 participants compared varenicline with combination NRT and did not detect evidence of a clear difference in the number of people who quit smoking, although confidence intervals indicate imprecision, which reduces our certainty in the effect (RR 1.02, 95% CI 0.87 to 1.20; I² = 0%; low‐certainty evidence; Analysis 11.1).

11.1 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

Adverse events

Studies comparing varenicline with combination NRT found that people randomised to receive varenicline were more likely to report experiencing nausea (RR 1.76, 95% CI 1.45 to 2.15; I² = 47%; 3 studies, 1609 participants; Analysis 11.2), insomnia (RR 1.40, 95% CI 1.15 to 1.70; I² = 82%; 3 studies, 1609 participants; Analysis 11.3), and abnormal dreams (RR 1.59, 95% CI 1.22 to 2.08; 1 study; 549 participants; Analysis 11.4). However, they did not find evidence of a clear difference in the number of people reporting experiencing headache (RR 0.98, 95% CI 0.78 to 1.23; I² = 0%; 3 studies, 1609 participants; Analysis 11.5), depression (RR 1.08, 95% CI 0.83 to 1.40; I² = 82%; 3 studies, 1609 participants; Analysis 11.6), or suicidal ideation (RR 0.94, 95% CI 0.06 to 14.79; I² not estimable as events only in 1 study; 2 studies, 764 participants; Analysis 11.7). Statistical heterogeneity was substantial in several analyses, but we decided to present the pooled estimate because the point estimates of individual studies were almost entirely in the same direction.

11.2 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 2: Nausea (Figure not reproduced here; see the original article.)

11.3 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 3: Insomnia (Figure not reproduced here; see the original article.)

11.4 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 4: Abnormal dreams (Figure not reproduced here; see the original article.)

11.5 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 5: Headache (Figure not reproduced here; see the original article.)

11.6 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 6: Depression (Figure not reproduced here; see the original article.)

11.7 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 7: Suicidal ideation (Figure not reproduced here; see the original article.)

Serious adverse events

Serious adverse events

Pooled data from four studies of 1852 people showed more people in the varenicline arm reporting serious adverse events compared with combination NRT (RR 2.15, 95% CI 0.49 to 9.46; I² = 0%; low‐certainty evidence; Analysis 11.8). However, confidence intervals were very wide and included the potential for no difference or reduced risk.

11.8 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 8: SAEs (Figure not reproduced here; see the original article.)

Neuropsychiatric serious adverse events

Two studies of 764 people reported the number of people reporting neuropsychiatric serious adverse events. While the point estimate suggested participants receiving varenicline were more likely to report experiencing neuropsychiatric serious adverse events, confidence intervals were extremely wide, and incorporated both benefit and harm (RR 4.69, 95% CI 0.23 to 96.50; I² not estimable as events only in 1 study; low‐certainty evidence; Analysis 11.9).

11.9 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 9: Neuropsychiatric SAEs (not deaths) (Figure not reproduced here; see the original article.)

Cardiac serious adverse events

Two studies of 819 people reported the number of people reporting cardiac serious adverse events. While the point estimate suggested that participants receiving varenicline were less likely to report experiencing cardiac serious adverse events, confidence intervals were very wide, and incorporated both benefit and harm (RR 0.32, 95% CI 0.01 to 7.88; I² not estimable as events only in 1 study; low‐certainty evidence; Analysis 11.10).

11.10 AnalysisComparison 11: Varenicline vs combination NRT, Outcome 10: Cardiac SAEs, including deaths (Figure not reproduced here; see the original article.)

Varenicline versus e‐cigarettes

Smoking cessation

One study of 54 participants compared varenicline with e‐cigarettes and found that more people quit smoking in the varenicline arm (RR 3.25, 95% CI 1.21 to 8.71; very low‐certainty evidence; Analysis 12.1).

12.1 AnalysisComparison 12: Varenicline vs e‐cigarettes, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

Adverse events

The only one of our adverse event outcomes reported by this study was nausea. While the point estimate suggested that participants receiving varenicline were more likely to report experiencing nausea, confidence intervals were extremely wide, and incorporated both benefit and harm (RR 3.00, 95% CI 0.33 to 27.06; Analysis 12.2).

12.2 AnalysisComparison 12: Varenicline vs e‐cigarettes, Outcome 2: Nausea (Figure not reproduced here; see the original article.)

Serious adverse events

While the study reported serious adverse events, neuropsychiatric serious adverse events, and cardiac serious adverse events as outcomes, they reported no events among study participants in either arm.

Dianicline versus placebo

Smoking cessation

Tonstad 2011 (602 participants) compared dianicline with placebo and did not detect evidence of a clear difference in the number of people who quit smoking (RR 1.20, 95% CI 0.82 to 1.75; Analysis 13.1), however, results were imprecise and confidence intervals encompass the possibility of benefit and harm of dianicline.

13.1 AnalysisComparison 13: Dianicline vs placebo, Outcome 1: Abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

Adverse events

Tonstad 2011 reported that more people randomised to receive dianicline reported experiencing nausea (RR 2.83, 95% CI 1.88 to 4.27; 602 participants; Analysis 13.2) and depression (RR 8.05, 95% CI 1.01 to 63.99; 602 participants; Analysis 13.4) than those in the placebo arm. They did not detect a difference in the number of people reporting experiencing headaches (RR 1.23, 95% CI 0.82 to 1.85; 602 participants; Analysis 13.3). The study did not measure our other adverse event outcomes.

13.2 AnalysisComparison 13: Dianicline vs placebo, Outcome 2: Nausea (Figure not reproduced here; see the original article.)

13.4 AnalysisComparison 13: Dianicline vs placebo, Outcome 4: Depression (Figure not reproduced here; see the original article.)

13.3 AnalysisComparison 13: Dianicline vs placebo, Outcome 3: Headache (Figure not reproduced here; see the original article.)

Serious adverse events

Tonstad 2011 did not detect a difference in rates of serious adverse events (RR 1.01, 95% CI 0.20 to 4.95; 602 participants; Analysis 13.5) or cardiac serious adverse events (RR 1.01, 95% CI 0.06 to 16.02; 602 participants; Analysis 13.6) between participants in the dianicline and placebo study arms. However, in both instances confidence intervals were very wide and included the potential for both harm and benefit. The study did not measure neuropsychiatric serious adverse events.

13.5 AnalysisComparison 13: Dianicline vs placebo, Outcome 5: Serious adverse events (Figure not reproduced here; see the original article.)

13.6 AnalysisComparison 13: Dianicline vs placebo, Outcome 6: Cardiac SAEs, including deaths (Figure not reproduced here; see the original article.)

Discussion

Summary of main results

This review includes eight studies that investigated cytisine use in just under 9000 people, 68 studies that investigated varenicline use in over 37,000 people, and one study that investigated dianicline use in 602 people. Forty‐five of these studies are new to this update.

We found moderate‐certainty evidence that cytisine probably helps more people to quit smoking than placebo. While people randomised to receive cytisine were more likely to experience adverse events than those in the placebo arm, low‐certainty evidence gave no clear indication of an increased risk of serious adverse events. We found no data on neuropsychiatric or cardiac serious adverse events.

Our analysis did not find definitive evidence of a difference in cessation rates between cytisine and varenicline. The point estimate favoured varenicline, but this moderate‐certainty evidence is subject to imprecision and may change as more evidence becomes available. A component network meta‐analysis that is currently underway may reveal a more certain result by also employing data from indirect comparisons (Lindson 2022). Although the point estimates in the separate analyses comparing varenicline with placebo and cytisine with placebo did differ (with the varenicline analysis producing a higher risk ratio) the issue with this type of indirect comparison is it does not adjust for potential differences in baseline event rates. In our analysis, Dogar 2020 was the largest study that compared cytisine with placebo. It recruited people diagnosed with pulmonary tuberculosis who, as part of the behavioural aspect of the intervention, were informed of the dangers of continued tobacco use in people with tuberculosis. This made for a highly motivated population, who also happened to smoke fewer cigarettes per day than in other cytisine trials. These two characteristics may have contributed to the higher placebo arm quit rates in the cytisine studies and minimised the benefit gained from pharmacotherapy. These factors may also explain why the results from Dogar 2020 are less compelling than those of the other studies, and may also account for the statistical heterogeneity in the cytisine versus placebo analysis (I² = 83%).

Participants in the cytisine arm were less likely to experience nausea or abnormal dreams than those in the varenicline arm, and there was no evidence of a difference in rates of insomnia, headache, depression, or suicidal ideation. The same studies provided low‐certainty evidence of fewer people experiencing serious adverse events in the cytisine arm compared with varenicline. However, in all cases, confidence intervals indicated imprecision, and the potential for more adverse events when using either treatment. We found no data on neuropsychiatric or cardiac serious adverse events.

Low‐certainty evidence suggested that cytisine may help more people to quit than NRT monotherapy (Walker 2014). However, after the initial 25‐day course, participants in the cytisine arm also received vouchers for NRT. This may distort the results as some participants in the cytisine arm may have in fact received two pharmacotherapies, but study authors reported that few participants in the cytisine arm used their NRT vouchers. Low‐certainty evidence did not show a difference in the number of people reporting serious adverse events. We found no data on neuropsychiatric or cardiac serious adverse events.

Evidence on the effect of different lengths of cytisine treatment was sparse and inconclusive.

There is high‐certainty evidence that varenicline increases the chances of successful smoking cessation by more than two‐fold compared with placebo. Since the previous version of this review was published (Cahill 2016), this estimate has remained stable, despite the growing inclusion of pragmatic trials in real‐world settings and those conducted in particular groups of smokers previously excluded from clinical trials, such as those in lower‐ and middle‐income countries, and in disease‐specific populations.

We also found high‐certainty evidence that varenicline helped more people to quit than bupropion, or NRT monotherapy, with no clear evidence of difference between varenicline and bupropion in rates of serious adverse events, neuropsychiatric serious adverse events, or cardiac serious adverse events (all low‐certainty evidence), and low‐certainty evidence suggesting reduced risk of serious adverse events compared with NRT. We found no data comparing varenicline with NRT monotherapy for neuropsychiatric or cardiac serious adverse events.

Low‐certainty evidence did not show a difference in quit rates compared with combination NRT, and while low‐certainty evidence suggested potentially increased risk of serious adverse events and neuropsychiatric serious adverse events, and reduced risk of cardiac serious adverse events, in all cases confidence intervals were very wide, encompassing both substantial harm and benefit.

One small study of 54 people provided very‐low certainty evidence of more people quitting with varenicline than with e‐cigarettes (Ioakeimidis 2018); however this study was at high risk of bias and imprecise due to few events, and while they reported serious adverse events, neuropsychiatric serious adverse events, and cardiac serious adverse events as outcomes, they reported no events among study participants in either arm. Studies that tested varenicline versus placebo in specific populations and settings did not demonstrate varenicline working differently than it does in the general population in disease‐specific groups of patients (e.g. cardiovascular, chronic obstructive pulmonary disease, HIV, schizophrenia and psychiatric disorders, depression, alcohol dependence), or in specific subgroups or settings (e.g. hospital inpatients, light‐smokers, smokers who failed to quit on varenicline previously).

Analyses found evidence of increased rates of adverse events such as nausea, insomnia, abnormal dreams, and headache among people randomised to receive varenicline compared with placebo. However, we found no clear evidence of increased rates of depression or suicidal ideation, although confidence intervals indicated imprecision, and the potential for more or fewer adverse events when using varenicline compared with control. Moderate‐certainty serious adverse event data suggest there may be a 23% increased risk of such events among the varenicline groups compared with the controls. However, serious adverse events were still rare (2.7% to 4% of people on varenicline, compared with 2.7% of people without) and this finding is based on simple counts across the trials of participants reporting one or more such events, thus not distinguishing between events attributed and those unrelated to treatment. We did not find evidence of an increased risk of neuropsychiatric serious adverse events, but pooled results did suggest a potential increased risk of cardiac serious adverse events, although again these results were subject to imprecision, and we deemed this evidence to be low certainty because of its compatibility with both increased and decreased risk of harm.

One trial compared dianicline with placebo for smoking cessation and the results were inconclusive (Tonstad 2011).

Overall completeness and applicability of evidence

We conducted systematic searches of multiple online databases, including clinical trials registries and followed Cochrane methods for screening. We therefore expect that any published trials we have missed will be through chance rather than systematic error. We were able to assess publication bias for two comparisons by constructing funnel plots: varenicline versus placebo (Figure 4), and varenicline versus NRT monotherapy (Figure 5). Figure 5 appears to show a small amount of asymmetry that may suggest a lack of smaller trials with negative findings. However, the number of studies is still very low with few smaller studies, and so we cannot treat this as definitive evidence of publication bias. These were the only cessation comparisons with enough studies to construct a funnel plot, so we were unable to assess publication bias for other comparisons. As such, we cannot ignore the possibility of publication bias for some comparisons in this review.

4 Funnel plot of comparison 6: varenicline (1.0 mg 2/d) vs placebo, outcome: 6.1 abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

5 Funnel plot of comparison 13: varenicline vs nicotine replacement therapy monotherapy, outcome: 13.1 abstinence at longest follow‐up (Figure not reproduced here; see the original article.)

The benefits of varenicline for smoking cessation is now well established, with the point estimate remaining unchanged as more studies (including non‐manufacturer‐ (Pfizer) funded trials) accumulate. Trials are now being conducted and reported in areas where the evidence is less comprehensive, such as testing cytisine (against placebo and varenicline), and testing varenicline in specific populations and settings, and in variations of treatment dose or duration.

Quality of the evidence

We judged the evidence comparing varenicline with placebo for smoking cessation to be of high certainty. While we detected moderate heterogeneity (I² = 60%), all but three studies had a point estimate that favoured varenicline over placebo, so we did not downgrade on this basis. The effectiveness of varenicline for smoking cessation has remained constant through several updates of this review, and we think it is unlikely to change with further evidence. We judged the evidence on serious adverse events to be of moderate certainty, downgraded because of imprecision. For cardiac and neuropsychiatric serious adverse events, we downgraded evidence to low because of imprecision. Despite respectable numbers of studies and participants in each analysis, because of the rarity of these kinds of adverse events, there were very few events in the analyses, with some studies reporting no events at all.

We judged the evidence comparing cytisine with placebo to be of moderate certainty for smoking cessation and low certainty for serious adverse events, downgraded due to substantial unexplained heterogeneity and imprecision, respectively. We judged the evidence comparing cytisine with varenicline for smoking cessation and serious adverse events to be of moderate and low certainty, respectively, downgraded for imprecision in both cases.

We judged the evidence comparing varenicline with bupropion and NRT monotherapy for smoking cessation to be of high certainty, and with combination NRT to be of low certainty, limited by imprecision. Only one small study compared varenicline with e‐cigarettes for smoking cessation, and we graded this evidence as of very low certainty because of imprecision and risk of bias.

Potential biases in the review process

We have followed standard Cochrane methodology, which endeavours to minimise biases in the review process, so we are confident that any errors in our data will be through chance rather than systematic error. However, it is impossible to rule out individual errors in the review process.

A potential limitation to our review is that for data on harms we relied on adverse events and serious adverse events as defined by papers reporting included studies. This does not take into account whether those events were genuinely attributable to the tested interventions. Further, we only considered the number of participants reporting these events, which does not account for people who experienced more than one event.

Another potential limitation is that the majority of varenicline trials reported in this review received either funding or study medication from Pfizer Inc, the manufacturers of varenicline. Evidence from systematic reviews suggests that industry‐funded trials, although conducted to a high standard, are more likely to have outcomes favourable to the product sponsor than studies with other sponsors (Etter 2007; Walsh 2011). However, we deem the provision of study medication less likely to amount to the kind of sponsorship that may bias results, and modern trials increasingly report funders and medication providers as having no involvement in trial conduct or decision making.

Agreements and disagreements with other studies or reviews

Reviews of controlled studies of cytisine have focused upon its potential as an established and affordable aid to smoking cessation (Etter 2006; Etter 2008; Tutka 2005; Tutka 2006; Tutka 2008). Many of the early cytisine studies excluded from this review are discussed and evaluated in Etter 2006, who concluded that cytisine may be effective for smoking cessation. A systematic review and network meta‐analysis (Leaviss 2014), compared the benefits and cost‐effectiveness of cytisine (2 trials: Vinnikov 2008; West 2011), with varenicline (21 trials). While the analysis found both treatments to be effective for smoking cessation, cytisine delivered more quality‐adjusted life‐years at a lower cost than varenicline. Cytisine was also associated with lower rates of headache and nausea than varenicline. Our analyses on harms, using direct evidence, found lower rates of nausea, but did not find evidence of difference in rates of headache. A recent review of cytisine found similar results to ours, though with a slightly higher point estimate for smoking cessation (Tutka 2019). This is likely because they had broader inclusion criteria than our review, and included studies with shorter follow‐up periods.

A Cochrane overview and network meta‐analysis of a number of pharmacological interventions for smoking cessation assessed 12 Cochrane Reviews published to November 2012 (Cahill 2013), and therefore drew on the previous version of this review. Comparisons between varenicline, bupropion and single‐treatment NRT found varenicline to be superior to both treatments (OR 1.59, 95% credible interval 1.29 to 1.96 and OR 1.57, 95% credible interval 1.29 to 1.91, respectively). Varenicline demonstrated comparable benefits for smoking cessation to combination NRT (OR 1.06, 95% credible interval 0.75 to 1.48), but the number of NRT trials informing this comparison was low (9 trials). This review is currently being updated (Lindson 2022). A 2012 network meta‐analysis (Mills 2012), comparing high‐dose and combination NRT versus varenicline and versus bupropion across 146 RCTs, found varenicline (11 trials) to be superior to placebo and to bupropion at all time points, and similar in benefits for smoking cessation to standard and to high‐dose NRT, in line with our findings. A more recent systematic review with network meta‐analysis reported similar findings to ours, reporting a benefit from varenicline compared with placebo (OR 2.69, 95% CI 2.27 to 3.19), bupropion (OR 1.46, 95% CI 1.18 to 1.81), and standard‐dose NRT (OR 1.32, 95% CI 1.05 to 1.65; Thomas 2020). However, they did not find evidence of increased rates of serious adverse events amongst those randomised to receive varenicline compared with placebo (OR 1.09, 95% CI 0.91 to 1.34), contrary to the increased risk we detected. This may be due to their choice of a random‐effects rather than fixed‐effect model for their analysis. They did not find clear evidence of a difference in cardiac serious adverse events (OR 0.76, 95% CI 0.41 to 1.25) and neuropsychiatric serious adverse events (OR 0.96, 95% CI 0.76 to 1.21), which is in line with our findings.

An earlier systematic review and meta‐analysis of 39 RCTs (10,761 participants) by the same team assessed the risk of neuropsychiatric adverse events among users of varenicline (Thomas 2015). In line with our findings, the authors found no clear evidence of an increased risk of suicide or attempted suicide (Peto odds ratio (OR) 1.67, 95% CI 0.33 to 8.57), suicidal ideation (Peto OR 0.58, 95% CI 0.28 to 1.20), depression (Peto OR 0.96, 95% CI 0.75 to 1.22) or death (Peto OR 1.05, 95% CI 0.47 to 2.38) associated with varenicline. Lee 2016 compared cardiovascular serious adverse event rates between people randomised to receive varenicline or placebo. They did not find evidence of increased risk of cardiovascular serious adverse events (RR 1.03, 95% CI 0.72 to 1.49) in 38 trials of 12,706 people. This result was consistent among cardiovascular (RR 1.04, 95% CI 0.57 to 1.89) and non‐cardiovascular patients (RR 1.03, 95% CI 0.64 to 1.64).

Authors' conclusions

What's new

History

Protocol first published: Issue 3, 2006
Review first published: Issue 1, 2007

Acknowledgements

This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure and Cochrane Programme Grant funding to the Cochrane Tobacco Addiction Group. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service, or the Department of Health and Social Care.

We are very grateful for the contributions of everyone who has provided information or assistance to previous versions of this review. For this most recent update we would like to thank previous authors, including Kate Cahill, as well as Kevin Gray, Nathanial Baker, Marc Steinberg, Ugo Pastorino, Omara Dogar, Ada Keding, and Kamran Siddiqui for providing additional results data on included studies. We are also grateful to Aditi Hombali for helping with data extraction and Min Gao for translating and extracting Chinese‐language studies.

The following people conducted the editorial process for the most recent update:

Sign‐off Editor (final editorial decision): Lisa Bero, Cochrane Editorial Board,

• Managing Editor (selected peer reviewers, collated peer‐reviewer comments, provided editorial guidance to authors, edited the article): Sam Hinsley, Cochrane Central Editorial Service

• Editorial Assistant (conducted editorial policy checks and supported editorial team): Leticia Rodrigues, Cochrane Central Editorial Service

• Copy Editor (copy editing and production): Denise Mitchell, Cochrane Evidence Production and Methods Directorate

• Peer‐reviewers (provided comments and recommended an editorial decision): Jennifer Hilgart, Cochrane Evidence Production and Methods Directorate (methods), Steve MacDonald, Cochrane Australia (search), Michael B. Steinberg, MD, MPH; Rutgers Center for Tobacco Studies and Robert Wood Johnson Medical School (clinical), Ryan J Courtney, UNSW Sydney, National Drug and Alcohol Research Centre (clinical), Timothy B. Baker Department of Medicine University of Wisconsin School of Medicine and Public Health (clinical).

Appendices

Appendix 1. Search strategy

CTAG Specialised Register (CRS web)

1. (cytisine or Tabex or dianicline or varenicline or champix or chantix):TI,AB,MH,EMT,XKY,KY,KW
2. MeSH DESCRIPTOR Nicotine WITH AG AI
3. MeSH DESCRIPTOR Nicotinic Agonists
4. MeSH DESCRIPTOR Nicotinic Antagonists
5. nicotinic agonist*:TI,AB,MH,EMT,XKY,KY,KW
6. nicotinic antagonist*:TI,AB,MH,EMT,XKY,KY,KW
7. nicotin* NEAR2 partial:TI,AB,MH,EMT,XKY,KY,KW
#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7

Appendix 2. Glossary of tobacco‐related terms

Data and analyses

6.4 AnalysisComparison 6: Varenicline: variations in usage, Outcome 4: 6 week vs 1 week preloading (Figure not reproduced here; see the original article.)

10.9 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 9: Neuropsychiatric SAEs (not deaths) (Figure not reproduced here; see the original article.)

10.10 AnalysisComparison 10: Varenicline vs NRT monotherapy, Outcome 10: Cardiac SAEs, including deaths (Figure not reproduced here; see the original article.)

12.3 AnalysisComparison 12: Varenicline vs e‐cigarettes, Outcome 3: SAEs (Figure not reproduced here; see the original article.)

12.4 AnalysisComparison 12: Varenicline vs e‐cigarettes, Outcome 4: Neuropsychiatric SAEs (not deaths) (Figure not reproduced here; see the original article.)

12.5 AnalysisComparison 12: Varenicline vs e‐cigarettes, Outcome 5: Cardiac SAEs, including deaths (Figure not reproduced here; see the original article.)

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of studies awaiting classification [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Differences between protocol and review

For this update we did some restructuring of the meta‐analyses and summary of findings tables to better present the evidence available, including adding analyses of adverse events for comparisons of varenicline with other pharmacotherapies. We excluded previously included studies as these studies recruited already‐abstinent participants (Evins 2014; Tonstad 2006; Tønnesen 2013; NCT00828113), and because follow‐up was under six months (Hajek 2015). We also excluded Brandon 2011; Ebbert 2011b; Faessel 2009; Fagerström 2010; Garza 2011; Hughes 2011; McClure 2013; Meszaros 2013; Mitchell 2012, which had previously been included for data on harms only but do not meet all inclusion criteria.

Contributions of authors

JL‐B led this review update, updating the text and analyses. JL‐B, AT, AH, and NL screened for new studies and JL‐B, AT, AH, LH, TRF, and KT performed data extraction and study evaluation. All authors contributed to text and findings, and approved the final version of the review.

Sources of support

Internal sources

• Nuffiled Department of Primary Care Health Sciences, University of Oxford, UK Editorial base for the Cochrane Tobacco Addiction Group

External sources

• National Institute for Health and Care Research, UK Infrastructure and programme grant funding for the Cochrane Tobacco Addiction Group

Declarations of interest

JL‐B is employed by the University of Oxford to work as a Managing Editor for the Cochrane Tobacco Addiction Review Group. He was not involved in the editorial process for this review. Core infrastructure funding for the Cochrane Tobacco Addiction Group is provided by the NIHR to the University of Oxford. JLB has no conflicts of interest.

TF: none known

KT published an opinion piece on varenicline (Davies 2017). KT is on the Specialist Register in the UK as a Consultant in Public Health Medicine, employed by the University of Bristol as an Associate Professor in Public Health Medicine, and currently holds Honorary status as a Consultant in Public Health at South Gloucestershire Council, and is Clinical Director for the NIHR CRN West of England. KT has no conflicts of interest.

AH: none known

AT: none known

LH: none known

NL is employed by the University of Oxford to work as a Managing Editor for the Cochrane Tobacco Addiction Review Group. She was not involved in the editorial process for this review. Core infrastructure funding for the Cochrane Tobacco Addiction Group is provided by the NIHR to the University of Oxford. NL has written pieces for The Conversation on the findings of Cochrane Reviews assessing the effects of treatments for smoking cessation. These are evidence‐based and not based on personal opinion. NL receives funding from CRUK and the NIHR (a part of the NHS) who both have interests in people stopping smoking and run educational campaigns, and in the latter case provide treatment to encourage people to stop smoking. NL has no conflicts of interest.

New search for studies and content updated (conclusions changed)

References

References to studies included in this review

Anthenelli 2013 {published and unpublished data}

Ashare 2019 {published data only}

Aubin 2008 {published data only}

Baker 2016 {published data only}

Baker 2021 {published data only}

Benli 2017 {published data only}

Bohadana 2020 {published data only}

Bolliger 2011 {published data only}

Carson‐Chahhoud 2020 {published and unpublished data}

Chen 2020 {published data only}

Chengappa 2014 {published and unpublished data}

Cinciripini 2013 {published and unpublished data}

Cinciripini 2018 {published data only}

Courtney 2021 {published data only}

Cox 2022 {published data only}

De Dios 2012 {published data only}

Dogar 2020 {published data only}

EAGLES 2016 {published and unpublished data}

Ebbert 2015 {published and unpublished data}

Ebbert 2016 {published data only}

Fouz‐Roson 2017 {published data only}

Gonzales 2006 {published data only}

Gonzales 2014 {published and unpublished data}

Gray 2019 {published data only}

Heydari 2012 {published data only}138901111878N2

Hong 2015 {published data only}

Hurt 2018 {unpublished data only}

Ikonomidis 2017 {published data only}

Ioakeimidis 2018 {published data only}

Johns 2017a {published data only}

Johns 2017b {published data only}

Jorenby 2006 {published data only}

King 2022 {published data only}

Le Mao 2020 {published data only}

Lerman 2015 {published data only}

Littlewood 2017 {published data only}

Mercie 2018 {published data only}

Nahvi 2014a {published and unpublished data}

Nakamura 2007 {published data only}

NCT01162239 {published data only}

Niaura 2008 {published data only}

Nides 2006 {published data only}

O'Malley 2018 {published data only}

Oncken 2006 {published data only}

Pastorino 2022 {published and unpublished data}

Qin 2021 {published data only}

Rennard 2012 {published and unpublished data}

Rigotti 2010 {published data only}

Rohsenow 2017 {published data only}

Rose 2013 {unpublished data only}

Scharfenberg 1971 {published data only}

Schnoll 2019 {published data only}

Stein 2013 {unpublished data only}

Steinberg 2011 {published data only}

Steinberg 2018 {published data only}

Tashkin 2011 {published data only}

Tonstad 2011 {published data only}

Tsai 2007 {published data only}

Tsukahara 2010 {published data only}

Tuisku 2016 {published data only}

Tulloch 2016 {published data only}

Vinnikov 2008 {published data only}

Walker 2014 {published data only}

Walker 2021 {published data only}

Wang 2009 {published data only}

West 2011 {published data only}37568749

Westergaard 2015 {published data only}

Williams 2007 {published and unpublished data}

Williams 2012 {unpublished data only}

Windle 2018 {published data only}

Wong 2012 {unpublished data only}

Yang 2016 {published data only}

Zawertailo 2020 {published data only}

Zhang 2022 {published data only}

Zincir 2013 {published data only}

References to studies excluded from this review

Brandon 2011 {published data only}

Bullen 2018 {published data only}

Burstein 2006 {published data only}

Chantix 2006 {published data only}

Cui 2012 {published data only}

Dezee 2013 {published data only}

Dutra 2012 {published data only}

Ebbert 2009a {published data only}

Ebbert 2009b {published data only}

Ebbert 2011b {published data only}

Ebbert 2014 {unpublished data only}

Evins 2014 {published and unpublished data}

Faessel 2009 {published data only}

Fagerström 2010 {published data only}

Falk 2014 {published data only}

Fatemi 2013 {published data only}

Ferketich 2012 {published data only}

Ferketich 2013 {published data only}

Fertig 2015 {published data only}

Frye 2013 {published data only}

Fucito 2011 {published data only}

Garza 2011 {published data only}

Granatowicz 1976 {published data only}

Gray 2012 {published data only}

Hajek 2011 {published data only}

Hajek 2013 {published data only}

Hajek 2015 {published data only}

Hartwell 2014 {published data only}

Hawk 2012 {published and unpublished data}

Hong 2011 {unpublished data only}

Hoogsteder 2014 {published data only}

Hsueh 2014 {published data only}

Hsueh 2021 {published data only}

Hughes 2011 {published data only}

IRCT20100127003210N {published data only}

Jain 2014 {published data only}

Jennings 2014 {published data only}22073647

Jiménez‐Ruiz 2013 {published data only}

Kempe 1967 {published data only}

Koegelenberg 2014 {published data only}

Maliszewski 1972 {published data only}

Marakulin 1984 {published data only}

McClure 2013 {unpublished data only}

McColl 2008 {published data only}

McNaughton 2013 {published data only}

Meszaros 2013 {published data only}

Metelitsa 1987 {published data only}

Mitchell 2012 {published data only}

Mocking 2013 {published data only}

Monova 2004 {unpublished data only}

Nahvi 2014b {published data only}

Nahvi 2020 {published data only}

NCT00387946 {unpublished data only}

NCT00502216 {unpublished data only}

NCT00554840 {unpublished data only}

NCT00828113 {unpublished data only}

NCT01093937 {unpublished data only}

NCT01413516 {published data only}

NCT01532232 {published data only}

NCT01574703 {unpublished data only}

NCT01592695 {published data only}

NCT01639560 {unpublished data only}

NCT01771627 {published data only}

NCT01772641 {published data only}

NCT01806779 {unpublished data only}

NCT01892813 {published data only}

NCT02048917 {published data only}

NCT02147132 {published data only}

NCT02271919 {published data only}

NCT02501265 {published data only}

NCT03709823 {published data only}

Nides 2021 {published data only}

Nollen 2011 {published data only}

Ostrovskaia 1994 {published data only}

Park 2011 {published data only}

Patterson 2010 {unpublished data only}

Paun 1968 {published data only}

Pfeifer 2019 {published data only}

Pfizer 2006 {unpublished data only}

Poling 2010 {published data only}

Ramon 2014 {published data only}

Rose 2014 {unpublished data only}

Schlienz 2014 {published data only}

Schmidt 1974 {published data only}

Schnoll 2011 {published data only}

Shim 2011 {published data only}

Sicras‐Mainar 2010 {unpublished data only}

Smith 2013 {unpublished data only}

Stapleton 2008 {published data only}

Stoyanov 1972 {published data only}

Swan 2010 {published data only}

Tonstad 2006 {published data only}

Tønnesen 2013 {published and unpublished data}

Weiner 2011 {published data only}

Zatonski 2006 {unpublished data only}

References to studies awaiting assessment

Wiratmoko 2013 {published data only}

Yujie 2014 {published data only}

References to ongoing studies

Berlin 2019 {published data only}

Caponnetto 2019 {published data only}

ChiCTR1900021400 {published data only}

IRCT20200719048133N1 {published data only}

Lawson 2021 {published data only}

NCT00906386 {unpublished data only}

NCT01243203 {published data only}

NCT01312909 {unpublished data only}

NCT01800019 {published data only}

NCT02106637 {published data only}

NCT02162849 {published data only}

NCT02378714 {published data only}

NCT02460900 {published data only}

NCT02856581 {published data only}

NCT02991781 {published data only}

NCT03365362 {published data only}

NCT03557294 {published data only}

NCT04011280 {published data only}

NCT04015414 {published data only}

NCT04188873 {published data only}

NCT04525755 {published data only}

NCT04604509 {published data only}

NCT05102123 {published data only}

NCT05311085 {published data only}

Reid 2010 {unpublished data only}

Russo 2021 {unpublished data only}

TCTR20180312001 {published data only}

Tindle 2020 {published data only}

Additional references

ASH 2006

ASH 2019

Cahill 2013

Coe 2005

Davies 2017

Deeks 2022

Ebbert 2011a

Etter 2006

Etter 2007

Etter 2008

Fabbri 2022

FDA 2008

Foulds 2004

Gotti 2021

Higgins 2003

Higgins 2011

Hughes 2003

Kirchhoff 2009

Leaviss 2014

Lee 2016

Liberati 2009

Lindson 2022

Lindson‐Hawley 2016

Livingstone‐Banks 2019

Livingstone‐Banks 2022a

Livingstone‐Banks 2022b

Mills 2012

NICE 2007

Rigotti 2022

Schünemann 2013

Schünemann 2022

Shiffman 2004

Stead 2003

Thomas 2015

Thomas 2020

Tutka 2005

Tutka 2006

Tutka 2008

Tutka 2019

USDHHS 2020

Walsh 2011

West 2005

WHO 2021

WHO 2022

References to other published versions of this review

Cahill 2007

Cahill 2008

Cahill 2010

Cahill 2012

Cahill 2016

Hey 2006

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