Nicotine receptor partial agonists for smoking cessation

Jonathan Livingstone-Banks; Thomas R Fanshawe; Kyla H Thomas; Annika Theodoulou; Anisa Hajizadeh; Lilian Hartman; Nicola Lindson

doi:10.1002/14651858.CD006103.pub8

. 2023 May 5;2023(5):CD006103. doi: 10.1002/14651858.CD006103.pub8

Nicotine receptor partial agonists for smoking cessation

Jonathan Livingstone-Banks ^1,^✉, Thomas R Fanshawe ¹, Kyla H Thomas ², Annika Theodoulou ¹, Anisa Hajizadeh ¹, Lilian Hartman ³, Nicola Lindson ¹

Editor: Cochrane Tobacco Addiction Group

PMCID: PMC10169257 PMID: 37142273

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.

Plain language summary

Can medications like varenicline and cytisine (nicotine receptor partial agonists) help people to stop smoking and do they cause unwanted effects?

Key messages

· Varenicline can help people to stop smoking for at least 6 months. Evidence shows it works better than bupropion and using only one type of nicotine replacement therapy (e.g. only patches). Quit rates might be similar to using more than one type of nicotine replacement therapy at the same time (e.g. patches and gum together).

· Cytisine can help people to stop smoking for at least 6 months. It may work as well as varenicline, but future evidence may show that while it helps, it is not quite as helpful as varenicline.

· Future studies should test the effectiveness and safety of cytisine compared with varenicline and other stop‐smoking medications, and should also investigate giving cytisine or varenicline at different doses and for different lengths of time.

What are 'nicotine receptor partial agonists'?

Smoking tobacco is extremely bad for people’s health. For people who smoke, quitting is the best thing they can do to improve their health. Many people find it difficult to quit smoking. Nicotine receptor partial agonists (NRPAs) are a type of medication used to help people to stop smoking. They help to reduce the withdrawal symptoms people experience when they stop smoking, like cravings and unpleasant mood changes. They also reduce the pleasure people usually experience when they smoke. The most widely‐available treatment in this drug type is varenicline. Cytisine is another, similar medication. They may cause unwanted effects such as feeling sick (nausea) and other stomach problems, difficulties sleeping, abnormal dreams, and headache. They may also lead to potentially serious unwanted effects, such as suicidal thoughts, heart problems and raised blood pressure.

What did we want to find out?

We wanted to find out if using NRPAs can help people to quit smoking, and if they cause unwanted effects. We wanted to know:

· how many people stopped smoking for at least 6 months; and

· how many people had unwanted effects.

What did we do?

We searched for studies that investigated NRPAs used to help people quit smoking. People in the studies had to be chosen at random to receive an NRPA, or another NRPA, placebo (medication like the NRPA but with no active ingredients) or no treatment. They had to be adult tobacco smokers who wanted to stop smoking.

What did we find?

We found 75 studies that compared NRPAs with:

· placebo or no medicine;

· nicotine replacement therapy, such as patches or gum;

· bupropion (another medicine to help people stop smoking);

· another NRPA;

· e‐cigarettes.

The USA hosted the most studies (28 studies). Other studies took place in a range of countries across the world, some in several countries.

Main results

People are more likely to stop smoking for at least six months using varenicline than using placebo (41 studies, 17,395 people), bupropion (9 studies, 7560 people), or just one type of nicotine replacement therapy, like patches alone (11 studies, 7572 people). They may be just as likely to quit as people using two or more kinds of nicotine replacement therapy, like patches and gum together (5 studies, 2344 people).

Cytisine probably helps more people to stop smoking than placebo (4 studies, 4623 people) and based on studies that compared cytisine with varenicline (2 studies, 2131 people), there may be a benefit from varenicline for quitting smoking, however further evidence could strengthen this finding or show a benefit from cytisine.

For every 100 people using varenicline to stop smoking, 21 to 25 might successfully stop, compared with only 18 of 100 people using bupropion, 18 of 100 people using a single form of nicotine‐replacement therapy, and 20 of 100 using two or more kinds of nicotine‐replacement therapy. For every 100 people using cytisine to stop smoking, 18 to 23 might successfully stop.

The most common unwanted effect of varenicline is nausea, but this is mostly at mild or moderate levels and usually clears over time. People taking varenicline likely have an increased chance of a more serious unwanted effect that could result in going to hospital, however these are still rare (2.7% to 4% of people on varenicline, compared with 2.7% of people without) and may include many that are unrelated to varenicline. People taking cytisine may also have a slightly increased chance of serious unwanted effects compared with people not taking it, but this may be less likely compared with varenicline.

What are the limitations of the evidence?

The evidence for some of our results is very reliable. We’re very confident that varenicline helps people to quit smoking better than many alternatives. We’re less sure of some other results because fewer or smaller studies provided evidence.

Several results suggest one treatment is better or less harmful than another, but the opposite could still be true.

How up to date is the evidence?

The evidence is up to date to 29 April 2022.

Summary of findings

Summary of findings 1. Varenicline versus placebo or no medication for smoking cessation.

Varenicline versus placebo or no medication for smoking cessation
Patient or population: people who smoke tobacco Setting: smoking cessation clinics, hospitals, universities and other research centres Intervention: varenicline Comparison: placebo or no medication
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo or no medication	Corresponding risk with varenicline	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Smoking abstinence at longest follow‐up (6+ months) (varenicline vs placebo)	99 per 1000	230 per 1000 (213 to 249)	RR 2.32 (2.15 to 2.51)	17,395 (41 studies)	⊕⊕⊕⊕^a High
SAEs (varenicline vs placebo or no medication)	27 per 1000	33 per 1000 (27 to 40)	RR 1.23 (1.01 to 1.48)	14,356 (26 studies)	⊕⊕⊕⊝^b Moderate
Neuropsychiatric SAEs (varenicline vs placebo or no medication)	11 per 1000	10 per 1000 (7 to 14)	RR 0.89 (0.61 to 1.29)	7846 (22 studies)	⊕⊕⊝⊝^c Low
Cardiac SAEs (varenicline vs placebo or no medication)	11 per 1000	13 per 1000 (8 to 20)	RR 1.20 (0.79 to 1.84)	7151 (18 studies)	⊕⊕⊝⊝^c Low
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is calculated as the median risk in control groups.  CI: confidence interval; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Cytisine versus placebo or no medication for smoking cessation
Patient or population: people who smoke tobacco Setting: smoking cessation clinics, hospitals, universities and other research centres Intervention: cytisine Comparison: placebo or no medication
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo or no medication	Corresponding risk with cytisine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Smoking abstinence at longest follow‐up (6+ months) (cytisine vs placebo)	158 per 1000	205 per 1000 (181 to 232)	RR 1.30 (1.15 to 1.47)	4623 (4 studies)	⊕⊕⊕⊝^a Moderate
SAEs (cytisine vs placebo or no medication)	46 per 1000	48 per 1000 (36 to 63)	RR 1.04 (0.78 to 1.37)	3781 (3 studies)	⊕⊕⊝⊝^b Low
Neuropsychiatric SAEs (cytisine vs placebo or no medication)	No data	No data	No data	No data	No data
Cardiac SAEs (cytisine vs placebo or no medication)	No data	No data	No data	No data	No data
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is calculated as the median risk in control groups.  CI: confidence interval; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Cytisine versus varenicline for smoking cessation
Patient or population: people who smoke tobacco Setting: community, community pharmacy, participants' homes Intervention: cytisine Comparison: varenicline
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with varenicline	Corresponding risk with cytisine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Smoking abstinence at longest follow‐up (6+ months)	132 per 1000	109 per 1000 (87 to 138)	RR 0.83 (0.66 to 1.05)	2131 (2 studies)	⊕⊕⊕⊝^a Moderate
SAEs	49 per 1000	33 per 1000 (21 to 50)	RR 0.67 (0.44 to 1.03)	2017 (2 studies)	⊕⊕⊝⊝^b Low
Neuropsychiatric SAEs	No data	No data	No data	No data	No data
Cardiac SAEs	No data	No data	No data	No data	No data
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is calculated as the median risk in control groups.  CI: confidence interval; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Cytisine versus nicotine replacement therapy for smoking cessation
Patient or population: people who smoke tobacco Setting: participants' homes (participants were callers to a national Quitline) Intervention: cytisine Comparison: nicotine replacement therapy (NRT)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with NRT	Corresponding risk with cytisine	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Smoking abstinence at longest follow‐up (6+ months)	153 per 1000	218 per 1000 (173 to 275)	RR 1.43 (1.13 to 1.80)	1310 (1 study)	⊕⊕⊝⊝^a,b Low
SAEs	60 per 1000	68 per 1000 (45 to 104)	RR 1.15 (0.76 to 1.75)	1310 (1 study)	⊕⊝⊝⊝^a,c Very low
Neuropsychiatric SAEs	No data	No data	No data	No data	No data
Cardiac SAEs	No data	No data	No data	No data	No data
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is calculated as the median risk in control groups.  CI: confidence interval; NRT: nicotine replacement therapy; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Varenicline versus bupropion for smoking cessation
Patient or population: people who smoke tobacco Setting: smoking cessation clinics, hospitals, universities and other research centres Intervention: varenicline Comparison: bupropion
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with bupropion	Corresponding risk with varenicline	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Smoking abstinence at longest follow‐up (6+ months)	177 per 1000	241 per 1000 (222 to 264)	RR 1.36 (1.25 to 1.49)	7560 (9 studies)	⊕⊕⊕⊕ High
SAEs	20 per 1000	18 per 1000 (12 to 27)	RR 0.89 (0.61 to 1.31)	5317 (5 studies)	⊕⊕⊝⊝^a Low
Neuropsychiatric SAEs	2 per 1000	2 per 1000 (0 to 16)	RR 1.05 (0.16 to 7.04)	866 (2 studies)	⊕⊕⊝⊝^a Low
Cardiac SAEs	0 per 1000	0 per 1000 (0 to 0)	RR 3.17 (0.33 to 30.18)	866 (2 studies)	⊕⊕⊝⊝^a Low
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is calculated as the median risk in control groups.  CI: confidence interval; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Varenicline versus nicotine replacement therapy (NRT) monotherapy for smoking cessation
Patient or population: people who smoke tobacco Setting: smoking cessation clinics, hospitals, universities and other research centres Intervention: varenicline Comparison: nicotine replacement therapy (NRT) monotherapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with NRT monotherapy	Corresponding risk with varenicline	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Smoking abstinence at longest follow‐up (6+ months)	180 per 1000	225 per 1000 (205 to 247)	RR 1.25 (1.14 to 1.37)	7572 (11 studies)	⊕⊕⊕⊕ High
SAEs	9 per 1000	6 per 1000 (5 to 9)	RR 0.70 (0.50 to 0.99)	6535 (6 studies)	⊕⊕⊝⊝^a Low	No events in two studies
Neuropsychiatric SAEs	Not estimable (no events in analysis)	Not estimable (no events in analysis)	Not estimable (no events in analysis)	137 (1 study)
Cardiac SAEs	Not estimable (no events in analysis)	Not estimable (no events in analysis)	Not estimable (no events in analysis)	137 (1 study)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is calculated as the median risk in control groups.  CI: confidence interval; NRT: nicotine replacement therapy; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Varenicline versus combination nicotine replacement therapy for smoking cessation
Patient or population: people who smoke tobacco Setting: smoking cessation clinics, hospitals, universities and other research centres Intervention: varenicline Comparison: combination nicotine replacement therapy (NRT)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with combination NRT	Corresponding risk with varenicline	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Smoking abstinence at longest follow‐up (6+ months)	195 per 1000	199 per 1000 (170 to 234)	RR 1.02 (0.87 to 1.20)	2344 (5 studies)	⊕⊕⊝⊝^a Low
SAEs	2 per 1000	5 per 1000 (1 to 20)	RR 2.15 (0.49 to 9.46)	1852 (4 studies)	⊕⊕⊝⊝^b Low
Neuropsychiatric SAEs	0 per 1000	0 per 1000 (0 to 0)	RR 4.69 (0.23 to 96.50)	764 (2 studies)	⊕⊕⊝⊝^b Low	Only one study reported any events
Cardiac SAEs	2 per 1000	1 per 1000 (0 to 19)	RR 0.32 (0.01 to 7.88)	819 (2 studies)	⊕⊕⊝⊝^b Low	Only one study reported any events
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is calculated as the median risk in control groups.  CI: confidence interval; NRT: nicotine replacement therapy; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Varenicline versus e‐cigarettes for smoking cessation
Patient or population: people who continued to smoke tobacco following acute coronary syndrome Setting: hospital Intervention: varenicline Comparison: e‐cigarettes
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with e‐cigarettes	Corresponding risk with varenicline	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Smoking abstinence at longest follow‐up (6+ months)	148 per 1000	481 per 1000 (179 to 1000)	RR 3.25 (1.21 to 8.71)	54 (1 study)	⊕⊝⊝⊝^a,b Very low
SAEs	Not estimable (no events in analysis)	Not estimable (no events in analysis)	Not estimable (no events in analysis)	54 (1 study)
Neuropsychiatric SAEs	Not estimable (no events in analysis)	Not estimable (no events in analysis)	Not estimable (no events in analysis)	54 (1 study)
Cardiac SAEs	Not estimable (no events in analysis)	Not estimable (no events in analysis)	Not estimable (no events in analysis)	54 (1 study)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk in the comparison group is calculated as the median risk in control groups.  CI: confidence interval; RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Date	Event	Description
4 May 2023	New search has been performed	New searches conducted 29 April 2022 adding 45 new studies
4 May 2023	New citation required and conclusions have changed	New searches conducted 29 April 2022. Analyses and conclusions updated

Date	Event	Description
31 January 2016	New citation required and conclusions have changed	Additional comparisons. Analyses expanded and restructured. SAE information updated
31 January 2016	New search has been performed	39 trials of varenicline now included
16 May 2013	Amended	Minor change made to labelling on forest plot.
14 March 2012	New search has been performed	Seven new included studies (5 varenicline, 1 cytisine, 1 dianicline) and 14 new excluded studies added, plus safety data.
14 March 2012	New citation required and conclusions have changed	Safety profile modified, as new possible cardiovascular and psychiatric adverse events information incorporated. Efficacy findings unchanged but confirmed.
13 January 2011	Amended	Vinnikov trial of cytisine added to Studies awaiting Classification, for inclusion in next update.
8 November 2010	New search has been performed	Six new RCTs added; sources of funding added for all trials. Ongoing trials section expanded.
8 November 2010	New citation required and conclusions have changed	Surveillance data and secondary analyses do not support fears about safety. Efficacy conclusions strengthened but unchanged.
17 July 2008	Amended	Date of last search amended (2007 corrected to 2008); Source of support added.
12 May 2008	New citation required and conclusions have changed	Three new included trials, switch in the MA metric from OR to RR, updated background section and new safety information.
15 March 2008	New search has been performed	New search conducted.
30 August 2007	Amended	Converted to new review format.
15 November 2006	New citation required and conclusions have changed	Substantive amendment.

Term	Definition
Abstinence	A period of being quit, i.e. stopping the use of cigarettes or other tobacco products. May be defined in various ways; see also: point prevalence abstinence; prolonged abstinence; continuous/sustained abstinence
Biochemical verification	Also called 'biochemical validation' or 'biochemical confirmation' A procedure for checking a tobacco user's report that he or she has not smoked or used tobacco. It can be measured by testing levels of nicotine or cotinine or other chemicals in blood, urine, or saliva, or by measuring levels of carbon monoxide in exhaled breath or in blood.
Bupropion	A pharmaceutical drug originally developed as an antidepressant, but now also licensed for smoking cessation; trade names Zyban, Wellbutrin (when prescribed as an antidepressant)
Carbon monoxide (CO)	A colourless, odourless, highly poisonous gas found in tobacco smoke and in the lungs of people who have recently smoked, or (in smaller amounts) in people who have been exposed to tobacco smoke. May be used for biochemical verification of abstinence.
Cessation	Also called 'quitting' The goal of treatment to help people achieve abstinence from smoking or other tobacco use, also used to describe the process of changing behaviour.
Continuous abstinence	Also called 'sustained abstinence' A measure of cessation often used in clinical trials involving avoidance of all tobacco use since the quit day until the time the assessment is made. The definition occasionally allows for lapses. This is the most rigorous measure of abstinence.
'Cold turkey'	Quitting abruptly, and/or quitting without behavioural or pharmaceutical support.
Craving	A very intense urge or desire (to smoke) See: Shiffman 2004
Dopamine	A neurotransmitter in the brain that regulates mood, attention, pleasure, reward, motivation and movement
Efficacy	Also called 'treatment effect' or 'effect size' The difference in outcome between the experimental and control groups
Harm reduction	Strategies to reduce harm caused by continued tobacco/nicotine use, such as reducing the number of cigarettes smoked, or switching to different brands or products, e.g. potentially reduced exposure products (PREPs), smokeless tobacco
Lapse/slip	Terms sometimes used for a return to tobacco use after a period of abstinence. A lapse or slip might be defined as a puff or two on a cigarette. This may proceed to relapse, or abstinence may be regained. Some definitions of continuous, sustained or prolonged abstinence require complete abstinence, but some allow for a limited number or duration of slips. People who lapse are very likely to relapse, but some treatments may have their effect by helping people recover from a lapse.
nAChR	Neural nicotinic acetylcholine receptors Areas in the brain that are thought to respond to nicotine, forming the basis of nicotine addiction by stimulating the overflow of dopamine
Nicotine	An alkaloid derived from tobacco, responsible for the psychoactive and addictive effects of smoking
Nicotine replacement therapy (NRT)	A smoking cessation treatment in which nicotine from tobacco is replaced for a limited period by pharmaceutical nicotine. This reduces the craving and withdrawal experienced during the initial period of abstinence while users are learning to be tobacco‐free. The nicotine dose can be taken through the skin, using patches, by inhaling a spray, or by mouth using gum or lozenges.
Outcome	Often used to describe the result being measured in trials that is of relevance to the review. For example smoking cessation is the outcome used in reviews of ways to help smokers quit. The exact outcome in terms of the definition of abstinence and the length of time that has elapsed since the quit attempt was made may vary from trial to trial.
Pharmacotherapy	A treatment using pharmaceutical drugs, e.g. nicotine replacement therapy, bupropion
Point prevalence abstinence (PPA)	A measure of cessation based on behaviour at a particular point in time, or during a relatively brief specified period, e.g. 24 hours, 7 days. It may include a mixture of recent and long‐term quitters. cf. prolonged abstinence, continuous abstinence
Prolonged abstinence	A measure of cessation that typically allows a 'grace period' following the quit date (usually of about two weeks), to allow for slips/lapses during the first few days when the effect of treatment may still be emerging. See: Hughes 2003
Relapse	A return to regular smoking after a period of abstinence
Secondhand smoke	Also called passive smoking or environmental tobacco smoke (ETS) A mixture of smoke exhaled by smokers and smoke released from smouldering cigarettes, cigars, pipes, bidis, etc. The smoke mixture contains gases and particulates, including nicotine, carcinogens and toxins.
Self‐efficacy	The belief that one will be able to change one's behaviour, e.g. to quit smoking
SPC [Summary of Product Characteristics]	Advice from the manufacturers of a drug, agreed with the relevant licensing authority, to enable health professionals to prescribe and use the treatment safely and effectively.
Tapering	A gradual decrease in dose at the end of treatment, as an alternative to abruptly stopping treatment
Titration	A technique of dosing at low levels at the beginning of treatment, and gradually increasing to full dose over a few days, to allow the body to get used to the drug. It is designed to limit side effects.
Withdrawal	A variety of behavioural, affective, cognitive and physiological symptoms, usually transient, which occur after use of an addictive drug is reduced or stopped. See: Shiffman 2004

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Abstinence at longest follow‐up	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1.1 Cytisine vs placebo	4	4623	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [1.15, 1.47]
1.1.2 Cytisine vs no medication	1	869	Risk Ratio (M‐H, Fixed, 95% CI)	4.44 [3.06, 6.46]
1.2 Adverse events	4	4052	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [1.07, 1.39]
1.3 Serious adverse events	3	3781	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.78, 1.37]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Abstinence at longest follow‐up	1	470	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.98, 1.67]
2.1.1 84 days vs 40 days	1	470	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.98, 1.67]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Abstinence at longest follow‐up	2	2131	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.66, 1.05]
3.2 Nausea	2	2017	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.33, 0.50]
3.3 Abnormal dreams	2	2017	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.50, 0.73]
3.4 Insomnia	2	2017	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.73, 1.10]
3.5 Headache	2	2017	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.79, 1.33]
3.6 Depression	1	679	Risk Ratio (M‐H, Fixed, 95% CI)	3.04 [0.12, 74.47]
3.7 Suicidal ideation	2	2017	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.02]
3.8 SAEs	2	2017	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.44, 1.03]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Abstinence at longest follow‐up	1	1310	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [1.13, 1.80]
4.2 Nausea	1	1310	Risk Ratio (M‐H, Fixed, 95% CI)	15.00 [3.60, 62.51]
4.3 SAEs	1	1310	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.76, 1.75]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Abstinence at longest follow‐up	46		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1.1 Varenicline vs placebo	41	17395	Risk Ratio (M‐H, Fixed, 95% CI)	2.32 [2.15, 2.51]
5.1.2 Varenicline vs no medication	5	1050	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [1.37, 1.80]
5.2 Nausea	36	17080	Risk Ratio (M‐H, Fixed, 95% CI)	2.61 [2.44, 2.80]
5.3 Insomnia	35	16803	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [1.27, 1.47]
5.4 Abnormal dreams	32	16211	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [1.67, 1.97]
5.5 Headache	31	16326	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [1.03, 1.19]
5.6 Depression	32	15922	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.91, 1.20]
5.7 Suicidal ideation	22	12343	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.44, 1.08]
5.8 SAEs	26	14356	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [1.01, 1.48]
5.9 Neuropsychiatric SAEs (not deaths)	22	7846	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.61, 1.29]
5.10 Cardiac SAEs, including deaths	18	7151	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.79, 1.84]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Low‐dose varenicline vs placebo	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1.1 1 mg per day	3	946	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [1.35, 2.60]
6.1.2 As desired	1	320	Risk Ratio (M‐H, Fixed, 95% CI)	2.92 [1.57, 5.41]
6.2 Higher‐dose varenicline versus lower‐dose varenicline	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.2.1 2 mg per day vs 1 mg per day	4	1563	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.97, 1.30]
6.2.2 2 mg per day vs 0.3 mg per day	1	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.84 [0.89, 3.84]
6.2.3 1 mg per day vs 0.3 mg per day	1	254	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.28, 1.81]
6.3 Longer vs standard duration varenicline	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.3.1 24 weeks vs 12 weeks	2	1458	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.77, 1.23]
6.3.2 52 weeks vs 12 weeks	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.70, 2.43]
6.4 6 week vs 1 week preloading	1	242	Risk Ratio (M‐H, Fixed, 95% CI)	5.60 [2.24, 14.02]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Cardiovascular disease	2	1006	Risk Ratio (M‐H, Fixed, 95% CI)	1.88 [1.44, 2.47]
7.2 COPD	4	860	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [1.28, 1.69]
7.3 Asthma	1	52	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.38, 4.14]
7.4 Schizophrenia/bipolar/psychiatric disorder	3	2245	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [1.78, 2.86]
7.5 Depression	2	745	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [1.45, 3.24]
7.6 Substance use disorder/ methadone‐maintained at 24 weeks	2	294	Risk Ratio (M‐H, Fixed, 95% CI)	3.72 [0.50, 27.59]
7.7 Alcohol‐dependence	3	195	Odds Ratio (M‐H, Fixed, 95% CI)	3.01 [0.92, 9.92]
7.8 HIV	2	427	Risk Ratio (M‐H, Fixed, 95% CI)	1.96 [1.06, 3.63]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Hospital inpatients/perioperative patients	6	1324	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [1.12, 1.43]
8.2 Smokers with a previous quit attempt on varenicline	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8.3 Light or heavy smokers	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8.3.1 Light smokers	2	114	Risk Ratio (M‐H, Fixed, 95% CI)	4.16 [1.58, 10.97]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Abstinence at longest follow‐up	9	7560	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [1.25, 1.49]
9.2 Nausea	4	5808	Risk Ratio (M‐H, Fixed, 95% CI)	2.46 [2.20, 2.75]
9.3 Insomnia	6	6789	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.75, 0.93]
9.4 Abnormal dreams	4	5808	Risk Ratio (M‐H, Fixed, 95% CI)	1.56 [1.39, 1.76]
9.5 Headache	3	4888	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [1.06, 1.45]
9.6 Depression	2	4210	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.35, 2.35]
9.7 Suicidal ideation	2	4210	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [0.18, 21.93]
9.8 SAEs	5	5317	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.61, 1.31]
9.9 Neuropsychiatric SAEs (not deaths)	2	866	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.16, 7.04]
9.10 Cardiac SAEs, including deaths	2	866	Risk Ratio (M‐H, Fixed, 95% CI)	3.17 [0.33, 30.18]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Abstinence at longest follow‐up	11	7572	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [1.14, 1.37]
10.2 Nausea	6	6500	Risk Ratio (M‐H, Fixed, 95% CI)	2.69 [2.41, 3.01]
10.3 Insomnia	5	6319	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.96, 1.21]
10.4 Abnormal dreams	4	5803	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.83, 1.05]
10.5 Headache	4	6287	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [1.01, 1.28]
10.6 Depression	3	5541	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.76, 1.16]
10.7 Suicidal ideation	2	4876	Risk Ratio (M‐H, Fixed, 95% CI)	5.00 [0.87, 28.77]
10.8 SAEs	6	6535	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.50, 0.99]
10.9 Neuropsychiatric SAEs (not deaths)	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
10.10 Cardiac SAEs, including deaths	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Abstinence at longest follow‐up	5	2344	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.87, 1.20]
11.2 Nausea	3	1609	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [1.45, 2.15]
11.3 Insomnia	3	1609	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [1.15, 1.70]
11.4 Abnormal dreams	1	549	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [1.22, 2.08]
11.5 Headache	3	1609	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.78, 1.23]
11.6 Depression	3	1609	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.83, 1.40]
11.7 Suicidal ideation	2	764	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.06, 14.79]
11.8 SAEs	4	1852	Risk Ratio (M‐H, Fixed, 95% CI)	2.15 [0.49, 9.46]
11.9 Neuropsychiatric SAEs (not deaths)	2	764	Risk Ratio (M‐H, Fixed, 95% CI)	4.69 [0.23, 96.50]
11.10 Cardiac SAEs, including deaths	2	819	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 7.88]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Abstinence at longest follow‐up	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [1.21, 8.71]
12.2 Nausea	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.33, 27.06]
12.3 SAEs	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
12.4 Neuropsychiatric SAEs (not deaths)	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
12.5 Cardiac SAEs, including deaths	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Abstinence at longest follow‐up	1	602	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.82, 1.75]
13.2 Nausea	1	602	Risk Ratio (M‐H, Fixed, 95% CI)	2.83 [1.88, 4.27]
13.3 Headache	1	602	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.82, 1.85]
13.4 Depression	1	602	Risk Ratio (M‐H, Fixed, 95% CI)	8.05 [1.01, 63.99]
13.5 Serious adverse events	1	602	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.20, 4.95]
13.6 Cardiac SAEs, including deaths	1	602	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.06, 16.02]

*Study characteristics*
Methods	Country: USA (9 centres) and international (24 centres, across Bosnia & Herzogovina, Croatia, Germany, Hungary, Romania, Russian Federation, Spain) Setting: academic clinical trial centres and SC clinics Aim: to assess the efficacy and safety of 12 weeks of varenicline treatment or placebo for SC, with 40 weeks of non‐treatment follow‐up, in adults with current or past depression (MDD) Study design: double‐blind placebo‐controlled RCT Dates conducted: March 2010 ‐ June 2012
Participants	525 adult smokers, aged 18‐75, smoking at least 10 CPD, motivated to quit, diagnosed with unipolar MDD without psychotic features. 37% male, mean age 46, average CPD at baseline 22, mean FTND 5.9. Allocated to varenicline (256) or placebo (269) Exclusion criteria: current or past diagnosis of dementia, schizophrenia, schizoaffective disorder, or other psychotic disorder, bipolar I disorder, bipolar II disorder. People with antisocial, schizotypal, or any other personality disorder severe enough to compromise their ability to comply with the study requirements Current use of either bupropion or nortriptyline
Interventions	Varenicline 1 mg x 2/day, titrated for first week Placebo inactive tablets, same regimen All participants received manual‐guided SC support, telephone support and one‐to‐one 10‐min counselling by the same person where possible. Participants in both groups could reduce the dosage if they wished TQD was set for week 1 visit Treatment period was 12 weeks. Visits at screening, baseline, weekly for weeks 1‐12, and then at weeks 13, 16, 24, 32, 40, 52 (or early termination); phone calls at weeks 14, 20, 28, 36, 44 and 48. Weekly pill counts to assess adherence Safety data were reviewed regularly by an external independent data safety monitoring committee
Outcomes	Primary: CO‐confirmed CAR for weeks 9‐12 Secondary: CO‐confirmed CAR for weeks 9‐24, 9‐52; 7‐day PPA at weeks 12, 24, 52; AEs and SAEs Verification: CO < 10 ppm
Notes	New for 2016 update Study funding: "This study was funded by Pfizer. Dr. Anthenelli’s writing of this manuscript was funded, in part, by a Department of Veterans Affairs Merit Review award (NEUA‐003‐08S) and by a National Institute on Alcohol Abuse and Alcoholism grant (AA019720). Dr. Morris was supported, in part, by grants from the University of California, San Francisco, Smoking Cessation Leadership Center, and Colorado Department of Public Health and Environment. Drs. Ramey, Tsilkos, Russ, and Yunis and Ms. Dubrava are employees of Pfizer. Editorial support was provided by Abegale Templar, PhD, of Engage Scientific and funded by Pfizer." Author declaration of interests: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Eligible participants were randomly assigned to varenicline or placebo in a 1:1 ratio by using a computer generated, 4‐block randomization scheme at each site."
Allocation concealment (selection bias)	Low risk	"Randomization was stratified by antidepressant medication use at baseline (any vs. none) and baseline Montgomery–Åsberg Depression Rating Scale (MADRS) score (11 vs. 11) (32). Investigators obtained participant identification numbers and randomized study drug assignments by using a Web‐based or telephone call‐in computerized drug management system."
Blinding (performance bias and detection bias) All outcomes	Low risk	"The study drug was supplied in blinded bottles by the sponsor to the study sites, where they were dispensed according to computerized instructions."
Incomplete outcome data (attrition bias) All outcomes	Low risk	68.4% of varenicline group completed study (lost 15.6% in treatment and 16% in follow‐up); 66.6% of placebo group completed study (lost 21.9% in treatment and 11.5% in follow‐up)
Selective reporting (reporting bias)	Low risk	Results reported for all outcomes pre‐specified in NCT record.

PERMALINK

Nicotine receptor partial agonists for smoking cessation

Jonathan Livingstone-Banks

Thomas R Fanshawe

Kyla H Thomas

Annika Theodoulou

Anisa Hajizadeh

Lilian Hartman

Nicola Lindson

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Varenicline versus placebo or no medication for smoking cessation.

Summary of findings 2. Cytisine versus placebo or no medication for smoking cessation.

Summary of findings 3. Cytisine versus varenicline for smoking cessation.

Summary of findings 4. Cytisine versus nicotine replacement therapy for smoking cessation.

Summary of findings 5. Varenicline versus bupropion for smoking cessation.

Summary of findings 6. Varenicline versus nicotine replacement therapy monotherapy for smoking cessation.

Summary of findings 7. Varenicline versus combination nicotine replacement therapy for smoking cessation.

Summary of findings 8. Varenicline versus e‐cigarettes for smoking cessation.

Background

Description of the condition

Description of the intervention and how it might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Cytisine

Varenicline

Setting

Participants

Interventions

Comparators

Outcomes

Dianicline

Study funding

Excluded studies

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

*Study characteristics*
Methods	Country: USA Setting: not explicitly reported, likely at home and in hospital Aim: to evaluate the safety and efficacy of varenicline for SC among people living with HIV Study design: parallel placebo‐controlled phase 3 RCT Dates conducted: October 2012‐September 2018
Participants	179 adult smokers all with a confirmed HIV diagnosis, currently smoking and motivated to quit. All treated with antiretroviral therapy with HIV loads < 1000 copies/mL and CD4+ counts > 200 cells/mm³. 32% female, mean age 48.6, average CPD at baseline 11.5
Interventions	Varenicline 1 mg x 2/day Placebo inactive tablets, same regimen All participants received 6 sessions over 9 weeks of interactive behavioural support in person or by telephone. Treatment period was 12 weeks.
Outcomes	Primary: 7‐day PPA, CO‐confirmed, at weeks 12 and 24 Secondary: CA and time to relapse
Notes	New for 2022 update Funding source: "National Institute on Drug Abuse, Penn Center for AIDS Research, Penn Mental Health AIDS Research Center. Pfizer provided medication and placebo free of charge" Declaration of interests: "Dr. Schnoll has provided consultation to Pfizer, GlaxoSmithKline, and Curaleaf. Dr. Gross serves on a Pfizer Data and Safety Monitoring Board for a drug unrelated to smoking or HIV. Dr. Ashare has an investigator‐initiated grant from Novo Nordisk for a drug unrelated to the current study."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Eligible participants were randomized 1:1 by a computer‐generated protocol provided by the study statistician to the University of Pennsylvania’s Investigational Drug Service (IDS)"
Allocation concealment (selection bias)	Low risk	Randomisation conducted separately by the University of Pennsylvania’s Investigational Drug Service (IDS), and all other study personnel were blinded. Therefore, concealment was likely adequate.
Blinding (performance bias and detection bias) All outcomes	Low risk	Abstinence was biochemically validated and "All participants and study personnel, aside from IDS [Investigational Drug Service], were blinded from treatment arm allocation throughout the trial."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition rates were similar between study arms.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes from trial registry entry all reported in published results

*Study characteristics*
Methods	Country: Belgium, France, Netherlands, UK, USA Setting: 24 research centres Aim: to compare the efficacy of varenicline with nicotine patch, both open‐label Dates conducted: January 2005‐June 2006 Study design: open‐label randomised trial
Participants	757 healthy adults, recruited from SC clinics or by local advertising, aged 18‐75, weight > 45.5 kg, BMI 15‐38, smoking ≥ 15 CPD. Varenicline arm 378, NRT arm 379. Mean age 42.9, 49.2% men, 93% white. Mean CPD 22.7. Previous use of nicotine patch 47.4%, previous use of bupropion 20%. Mean FTND 5.5. Exclusion criteria: standard pharmacotherapy trial criteria, + participants must not have been in a varenicline trial in previous year, or used NRT in previous 6 months
Interventions	Varenicline 1 mg x 2/day for 12 weeks, titrated 1st week Nicotine patch (21 mg weeks 2‐6, 14 mg weeks 7‐9, 7 mg weeks 10‐11) All participants received Clearing the Air booklet at baseline, and brief counselling (≤ 10 min) at each clinic visit or by phone. TQD was at week 1 visit. Weekly visits throughout treatment phase, plus a phone call 3 days post‐TQD In follow‐up phase, clinic visits at weeks 13, 16, 24, 32, 40, 48 and 52, plus brief phone calls at weeks 14, 20, 28, 36 and 44
Outcomes	CO‐confirmed CAR for last 4 weeks' treatment (varenicline weeks 9‐12, NRT weeks 8‐11) CO‐confirmed CAR at weeks 9‐24 and 9‐52 (varenicline) and 8‐24 and 8‐52 (NRT) 7‐day PPA at EoT and at weeks 24 and 52 Other outcomes: weight change, withdrawal symptoms (using MNWS and mCEQ), AEs Validation was by expired CO ≤ 10 ppm Dropouts and losses to follow‐up were included in the analyses as continuing smokers (ITT analysis) Attrition in treatment phase was 17.3% varenicline, 20.3% NRT. Losses to follow‐up 17% in each group 65.7% of varenicline and 62.2% of NRT groups completed study
Notes	New for 2008 update Study funding: study funded by Pfizer Author declaration of interests: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Using a central computer‐generated sequence"
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding (performance bias and detection bias) All outcomes	Low risk	"Using an open‐label design". However, comparators were two active treatments, minimising risk of performance bias, and abstinence was biochemically validated
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Missing CO data were assumed to be < 10 ppm provided other conditions were met", i.e. no NRT other than prescribed patches. Missing = negative assumption reduced successes by 1 in each group
Selective reporting (reporting bias)	Low risk	All predicted outcomes fully reported

*Study characteristics*
Methods	Country: USA Setting: 2 University sites in Wisconsin (Madison, Milwaukee) Aim: to compare the efficacy of varenicline with nicotine patch, and with combination NRT (C‐NRT) Dates conducted: May 2012‐November 2015 Study design: open‐label randomised trial (no placebo)
Participants	1086 healthy adults, recruited from participants in the ongoing Wisconsin Smokers Health Study or by media and community outreach, aged 17+, smoking ≥ 5 CPD, motivated to quit Varenicline arm 424, nicotine patch arm 241, combination NRT arm 421 Mean age 48.1, 47.9% men, 67% white. Mean CPD 17. Mean FTND 4.8 Exclusion criteria: standard pharmacotherapy trial criteria, CO < 4 ppm, no suicide attempts in previous 5 years, or current suicidal ideation, diagnosis or treatment of psychoses in previous 10 years
Interventions	Varenicline 1 mg x 2/day for 12 weeks, titrated 1st week Nicotine patch: 11+ CPD on 21 mg weeks 1‐8, 14 mg weeks 9‐10, 7 mg weeks 11‐12; 5‐10 CPD on 14 mg weeks 1‐10, 7 mg weeks 11‐12 Nicotine patch as above, plus nicotine lozenge (2 mg or 4 mg), at least 5 times a day for 12 weeks All participants received counselling (20 min at visits 1, 2 and 3, and 10 min by phone and at visits 4, 5) at 1 week pre‐TQD and at TQD, weeks 1, 4, 12 post‐TQD, plus phone call at week 8 In follow‐up phase, participants were contacted at weeks 26 and 52 by phone
Outcomes	All comparisons were based on varenicline and C‐NRT versus patch (reference arm), and on varenicline versus C‐NRT CO‐confirmed PPA at week 26 CO‐confirmed PA from day 7 post‐TQD to day 181 CO‐confirmed PPA at weeks 4, 12, 52 Other outcomes: adherence, withdrawals, AEs Validation was by expired CO ≤ 9 ppm and ≤ 5 ppm Dropouts and losses to follow‐up were included in the analyses as continuing smokers (ITT analysis) Withdrawal rates were 8.3% varenicline, 6.2% nicotine patch, 3.1% C‐NRT
Notes	The trial was funded by grant 5R01HL109031 from National Heart, Lung, and Blood Institute, and by grant K05CA139871 from the National Cancer Insitute New for 2016 update Author declaration of interests: "All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Stein reports receipt of data and safety monitoring board honoraria from Lilly and Abbott. No other disclosures were reported."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐based randomisation"
Allocation concealment (selection bias)	High risk	"Treatment assignment was unblinded" (open‐label)
Blinding (performance bias and detection bias) All outcomes	High risk	"Treatment assignment was unblinded" (open‐label) "The follow‐up telephone assessments were intended to be blinded, but a database search by interviewers could have revealed treatment assignment"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Low rates of attrition, ITT analysis used
Selective reporting (reporting bias)	Low risk	All predicted outcomes reported, protocol available

*Study characteristics*
Methods	Country: USA Setting: 2 research clinics in Wisconsin Aim: to compare combinations of varenicline plus the nicotine or placebo patch vs combinations used for either 12 weeks (standard duration) or 24 weeks (extended duration) Study design: double‐blind, 2 × 2 factorial RCT
Participants	1251 adult smokers, smoking at least ≥ 5 CPD and motivated to quit. 54% female, mean age 49.1, average CPD at baseline 16
Interventions	Varenicline monotherapy for 12 weeks. 1 mg x 2/day, titrated for first week Varenicline 1 mg x 2/day for 12 weeks, titrated for first week. Plus nicotine patch 14 mg/day for 12 weeks Varenicline monotherapy for 24 weeks. 1 mg x 2/day, titrated for first week Varenicline 1 mg x 2/day for 24 weeks, titrated for first week. Plus nicotine patch 14 mg/day for 24 weeks All participants received a total of 1.5 h (6 x 15 min over 10 weeks) of interactive behavioural support, either as face‐to‐face consultations or via telephone. Treatment period was either 12 or 24 weeks
Outcomes	Primary outcome: CO‐confirmed self‐reported 7‐day PPA at 52 weeks Secondary outcome: prolonged CO‐confirmed self‐reported abstinence ‐ from day 7‐week 52 after TQD) Verification: CO ≤ 5 ppm
Notes	New for 2022 update. Study funding: "Pfizer supplied the study with free active and placebo varenicline as per an investigator‐initiated research agreement. This research was supported by grant 5R01HL109031 from the National Heart, Lung, and Blood Institute and grant K05CA139871 from the National Cancer Institute (both awarded to the University of Wisconsin Center for Tobacco Research and Intervention)." Author declaration of interests: "Dr Baker reported receiving personal fees from the National Cancer Institute for editing a monograph and grants from the National Cancer Institute. Dr Bolt reported receiving grants from the National Institutes of Health. Dr Fiore reported receiving personal fees from the National Cancer Institute. No other disclosures were reported."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Use of software (SASProcPlanversion9.4) to generate randomisation schedule. Quote: "Participants were randomized to 1 of 2 levels of the 2 experimental factors (medication type and medication duration) via a database that used stratified permuted block randomization."
Allocation concealment (selection bias)	Unclear risk	Allocation process not reported (how interventions (active or placebo pills and patches) were put into the letters and sent to participants)
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and study personnel blinded to allocation. Abstinence biochemically validated
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up < 50% overall, loss similar across treatment arms, missing observations were assumed to reflect current smoking
Selective reporting (reporting bias)	Low risk	Outcomes pre‐specified in trial registry all reported in results paper

*Study characteristics*
Methods	Study design: RCT Country: Turkey Setting: SC clinic Recruitment method: participants applied to the SC clinic directly by calling the Turkish Ministry of Health's 'stop smoking' helpline and making an appointment.
Participants	An unspecified number of participants were randomised. 405 participants were analysed. 17.5% female; average age 35.2; average age 35.2; average CPD 23; mean FTND 6.3
Interventions	Bupropion. Provided for 3 months Varenicline. Provided for 3 months Common components: behavioural therapy support with a biopsychosocial approach
Outcomes	SC: 7‐day PPA at 12 months. Validated by a CO level ≤ 5 ppm
Notes	Funding source: no funding Author conflicts of interest: the authors declare that they have no competing interests Unclear from study reporting if study is a genuine trial or a follow‐up of treatment in a clinic. However, treatment was randomly allocated, so we have treated this study as a trial.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “Patients who were to receive the medication were randomly determined by the medication support center in order to provide a constant distribution rate of varenicline and bupropion and so that physicians would not be aware of the medication distribution.” Comment: no further detail is provided.
Allocation concealment (selection bias)	Unclear risk	Quote: “Patients who were to receive the medication were randomly determined by the medication support center in order to provide a constant distribution rate of varenicline and bupropion and so that physicians would not be aware of the medication distribution.” Comment: no further detail is provided.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Quote: “Patients who were to receive the medication were randomly determined by the medication support center in order to provide a constant distribution rate of varenicline and bupropion and so that physicians would not be aware of the medication distribution” Comment: some attempt appears to have been made to blind physicians to group assignment, however no further detail is given, so it is unclear whether participants and outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	Only those followed up at 12 months are included in analysis
Selective reporting (reporting bias)	Unclear risk	No protocol found

*Study characteristics*
Methods	Country: Israel Setting: Pulmonary Institute of Shaare Zedek Medical Center (SZMC), Jerusalem, Israel, in participants' home Aim: to assess whether varenicline preloading for 6 weeks prior to the TQD reduced pre‐quit smoke intake and enhanced 6‐month abstinence outcomes compared with the standard 1‐week preloading. Study design: parallel placebo‐controlled RCT
Participants	242 daily smokers, smoking ≥ 10 CPD, and had smoked for ≥ 5 pack years, and were motivated to quit. 27% female, mean age 48, average CPD at baseline 25
Interventions	1 week of varenicline preload: 5 mg of varenicline once daily for 3 days and 0.5 mg twice daily for 4 days (week 1), followed by varenicline 1 mg twice daily for 5 additional weeks 6 weeks of varenicline preload: matched placebo tablets for 5 weeks, followed by a 1‐week titration of varenicline as in group 1 TQD was 6 weeks post‐initiation of treatment.
Outcomes	Primary: 24‐week biochemically verified CAR from weeks 6–30 Secondary: 23‐week CAR from 1‐week post‐TQD (week 7) to week 30; 7‐day PPA at week 30 Biochemically validated: expired CO ≤ 5 ppm and urine cotinine equivalent concentration ≤ 1 mg/mL
Notes	New for 2022 update Study funding: "2013 Global Research Award for Nicotine Dependence (GRAND) supported by Pfizer, Inc. (#WI182915)" Author declaration of interests: "None"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomisation was accomplished by extracting a systematic sample via a pre‐prepared list of alternate allocations"
Allocation concealment (selection bias)	Unclear risk	"These procedures were performed by the randomisation monitor (VP) in a secure room where the study medication, provided free of charge by Pfizer Inc., NY, was stored in identically packaged, blinded bottles containing varenicline or placebo. Participants were referred to the secure room where they were randomly allocated (in a 1:1 ratio) to the experimental group."
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind during preloading phase (open‐label afterwards as both groups were receiving identical treatments).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition similar in both groups, overall < 50%
Selective reporting (reporting bias)	Low risk	Outcomes reported as in clinical trials record

*Study characteristics*
Methods	Countries: Brazil, Colombia, Costa Rica, Egypt, Jordan, Lebanon, Mexico, Saudi Arabia, South Africa, United Arab Emirates, Venezuela Setting: 42 research centres (51.2% Latin America, 30.6% Africa, 18.2% Middle East) Aim: to test the efficacy and tolerability of varenicline in regions not previously exposed to SC RCTs of varenicline Dates conducted: April 2008‐August 2009 Study design: double‐blind placebo‐controlled RCT
Participants	593 adults, recruited from SC clinics, aged 18‐75, weight > 45.5 kg, BMI 15‐38, smoking ≥ 10 CPD, motivated to quit. Randomised to varenicline 394 (390 got medication), or placebo 199 (198 got medication). Mean age 43.5, 63.6% men, mean CPD 23.8, mean FTND 6.0. 55% had no prior quit attempt Exclusion criteria: standard pharmacotherapy trial criteria, + participants must not have used NRT, bupropion, clonidine or nortriptyline in previous 6 months
Interventions	Varenicline 1 mg x 2/day, titrated during week 1 Placebo inactive tablets, same regimen Treatment period was 12 weeks. All participants received You can quit smoking self‐help booklet (available in English, Spanish, Portugese and Arabic) at baseline, and brief counselling (≤ 10 min) at each clinic or telephone contact. TQD set for week 1. Clinic visits at weeks 2, 3, 4, 6, 8, 10 and 12 throughout treatment phase, plus a phone call 3 days post‐TQD In follow‐up phase, clinic visits at weeks 13, 16, 20 and 24, plus brief phone calls at weeks 14, 18 and 22
Outcomes	Primary outcome: CO‐validated CAR at 9‐12 weeks Secondary outcomes: CO‐validated CAR at 9‐24 weeks; 7‐day PPA at weeks 12 and 24 Other outcomes: AEs, clinically significant changes in vital signs, SAEs Abstinence was assessed using the Nicotine‐Use Inventory (NUI); validation was by expired CO ≤ 10 ppm Dropouts and losses to follow‐up were included in the analyses as continuing smokers (ITT analysis). [4 (V) 1 (P) who did not receive allocated intervention re‐included in denominators in this analysis.] Attrition in treatment phase was 11.2% (V) and 20.6% (P); in follow‐up phase 2.5% (V) and 0.5% (P)
Notes	New for 2012 update The study was funded and managed by Pfizer Inc Author declaration of interests: "(1) the institutions of Drs. Bolliger, Issa, Posadas‐Valay, and Safwat received financial support from Pfizer for the clinical trial; (2) Drs. Bolliger, Issa, Posadas‐Valay, and Safwat received no financial support from Pfizer for the submitted work; (3) Drs. Bolliger, Issa, Posadas‐Valay, and Safwat have specified relationships with Pfizer that might have an interest in the submitted work in the previous 3 years, including investigator payments, consulting honoraria, and grants; (4) their spouses, partners, and children have no financial relationships that may be relevant to the submitted work; and (5) Drs. Bolliger, Issa, Posadas‐Valay, and Safwat have no nonfinancial interests that may be relevant to the submitted work. Drs. Bolliger, Issa, Posadas‐Valay, and Safwat did not receive financial support with respect to the writing or development of the manuscript. Dr. Abreu, Mr. Correia, Dr. Park, and Mr. Chopra are employees of, and stockholders in, Pfizer."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Using a block randomization within each site, eligible participants were randomly assigned in a 2:1 ratio to receive varenicline or placebo"
Allocation concealment (selection bias)	Low risk	"a web‐based or telephone call‐in drug management system directed by the sponsor"
Blinding (performance bias and detection bias) All outcomes	Low risk	"All of the study personnel and participants were blinded to treatment assignment until the end of the nontreatment follow‐up phase"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropouts and attrition fully reported
Selective reporting (reporting bias)	Low risk	All predicted and expected outcomes reported

*Study characteristics*
Methods	Country: Australia Setting: respiratory, cardiology, neurology, vascular and general medicine wards of 3 Adelaide (South Australia) hospitals Aim: to evaluate efficacy and safety of varenicline + quitline counselling vs quitline counselling alone in people admitted with smoking‐related acute illnesses Study design: phase II/III open‐label single‐blind RCT Dates conducted: August 2008‐December 2011 Study name: Smoking Termination Opportunity for inPatients (STOP)
Participants	392 adult smokers, aged 18‐75, smoking 10 CPD+, willing to quit, admitted with acute smoking‐related illnesses; randomised to varenicline + counselling (196) or counselling alone (196) Mean age 53, 32% women, 96% white, mean CPD 25, mean FTND 5.6 Exclusion criteria: standard pharmacotherapy criteria, acute or pre‐existing psychiatric illness, history of psychosis or suicidal ideation, use of varenicline in past 12 months
Interventions	Varenicline 1.0 mg x 2/d for 12 weeks, including week 1 at titrated dose (described as standard MIMS dosing schedule), + counselling Counselling only Both groups received Quit SA 5A behavioural counselling, i.e. maximum of 8 calls over 3 months. Also booklet Quit because you can, + stickers and fridge magnets. Participants had to set a TQD within first 2 weeks Contacts were attempted with all participants at days 3 and 5, weeks 1, 2, 3, 4, 12 (EoT). Additional contacts at weeks 26 and 52
Outcomes	Primary outcome: self‐reported CAR (< 5 cigarettes in total) (2 weeks‐12 months) Secondary outcomes: CAR at 4, 12 and 26 weeks. 7‐day PPA each week for first 4 weeks; craving; reduced hospital bed utilisation; reduction in healthcare costs CO validation ≤ 10 ppm used only in "a random sub‐set of subjects"
Notes	Partially funded by the Department of Respiratory Medicine, Queen Elizabeth Hospital, Adelaide, SA New for 2012 update (study ID was Smith 2012; changed for 2015 update) Author declaration of interests: "The authors have read the journal’s policy and have the following potential competing interests: KVCC was paid an honorarium and provided with economy airfares and accommodation by Pfizer Australia to present at the 2019 Smoking Exchange Summit in New South Wales where she spoke about ‘culturalspecific issues in smoking cessation’ and as an invited panellist in a plenary session about ‘a national approach to smoking cessation’. In 2017 she received an honorarium and provided with economy airfares and accommodation to speak about 12‐month results of the STOP trial at the annual Pfizer Australia conference in New South Wales, Hunter Valley. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A pre‐defined, central, computer‐generated randomization sequence was used to assign subjects in a 1:1 ratio to either 12 weeks of treatment with varenicline plus Quitline‐counseling or 12 weeks of Quitline‐counseling alone."
Allocation concealment (selection bias)	Low risk	"using opaque, sealed envelopes with consecutive numbers"
Blinding (performance bias and detection bias) All outcomes	High risk	Open‐label design. Attempt at single‐blinding (statistical investigator). "Participants and investigators were not blinded to treatment assignment". "Randomization and allocation concealment were performed by respiratory staff independent of the study". Biochemical validation of abstinence conducted in a random subset of participants via exhaled CO levels ≤ 10 ppm
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	"Missing data from questionnaire (e.g., a question missed when administering follow‐up) were randomly imputed via a computer programme" 84% varenicline completed the study at 52 weeks, vs 82% in the placebo group
Selective reporting (reporting bias)	Unclear risk	Reuslts unavailable for some secondary outcomes prespecified in NCT record, however results may still be forthcoming in future publications

*Study characteristics*
Methods	Country: USA Aim: to compare the efficacies of cNRT and varenicline with one another and with placebo, as a function of the rs16969968 genotype Dates: May 2015‐August 2019 Study design: genotype‐stratified randomised, double‐blind, placebo‐controlled clinical trial
Participants	822 current smokers, smoking > 5 CPD, with exhaled CO ≥ 8 ppm. 54.6% female, mean age 46.5, baseline average CPD 17.6
Interventions	Placebo cNRT (nicotine patch 21 mg/day + nicotine lozenge 2 or 4 mg/day) Varenicline 2 x 1 mg/day Randomisation was stratified by rs16969968 genotype in blocks of 6 patients (2 per treatment per block)
Outcomes	Primary: 7‐day PPA at week 12 Secondary: 7‐day PPA with CO verification at 6 months; 7‐day PPA at 1 year by self‐report; AEs, and adherence Abstinence was defined as no self‐reported smoking for at least 7 days before the assessment with biochemical verification (CO < 8 ppm) for those self‐reporting abstinence.
Notes	New for 2022 update Funding by National Institute on Drug Abuse, Siteman Cancer Center and NCI Cancer Center Support Grant. Pfizer supplied the study medication free of charge. Author declaration of interests: "L.‐S.C. received free supply of study medication (varenicline and placebo) for this research project via an investigator‐initiated research agreement (IIR) from Pfizer. This free Pfizer product constitutes the support for this study. Pfizer supports the Principal Investigator to exercise the academic freedom and encourages publication of study results whether or not they are favorable for the Pfizer Product. R.M.C. or a member of his family owns stock in Pfizer Inc. L.J.B. is listed as an inventor on Issued US Patent 8,080,371 “Markers for Addiction” covering the use of certain single nucleotide polymorphisms in determining the diagnosis, prognosis, and treatment of addiction, and served as a consultant for the pharmaceutical company Pfizer Inc. (New York City, NY) in 2008. The spouse of N.L.S. is also listed as an inventor on Issued US Patent 8,080,371 “Markers for Addiction.” All other authors declared no competing interests for this work."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"SAS Version 9 statistical software will be used to generate the random assignment table stratified by CHRNA5 genotype rs16969968" From protocol
Allocation concealment (selection bias)	Low risk	"The group assignment and genotype will be coded to ensure that the double blind is maintained, and the interface will prevent staff from having access to the participant’s assignment and genotype until after the baseline and post treatment assessments have been completed."
Blinding (performance bias and detection bias) All outcomes	Low risk	Placebo‐controlled and matched contact between groups
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition < 50% and similar between arms
Selective reporting (reporting bias)	Low risk	Results for all prespecified outcomes reported

*Study characteristics*
Methods	Country: Pittsburgh, USA Setting: 2 outpatient clinics, Western Psychiatric Institute and Clinic; and Dubois Medical Regional Center, Pennsylvania Aim: to assess the efficacy and safety of varenicline to assist in SC among patients with bipolar disorder who were euthymic and motivated to quit smoking Study design: double‐blind placebo‐controlled RCT Dates conducted: February 2010‐March 2013
Participants	60 outpatient smokers with DSM‐IV‐diagnosed bipolar disorder, aged 18‐65, stable state or on medication, willing to quit in the next 30 days, 10+ CPD; randomised to varenicline (31) or placebo (29) Mean age 46, 69% women, 66% white, mean CPD 18.1, mean FTND 6.2 Exclusions: bupropion use (for SC); usual pharmacological criteria
Interventions	Varenicline 1 mg x 2/day, titrated for first week Placebo inactive tablets, same regimen All participants received 15‐min SC counselling at each visit. CO tested and pill counts at each visit. Participants in both groups could reduce the dosage if they wished. TQD was set for week 2 onwards (i.e. full dosage reached) Treatment period was 12 weeks. Weekly pill counts to assess adherence Safety data were reviewed blind monthly by an external independent data safety and monitoring board (DSMB)
Outcomes	Primary: 7‐day PPA, CO‐verified, at 12 weeks Secondary outcomes: 7‐day PPA at 24 weeks; CA at 12, 24 weeks Validation: CO < 10 ppm
Notes	New for 2016 update Study funding: "The National Institute of Mental Health (NIMH) of the NIH, under award R21MH087928 (Dr Chengappa), provided the main funding for this study. Pfizer provided drug/placebo and an investigator‐initiated grant, WS‐515343 (Dr Chengappa). These monies channeled through the University of Pittsburgh were used to offset costs of study procedures, participant payments, and a percentage of the time and effort of research staff and faculty salaries." Author declaration of interests: "Dr Turkin has served on the speaker’s bureau of Forest, Sunovion, and Otsuka; and owns shares of Pfizer stock. Dr George has received investigator‐initiated and contract research support from Pfizer, served as a consultant to Novartis, and received honoraria from National Institutes of Health (NIH) and American College of Neuropsychopharmacology. Drs Chengappa, Perkins, Brar, and Levine, and Mss Schlicht and Hetrick and have no financial disclosures with regards to this study."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not stated, other than "stratified by gender"
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	Low risk	"The treatment assignment was blinded to participating subjects, raters, investigators and statisticians"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	24 participants in each group completed treatment phase, and 24 (77%) and 20 (69%) completed full study in varenicline and placebo groups respectively Data were analysed using ITT with LOCF
Selective reporting (reporting bias)	Low risk	Prespecified outcomes from trial registry all reported
Other bias	Unclear risk	8 participants (4 in each arm) were on bupropion for depression; 3/15 varenicline quitters and 1/3 placebo quitters were on long‐term bupropion