Annals of the American Thoracic Society

Rationale: Not all individuals with tobacco dependence are ready to give up smoking. Research reveals behavioral differences between adults ready to discontinue tobacco use and those who are not. Thus, the interventions applied to these populations might differ. However, the evidence of using varenicline in individuals who are not ready to discontinue tobacco use is uncertain.

Objectives: To determine if, in tobacco-dependent adults who report not being ready to discontinue tobacco use, clinicians should begin treatment with varenicline or wait until subjects are ready to discontinue tobacco use.

Methods: We conducted a systematic review to assess the effectiveness and safety of treatment with varenicline in tobacco-dependent adults who are not ready to discontinue tobacco use. We systematically searched the Cumulative Index to Nursing and Allied Health Literature, Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials comparing varenicline versus placebo for individuals who were not ready to discontinue tobacco use. Outcomes of interest include point prevalence abstinence during treatment or at six months or longer, smoking reduction, motivation to quit, adverse events, and withdrawal symptoms. Two authors independently extracted data and assessed eligibility and risk of bias using a standardized data collection form. We followed the Grading of Recommendations, Assessment, Development and Evaluations approach to assess the certainty of evidence.

Results: Five trials met our inclusion criteria. All 2,616 participants were adults who were not ready to discontinue tobacco use at study entry. For 7-day point prevalence abstinence at six months or longer, high-certainty evidence suggested that varenicline increased abstinence compared with placebo (relative risk, 2.00 [95% confidence interval (CI), 1.70–2.35]; absolute risk reduction, 173 more per 1,000 [95% CI, 121 more to 234 more]). We identified moderate-certainty evidence suggesting that varenicline increased serious adverse events (relative risk, 1.75 [95% CI, 0.98–3.13]; absolute risk reduction, 12 more per 1,000 [95% CI, 0 fewer to 35 more]). For withdrawal, low-certainty evidence suggested that varenicline treatment was associated with a lower symptom score (mean difference, 1.54 points lower; 95% CI, 2.15–0.93 points lower; low certainty) assessed using the Brief Questionnaire of Smoking Urges.

Conclusions: In tobacco-dependent adults who are not ready to discontinue tobacco use, initiating varenicline treatment results in a large increase in abstinence and likely results in a slight increase in serious adverse events.

Globally, tobacco use is still the single most preventable cause of disease, disability, and mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study estimated that the age-standardized prevalence of daily smoking was 25.0% for men and 54% for women, and smoking accounted for 7.69 million deaths and 200 million disability-adjusted life-years globally in 2019 (1). Previous guidelines have established the first principle of clinical practice: all patients who use tobacco should receive treatment for their dependence and not simply be encouraged to stop (2, 3). Despite traditional treatment approaches consisting of an abrupt cessation with a quit date, some individuals with tobacco dependence prefer gradual cessation. Gradual cigarette reduction using varenicline (4, 5) or nicotine replacement therapy (6) appears reasonable to achieve short- and long-term abstinence.

When starting tobacco dependence treatment, informed by a transtheoretical model of behavior change, assessing the readiness to quit intention is widely accepted (7). More recently, however, the assessment of quitting intention has been called to attention because behavior change has proved to be a dynamic process (8). Although patients may not be ready to abstain, they may be willing to try tobacco dependence treatment (5). Studies have suggested that after tobacco dependence treatment, a significant proportion of patients who were not ready to set a quit date ended up achieving sustained compulsion control (9, 10). So, treatment of tobacco users may increase the number of patients who would stop smoking (4, 1114), and a gradual reduction approach may be beneficial.

Pharmacotherapies for tobacco dependence may aid the gradual reduction approach rather than an abrupt quitting approach. In tobacco-dependent adults who are not ready to discontinue tobacco use, varenicline’s mechanisms of action (agonist and antagonist effects at the α4β2 neuronal nicotinic acetylcholine receptor) provided pharmacological support for cigarette reduction. If individuals with tobacco dependence consume fewer cigarettes without much increase in craving and withdrawal, motivation to quit may increase (15).

There is only very low quality evidence on whether cutting down on smoking before quitting helps more people quit smoking than no treatment (16). Furthermore, there is no systematic review to examine the evidence on the effect of varenicline as an aid to the gradual reduction approach.

The aim of this systematic review is to determine if, in tobacco-dependent adults who report not being ready to discontinue tobacco use, clinicians should begin treatment with varenicline or wait until subjects are ready to discontinue tobacco use.

We systematically searched, summarized, and critically appraised the relevant evidence. The systematic review was performed following the Cochrane Handbook for Systematic Reviews of Interventions (17) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (18). The systematic review was performed as a component of the American Thoracic Society clinical practice guideline on initiating pharmacologic treatment in tobacco-dependent adults.

Literature Search

The following concepts were used in search terms: tobacco dependence, varenicline, and smokers who are not ready to discontinue tobacco use. We used the Boolean operator OR to combine the controlled vocabulary (e.g., Medical Subject Heading, Emtree, including “exploded” terms) and free-text terms. We also used the Scottish Intercollegiate Guidelines Network search filter to identify randomized controlled trials. We searched MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the National Institute of Health Research Centre for Reviews and Dissemination database, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to December 2021. Full search strategies for all databases are available in the data supplement.

Study Selection and Inclusion Criteria

Reviewers working in pairs conducted an initial screening of titles and abstracts and obtained the full texts of studies that appeared eligible according to the inclusion criteria by either reviewer. Two reviewers conducted the full-text review in duplicate and resolved disagreement through consensus discussion. If necessary, a third reviewer was consulted.

The screening process followed a priori inclusion criteria delineated according to the study population, intervention, comparison, and study design. Studies are eligible if they are randomized control trials, blinded or not, of tobacco-dependent adults who are not ready to discontinue tobacco use, comparing varenicline versus placebo. No proactive nicotine replacement therapy, other pharmacotherapy, or behavioral therapy was allowed before the first attempt to quit smoking in both arms (varenicline or placebo).

Outcomes of interest included point prevalence abstinence during treatment or at six months or longer, the incidence of serious adverse events (SAEs), tobacco use relapse, increase or decrease in other substance abuse (including alcohol, marijuana, cocaine, and opioids), quality of life, and severity of withdrawal. We also considered the number of cigarettes smoked, quit attempts, and motivation to stop smoking. We defined SAEs as life-threatening adverse events, in the trialists’ opinion, that were attributable to pharmacological treatment. These could include psychological disorders such as depression, anxiety, suicidal ideation, or suicidal behavior and neurological events such as seizures or reported as SAEs by study authors.

Data Extraction and Quality Assessment

A standardized data form was developed for data extraction. Extracted information included study design (including the setting and duration of follow-up), population (including demographics and baseline characteristics), details of the intervention, comparator, and the outcomes. We assessed and reported the risk of bias of included studies by the outcome, following the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions, in the following individual domains: random sequence generation, allocation concealment, blinding of healthcare personnel and patients, blinding of outcome assessors, attrition, and selective reporting of outcomes (19). We present our assessment in the risk-of-bias summary figure. Data extraction and risk-of-bias assessment were performed independently and in duplicate by two authors. Disagreements were resolved through discussion and consensus. In rare cases, a third author arbitrated the disagreements.

Data Analysis

We performed meta-analyses with head-to-head comparison using the Mantel-Haenszel method with random effects. The chi-square test and I2 statistic were used to assess heterogeneity (RevMan version 5.3; The Nordic Cochrane Centre). Relative risk (RR) or odds ratio (OR) was used for dichotomous outcomes, mean difference (MD) for continuous outcomes, and hazard ratio (HR) for time-to-event outcomes, all accompanied by the 95% confidence interval (CI) for the effect estimate. The absolute risk reduction (ARR) was estimated by multiplying the median of risks observed in control groups by the pooled risk ratio and then presenting the anticipated increase or decrease in patients experiencing the effect per 1,000 patients treated. We tested for heterogeneity by inspecting the similarity among point estimates, the overlap of CIs, statistical tests, and I2 statistics. We considered a value greater than 50% to represent substantial heterogeneity (20). We assumed that severe tobacco dependence would be associated with poor outcomes and planned a subgroup analysis according to tobacco dependence severity. We planned to use the funnel plot to assess publication bias when feasible (>10 studies) (21).

Certainty of Evidence

We used the Grading of Recommendations, Assessment, Development and Evaluations approach to assess the certainty of evidence per outcome (2225). We categorized certainty of evidence into four categories ranging from very low to high, considering the risk of bias, imprecision, inconsistency, indirectness, and publication bias. We prepared a summary table of the findings (2225).

Study Characteristics

Our search identified 706 potentially relevant articles. Figure 1 shows the process of study selection. After screening the titles and abstracts, we assessed the full texts of 37 studies and included 5 randomized, placebo-controlled trials (4, 5, 2628). All studies blinded patients and clinicians. Four trials addressed the efficacy of initiation of tobacco dependence treatment in individuals unready to abstain (4, 5, 27, 28). A fifth study evaluated the 15-day experimental effect of varenicline in tobacco-dependent adults who were not seeking treatment to quit smoking (26). All studies were conducted after 2010. Three studies were conducted in the United States, and the other two were multicenter, involving 10 or 14 countries. The sample size varied from 88 (5) to 1,562 (4) participants. The mean age of the study population in included studies ranged from 41 to 46 years. Between 40% and 50% of participants were female (Table 1).

Trials defined individuals with tobacco dependence as not being ready to discontinue tobacco use if they were unwilling to quit but were ready to reduce cigarette consumption and make a quit attempt in subsequent months (Table 1).

Table 1. Characteristics of included studies

StudyCountryFemale (%)Age (y), Mean (SD)Average Number of Cigarettes per Day at BaselineDefinition of Not Ready to QuitFundingHealthcare SettingSample SizeFollow-Up (wk)Treatment Process (Dose/Duration at Each Stage)
Brandon and colleagues (2011) (26)United StatesVarenicline: 45.8
Placebo: 41.2
Varenicline: 45.8 (9.4)
Placebo 41.2 (11.5)
Varenicline:22.9 (SD = 9.2)
Placebo: 26.1 (SD = 11.5)
Non-treatment-seeking adults with daily tobacco dependencePrivate for-profitAmbulatory community1632Varenicline: 0.5 mg on Days 1–3, 1 mg (0.5 mg twice daily) on Days 4–7, and 2 mg (1 mg twice daily) on Days 8–15
Control: placebo
Hughes and colleagues (2011) (27)United StatesVarenicline: 39
Placebo: 43
Varenicline: 44 (13)
Placebo: 41 (13)
Varenicline: 19.5
Placebo: 17.5
Tobacco-dependent adults with no intention to quit smoking in the next monthPrivate for-profitAmbulatory community22024Varenicline: 0.5 mg on Days 1–3, 1 mg (0.5 mg twice daily) on Days 4–7, and 2 mg (1 mg twice daily) for the remainder of treatment up to 8 wk
Control: placebo
Rennard and colleagues (2012) (28)14 countries*Varenicline: 40
Placebo: 40.9
Varenicline: 43.9 (12.5)
Placebo: 43.2 (12.2)
Varenicline: 21.3 (range, 10–70)
Placebo: 21.5 (range, 10–65)
Tobacco-dependent adults with flexible quit dates (without fixed quit dates)Private for-profitResearch centers, private practice offices, and research clinics65924Varenicline: 0.5 mg on Days 1–3, 1 mg (0.5 mg twice daily) on Days 4–7, and 2 mg (1 mg twice daily) for the remaining 11 wk
Control: placebo
Steinberg and colleagues (2018) (5)United StatesVarenicline: 53.8
Placebo: 55.6
Varenicline: 46.08 (9.07)
Placebo: 43.68 (12.39)
Not reportedTobacco-dependent adults who are interested in cutting down but not in quitting in the next 30 dPrivate for-profitAmbulatory community6424Varenicline: 0.5 mg on Days 1–3, 1 mg (0.5 mg twice daily) on Days 4–7, and 2 mg (1 mg twice daily) for the remainder of treatment (28 d)
Control: placebo
Ebbert and colleagues (2015) (4)10 countriesVarenicline: 44.1
Placebo: 43.2
Varenicline: 44.7 (11.8)
Placebo: 44.4 (12.0)
Not reportedTobacco-dependent adults who are not willing or able to quit smoking within the next month but are willing to reduce their smoking and make a quit attempt within the next 3 moPrivate for-profit61 centers1,51052Varenicline: 0.5 mg on Days 1–3, 1 mg (0.5 mg twice daily) on Days 4–7, and 2 mg (1 mg twice daily) for the remainder of treatment (24 wk)
Control: placebo

Definition of abbreviation: SD = standard deviation.

*Argentina, Brazil, Canada, China, Czech Republic, France, Germany, Hungary, Italy, Mexico, Republic of Korea, Taiwan, United Kingdom, and United States.

Australia, Canada, Czech Republic, Egypt, Germany, Japan, Mexico, Taiwan, United Kingdom, and United States.

Although each study differed in how it defined not being ready to discontinue tobacco use, each study did require a demonstration of participants’ willingness to change smoking behavior; this is different from not being ready to make any changes. It was impossible to infer whether the recruited populations showed variations in this criterion. For example, one study excluded participants who self-reported inability to abstain from noncigarette tobacco (4). Another study reported that even though at screening, all participants stated that they did not plan to stop smoking in the next month, on the baseline form filled out at the first visit, 48% stated that they were seriously thinking of quitting in the next month (27).

All studies excluded participants with current or histories of medical or psychological problems that would, in the judgment of the investigators, place the participants at significant risk of adverse events, including lifetime suicidal attempts or depression, psychosis, panic attacks, anxiety disorders, and bipolar disorder. It also excluded those with histories of drug (except nicotine) or alcohol abuse/dependence and those with a positive urine drug screen for drugs of abuse/potential abuse.

Three studies (4, 5, 27) used advertisements, such as flyers, newspapers, and radio, to recruit participants. In two studies, participants received up to $75 financial compensation depending on their time spent on phone visits, traveling, and at clinics. All included studies used the same titration protocol for varenicline, starting from 0.5 mg/d for 3 days, 1 mg/d (0.5 mg twice daily) for 4 days, and then 2 mg/d (1.0 mg twice daily) for the remaining treatment duration. The treatment duration ranged from 2 to 24 weeks, with a median of 8 weeks. Three studies (n = 2,387) evaluated abstinence rates at six months or longer after treatment initiation, two of which were assessed during the treatment period. Self-reported abstinence was biochemically confirmed with exhaled carbon dioxide (CO) in all included trials. Four studies (4, 5, 27, 28) reported SAEs. Because of the limited number of eligible studies, subgroup analysis and the funnel plot for assessment of publication bias were not feasible.

Risk of Bias

Figure 2 presents the summary of the risk-of-bias assessment. We classified three studies (4, 27, 28) as having low risk of selection bias on the basis of the reported method of random sequence generation and allocation concealment. Two studies (5, 26) did not give enough detail on one or both of these aspects, so we rated the risk of bias as unclear. For all studies, blinding of participants or personnel and outcome assessment were classified as low risk of bias.

We considered three studies (5, 26, 27) to have a high risk of attrition bias. Brandon and colleagues (26) did not specify the use of intention-to-treat or per-protocol analysis. Between the first and the third assessments, 17.9% of participants in the varenicline group versus 7.4% in the control group were lost to follow-up. In addition, there was unbalanced missing data between groups. In Hughes and colleagues’ 2011 study (27), the percentage of participants with missing information was 28% for the varenicline group and 32% for the placebo group. However, this study assumed that participants with incomplete outcomes indicated no abstinence during that time. We classified this study as low risk of bias for the abstinence outcome in incomplete outcome data and high risk of bias for other outcomes. For Steinberg and colleagues’ 2018 study (5), although all analyses were conducted using a modified intention-to-treat approach, there was a high rate of loss to follow-up (30%) for varenicline. Because of this, we classified this study as high risk of bias for outcomes of quit attempts and smoking reduction. We further classified one study (5) as high risk of selective reporting bias. According to the trial registration, the authors planned (NCT 01308736) but did not report smoke reduction with sufficient details. We could not make judgments for two other studies (26, 27), because there were no published protocols or registration.

Effects of Intervention
Point prevalence abstinence at six months or longer and during the treatment

For point prevalence abstinence at six months or longer, a pooled estimate combining the three included studies with 2,387 participants showed that varenicline treatment increased 7-day point prevalence abstinence compared with placebo (RR, 2.00 [95% CI, 1.70–2.35]; ARR, 173 more per 1,000 patients [95% CI, 121 more to 234 more]; high certainty; Table 2 and Figure 3). Varenicline also increased 7-day point prevalence abstinence compared with placebo (RR, 2.49 [95% CI, 2.09–2.98]; ARR, 308 more per 1,000 patients [95% CI, 225 more to 409 more]; high certainty; Table 2 and Figure 4).

Table 2. Summary of findings

OutcomesNumber of Participants (Studies)Certainty of the Evidence (GRADE)Relative Effect (95% CI)Anticipated Absolute Effects* (95% CI)
Risk with Wait List until Patients Are Ready to Stop Tobacco UseRisk Difference with Varenicline
Point abstinence at 6 mo or longer
Assessed by self-report and exhaled carbon monoxide concentration verification
Follow-up: 6 mo to 1 yr
2,387 (3 RCTs) (4, 27, 28)⨁⨁⨁⨁ (high)RR, 2.00 (1.70–2.35)173 per 1,000173 more per 1,000 (121 more to 234 more)
Point abstinence during treatment
Assessed by self-report and exhaled carbon monoxide concentration verification
Follow-up: 24 wk
2,169 (2 RCTs) (4, 28)⨁⨁⨁⨁ (high)RR, 2.49 (2.09–2.98)207 per 1,000308 more per 1,000 (225 more to 409 more)
Quality of life: not reported
Serious adverse events2,415 (4 RCTs) (4, 5, 27, 28)⨁⨁⨁◯ (moderate)RR, 1.75 (0.98–3.13)16 per 1,00012 more per 1,000 (0 fewer to 35 more)
Relapse: not reported
Other substance use: not reported
Withdrawal
Assessed using Questionnaire of Smoking Urges: tonic craving (scale from 1 to 7; lower score indicates better outcome)
Follow-up: 12–15 d
100 (1 RCT) (26)⨁⨁◯◯ (low)§MD, 1.54 lower (2.15 lower to 0.93 lower)
Withdrawal
Assessed using Wisconsin Smoking Withdrawal Scale: tonic craving (scale from 0 to 8; lower score indicates better outcome)
Follow-up: 12–15 d
100 (1 RCT) (26)⨁⨁◯◯ (low)§MD, 1.26 lower (1.34 lower to 1.18 lower)
Smoking reduction
Assessed as reduction of 50% or more
Follow-up: 4 wk
1,563 (2 RCTs) (4, 5)⨁⨁⨁◯ (moderate)ǁOR, 1.95 (1.59–2.41)
Smoking reduction
Assessed as reduction of 50% or more
Follow-up: 3 mo
1,563 (2 RCTs) (4, 5)⨁⨁⨁◯ (moderate)ǁOR, 2.03 (1.57–2.61)
Smoking reduction
Assessed as reduction of 50% or more
Follow-up: 6 mo
153 (1 RCT) (5)⨁◯◯◯ (very low)§ǁOR, 2.45 (0.53–11.22)
Quit attempt865 (3 RCTs) (5, 27, 28)⨁◯◯◯ (very low)ǁ**††RR, 1.17 (0.98–1.40)626 per 1,000106 more per 1,000 (13 fewer to 250 more)

Definition of abbreviations: CI = confidence interval; GRADE = Grading of Recommendations, Assessment, Development and Evaluations; MD = mean difference; OR = odds ratio; RCT = randomized controlled trial; RR = relative risk.

*The risk with wait list is based on the median risk of the control groups of included studies. The risk difference (and its 95% confidence interval) is based on the risk with wait list and the relative effect of the varenicline (and its 95% CI).

The number of events is small.

Brandon and colleagues (26) did not specify if they used intention-to-treat or per-protocol analysis. After unblinding, it was revealed that greater attrition from assessments 1–3 occurred for the varenicline condition (17.9%) compared with the placebo condition (7.4%).

§We are unaware of the minimal clinical important difference for this measurement. But empirically, the total sample size is too small to provide a precise estimate.

ǁSmoking reduction or quit attempt is a surrogate outcome for abstinence.

Steinberg and colleagues (5) had a high proportion of loss to follow-up. In addition, the number of participants in the outcome smoking reduction or quit attempt is unclear.

**In Hughes and colleagues (27), 28% of varenicline group and 32% of placebo group participants were not included in the analysis for this outcome. The high proportion of exclusion from the analysis may create an unbalanced comparison.

††The confidence interval includes 1, meaning that depending on whether we consider the lower or upper limit of the confidence interval, the conclusion regarding the benefit of varenicline will be different.

SAEs

Four studies with 2,415 participants showed that varenicline likely slightly increased SAEs associated with treatment (RR, 1.75 [95% CI, 0.98–3.13]; ARR, 12 more per 1,000 patients [95% CI, 0 fewer to 35 more]; moderate certainty because of serious imprecision; Table 2 and Figure 5).

Other outcomes

Withdrawal symptoms assessed using several validated instruments suggested a small but significant reduction among those receiving varenicline treatment compared with those who were not. Estimates of effect on withdrawal symptoms, in which lower scores indicate better outcomes, were lower, with an MD of −1.54 (95% CI, 2.15 lower to 0.93 lower; low certainty because of serious risk of bias and imprecision; Table 2) when assessed using the Brief Questionnaire of Smoking Urges and an MD of −1.26 (95% CI, 1.34 lower to 1.18 lower; low certainty because of serious risk of bias and imprecision) when assessed using the Wisconsin Smoking Withdrawal Scale. We did not find evidence on the optimal duration of treatment, quality of life, patient adherence, and other substance use. Two trials with 1,563 participants suggested that initiating versus not initiating varenicline probably led to a smoking reduction (defined as a reduction of 50% or more in the number of cigarettes) in those who are not ready to discontinue tobacco use (OR, 1.95 [95% CI, 1.59–2.41] at four weeks after treatment initiation, moderate certainty because of serious indirectness; OR, 2.03 [95% CI, 1.57–2.61] at three months after treatment initiation, moderate certainty because of serious indirectness; OR, 2.45 [95% CI, 0.53–11.33] at six months after treatment initiation, very low certainty because of serious risk of bias, indirectness, and imprecision; Figure 6 and Table 2). Three trials with 865 participants suggested that varenicline may increase quit attempts (RR, 1.17; [95% CI, 0.98–1.40]; Figure 7 and Table 2). However, the certainty of the evidence is very low because of the serious risk of bias, indirectness, and imprecision.

Main Findings

To our knowledge, this is the first systematic review to compare the effectiveness and safety of initiating varenicline versus placebo in tobacco-dependent adults who are not ready to discontinue tobacco use. High-quality evidence suggested that the initiation of varenicline treatment increased the likelihood of abstinence. Moderate quality evidence showed that initiating treatment probably leads to a small increase in the risk of SAEs. In addition to reporting abstinence outcomes and SAEs, this systematic review also suggested that initiation of varenicline before tobacco-dependent adults are ready to quit may increase willingness to quit and control withdrawal symptoms such as the urge to smoke.

Strengths and Limitations

Our systematic review has several strengths. First, we have a comprehensive search strategy developed in collaboration with a bioinformatics specialist, ensuring that our search was systematic and comprehensive. Second, we conducted this review to support the American Thoracic Society tobacco dependence clinical practice guideline, developed with an international panel including patients, clinical practitioners, and methodologists. The guideline panel provided guidance and feedback at every step of the systematic review development process. For instance, panels provided input to the search strategy, helped identify unpublished studies, and selected patient-important and practice-informing outcomes despite their rare reporting in available literature (e.g., abstinence, SAEs, quality of life, motivation to quit, compulsion to smoke).

This review is also subject to limitations. Although we have high-quality evidence for abstinence and SAEs, the quality of evidence for withdrawal symptoms and smoking reduction was rated low or very low. There was no information on the quality of life, relapse, or other substance use. Furthermore, we could not examine the association between adherence to pharmacotherapy and its effects. We could not assess heterogeneity and publication bias because of the small number of included studies.

Implications for Clinical Practice

Our systematic review compiled comprehensive effectiveness and safety evidence on initiating varenicline in tobacco-dependent individuals who are not ready to discontinue tobacco use. Compared with placebo, the body of evidence supported a strong recommendation to initiate treatment in patients who have the intention to quit at some point but are unready to set a quit date. Clinicians and patients should apply this in most scenarios considering patients’ expectations and treatment goals. However, caution is warranted when implementing the recommendation to a population with comorbidities, such as chronic obstructive pulmonary disease, depression, and schizophrenia, because of a lack of evidence regarding these conditions.

Implications for Research

Although high-quality evidence suggested that varenicline is beneficial for those who are not ready to discontinue tobacco use, we did not find evidence on the optimal duration of treatment, quality of life, patient adherence, and the use of other substances. Future research needs to include these important patient outcomes and individuals who are not ready to discontinue tobacco use and have comorbidities. In addition, studies on the effect of combination therapy, especially nicotine replacement therapy and varenicline, on treatment outcomes are warranted. Finally, it is also necessary to understand patient preferences on the initiation of treatment before they are ready to discontinue tobacco use.

Conclusions

Our systematic review suggested that the initiation of varenicline for individuals who are not ready to discontinue tobacco use can lead to a large benefit in abstinence and a small increase in the number of SAEs. This systematic review supported a strong recommendation for initiating treatment with varenicline in this population until they are ready to discontinue tobacco use. Further studies on the optimal duration of treatment, its effects on several populations with comorbidities, and the effects of other pharmacotherapy strategies are necessary.

This work was supported by the American Thoracic Society (ATS) to inform guideline recommendations in the clinical practice guideline on initiating pharmacological treatment in tobacco-dependent adults. The authors thank the guideline panelists for their input on the clinical guideline development and interpretation of the clinical evidence. The authors also thank Dr. Kevin Wilson (ATS documents editor) and Ms. Kimberly Lawrence (ATS staff) for their assistance in the systematic review and guideline development process.

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Correspondence and requests for reprints should be addressed to Yu-Qing Zhang, M.D., M.Sc., Ph.D., Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1 Canada. E-mail: .

Supported by an acupuncture clinical and methodological research grant (ZZ20191604), China Academy of Chinese Medical Sciences.

Author Contributions: L.C.L., Y.Z., Y.-Q.Z., M.Z., S.R., and I.F. contributed to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work. L.C.L., Y.Z., S.R., I.F., M.Z., K.K.O’B., S.P., F.T.L., D.P.L.S., H.K., R.L.M., and Y.-Q.Z. drafted the work or revised it critically for important intellectual content. All authors read and approved the final version of the manuscript.

This article has a data supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Author disclosures are available with the text of this article at www.atsjournals.org.

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