Abstract
According to the Global Burden of Disease (GBD) Study conducted in 2019, smoking tobacco leads to over 8 million deaths each year. Hence, it is crucial to identify optimal smoking cessation therapy. To compare the efficacy of varenicline versus bupropion for smoking cessation by performing a meta-analysis of randomized controlled trials (RCTs). Protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO). The Patient intervention comparison outcome time (PICOT) format is used in the study. Patients having nicotine use disorder treated with varenicline or bupropion were included, and the continuous abstinence rate (CAR) was assessed at 12, 24, and 52 weeks. The PubMed and Google Scholar databases were systematically searched, and after the screening, RCTs involving a comparison of varenicline and bupropion in smoking cessation were included. We performed a meta-analysis of three RCTs (10110 patients) by RevMan 5.4.1 statistical software to determine the efficacy of varenicline compared with bupropion in smoking cessation. The CAR at 9- to 12-week follow-up of varenicline is superior to bupropion (OR = 1.79, CI range: 1.59-2.02, P < 0.001). Similarly, the CAR of varenicline is superior to bupropion for weeks 9–24 (1.51, 1.32 to 1.72) and weeks 9–52 (1.60, 1.22 to 2.12), suggesting the absolute advantage of varenicline over bupropion for smoking cessation in terms of efficacy. Both varenicline and bupropion are efficacious therapies for smoking cessation. Compared with bupropion, varenicline can significantly improve the CAR at the end of treatment, at 24 weeks, and at 52 weeks of follow-up.
Keywords: Bupropion, meta-analysis, smoking cessation, varenicline
INTRODUCTION
Smoking tobacco is the principal preventable cause of illness and premature death worldwide.[1] As per the Global Burden of Disease (GBD) Study 2019, smoking tobacco kills more than 8 million people each year. Seven million of these deaths are the consequence of direct tobacco use, while around 1.2 million deaths are a consequence of nonsmokers being exposed to secondhand smoke.[2] The World Health Organization has predicted that tobacco-related deaths in India may exceed 1.5 million annually by 2020.[3] In India, 16% of the population (29.3% men and 2.3% women) smoked tobacco and were aged 15 years and above. Cigarette smoking has a higher prevalence in the poor and less educated. Smoking tobacco is the principal risk factor causing lung cancer in the Indian population. 70% of deaths in India (100,000 among women and 600,000 among men) will occur in middle age rather than old age.[4] Three medications have been approved for smoking cessation in the United States and India: nicotine replacement therapy, bupropion, and varenicline.
Bupropion, an atypical antidepressant, is the first non-nicotine-based drug approved by the Food and Drug Administration (FDA) in the United States in 1997 for smoking cessation in adults. It acts by inhibiting dopamine reuptake into neuronal synaptic vesicles. It has a weak noradrenaline reuptake inhibitory effect and no effect on serotonin levels. Clinical trials show that bupropion helps one in five smokers stop smoking.[3] Bupropion was approved by the Drugs Controller General of India (DCGI) in 2001 to aid smoking cessation treatment in adults.
Varenicline was approved by the FDA in 2006, and it works as a selective nicotinic receptor partial agonist.[5] It was designed to selectively activate the α4β2nAChR, mimicking the action of nicotine and causing a moderate and sustained release of mesolimbic dopamine. This mechanism would counteract withdrawal symptoms consequent upon low dopamine release during smoking cessation attempts.[4,6] Varenicline was approved by DCGI in 2007 to aid smoking cessation treatment in adults.
According to the European Action on Secondary and Primary Prevention by Intervention to Reduce Events III (EUROASPIRE III) survey, smoking cessation treatment is underused, and therefore, smoking continues to cause 50% of avoidable deaths in smokers, especially deaths of cardiovascular etiology.[7] There are various pharmacological agents available, which can reduce the craving for nicotine. Varenicline and bupropion are the only FDA-approved non-nicotine oral prescription drugs for smoking cessation. However, there is a paucity of data regarding the head-to-head comparison of these drugs. Therefore, this meta-analysis was performed using randomized controlled trials (RCTs) focused on the continuous abstinence rate (CAR) for up to 24 weeks as an efficacy endpoint for varenicline and bupropion for smoking cessation.
MATERIALS AND METHODS
Search strategy
This systematic review searched studies evaluating the efficacy of varenicline and bupropion from the RCTs in the PubMed and Google Scholar databases until September 2020. The search was performed using the MeSH terms and Boolean operator in PubMed and Google Scholar using the following strategy ((varenicline [MeSH Terms]) AND (bupropion [MeSH Terms])) AND (smoking cessation[MeSH Terms]). Two investigators (AP and JP) independently selected articles according to the search criteria described above. The trials were compiled from an electronic database, and abstracts were reviewed to identify RCTs of interventions for smoking cessation. The relevant full-text articles were reviewed, and eligibility was determined as per inclusion criteria. Study selection, as illustrated in Figure 1, was performed independently by two authors, and if there was disagreement, then a third author (CD) was consulted. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (ID CRD42020207456).
Figure 1.
PRISMA flowchart for study selection in meta-analysis
Inclusion and exclusion criteria
According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, all the RCTs comparing varenicline vs. bupropion were included in this meta-analysis.
The following PICOT format inclusion criteria were applied for this study:
-
a)
Adult smokers aged 18–65 years having nicotine use disorder
-
b)
RCTs up to September 2020
-
c)
Studies comparing efficacy outcomes in patients treated with varenicline and bupropion
-
d)
CAR efficacy reported at the end of 12-week treatment and followed up for at least 24 weeks.
The following exclusion criteria were applied for this study:
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a)
Patients having other addictions
-
b)
Animal studies, review articles, case reports, case series, cohort studies, and diagnostic studies.
Data extraction
The data extraction was performed independently by two authors (AP and JP) for the following variables: the study characteristics—first author’s name, the year of publication, sample size, and intervention performed and patient characteristics —the number of males/females in each study, current smoking rate and smoking history, race and the mean age of patients, intervention of each group, and primary efficacy endpoints till follow-up duration were noted.
The primary outcomes included CAR between weeks 9 and 12. CAR was confirmed at every weekly visit through a carbon monoxide (CO) test in the lungs of less than 10 ppm. All trials were 12-week treatment followed by smoking status through week 52. The secondary outcomes were CAR between weeks 12–24 and weeks 12–52. The follow-up from weeks 12 through 52 was made by a phone call where patients reported self-abstinence.
Quality assessment and statistical analysis
The PRISMA guideline was followed for this review.[8]
The risk-of-bias assessment of the included studies would be performed by two authors independently using the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.4.1).[9] The Cochrane risk of bias tool would be used to assess potential sources of bias in included clinical trials. The risk of bias graph reviews judgments about each risk of bias item for each included study. Green = ‘low’ risk of bias; Yellow = ‘unclear’ risk of bias; Red = ‘high’ risk of bias.
The efficacy parameters for the population consisted of all randomized subjects. The main and secondary outcomes were extracted in odds ratio (OR). Meta-analysis was performed using RevMan 5.4.1, and funnel plots were generated to assess the risk of publication bias. In the inverse variance statistical method with the fixed-effects (FE) analysis model, the odds ratio (OR) and 95% confidence interval (CI) were used to analyze the results. As for continuous clinical parameters, the weighted mean difference (WMD) was utilized. The heterogeneity across the trials was measured by the I2 test. The FE model was used when I2 was less than 50%. Heterogeneity was calculated at cutoff at I2 > 50% or P < 0.1. A funnel plot was used to evaluate whether the asymmetry was due to publication bias or a relationship between trial size and effect size.[10]
Outcomes
CAR for the last four weeks of study treatment (weeks 9–12)
For all studies, the CAR (weeks 9–12) endpoint was CO-confirmed, which was defined as no reported smoking (not even a puff), as verified by CO levels <10 ppm.
CAR for the follow-up period (weeks 9–24)
For all studies, the CAR (weeks 9–24) endpoint was CO-confirmed, which was defined as no reported smoking, verified by CO levels <10 ppm and the 7-day point prevalence of abstinence during the treatment and nontreatment phases. The point prevalence of smoking abstinence was determined by subjects reporting no smoking or use of other nicotine-containing products during the treatment period (or tobacco products during follow-up) for the last seven days and confirmed by CO measurements at each clinic visit.
CAR for the follow-up period (weeks 9–52)
For Gonzales (2006)[11] and Jorenby (2006),[12] the CAR (weeks 9–52) endpoint was CO-confirmed, which was defined as no reported smoking, verified by CO levels <10 ppm and the 7-day point prevalence of abstinence during the treatment and nontreatment phases. However, CAR (weeks 9–52) was not reported for Anthenelli (2016)[13] as the study was only for a 24-week duration.
RESULTS
Search results
A total of 768 studies related to varenicline and bupropion in smoking cessation were included. After removing duplicates, 758 articles remained. Of 758 articles, all the studies that did not meet the inclusion/exclusion criteria were excluded. Finally, three studies that compared the efficacy of varenicline compared with bupropion were included in the meta-analysis. The search process is illustrated in Figure 1.
Study characteristics
All the articles included in this meta-analysis were RCTs published before September 2020. Overall, the patient’s average age ranged from 42 to 46. The duration of follow-up ranged from 24 to 52 weeks. We summarized the characteristics of the included RCTs in Table 1.
Table 1.
Summary of study characteristics
| Studies | Anthenelli, 2016 | Gonzales, 2006 | Jorenby, 2006 | |||
|---|---|---|---|---|---|---|
| Study design | Multinational, multicenter, randomized, double-blind, triple dummy performed at 140 centers in 16 countries across five continents. Study sites included clinical trial centers, academic centers, and outpatient clinics | Randomized, double-blind, parallel-group, phase 3 clinical trial conducted at 19 US centers from June 19, 2003, to April 22, 2005 | A randomized, double-blind, placebo-controlled trial was conducted between June 2003 and March 2005 at 14 research centers | |||
| Demographic characteristics of participants | Patients enrolled (No. (%)) | Total enrolled | Varenicline | 2016 (100%) | 352 (100%) | 344 (100%) |
| Bupropion | 2006 (100%) | 329 (100%) | 342 (100%) | |||
| Placebo | 2014 (100%) | 344 (100%) | 341 (100%) | |||
| Male | Varenicline | 902 (45%) | 176 (50.0%) | 190 (55.2) | ||
| Bupropion | 890 (44%) | 192 (58.4) | 206 (60.2) | |||
| Placebo | 876 (43%) | 186 (54.1) | 198 (58.1) | |||
| Female | Varenicline | 1114 (55%) | 176 (50.0%) | 154 (44.8%) | ||
| Bupropion | 1116 (55%) | 137 (41.6%) | 136 (39.8%) | |||
| Placebo | 1138 (56%) | 158 (45.9%) | 146 (54.1%) | |||
| Age( mean (SD)) | Varenicline | 45.8 (13.0) | 42.5 (11.1) | 44.6 (11.4) | ||
| Bupropion | 46.0 (13.0) | 42.0 (11.7) | 42.9 (11.9) | |||
| Placebo | 45.9 (12.8) | 42.6 (11.8) | 42.3 (11.6) | |||
| Race | White | Varenicline | 1668 (83%) | 280 (79.5%) | 294 (85.5%) | |
| Bupropion | 1636 (82%) | 264 (80.2%) | 283 (82.7%) | |||
| Placebo | 1639 (82%) | 262 (76.2%) | 290 (85%) | |||
| Black | Varenicline | 280 (14%) | 36 (10.2%) | 31 (9%) | ||
| Bupropion | 281 (14%) | 28 (8.5%) | 36 (10.5%) | |||
| Placebo | 281 (14%) | 49 (14.2%) | 26 (7.6%) | |||
| Asian | Varenicline | 19 (1%) | 4 (1.1%) | 8 (2.3%) | ||
| Bupropion | 26 (2%) | 5 (1.5%) | 4 (1.2%) | |||
| Placebo | 26 (2%) | 9 (2.6%) | 6 (1.8%) | |||
| Other | Varenicline | 49 (3%) | 32 (9.1%) | 11 (3.2%) | ||
| Bupropion | 67 (4%) | 32 (9.7%) | 19 (5.6%) | |||
| Placebo | 67 (4%) | 24 (7%) | 19 (5.6%) | |||
| Smoking characteristics | No. of years smoked (mean (SD)) | Varenicline | 27.8 (12.8) | 24.3 (11.5) | 27.1 (11.5) | |
| Bupropion | 28.3 (13.0) | 24.1 (11.5) | 25.4 (12.0) | |||
| Placebo | 28.2 (12.6) | 24.7 (12.1) | 24.4 (11.6) | |||
| No. of cigarettes/day in the past month (mean (SD)) | Varenicline | 20.8 (8.3) | 21.1 (9.47) | 22.5 (9.5) | ||
| Bupropion | 20.6 (7.8) | 21.0 (8.52) | 21.8 (8.7) | |||
| Placebo | 20.5 (7.9) | 21.5 (9.51) | 21.5 (8.7) | |||
| Participates with at least one previous attempt to quit (No. (%)) | Varenicline | 1617 (83%) | 297 (84.4%) | 288 (83.7%) | ||
| Bupropion | 1651 (83%) | 284 (86.3%) | 291 (85.1%) | |||
| Placebo | 1649 (82%) | 288 (83.7%) | 291 (85.3%) | |||
| Intervention and control description | Varenicline | Participants received brief counseling at each visit and varenicline (1 mg twice per day) orally for 12 weeks, with 12 weeks of nontreatment follow-up | Participants received brief counseling and varenicline titrated to 1 mg twice per day orally for 12 weeks, with 40 weeks of nondrug follow-up | Varenicline titrated to 1 mg twice daily for 12 weeks, plus weekly brief smoking cessation counseling | ||
| Bupropion | Participants received brief counseling at each visit and bupropion (150 mg twice per day) orally for 12 weeks, with 12 weeks of nontreatment follow-up | Participants received brief counseling, and bupropion SR was titrated to 150 mg twice per day orally for 12 weeks, with 40 weeks of nondrug follow-up | Bupropion SR titrated to 150 mg twice daily for 12 weeks, plus weekly brief smoking cessation counseling | |||
| Placebo | Participants received brief counseling at each visit, placebo orally for 12 weeks, and 12 weeks of nontreatment follow-up | Participants received brief counseling and a placebo orally for 12 weeks, with 40 weeks of nondrug follow-up | Placebo for 12 weeks, plus weekly brief smoking cessation counseling | |||
Analysis of bias
All studies were randomized and multicentered. These studies reported that the list of random numbers was generated by a computer for assigning patients to different study groups. All RCTs reported double blinding of the investigators and participants. Anthenelli’s 2016 trial used a triple dummy during treatment, further reducing the risk of bias. Attrition bias was detected in one study, as shown in Figure 2. There are only three studies that met your quality criteria, and two follow-up studies were not long enough, and hence, it requires the evidence base for further exploration with larger longer-term studies.
Figure 2.
Risk-of-bias summary: a review of authors’ judgments about risk-of-bias item for each study
The only recent study was industry-funded and performed across a large number of centers. A large number of centers likely make the study population heterogeneous. The industry sponsorship is also a conflict of interest. Since tobacco is a global public health challenge, it is important to do more research supported by academia.
The symmetric inverted funnel shape arises from a “well-behaved” data set, in which publication bias is unlikely. An asymmetric funnel indicates a relationship between treatment effect estimate and study precision.[14] As depicted in the funnel plot in Figure 3, publication bias is highly unlikely.
Figure 3.
Funnel plot (RCTs of varenicline vs. bupropion)
Results of meta-analysis
Smoking cessation at 12 weeks
All RCTs shown in Figure 4 represent the CAR for four weeks of treatment, weeks 9 to 12. There was no statistically significant heterogeneity (Chi2 = 0.44, df = 2, I2 = 0%, P = 0.80), which justifies using a FE model. For the overall effect of the CAR for the last four weeks of study treatment (weeks 9–12), a significant difference in the OR (OR = 1.79, CI range: 1.59-2.02, P < 0.001) was found for varenicline compared with bupropion at 95% CI.
Figure 4.
Forest plot of comparison: varenicline vs. bupropion, outcome: CAR for last four weeks of study treatment (weeks 9–12)
Smoking cessation at 24 weeks
All three RCTs shown in Figure 5 represent the CAR through the follow-up period, weeks 9–24. There was no statistically significant heterogeneity (Chi2 = 0.83, df = 2, I2 = 0%, P = 0.66), which justifies using a FE model. For the overall effect of the CAR through the follow-up period (weeks 9–24), a significant difference in OR (OR = 1.51, CI range: 1.32-1.72, P < 0.001) was found for varenicline compared with bupropion at 95% CI.
Figure 5.
Forest plot of comparison: varenicline vs bupropion, outcome: CAR through follow-up period (weeks 9–24)
Smoking cessation at 52 weeks
For Gonzales and Jorenby, RCTs, as shown in Figure 6, represent the CAR through the follow-up period, weeks 9–52. There was no statistically significant heterogeneity (Chi2 = 0.46, df = 1, I2 = 0%, P = 0.50), which justifies the use of the FE model. For the overall effect of the CAR through the follow-up period (weeks 9–52), a significant difference in OR (OR = 1.60, CI range: 1.22-2.12, P = 0.001) was found for varenicline compared with bupropion at 95% CI.
Figure 6.
Forest plot of comparison: varenicline vs. bupropion, outcome: CAR through follow-up period (weeks 9–52)
DISCUSSION
This meta-analysis from three trials (10110 patients) indicates that varenicline and bupropion both have greater efficacy for smoking cessation than placebo. All trials have almost equal recruitment for male and female patients. Average participants smoked for 26 years before enrolment in the study, with an average of 20 or more cigarette smoking per day in the past month. Trials were conducted in the multicenter across the United States and other countries. The mean years of age for patients in this study were between 40 and 50 years, and patients were randomized. All trials reported double-blind and computer-generated randomization for lists and sites to assign treatment groups to participants.
The only recent study was industry-funded and performed across a large number of centers. A large number of centers likely make the study population heterogeneous. The industry sponsorship is also a conflict of interest. Since tobacco is a global public health challenge, it is important to do more research supported by academia.
Exhaled carbon monoxide test, was used for separating smokers (levels >10 ppm) from non-smokers for the assessment of continuous abstinence rate(CAR). Exclusion criteria included any prior exposure to bupropion or varenicline. More than 80% of participants were smokers who attempted to quit more than once and had abstinence of fewer than three months at any time in the past year.
Gonzales and Jorenby had a similar design of the trial, and they were conducted in parallel time, which was sponsored by Pfizer. The Earn Respect Act Responsibly Grow Stronger and Wiser Lead by Example Excel in Education Show Kindness (EAGLES) trial was conducted in 2016, which was triple-blind and provided similar results compared with earlier RCTs in 2006 by Gonzales and Jorenby. All studies have long-term follow-up data and heavy smokers with high nicotine dependence and big population size, which gives more analysis power.
Varenicline showed a superior CAR than bupropion in 12 weeks of treatment and was sustained through 24 weeks and 52 weeks of follow-up. These findings are consistent with previous studies conducted by Nides et al.[15,16] In a randomized controlled trial, patients achieved a better abstinence rate with varenicline. The carbon monoxide-confirmed continuous abstinence rates from week 4 to week 52 was significantly higher in the varenicline, 1 mg twice daily group compared with the placebo group (14.4% vs. 4.9%; P = .002). The continuous abstinence rates for bupropion were 6.3% (P =.60 vs. placebo). This trial had follow-up for one year, and the quit rate with bupropion was 33.3% (P = .002) compared with placebo.[16]
Varenicline is also efficacious in patients with chronic pulmonary disease and/or cardiovascular diseases for helping them quit smoking. One study reported the efficacy of varenicline being enhanced with preloading, a gradual quitting method for patients who are unable or unwilling to quit cigarettes abruptly. Extended treatment with varenicline is proven efficacious as it helps maintain abstinence. After extensive evaluation and risk–benefit analysis, varenicline is proven safe overall and does not increase the risk of cardiovascular and neuropsychiatric adverse reactions.[17]
Comparative Bayesian effectiveness analysis concluded that varenicline was the treatment of choice for smoking cessation in patients with more cigarette-related stimuli than pleasant stimuli of neural activation.[18] A double-blind, randomized, pilot trial performed in adolescent subjects aged 15–20 years has shown the feasibility and safety to conduct further efficacy studies of varenicline and bupropion XL compared with a placebo.[19]
In 2010, another study compared varenicline to bupropion, or placebo, by analyzing immediate vs. delayed quitting and relapse rates among smokers. This study considered immediate quitters (IQs) who remained continuously abstinent for weeks 2 to 12 and delayed quitters (DQs) who smoked during one or more weeks for weeks 2 to 8. Overall IQs for varenicline were 24% compared with bupropion (18%, P = 0.007) or placebo (10.2%, P < 0.001). Overall DQs for varenicline were 20% compared with bupropion (11.6%, P < 0.001) or placebo (7.5%, P < 0.001) with posttreatment relapse being similar across all groups. The results from this trial support continuing cessation treatments without interruption for subjects motivated to quit cigarettes despite the lack of success early in the treatment.[20]
A study published by Anthenelli was performed across a large number of centers, and this would make the study population heterogeneous. All studies included in this meta-analysis were industry-funded. The industry sponsorship is also a conflict of interest. Since tobacco is a global public health challenge, it is important to do more research supported by academia.
Limitation
There are only three studies that met our quality criteria, and two follow-up studies might not be long enough, and hence, it requires the evidence base for further exploration with larger longer-term studies.
Most patients recruited in these trials were White patients or African American patients. Approximately 2 percent of patients were of Asian race, and hence, these clinical trial results might not be representative of the generalized population.
CONCLUSION
This meta-analysis shows that few RCTs have investigated the efficacy of varenicline vs. bupropion for smoking cessation treatment. It is inferred that both varenicline and bupropion are efficacious therapies for smoking cessation. However, the studies had recruited the majority of patients of the White or African American race. Hence, there is a need to compare the efficacy of varenicline compared with bupropion in the Asian race, especially the Indian population. The meta-analysis shows that more smokers quit successfully with varenicline compared with either placebo or bupropion. Furthermore, long-term follow-up studies suggest that the use of varenicline (three trials of 24 weeks and two trials of 52 weeks) delivered an unequivocal efficacy of varenicline over bupropion for smoking cessation.
Review Registration Number: Prospero ID CRD42020207456.
Ethical approval
All analyses included in this meta-analysis were based on previously published RCTs; hence, the protocol was registered in PROSPERO.
Financial support and sponsorship
Nil.
Conflicts of interest
All authors in this systematic review and meta-analysis declare no conflicts of interest. However, funding/grants from the pharmaceutical industry to the authors in included RCTs have been reported in the financial disclosures in the RCTs.
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