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1.  A Double-Blind Placebo-Controlled Randomized Trial of Varenicline for Smokeless Tobacco Dependence in India 
Nicotine & Tobacco Research  2013;16(1):50-57.
Introduction:
The rate of smokeless tobacco use in India is 20%; its use causes serious health problems, and no trial has assessed behavioral or pharmacological treatments for this public health concern. This trial evaluated varenicline for treating smokeless tobacco dependence in India.
Methods:
This was a double-blind placebo-controlled randomized trial of varenicline (12 weeks, 1mg, twice per day) with 237 smokeless tobacco users in India. All participants received behavioral counseling. Outcomes included self-reported and biochemically verified abstinence at the end of treatment (EOT), lapse and recovery events, safety, and medication adherence.
Results:
Self-reported EOT abstinence was significantly greater for varenicline (43%) versus placebo (31%; adjusted odds ratio [AOR] = 2.6, 95% CI = 1.2–4.2, p = .009). Biochemically confirmed EOT abstinence was greater for varenicline versus placebo (25.2% vs. 19.5%), but this was not statistically different (AOR = 1.6, 95% CI = 0.84–3.1, p = .15). Compared with placebo, varenicline did not reduce the risk for a lapse (hazard ratio [HR] = 0.86, 95% CI = 0.69–1.1, p = .14), but it did increase the likelihood of recovery to abstinence (HR = 1.2, 95% CI = 1.02–1.4, p = .02). Greater adherence increased EOT cessation rates for varenicline (39% vs. 18%, p = .003) but not for placebo (28% vs. 14%, p = .06). There were no significant differences between varenicline and placebo in rate of side effects, serious adverse events, hypertension, or stopping or reducing medication.
Conclusions:
Varenicline is safe for treating smokeless tobacco dependence in India, and further examination of this medication for this important public health problem is warranted.
doi:10.1093/ntr/ntt115
PMCID: PMC3864491  PMID: 23946326
2.  Maintenance Treatment With Varenicline for Smoking Cessation in Patients With Schizophrenia and Bipolar Disorder 
Importance
It is estimated that more than half of those with serious mental illness smoke tobacco regularly. Standard courses of pharmacotherapeutic cessation aids improve short-term abstinence, but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy.
Objective
To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with standard treatment.
Design, Setting, and Participants
Randomized, double-blind, placebo-controlled, parallel-group, relapse-prevention clinical trial conducted in 10 community mental-health centers. Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012, 203 received 12-weeks' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention.
Interventions
Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were randomly assigned to receive cognitive behavioral therapy and double-blind varenicline (1 mg, 2 per day) or placebo from weeks 12 to 52. Participants then discontinued study treatment and were followed up to week 76.
Main Outcomes and Measures
Seven-day rate of continuous abstinence at study week 52, the end of the relapse-prevention phase, confirmed by exhaled carbon monoxide. Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76, based on self-reported smoking behavior.
Results
Sixty-one participants completed the relapse-prevention phase; 26 discontinued participation (7 varenicline, 19 placebo) and were considered to have relapsed for the analyses; 18 of these had relapsed prior to dropout. At week 52, point-prevalence abstinence rates were 60% in the varenicline group (24 of 40) vs 19% (9 of 47) in the placebo group (odds ratio [OR], 6.2; 95% CI, 2.2-19.2; P < .001). From weeks 12 through 64,45% (18 of 40) among those in the varenicline group vs 15% (7 of 47) in the placebo group were continuously abstinent (OR, 4.6; 95% CI, 1.5-15.7; P = .004), and from weeks 12 through 76,30% (12 of 40) in the varenicline group vs 11% (5 of 47) in the placebo group were continuously abstinent (OR, 3.4; 95% CI, 1.02-13.6; P = .03). There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events.
Conclusions and Relevance
Among smokers with serious mental illness who attained initial abstinence with standard treatment, maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation.
doi:10.1001/jama.2013.285113
PMCID: PMC4124884  PMID: 24399553
3.  Combination Varenicline and Bupropion SR for Tobacco Dependence Treatment in Cigarette Smokers: A Randomized Trial 
Importance
Combining pharmacotherapies for tobacco dependence treatment may increase smoking abstinence.
Objective
Determine efficacy and safety of combination therapy with varenicline and sustained-release bupropion compared to varenicline monotherapy in cigarette smokers.
Design, Setting, and Participants
Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and 52-week follow-up conducted between October 2009 and April 2013 at three midwestern clinical research sites. Five hundred six adult (≥ 18 years) cigarette smokers were randomized and 315 (62%) completed the study.
Intervention
Twelve weeks of: (1) varenicline/bupropion SR (combination therapy); or (2) varenicline/placebo (varenicline monotherapy).
Main Outcome
Primary outcome was the prolonged (no smoking from 2 weeks after the target quit date) and 7-day point-prevalence (no smoking past 7 days) abstinence rates at week 12. Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomes were biochemically-confirmed.
Results
At 12 weeks, 53% of the combination therapy group achieved prolonged and 56.2% achieved 7-day point-prevalence smoking abstinence compared to 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR] 1.49, 95% confidence interval [CI], 1.05–2.12; P = .028 and OR 1.36, 95% CI, 0.95–1.93; P = .090, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared to 27.6% and 31.9% in varenicline monotherapy (OR 1.52, 95% CI, 1.04–2.22; P = .031 and OR 1.32, 95% CI, 0.91–1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared to 24.5% and 29.2% in varenicline monotherapy (OR 1.39, 95% CI, 0.93–2.07; P = .106 and OR 1.40, 95% CI, 0.96–2.05; P = .077, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%, P = .044) and depressive symptoms (3.6% vs 0.8%; P = .034).
Conclusions and Relevance
Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks; neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination treatment in smoking cessation.
doi:10.1001/jama.2013.283185
PMCID: PMC3959999  PMID: 24399554
4.  Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis 
Background:
There have been postmarketing reports of adverse cardiovascular events associated with the use of varenicline, a widely used smoking cessation drug. We conducted a systematic review and meta-analysis of randomized controlled trials to ascertain the serious adverse cardiovascular effects of varenicline compared with placebo among tobacco users.
Methods:
We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, websites of regulatory authorities and registries of clinical trials, with no date or language restrictions, through September 2010 (updated March 2011) for published and unpublished studies. We selected double-blind randomized controlled trials of at least one week’s duration involving smokers or people who used smokeless tobacco that reported on cardiovascular events (ischemia, arrhythmia, congestive heart failure, sudden death or cardiovascular-related death) as serious adverse events asociated with the use of varenicline.
Results:
We analyzed data from 14 double-blind randomized controlled trials involving 8216 participants. The trials ranged in duration from 7 to 52 weeks. Varenicline was associated with a significantly increased risk of serious adverse cardiovascular events compared with placebo (1.06% [52/4908] in varenicline group v. 0.82% [27/3308] in placebo group; Peto odds ratio [OR] 1.72, 95% confidence interval [CI] 1.09–2.71; I2 = 0%). The results of various sensitivity analyses were consistent with those of the main analysis, and a funnel plot showed no publication bias. There were too few deaths to allow meaningful comparisons of mortality.
Interpretation:
Our meta-analysis raises safety concerns about the potential for an increased risk of serious adverse cardiovascular events associated with the use of varenicline among tobacco users.
doi:10.1503/cmaj.110218
PMCID: PMC3168618  PMID: 21727225
5.  Is a combination of varenicline and nicotine patch more effective in helping smokers quit than varenicline alone? A randomised controlled trial 
BMC Medicine  2013;11:140.
Background
Nicotine replacement therapy (NRT) and varenicline are both effective in helping smokers quit. There is growing interest in combining the two treatments to improve treatment outcomes, but no experimental data exist on whether this is efficacious. This double-blind randomised controlled trial was designed to evaluate whether adding nicotine patches to varenicline improves withdrawal relief and short-term abstinence rates.
Methods
117 participants seeking help to stop smoking were randomly allocated to varenicline plus placebo patch or varenicline plus nicotine patch (15 mg/16 hour). Varenicline use commenced one week prior to the target quit date (TQD), patch use started on the TQD. Ratings of urges to smoke and cigarette withdrawal symptoms were collected weekly over 4 weeks post-TQD. Medication use and smoking status were established at 1, 4 and 12 weeks. Participants lost to follow-up were included as continuing smokers.
Results
92% of participants used both medications during the first week after the TQD. The combination treatment generated no increase in nausea or other adverse effects. It had no overall effect on urges to smoke or on other withdrawal symptoms. The combination treatment did not improve biochemically validated abstinence rates at 1 week and 4 weeks post-TQD (69% vs 59%, p=0.28 and 60% vs 59%, p=0.91, in the nicotine patch and placebo patch arm, respectively), or self reported abstinence rates at 12 weeks (36% vs. 29%, p=0.39, NS).
Conclusions
The efficacy of varenicline was not enhanced by the addition of nicotine patches, although further trials would be useful to exclude the possibility of type II error.
Trial Registration
Clinicaltrials.gov Registration Number: NCT01184664
doi:10.1186/1741-7015-11-140
PMCID: PMC4231450  PMID: 23718718
Smoking cessation; Varenicline; Nicotine patch
6.  Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease 
Circulation  2010;121(2):221-229.
Background
Smoking cessation is a key component of secondary cardiovascular disease prevention. Varenicline, a partial α4β2 nicotinic acetylcholine receptor agonist, is effective for smoking cessation in healthy smokers, but its efficacy and safety in smokers with cardiovascular disease are unknown.
Methods and Results
A multicenter, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease. Participants received varenicline (1 mg twice daily) or placebo, along with smoking-cessation counseling, for 12 weeks. Follow-up lasted 52 weeks. The primary end point was carbon monoxide–confirmed continuous abstinence rate for weeks 9 through 12 (last 4 weeks of treatment). The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 (47.0% versus 13.9%; odds ratio, 6.11; 95% confidence interval [CI], 4.18 to 8.93) and weeks 9 through 52 (19.2% versus 7.2%; odds ratio, 3.14; 95% CI, 1.93 to 5.11). The varenicline and placebo groups did not differ significantly in cardiovascular mortality (0.3% versus 0.6%; difference, −0.3%; 95% CI, −1.3 to 0.7), all-cause mortality (0.6% versus 1.4%; difference, −0.8%; 95% CI, −2.3 to 0.6), cardiovascular events (7.1% versus 5.7%; difference, 1.4%; 95% CI, −2.3 to 5.0), or serious adverse events (6.5% and 6.0%; difference, 0.5%; 95% CI, −3.1 to 4.1). As a result of adverse events, 9.6% of varenicline and 4.3% of placebo participants discontinued study drug.
Conclusions
Varenicline is effective for smoking cessation in smokers with cardiovascular disease. It was well tolerated and did not increase cardiovascular events or mortality; however, trial size and duration limit definitive conclusions about safety.
Clinical Trial Registration Information
URL: http://www.clinicaltrials.gov/ct2/show/NCT00282984. Unique identifier: NCT00282984
doi:10.1161/CIRCULATIONAHA.109.869008
PMCID: PMC4096941  PMID: 20048210
cardiovascular diseases; cerebrovascular disorders; peripheral vascular diseases; smoking; trials
7.  Retreatment With Varenicline for Smoking Cessation in Smokers Who Have Previously Taken Varenicline: A Randomized, Placebo-Controlled Trial 
The efficacy and safety of retreatment with varenicline in smokers attempting to quit were evaluated in this randomized, double-blind, placebo-controlled, multicenter trial (Australia, Belgium, Canada, the Czech Republic, France, Germany, the United Kingdom, and the United States). Participants were generally healthy adult smokers (≥10 cigarettes/day) with ≥1 prior quit attempt (≥2 weeks) using varenicline and no quit attempts in ≤3 months; they were randomly assigned (1:1) to 12 weeks' varenicline (n = 251) or placebo (n = 247) treatment, with individual counseling, plus 40 weeks' nontreatment follow-up. The primary efficacy end point was the carbon monoxide–confirmed (≤10 ppm) continuous abstinence rate for weeks 9–12, which was 45.0% (varenicline; n = 249) vs. 11.8% (placebo; n = 245; odds ratio: 7.08; 95% confidence interval: 4.34, 11.55; P < 0.0001). Common varenicline group adverse events were nausea, abnormal dreams, and headache, with no reported suicidal behavior. Varenicline is efficacious and well tolerated in smokers who have previously taken it. Abstinence rates are comparable with rates reported for varenicline-naive smokers.
doi:10.1038/clpt.2014.124
PMCID: PMC4151018  PMID: 24911368
8.  Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial 
Thorax  2008;63(8):717-724.
Background:
Varenicline, a new treatment for smoking cessation, has demonstrated significantly greater efficacy over placebo and sustained release bupropion (bupropion SR). A study was undertaken to compare a 12-week standard regimen of varenicline with a 10-week standard regimen of transdermal nicotine replacement therapy (NRT) for smoking cessation.
Methods:
In this 52-week, open-label, randomised, multicentre, phase 3 trial conducted in Belgium, France, the Netherlands, UK and USA, participants were randomly assigned (1:1) to receive varenicline uptitrated to 1 mg twice daily for 12 weeks or transdermal NRT (21 mg/day reducing to 7 mg/day) for 10 weeks. Non-treatment follow-up continued to week 52. The primary outcome was the biochemically confirmed (exhaled carbon monoxide ⩽10 ppm) self-reported continuous abstinence rate (CAR) for the last 4 weeks of the treatment period in participants who had taken at least one dose of treatment. Secondary outcomes included CAR from the last 4 weeks of treatment through weeks 24 and 52, and measures of craving, withdrawal and smoking satisfaction.
Results:
A total of 376 and 370 participants assigned to varenicline and NRT, respectively, were eligible for analysis. The CAR for the last 4 weeks of treatment was significantly greater for varenicline (55.9%) than NRT (43.2%; OR 1.70, 95% CI 1.26 to 2.28, p<0.001). The week 52 CAR (NRT, weeks 8–52; varenicline, weeks 9–52) was 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI 0.99 to 1.99, p = 0.056). Varenicline significantly reduced craving (p<0.001), withdrawal symptoms (p<0.001) and smoking satisfaction (p<0.001) compared with NRT. The most frequent adverse event was nausea (varenicline, 37.2%; NRT, 9.7%).
Conclusions:
The outcomes of this trial established that abstinence from smoking was greater and craving, withdrawal symptoms and smoking satisfaction were less at the end of treatment with varenicline than with transdermal NRT.
Trial registration number:
NCT00143325.
doi:10.1136/thx.2007.090647
PMCID: PMC2569194  PMID: 18263663
9.  A Pilot Study of the Efficacy of Varenicline for the Treatment of Smokeless Tobacco Users in Midwestern United States 
Nicotine & Tobacco Research  2011;13(9):820-826.
Introduction:
Long-term smokeless tobacco (ST) use is known to increase the risk for oropharyngeal cancer, heart attack, and stroke. Varenicline has recently been demonstrated to increase ST abstinence rates among Swedish snus users. We have conducted a pilot study to obtain preliminary evidence of efficacy of varenicline for the treatment of ST users in Midwestern United States.
Methods:
We conducted a randomized, placebo-controlled Phase II clinical trial to evaluate the potential efficacy of 12 weeks of varenicline for the treatment of ST users with an a priori decision rule that a 1-tailed p < .20 for the comparison of the primary endpoint was evidence to conclude that future studies were warranted. Subjects were followed for 6 months after randomization.
Results:
We randomized 76 subjects (38 varenicline and 38 placebo). Subjects were similar at baseline with a mean age of 41 years, and all were male. The biochemically confirmed point prevalence tobacco abstinence rates at end of treatment were 55.3% for varenicline and 42.1% for placebo (p = .126) and 47.4% and 31.6% (p = .080), respectively, at 6 months. Point prevalence ST abstinence rates at end of treatment for varenicline were 57.9% and 42.1% for placebo (p = .084) and 57.9% and 31.6% (p = .011), respectively, at 6 months. Varenicline was associated with significantly less craving compared with placebo. Varenicline was well tolerated with nausea and sleep disturbance being the most common side effects.
Conclusions:
Varenicline decreases craving and may be effective for increasing tobacco abstinence rates among ST users. Larger trials may be warranted to confirm these results.
doi:10.1093/ntr/ntr078
PMCID: PMC3168243  PMID: 21504885
10.  A Randomized Placebo-Controlled Trial of Varenicline for Smoking Cessation Allowing Flexible Quit Dates 
Nicotine & Tobacco Research  2011;14(3):343-350.
Introduction:
Current smoking cessation guidelines recommend setting a quit date prior to starting pharmacotherapy. However, providing flexibility in the date of quitting may be more acceptable to some smokers. The objective of this study was to compare varenicline 1 mg twice daily (b.i.d.) with placebo in subjects using a flexible quit date paradigm after starting medication.
Methods:
In this double-blind, randomized, placebo-controlled international study, smokers of ≥10 cigarettes/day, aged 18–75 years, and who were motivated to quit were randomized (3:1) to receive varenicline 1 mg b.i.d. or placebo for 12 weeks. Subjects were followed up through Week 24. Subjects were instructed to quit between Days 8 and 35 after starting medication. The primary endpoint was carbon monoxide–confirmed continuous abstinence during Weeks 9–12, and a key secondary endpoint was continuous abstinence during Weeks 9–24.
Results:
Overall, 493 subjects were randomized to varenicline and 166 to placebo. Continuous abstinence was higher for varenicline than for placebo subjects at the end of treatment (Weeks 9–12: 53.1% vs. 19.3%; odds ratio [OR] 5.9; 95% CI, 3.7–9.4; p < .0001) and through 24 weeks follow-up (Weeks 9–24: 34.7% vs. 12.7%; OR 4.4; 95% CI, 2.6–7.5; p < .0001). Serious adverse events occurred in 1.2% varenicline (none were psychiatric) and 0.6% placebo subjects. Fewer varenicline than placebo subjects reported depression-related adverse events (2.3% vs. 6.7%, respectively).
Conclusions:
Varenicline 1 mg b.i.d. using a flexible quit date paradigm had similar efficacy and safety compared with previous fixed quit date studies.
doi:10.1093/ntr/ntr220
PMCID: PMC3281242  PMID: 22080588
11.  Combining varenicline and nicotine patches: a randomized controlled trial study in smoking cessation 
BMC Medicine  2014;12(1):172.
Background
Some smokers may benefit from a therapy that combines different nicotine replacement therapies (NRT) or drugs with different mechanisms of action.
The aim of this study was to determine the efficacy of the combined therapy of varenicline and nicotine patches versus varenicline monotherapy.
Methods
Three hundred forty-one smokers who smoked 20 or more cigarettes per day were recruited from a smoking cessation clinic between February 2012 and June 2013. The participants were randomized to receive a varenicline plus nicotine patch of 21 mg every 24 hours (170) or varenicline plus a placebo patch (171). All of the smokers received a standard 12-week course of varenicline and an 11-week course of either the placebo patch or the active patch after the target quit day. Both groups received behavioral support. The primary outcome was continuous abstinence for weeks 2 through 12 confirmed by exhaled levels of carbon monoxide. Post hoc subgroup analyses were performed to evaluate the treatment effects for a specific endpoint in subgroups of smokers.
Results
The combination of the nicotine patch with varenicline was not associated with higher rates of continuous abstinence at 12 weeks (39.1% versus 31.8%; odds ratio (OR) 1.24; 95% confidence interval (CI) 0.8 to 2.6) and 24 weeks (32.8% versus 28.2%; OR 1.17; 95% CI 0.4 to 1.9). When participants were analyzed by subgroups according to cigarette consumption, the abstinence rates among smokers who smoked more than 29 cigarettes per day at 12 weeks (OR 1.39; 95% CI 1.2 to 2.5) and 24 weeks (OR 1.46; 95% CI 1.2 to 2.8) were significantly higher in the combination group. Other post hoc analyses based on level of dependence and previous quit attempts did not show subgroup differences. No differences between the groups for the reported adverse events were observed (χ2 value 0.07; P 0.79).
Conclusions
The combination of varenicline with the nicotine patch does not improve abstinence rates at 12 and 24 weeks compared with varenicline used as monotherapy when all smokers were analyzed as a whole, independent of consumption level.
Trial registration
This study is registered at clinicaltrial.gov (NCT01538394).
doi:10.1186/s12916-014-0172-8
PMCID: PMC4198796  PMID: 25296623
Smoking cessation; Varenicline; Nicotine patches; Combination therapy; Randomized trial
12.  The Safety and Efficacy of Varenicline in Cocaine Using Smokers Maintained on Methadone: A Pilot Study 
In this double-blind, placebo-controlled trial, we compared varenicline (2 mg) to placebo for treatment for cocaine and tobacco dependence in 31 methadone-maintained subjects. Subjects received weekly counseling during the 12-week study participation. Our results indicate that varenicline is safe to give to this subject population, as there were no adverse events related to medication during this study. Varenicline was no more effective than placebo for abstinence from cocaine. Treatment with varenicline was associated with a reduced number of cigarettes smoked per day, even though subjects received only a brief education for smoking cessation. The self-report reduction in smoking was corroborated by CO levels and the Fagerström Test of Nicotine Dependence. However, self-ratings of positive mood on the Positive Affect Negative Affect Schedule did significantly decrease in the varenicline group as compared to the placebo group, although this appears to be due to randomization differences related to lifetime depression diagnosis. These preliminary findings may point to potential therapeutic value of varenicline for smoking cessation in cocaine users maintained on methadone.
doi:10.1111/j.1521-0391.2010.00066.x
PMCID: PMC2966972  PMID: 20716302
13.  Safety of Varenicline Among Smokers Enrolled in the Lung HIV Study 
Nicotine & Tobacco Research  2012;15(1):247-254.
Introduction:
The prevalence of smoking is high among the human immunodeficiency virus (HIV)-infected population, yet there are few studies of tobacco dependence treatment in this population. This paper reports the safety of varenicline versus nicotine replacement therapy (NRT) and describes preliminary results about the effectiveness of varenicline versus NRT in HIV-infected smokers.
Methods:
Participants completed 12 weeks of telephone counseling and either varenicline or NRT. Varenicline was encouraged as the preferred intervention; NRT was used for those unable/unwilling to take varenicline. Adverse events (AEs), related to pharmacotherapy, were monitored. Biochemically confirmed abstinence at 3 months was examined. Inverse probability of treatment weighted logistic regression models was fit to compare participants on varenicline to those on NRT.
Results:
Among participants on varenicline (n = 118), the most common AEs were nausea, sleep problems, and mood disturbances. One person reported suicidal ideation; there were no cardiovascular complications. There were no differences in the varenicline AE profile between participants on combination antiretroviral therapy (ART) and those not on ART. The percentages of confirmed abstainers were 11.8% in the NRT group and 25.6% in the varenicline group. The odds of being abstinent were 2.54 times as great in the varenicline group compared with the NRT group in the propensity weighted model (95% CI 1.43–4.49).
Conclusions:
In this preliminary study, the safety profile of varenicline among HIV-infected smokers resembles findings among smokers without HIV. In addition, varenicline may be more effective at promoting abstinence in this population. Future randomized clinical trials are warranted.
doi:10.1093/ntr/nts121
PMCID: PMC3524069  PMID: 22589421
14.  Varenicline for Smoking Cessation in Schizophrenia: Safety and Effectiveness in a 12-Week, Open-Label Trial 
Journal of dual diagnosis  2012;8(2):117-125.
Objectives
Varenicline was approved by the FDA in 2006. In 2009, based largely on case reports, the FDA issued a warning of possible adverse neuropsychiatric effects including depression and suicidal thoughts and behavior for varenicline and bupropion. Prospective trials of varenicline have not reported increased incidence of psychiatric adverse events other than sleep disturbance, but smokers with major mental illness have been excluded from large prospective trials of varenicline to date. We sought to evaluate the effect of a standard open-label 12-week varenicline trial on prospectively assessed safety and smoking outcomes in stable, treated adults with schizophrenia spectrum disorder and nicotine dependence.
Methods
One-hundred-and-twelve stable outpatients who smoked >10 cigarettes/day participated in a 12-week, open-label, smoking cessation trial of varenicline and weekly group cognitive behavioral therapy. Participants took varenicline for 4 weeks before attempting cessation. Trained raters collected safety and smoking outcome data weekly.
Results
Participants demonstrated improved psychotic symptoms, depressive symptoms and nicotine withdrawal symptoms from baseline to week 12 or early termination. At the end of 12 weeks open label treatment, the 14- and 28-day continuous abstinence rates were 47.3 and 34%, respectively. Expired CO declined significantly during treatment in those who did not achieve abstinence.
Conclusions
This prospective study suggests that varenicline may be well-tolerated and effective for smoking cessation in combination with group CBT in stable outpatients with schizophrenia, a group with high rates of smoking and smoking-attributable morbidity and mortality.
doi:10.1080/15504263.2012.663675
PMCID: PMC3414422  PMID: 22888309
Schizophrenia; smoking cessation; varenicline; CBT; open label; adverse events
15.  Varenicline, Smoking Cessation and Neuropsychiatric Adverse Events 
The American journal of psychiatry  2013;170(12):1460-1467.
Objective
In 2009 FDA issued a black box warning for varenicline and neuropsychiatric events. We studied efficacy (smoking cessation) of varenicline, and safety (neuropsychiatric events) in both randomized clinical trials (RCTs) and a large observational study. The observational study was included to determine the generalizability of the RCT findings to the general population.
Method
RCTs: Re-analysis of all 17 placebo controlled RCTs (n=8027) of varenicline conducted by Pfizer using complete intent-to-treat person-level longitudinal data.
Observational Study
Analysis of Department of Defense collected adverse neuropsychiatric adverse event data in inpatients and outpatients taking varenicline versus nicotine replacement therapy (NRT) (n=35,800). The primary endpoints for the RCTs were smoking abstinence and adverse event reports of suicidal thoughts and behavior, depression, aggression/agitation, and nausea. The effect of varenicline in patients with (n=1004) and without (n=7023) psychiatric disorders was examined. The primary endpoints for the observational study were anxiety, depression, drug induced mental disorder, episodic and mood disorder, other psychiatric disorder, post traumatic stress disorder, schizophrenia, suicide attempt, transient mental disorder.
Results
RCTs: Varenicline did not increase rates of suicidal events, depression, or aggression/agitation. Varenicline increased risk of nausea (OR=3.69, 95% CI = (3.03, 4.48), p<0.0001). Varenicline increased rate of abstinence by 124% compared to placebo (p<0.0001), and 22% compared to bupropion (p<0.0001). While having a current psychiatric disorder or history of psychiatric illness increased the risk of neuropsychiatric events, it did so equally in treated and control patients.
Observational Study
Following propensity score matching, overall rate of neuropsychiatric disorders was lower for varenicline versus NRT (2.28% versus 3.16%, p<0.0001).
Conclusions
In the RCTs, varenicline revealed no increased risk of neuropsychiatric adverse events relative to placebo. Varenicline provided greater benefit in terms of smoking cessation relative to both placebo and bupropion. The same results were observed in patients with and without a current psychiatric disorder or history of psychiatric illness. In the observational study, the overall rate of neuropsychiatric disorders was lower in patients treated with varenicline relative to NRT, revealing that the finding of no increased risk of neuropsychiatric adverse events in RCTs generalizes to the population of patients engaging in treatment with varenicline.
doi:10.1176/appi.ajp.2013.12121599
PMCID: PMC4238282  PMID: 24030388
16.  Varenicline’s effects on acute smoking behavior and reward and their association with subsequent abstinence 
Psychopharmacology  2010;210(1):45-51.
Rationale
Varenicline may aid smoking cessation by attenuating smoking behavior and reward. We compared the effects of varenicline versus placebo on smoking behavior and reward, assessed both prospectively and retrospectively, and related these effects to subsequent success in a brief simulated quit attempt with medication.
Materials and methods
Smokers (n=124) with high or low interest in quitting smoking participated in a double-blind crossover study of varenicline versus placebo effects on smoking behavior and reward. In each of two phases, subjects received a week of medication run-up with varenicline (0.5 mg, b.i.d.) or placebo while continuing to smoke, followed the next week by an attempt to quit while on medication. At the end of each run-up week, subjects completed retrospective measures of smoking reward (liking) and number of cigarettes over the prior 24 hrs, and they provided an expired air carbon monoxide (CO) measure. They then completed a prospective session in which they ad lib smoked and rated the rewarding effects of one of their preferred cigarettes while blind to brand.
Results
Varenicline decreased smoking reward significantly in the prospective assessment, but only marginally in the retrospective assessment. Varenicline did not alter smoking behavior prospectively, but did reduce CO and retrospective report of smoking amount. None of these effects of varenicline predicted subsequent days of abstinence due to varenicline.
Conclusions
During medication run-up, varenicline decreases acute smoking reward and may attenuate smoking behavior, but these effects do not appear to directly predict varenicline’s influence on smoking abstinence in a short-term test.
doi:10.1007/s00213-010-1816-9
PMCID: PMC2863002  PMID: 20306175
Smoking; Varenicline; Reward; Smoking cessation; Nicotine dependence
17.  Extended interactive voice response telephony (IVR) for relapse prevention after smoking cessation using varenicline and IVR: a pilot study 
BMC Public Health  2013;13:824.
Background
There is a significant resumption of smoking following smoking cessation using varenicline. Both smoking cessation medications and counseling have been shown to increase smoking quit rates at one year. Thus, the combination of varenicline and interactive voice response (IVR) telephony followed by extended IVR may further improve smoking cessation rates at one and two years.
Methods
101 participants were recruited from the community via newspaper advertisement. They attended a group counseling session and were given smoking information booklets from the Canadian Cancer Society.
After 12 weeks of varenicline and 9 IVR calls, all participants who had quit smoking were randomized into 2 groups matched by levels of motivation and addiction as per baseline questionnaire score. The intervention group continued to receive bi-weekly IVR support for weeks 13 – 52. The control group no longer received IVR. The primary end-point was self-reported abstinence and exhaled carbon monoxide levels of less than 10 ppm for weeks 12, 52 and 2 years. Data were analyzed by Fisher’s exact test or Wilcoxon rank-sum test.
Results
Of the 101 participants, 44 (43%) had stopped smoking after 12 weeks of varenicline and 9 IVR calls. Of these, 23 (52%) were randomized to receive IVR calls from weeks 13 to 52.
At 52 weeks, 26 (59%) participants remained smoke-free. Of the 23 with IVR, 12 (52.2%) stopped smoking compared to 14 of 21 (66.7%) without IVR. At 2 years, 40 of the 44 (90.9%) randomized participants were contacted and 24 of the 44 (54.5%) came in for testing. Fourteen (13% of the original cohort, 30% who were abstinent at 12 weeks and 53% who were abstinent at 52 weeks) remained smoke-free. Five of the 23 (21.7%) randomized to IVR and 9 of the 21 (42.9%) randomized to no IVR remained smoke-free at 2 years.
Conclusions
In this pilot study of an apparently healthy population, extended IVR did not affect abstinence rates. There was no relapse prevention benefit in offering 9 months of continued IVR to subjects who had stopped smoking after receiving 3 months of varenicline and IVR treatment.
Trial registration
ClinicalTrial.gov: NCT00832806
doi:10.1186/1471-2458-13-824
PMCID: PMC3848019  PMID: 24020450
Smoking; Non-smoking; Risk factors; Varenicline; Interactive voice response
18.  Randomized, placebo-controlled, double-blind trial of Swedish snus for smoking reduction and cessation 
Background
Epidemiological studies suggest that smokeless tobacco in the form of Swedish snus has been used by many smokers in Scandinavia to quit smoking, but the efficacy of snus has so far not been evaluated in controlled clinical trials.
Methods
We conducted a randomized, double-blind, placebo-controlled, clinical trial aimed at assessing the efficacy of snus to help adult cigarette smokers in Serbia to substantially reduce, and, eventually, completely stop smoking. The study enrolled 319 healthy smokers aged 20-65 years at two occupational health centers in Belgrade, Serbia. Most of them (81%) expressed an interest to quit rather than just reduce their smoking. Study products were used ad libitum throughout the 48-week study period. The main study objective during the first 24 weeks was smoking reduction. The primary end-point was defined as a biologically verified reduction of ≥ 50% in the average number of smoked cigarettes per day during week 21-24 compared to baseline. During week 25-48 participants were actively instructed to stop smoking completely. Outcome measures of biologically verified, complete smoking cessation included 1-week point prevalence rates at clinical visits after 12, 24, 36, and 48 weeks, as well as 4-, 12- and 24-week continued cessation rates at the week 36 and 48 visits.
Results
At the week 24 visit, the proportion of participants who achieved the protocol definition of a ≥ 50% smoking reduction was similar in the two treatment groups. However, the proportion that reported more extreme reductions (≥ 75%) was statistically significantly higher in the snus group than in the placebo group (p < 0.01). The results for biologically verified complete cessation suggested that participants in the snus group were more likely to quit smoking completely than the controls; the odds ratio (snus versus placebo) for the protocol estimates of cessation varied between 1.9 to 3.4, but these ratios were of borderline significance with p-values ranging from 0.04-0.10. Snus was well tolerated and only 2/158 (1.3%) participants in the snus group discontinued treatment due to an adverse event (in both cases unrelated to snus).
Conclusions
Swedish snus could promote smoking cessation among smokers in Serbia, that is, in a cultural setting without traditional use of oral, smokeless tobacco.
Trial registration
www.clinicaltrials.gov, identifier: NCT00601042
doi:10.1186/1477-7517-8-25
PMCID: PMC3186733  PMID: 21914165
Randomized trial; double-blind; placebo-controlled; Swedish snus; smoking reduction; smoking cessation
19.  Varenicline for smoking cessation: A review of the literature 
Background: Smoking is the leading preventable risk to human health. Various agents have been used to promote smoking cessation, but none has had long-term efficacy. Varenicline, a new nicotinic ligand based on the structure of cytosine, was approved by the US Food amd Drug Administration for use as a smoking cessation aid.
Objectives: The aims of this review were to provide an overview on the mechanism of action and preclinical and clinical data of the new drug, varenicline, and to discuss the current and future impact of varenicline as a treatment for smoking cessation.
Methods: MEDLINE, BIOSIS, and Google scholar databases were searched (March 1, 2007–July 1, 2008) using the terms varenicline, smoking cessation, and nicotinic receptors. Full-text articles in English were selected for reference, and articles presenting the mechanism of action, pharmacokinetics, and data from preclinical and clinical trials were included.
Results: The initial literature search yielded 70 papers. A total of 20 articles fulfilled the inclusion criteria. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, inhibits dopaminergic activation produced by smoking and decreases the craving and withdrawal syndrome that accompanies cessation attempts. In Phase III clinical trials, the carbon monoxide-confirmed 4-week continuous abstinence rates were significantly higher with varenicline than with buproprion sustained release or placebo for weeks 9 through 12. Varenicline has been found to be well tolerated, with nausea being the most commonly reported (28.1%) adverse event.
Conclusions: Varenicline is the first drug for smoking cessation that has been found to have significant effectiveness in long-term relapse prevention (up to 52 weeks). Varenicline, with its unique profile of agonist and antagonist properties, increased cessation rates (both short- and long-term) compared with both placebo and bupropion sustained release.
doi:10.1016/j.curtheres.2009.02.004
PMCID: PMC3969980  PMID: 24692831
varenicline; smoking cessation; nicotinic receptors; review
20.  A Pilot Clinical Trial of Varenicline for Smoking Cessation in Black Smokers 
Nicotine & Tobacco Research  2011;13(9):868-873.
Introduction:
Varenicline, a first-line non-nicotine medication, has not been evaluated in Black smokers, and limited attention has been paid to pharmacotherapy adherence in smoking cessation trials. This pilot study estimated quit rates for Black smokers treated with varenicline and tested a behavioral intervention to aid varenicline adherence.
Methods:
Seventy-two Black smokers (>10 cigarettes per day; cpd) were randomly assigned to adherence support (AS; n = 36) or standard care (n = 36). All participants received 3 months of varenicline and a single counseling session focused on making a quit plan. AS participants received 5 additional counseling sessions to encourage medication use. Outcome measures included salivary cotinine, and carbon monoxide confirmed smoking abstinence, reductions in self-reported cpd, and pill counts of varenicline adherence at Months 1, 2, and 3.
Results:
Sixty-one participants (84.7%) completed follow-up at Month 3. Participants were female (62.5%), 46.8 years of age, and smoked 16.3 cpd. No treatment group differences were found on the smoking or adherence outcome measures (p > .05). Collapsing across treatment, varenicline adherence was adequate (86.1%), yet despite a reduction of 12.2 (6.5) cpd from baseline to Month 3 (p < 0.001), only 23.6% were confirmed quit at Month 3. Participants who were quit at Month 3 had higher varenicline adherence rates (95.8%) than those who continued to smoke (80.8%, p ≤ .05).
Conclusions:
Studies are needed to examine the efficacy of varenicline among Black smokers. Interventions to facilitate adherence to pharmacotherapy warrant further attention as adherence is linked to improved tobacco abstinence.
doi:10.1093/ntr/ntr063
PMCID: PMC3203399  PMID: 21498427
21.  Varenicline in the treatment of tobacco dependence 
Varenicline, a partial agonist of α4β2 nicotinic acetylcholine receptors, is the most recently approved drug for smoking cessation. This paper reviews the outcomes of Phase 2 and Phase 3 clinical trials that assess the efficacy of varenicline in comparison to placebo and other smoking cessation pharmacotherapies, ie, sustained-release bupropion (bupropion SR) and nicotine transdermal patch. Varenicline has higher abstinence rates than placebo and the alternative active treatments at the end of standard regimen treatment periods. Significantly higher abstinence rates were also found with varenicline in comparison to both placebo and bupropion SR at the end of a 40-week non-treatment follow-up period. Varenicline typically tripled the abstinence rates compared with placebo. In addition, varenicline reduced craving and withdrawal symptoms as well as some of the positive experiences associated with smoking to a greater extent than placebo, bupropion SR, and nicotine replacement therapy (NRT). These findings are consistent with the proposed agonist/antagonist effects of varenicline. Preliminary studies assessing individual variables such as smoking dependency level and smoking reinforcement types provide justification to examine further the effects of varenicline according to these individual factors. Outcomes from such research could improve our understanding of varenicline’s mechanism of action and could ultimately help clinicians to develop individualized smoking cessation programs. Also, given varenicline’s ability to reduce the reward from smoking, it might be helpful to use it before cessation to motivate or prepare smokers for a quit attempt.
PMCID: PMC2518383  PMID: 18728741
varenicline; smoking cessation; nicotinic partial agonist
22.  Smoking Cessation Pharmacogenetics: Analysis of Varenicline and Bupropion in Placebo-Controlled Clinical Trials 
Neuropsychopharmacology  2011;37(3):641-650.
Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23–2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27–2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36–0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45–2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.
doi:10.1038/npp.2011.232
PMCID: PMC3260990  PMID: 22048466
varenicline; bupropion; pharmacogenetics; nicotine; nicotinic receptor; CYP2B6; pharmacogenetics/pharmacogenomics; addiction and substance abuse; clinical pharmacology/clinical trials; neuropharmacology; varenicline; bupropion; nicotine; smoking cessation; nicotinic receptors
23.  A pilot study to assess smokeless tobacco use reduction with varenicline 
Nicotine & Tobacco Research  2010;12(10):1037-1040.
Introduction:
Long-term smokeless tobacco (ST) use is known to increase the risk for oropharyngeal cancer, heart attack, and stroke. Extant literature on cigarette smokers suggests that smoking reduction increases smoking abstinence among smokers not interested in quitting. Similarly, a reduction strategy may reduce ST exposure and increase ST abstinence rates among ST users not interested in quitting.
Methods:
We conducted a pilot study to obtain preliminary data on the use of 12 weeks of varenicline as a tobacco reduction strategy among ST users not interested in quitting.
Results:
We enrolled 20 male ST users with a mean age of 42.8 ± 11.7 years who used an average of 3.9 ± 1.7 cans/pouches per week for 18.6 ± 8.6 years. At end of treatment (12 weeks), 60% (12/20) of subjects reduced their ST use by ≥50% and 15% (3/20) were biochemically confirmed abstinent from tobacco. At end of study (6 months), 50% (10/20) reduced by ≥50% of baseline use and 10% (2/20) were biochemically confirmed abstinent from tobacco. Varenicline reduced ST satisfaction, reward, and craving. Among subjects able to reduce ST, all subjects reported that reduction increased motivation and confidence in being able to maintain reduction and quit. The most common side effects were sleep disturbance (25%) and nausea (15%).
Discussion:
Varenicline may be effective in reducing ST use and achieving ST abstinence among ST users with no plans to quit but who are interested in reducing their ST use.
doi:10.1093/ntr/ntq134
PMCID: PMC2948050  PMID: 20724382
24.  The Effects of Varenicline and Bupropion-SR plus Intensive Counseling on Prolonged Abstinence from Smoking, Depression, Negative Affect and Other Symptoms of Nicotine Withdrawal 
JAMA psychiatry  2013;70(5):522-533.
Context
Smoking cessation clinical trial
Objective
Assess the relative efficacy of bupropion and varenicline on smoking cessation and emotional functioning.
Design
Placebo controlled randomized clinical trial
Setting
University Medical Center
Patients
294 community volunteers who wanted to quit smoking
Interventions
12 weeks of Varenicline, Bupropion-SR, or Placebo plus intensive smoking cessation counseling (10 sessions ~240 minutes).
Main Outcome Measures
Prolonged abstinence from smoking, and weekly measures of depression, negative affect and other symptoms of nicotine withdrawal
Results
Significant differences were found in abstinence at the end of treatment and through the 3-month post-quit follow-up favoring both active medications vs. placebo At the 6 month follow-up only the varenicline vs. placebo comparison remained significant. Varenicline was also associated with a generalized suppression of depression and reduced smoking reward compared to the other treatments, while both medications improved concentration, reduced craving, and decreased negative affect and sadness compared to placebo, while having little impact (increase or decrease) on anxiety and anger. No differences were noted in self-reported rates of neuropsychiatric adverse events.
Conclusions
Varenicline exerts a robust and favorable impact on smoking cessation relative to placebo and may have a favorable (suppressive effect) on symptoms of depression and other affective measures with no clear unfavorable impact on neuropsychiatric adverse events in a community sample
doi:10.1001/jamapsychiatry.2013.678
PMCID: PMC4128024  PMID: 23536105
25.  Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis 
Objective To examine the risk of treatment emergent, cardiovascular serious adverse events associated with varenicline use for tobacco cessation.
Design Meta-analysis comparing study effects using four summary estimates.
Data sources Medline, Cochrane Library, online clinical trials registries, and reference lists of identified articles.
Review methods We included randomised controlled trials of current tobacco users of adult age comparing use of varenicline with an inactive control and reporting adverse events. We defined treatment emergent, cardiovascular serious adverse events as occurring during drug treatment or within 30 days of discontinuation, and included any ischaemic or arrhythmic adverse cardiovascular event (myocardial infarction, unstable angina, coronary revascularisation, coronary artery disease, arrhythmias, transient ischaemic attacks, stroke, sudden death or cardiovascular related death, or congestive heart failure).
Results We identified 22 trials; all were double blinded and placebo controlled; two included participants with active cardiovascular disease and 11 enrolled participants with a history of cardiovascular disease. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval −0.10 to 0.63; P=0.15), based on all 22 trials, was neither clinically nor statistically significant. For comparison, the relative risk (1.40, 0.82 to 2.39; P=0.22), Mantel-Haenszel odds ratio (1.41, 0.82 to 2.42; P=0.22), and Peto odds ratio (1.58, 0.90 to 2.76; P=0.11), all based on 14 trials with at least one event, also indicated a non-significant difference between varenicline and placebo groups.
Conclusions This meta-analysis—which included all trials published to date, focused on events occurring during drug exposure, and analysed findings using four summary estimates—found no significant increase in cardiovascular serious adverse events associated with varenicline use. For rare outcomes, summary estimates based on absolute effects are recommended and estimates based on the Peto odds ratio should be avoided.
doi:10.1136/bmj.e2856
PMCID: PMC3344735  PMID: 22563098

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