Following promising results in preclinical studies, together with a strong theoretical foundation for its use, testing of varenicline began in clinical safety and efficacy trials. summarizes the results of the ten clinical trials with varenicline since it was approved by the US FDA in 2006. These trials were conducted in Australia, Canada, Europe, Japan, South Korea, China, Thailand, Singapore, and the US, and enrolled both male and female subjects (age range, 18–75 years) with no major comorbidities in the past year. The primary end point in most of the studies was efficacy, which was assessed primarily in terms of the continuous abstinence rate (CAR) or continuous quit rate (CQR) based on subjective reporting and confirmation by exhaled carbon monoxide (CO) measurement (≤10 ppm). The second end points included the urge to smoke, withdrawal symptoms, and the reinforcing effects of nicotine. In addition, odds ratio (OR) meta-analysis was also used to measure the comparative efficacy and abstinence rates for various smoking cessation medications in some of those clinical trials.
Clinical efficacy (CARs) of varenicline in human clinical trials
One of the trials reported follow-up data to 24 weeks,53
and the others reported data to 52 weeks.54
During treatment with oral varenicline titrated to 1 mg twice per day (bid), CO-confirmed CQRs or CARs at week 12 ranged from 28.8% to 65.4%, at week-24 from 20.8% to 70.5%, and at week-52 from 14.4% to 43.6%. In all these trials, varenicline 1 mg bid was associated with significantly higher CARs or CQRs compared with placebo at either week 12, week 24, or week 52 when compared with placebo. Three trials reported significantly higher CARs or CQRs with varenicline 1 mg bid compared to bupropion,55
and one trial reported significantly higher CARs with varenicline compared with NRT ().62
In a relapse-prevention study, CARs were significantly improved at 24 weeks with varenicline relative to placebo (70.5% vs
Nides et al63
conducted a pooled data analysis from the Phase III trials by Gonzales et al57
and Jorenby et al58
to explore the relative efficacy of varenicline, bupropion, and placebo for smoking cessation. Pooled CARs for weeks 9 through 12 were significantly greater for varenicline compared with bupropion and placebo (44.0%, 29.7%, and 17.7%, respectively; both comparisons P
West et al64
conducted a similar analysis of pooled data from the same two Phase III trials57
to evaluate the effects of varenicline, bupropion, and placebo on craving and withdrawal symptoms among smokers. They used the Minnesota Nicotine Withdrawal Scale (MNWS) to score craving and withdrawal symptoms in abstinent smokers (n = 612) and the Modified Cigarette Evaluation Questionnaire (mCEQ) to score the reinforcing effects of smoking in nonabstinent smokers (n = 1,115). They found that among all participants, cravings (urge to smoke) were significantly reduced with varenicline or bupropion compared with placebo (both P
< 0.001) and with varenicline compared with bupropion (P
= 0.008). Overall, varenicline or bupropion significantly inhibited negative withdrawal syndromes (depression, irritability, anxiety, difficulty concentrating, and insomnia) compared with placebo. In addition, they also found that varenicline-treated patients had significantly lower pleasurable effects of smoking compared with those treated with bupropion and placebo, as assessed by mCEQ scores for smoking satisfaction, psychological reward and enjoyment of respiratory tract sensations.
Cahill et al65
conducted a systemic review and meta-analysis of the efficacy and tolerability of varenicline for smoking cessation in seven placebo-controlled trials, one relapse-prevention trial, and one open-label trial comparing varenicline with NRT. The nine trials covered 7,267 participants, 4,744 of whom used varenicline. The pooled ORs for CAR for varenicline versus
placebo at six months or longer was 2.33 (95% confidence interval [CI]: 1.95–2.80), for varenicline versus
bupropion at one year was 1.52 (95% CI: 1.22–1.88), and for varenicline versus
NRT at one year was 1.31 (95% CI: 1.01–1.71). These data suggest that varenicline is even more effective than bupropion or NRT.
Mills et al66
conducted large-scale pooled data analysis from nine trials with varenicline (n = 5,192), 101 clinical trials with NRT (n = 31,321), and 31 trials with bupropion (n = 11,118) in order to compare treatment effects across interventions. They found that the pooled ORs for smoking cessation at four weeks post-target quit data with varenicline, NRT, and bupropion were 3.16, 2.25, and 2.05, respectively (P
< 0.001, compared to placebo). Two trials evaluated head to head comparisons of varenicline and bupropion, and found a pooled OR 1.86 (P
< 0.001). Indirect comparison between varenicline and NRT was OR 1.56 (P
< 0.001), and between varenicline and bupropion OR 1.40 (P
Taken together, all these clinical data suggest that varenicline is superior to placebo, NRT, and bupropion for achieving abstinence from smoking in the short-term. Varenicline not only significantly attenuates the craving and withdrawal symptoms that occur during abstinence from smoking, but also significantly reduces the rewarding effects of nicotine and delay smoking relapse. Thus, varenicline, as the newest agent approved for smoking-cessation, offers a new therapeutic option for the treatment of nicotine addiction.