A Cochrane review included 39 trials involving a total of 25 766 participants testing varenicline. Varenicline was more effective than placebo for abstinence at six months or longer (RR 2.24, 95% CI 2.06 to 2.43; 27 studies, n=12 625; high-quality evidenc). Varenicline at lower or variable doses was also shown to be effective (RR 2.09, 95% CI 1.56 to 2.78; 4 studies, n=1 272). The RR for varenicline vs. bupropion at one year was 1.39 (95% CI 1.25 to 1.54; 5 studies, n=5 877; high-quality evidence) and for varenicline vs nicotine replacement therapy (NRT) for point prevalence abstinence at 24 weeks was 1.25 (95% CI 1.14 to 1.37; 8 studies, n=6 264; moderate-quality evidence). The number needed to treat (NNT) with varenicline for an additional beneficial outcome is 11 (95% CI 9 to 13). The 4 trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Post-marketing safety data raised questions about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation. The labelling of varenicline was amended in 2008. However, subsequent observational cohort studies and meta-analyses have not confirmed these fears, and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders, including suicidal ideation and suicidal behaviour.
Another Cochrane review included a network meta-analysis of 12 treatment-specific reviews (267 studies) involving 101 804 participants. Varenicline increased the odds of quitting compared with placebo (OR 2.88; 95% credible interval= CredI 2.40 to 3.47; direct comparisons, 15 trials). Varenicline was superior to single forms of NRT (OR 1.57; 95% CredI 1.29 to 1.91; indirect comparison), and to bupropion (OR 1.59; 95% CredI 1.29 to 1.96; indirect comparison). Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87; indirect comparison), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13; indirect comparison), and than 'other' NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48; indirect comparison).
The serious adverse events (SAEs) meta-analysis found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55 RR 1.06; 14 trials, n=6333 participants; event rates for any SAE were 2.1% in the varenicline arms and 2.0% in the placebo arms), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56).