Although we observed improved abstinence with varenicline in this study, relative to placebo, we did not observe more quit attempts in the active drug group. This is probably due to the fact that smokers entering a clinical trial are typically highly motivated to quit smoking; therefore, the vast majority of subjects in both treatment arms made at least one attempt. In addition, definitely unlike in prior studies (Gonzales et al., 2006; Jorenby et al., 2006), the time between the target quit date and follow-up varied among individuals, resulting in an increase in the days smokers in the varenicline group were at risk for relapse, since on average they quit earlier than the placebo group. However, this did not unfavorably influence the abstinence rates in the active treatment group.

The overall safety profile observed in this trial was similar to previous community trials with varenicline (Gonzales et al., 2006; Jorenby et al., 2006). Gastrointestinal and sleep-related adverse events were higher in the varenicline group compared with placebo, but few subjects discontinued treatment due to adverse events. In fact more placebo than varenicline subjects discontinued due to adverse events (7.9% vs. 4.9%, respectively). Psychiatric adverse events appeared to be less prevalent in the varenicline than in the placebo group. Exclusion of subjects with psychiatric illness was a limitation of this study. As discussed above, the odds of quitting with this protocol were within the range observed in studies in which subjects were required to set a quit date a priori, which possibly suggests no particular disadvantage to using a fixed quit date approach in terms of overall treatment efficacy.

However, such cross-study comparisons can be misleading; thus only a randomized trial would answer whether a fixed quit date or a flexible quit date protocol is superior. The present study was not designed to determine which cessation paradigm would be superior. By demonstrating similar effect size, however, the current study demonstrates that a flexible quit strategy is an effective option and that a study comparing flexible with fixed quit dates in a general population would need to be very large. Alternatively, if the two approaches to quitting are more suitable for different smoker populations, a direct comparison may not be relevant.

Our results are consistent with two prior studies examining the effect of precessation nicotine replacement therapy in conjunction with a flexible quit date (Hughes et al., 2010; Shiffman et al., 2009); however, these studies used a gradual cessation approach and were conducted among smokers who were less motivated to quit. Allowing smokers to start treatment without Dacomitinib setting a fixed quit date may make quitting more appealing to some smokers. Current guidelines recommend that all smokers should be counseled at every clinical encounter to quit (Fiore et al., 2008).