Combining varenicline and nicotine patches: a randomized controlled trial study in smoking cessation

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).

Discussion
The aim of the present study was to assess the efficacy of the combined use of varenicline and nicotine patches compared with varenicline alone in smoking cessation .In this study, the observed results showed that the combination of varenicline and the nicotine patch was not associated with an enhanced continuous abstinence rate at 12 and 24 weeks, as well as with the point prevalence abstinence rate at 24 weeks.

The combined use of the nicotine patch and varenicline compared with varenicline alone resulted in higher rates of abstinence at 12 and 24 weeks, but only among smokers of more than 29 cpd.

There are only three studies in the previous literature that measure the efficacy or effectiveness of combining varenicline with nicotine patches. An observational study by Ebbert et al. [7] reported no differences in the 30-day point prevalence abstinence rate between patients receiving the usual care and patients treated with varenicline and NRT at the six-month follow-up and in the reported data on the safety and tolerability of the combination of varenicline and NRT. A study by Hajek et al. [8], which used the same method as the present trial with medication started as per labelling found no effect of the combination treatment at three months. Koegelenberg et al. [9] found the combination more effective than varenicline alone at three and six months, but patch use was started two weeks prior to targetquit date. The three studies included smokers of 10 cigarettes or more, in contrast to this study in which the participants were smokers of 20 or more cigarettes. In the Hajek study [8], the continuous abstinence rate at 12 weeks was similar to that observed in this study for all smokers in the combination group as a whole (36% versus 39.1%, respectively), although in those studies, smokers had lower levels of nicotine dependence and more attempts to stop smoking than did the smokers in this study. The abstinence rates were also similar at 12 weeks, which may reflect the existence of other factors such as the size of the study sample. The study by Koegelenberg et al. [9] shows higher rates of abstinence than this study, which may be due to the inclusion criteria in relation to the amount of consumption (10 or more versus 20 or more cpd), the possible heterogeneity of the participants and that the nicotine patch was used for two weeks prior to the TQD. The results could reflect the effects of ‘nicotine preloading’ rather than any effects of medication combination.

However, in the sub-analysis of the smokers of 29 or fewer cpd and of those who smoked more than 29 cpd, the abstinence rates at 12 and 24 weeks were higher and more significant among the heavy smokers who had received the combination therapy. These results are similar to those of a study of the combination of bupropion and varenicline for smoking cessation [18].

This study’s sample size was sufficient to detect differences in the abstinence rates equal to or greater than 15% in one of the groups. The dropout rate in both groups was similar, and no significant differences were observed in the participants who withdrew from the study because of adverse events. In this study, the dropouts and the subjects who failed to provide validation data were considered relapsed [15,16], although not all of the smokers who dropped out may have actually relapsed, and an underestimation in the rates could have occurred. However, the number of subjects without information in each group was similar and was not considered to be a potential source of bias.

The different usage periods for both of the medications could represent a possible bias in the results. To control for these biases, the varenicline and patches were administered for 11 weeks. Using 21 mg/24 hours patches in combination therapy did not show an increase in adverse events. The number of patients experiencing headache, insomnia and nausea was similar in both groups and comparable with the rates reported in previous studies using 15 mg/16 hours patches [8,9]. Finally, another potential limitation is the possibility for bias in the non-pharmacological interventions. The study involved three different therapists trained in the standardized study protocol who were experts in smoking cessation. However, and although no differences were observed between different therapists, the counsellor may still have been a source of bias in this study [19]. To control for this potential source of variation, the therapist was introduced in the final model.

Conclusions
In conclusion, the combination of the varenicline with the nicotine patches does not improve abstinence rates at 12 and 24 weeks compared with varenicline used as monotherapy although the combination treatment may help patients smoking 29 or more cpd. Further research is needed to confirm this post hoc finding.

This article is adapted from Josep M Ramon12*, Sergio Morchon12, Antoni Baena1 and Cristina Masuet-Aumatell12, Combining varenicline and nicotine patches: a randomized controlled trial study in smoking cessation. Source article. This work is licensed under a Creative Commons Attribution License.