Efficacy of Varenicline Combined With Nicotine Replacement Therapy vs Varenicline Alone for Smoking Cessation: A Randomized Clinical Trial

Study Questions:

Does a combination of varenicline with nicotine replacement therapy improve smoking cessation?


This was a randomized, blinded, placebo-controlled clinical trial with a 12-week treatment period and a further 12-week follow-up conducted in seven centers in South Africa from April 2011 to October 2012. Four hundred forty-six generally healthy smokers were randomized (1:1); 435 were included in the efficacy and safety analyses. Participants were randomized to either nicotine or placebo patch treatment, which began 2 weeks before a target quit date (TQD) and continued for a further 12 weeks. Varenicline was begun 1 week prior to TQD, continued for a further 12 weeks, and tapered off during week 13. Tobacco abstinence was confirmed by exhaled carbon monoxide measurements at TQD and at intervals thereafter up to 24 weeks. The primary endpoint was the 4-week exhaled carbon monoxide–confirmed continuous abstinence rate for weeks 9-12 of treatment, i.e., the proportion of participants able to maintain complete abstinence from smoking for the last 4 weeks of treatment, as assessed using multiple imputation analysis. Secondary endpoints included point prevalence abstinence at 6 months, continuous abstinence rate from weeks 9-24, and adverse events.


A total of 446 participants (171 males; mean age, 46.3 years) were enrolled and randomized. Of these, 435 were included in the per-protocol efficacy and safety analyses. The combination treatment was associated with a higher continuous abstinence rate at 12 weeks (55.4% vs. 40.9%; odds ratio [OR], 1.85; 95% confidence interval [CI], 1.19-2.89; p = 0.007) and 24 weeks (49.0% vs. 32.6%; OR, 1.98; 95% CI, 1.25-3.14; p = 0.004), and point prevalence abstinence rate at 6 months (65.1% vs. 46.7%; OR, 2.13; 95% CI, 1.32-3.43; p = 0.002). In the combination treatment group, there was a numerically greater incidence of nausea, sleep disturbance, skin reactions, constipation, and depression, with only skin reactions reaching statistical significance (14.4% vs. 7.8%; p = 0.03); the varenicline-alone group experienced more abnormal dreams and headaches.


The investigators concluded that varenicline, in combination with nicotine replacement therapy, was more effective than varenicline alone at achieving tobacco abstinence at 12 weeks (end of treatment) and at 6 months. Further studies are needed to assess long-term efficacy and safety.


These data support the use of combination therapies for smoking cessation. However, as the authors suggest, the number of side effects increased with the combination of varenicline and nicotine replacement, which supports the need for studies on the long-term efficacy.

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