What are the effects of combining varenicline with nicotine patches and extending treatment duration on smoking cessation?

What are the effects of combining varenicline with nicotine patches and extending treatment duration on smoking cessation?
Deandra Lundeen, PharmD, Park Nicollet

Background: Various strategies and interventions to enhance the effectiveness of lasting smoking cessation have been explored. Previous research on the combination of nicotine replacement therapy (NRT) with varenicline versus varenicline alone has shown differing results. A meta-analysis performed on previous studies showed statistical benefit in favor of combination therapy. After reviewing this meta- analysis, the American Thoracic Society conditionally recommended the combination of varenicline plus NRT versus varenicline alone while most guidelines continue to recommend monotherapy of varenicline, bupropion, NRT, or combination therapy of different NRTs. Due to this, a randomized clinical trial was performed that evaluated the effects of combining varenicline with NRT and extending varenicline treatment duration since limited evidence has been seen thus far.

Purpose: To compare the effectiveness of varenicline plus a nicotine patch versus varenicline alone for 12 weeks or 24 weeks on smoking cessation treatment.

Study Design: The study was a double-blind, 2x2 factorial randomized clinical trial that began initial enrollment on November 11, 2017 and was completed on July 9, 2020. The visits throughout the study occurred in one of two research clinics in Wisconsin. Eligible participants were individuals who smoked at least five cigarettes per day in the last six months, spoke English, were at least 18 years old, had exhaled carbon monoxide (CO) of five parts per million or greater indicating that they smoke cigarettes consistently, had a desire to quit smoking, did not use any other tobacco products in the past 30 days, had phone access, and were willing and able to use both NRT and varenicline. A total of 1,251 people were randomized evenly into four different groups. The four groups were varenicline monotherapy for 12 weeks (n=315), varenicline plus nicotine patch for 12 weeks (n=314), varenicline monotherapy for 24 weeks (n=311), and varenicline plus nicotine patch for 24 weeks (n=311). Varenicline dosing was titrated to 2 mg daily after one week appropriately and participants in the patch groups received 14mg nicotine patches. Additionally, a placebo patch was given to participants that had varenicline monotherapy and placebo varenicline was given to participants who were in the 12 week duration study arms to be used during the remaining 12 weeks. The primary outcome collected was self-reported seven-day point prevalence abstinence at 52 weeks after the target quit day which was biochemically confirmed by CO testing.

Results: For the primary endpoint, 967 of the 1,251 participants provided self-reported data. Of the 967, 477 participants claimed abstinence and 317 of those underwent CO testing which confirmed abstinence in 247 of those participants. These results found no significant interaction between medication type or medication duration (1.03 [95% CI 0.91 - 1.17], P= 0.66). Additionally, for all secondary outcomes assessed, no significant findings were found.

Conclusion: Based on the study results, there was no significant difference in smoking cessation rates from the use of varenicline for 12 weeks when compared to a longer duration or addition of nicotine patches. No subgroup of participants showed significant results in favor of any specific treatment. This trial had several limitations. Some participants were not able to have a CO confirmation test at follow-up due to COVID-19 restrictions. Another limitation was that 23% of the sample population was lost to follow-up throughout the 52-week follow-up period and adherence to the medication(s) declined over time. The average initial adherence rate across the treatment groups were between 75-81% and by week 23 were between 40-55%.

Key Point: The use of varenicline in extended durations or in combination with nicotine replacement therapy did not show benefit in this study. Smoking cessation strategies are often very patient dependent. No treatment group showed to be safer than others, and for the usual population, combination therapy or increased duration did not improve outcomes in this study.


  1. Baker TB, Piper ME, Smith SS, Bolt DM, Stein JH, Fiore MC. Effects of combined varenicline with nicotine patch and of extended treatment duration on smoking cessation: a randomized clinical trial. JAMA. 2021;326(15):1485-1493. doi:10.1001/jama.2021.15333.