By Ellen Feldman, MD
SYNOPSIS: This randomized trial found that, for patients unable to stop smoking after six weeks of treatment, increasing the dose of either varenicline or combination nicotine replacement therapy (CNRT) or switching from CNRT to varenicline, leads to an increased likelihood of success.
SOURCE: Cinciripini PM, Green CE, Shete S, et al. Smoking cessation after initial treatment failure with varenicline or nicotine replacement: A randomized clinical trial. JAMA 2024;331:1722-1731.
The landmark 1964 Surgeon General report marked the beginning of a new era in public health by bluntly declaring, “Cigarette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial action.”1 Policies that followed this critical statement — such as mandatory smoke-free public areas, workplace tobacco restrictions, limited access for minors, higher tobacco taxes, and the now familiar Surgeon General’s warning on cigarette packs — have significantly reduced exposure to cigarette smoke.1,2 However, despite these advancements, many people who wish to stop smoking still struggle, with most unable to succeed on their first attempt.2-4
To address the need for evidence-based guidelines on treatment strategies following a failure of first-line smoking cessation therapies, Cinciripini et al conducted a randomized trial to evaluate subsequent treatment options. The study enrolled a diverse group of 490 adult smokers who reported smoking at least five cigarettes daily and had objective evidence of usage through expired carbon monoxide levels of at least 6 ppm.
Participants were initially randomized to receive either varenicline, slowly increasing to a maximum dose of 2 mg daily, or combined nicotine replacement therapy (CNRT), including a 21 mg nicotine patch and up to six nicotine lozenges daily. All participants also received weekly 15-minute counseling sessions.
After six weeks, participants with carbon monoxide measurements confirming abstinence continued these same interventions. The abstinence rates at this early mark were higher for the varenicline group (36%) compared to the CNRT group (22%).
Patients who still were smoking at six weeks were randomized into three groups: a control group that continued their initial treatment, a second group that increased varenicline to 3 mg total daily, and a third group that increased CNRT (double patch). Each group received a placebo version of the non-active treatment as well.
The primary outcome measured was smoking cessation at 12 weeks validated by self-report as well as biochemical confirmation via carbon monoxide expiration levels.
Results at 12 weeks indicated that, for those who failed initial CNRT treatment, switching to varenicline or increasing the CNRT dosage significantly improved abstinence rates. Specifically, rates reached 14% for either of these strategies compared to 8% for those who continued the original treatment. Even more impressive, for those who initially received varenicline, increasing the dosage yielded an abstinence rate of 20% vs. 3% for those who continued the original dosage and 0% for those who switched from varenicline to CNRT.
Follow-up at six months revealed that only the increased dosages of either varenicline or CNRT provided a significant benefit in continuous abstinence compared to continuing with the initial treatment.
Commentary
This study offers valuable insights for primary care practitioners (PCPs) and their patients who are struggling to stop tobacco use. By offering a structured approach to guide treatment decisions after initial failure, Cinciripini et al bridge the gap between theoretical research and practical clinical application. Their focus on patients who initially received varenicline or CNRT and the subsequent evaluation of strategies for those who did not quit smoking after the first six weeks reflects real-world clinical scenarios. In these settings, multiple attempts and treatment adjustments often are required for patients to quit smoking successfully.4,5
Cinciripini et al noted the higher initial response rate to varenicline was an “unexpected finding” in this study. A recently published comprehensive review of the literature found that response rates to specific smoking cessation strategies are influenced by multiple factors, including gender, socioeconomic status, genetic markers, and individual characteristics, such as age. The scope of this study did not include identifying which patients are more likely to benefit from varenicline vs. CNRT. Understanding the factors that predispose a better response to each treatment is an important area for future research.
For the PCP, the key takeaway may be the importance of flexible treatment strategies. The study demonstrates that, for patients who do not achieve abstinence with the initial treatment with 2 mg of varenicline, increasing the dose to 3 mg daily was more effective than continuing the standard dose or switching to CNRT. On the other hand, for patients treated with CNRT, both increasing the nicotine patch dose and switching to varenicline were beneficial. These findings suggest that higher doses of treatment or switching — at least from CNRT to varenicline — can be effective “rescue strategies” when initial therapies fail.
A notable aspect of the study is its pragmatic design, which mirrors everyday clinical practice by including short, structured counseling sessions alongside the prescribed interventions. This highlights the combined value of medication and counseling in supporting smoking cessation efforts. Counseling often is particularly meaningful in reinforcing patients’ commitment to quitting, addressing barriers, and enhancing adherence to pharmacotherapy.4,5
The study also provides valuable insights into long-term outcomes. While increasing the dose of varenicline or CNRT showed benefit at 12 weeks, continuous abstinence at six months was more likely among those who received intensified treatment. This suggests that more aggressive treatment strategies may help sustain long-term abstinence, which is essential in reducing smoking-related morbidity and mortality. However, Cinciripini et al caution against overgeneralizing these results, since study drop-outs may have skewed the findings at six months. They recommend conducting larger and longer trials with more diverse populations to validate these findings.
Finally, the study does not specifically focus on withdrawal side effects related to smoking cessation treatments, and there is no discussion of withdrawal symptoms associated with reducing or stopping nicotine use, discontinuing varenicline, or stopping CNRT. This omission reflects the primary focus of the study on treatment efficacy and abstinence rates, rather than management of withdrawal symptoms during smoking cessation. Clinically, addressing withdrawal often is central to stopping tobacco use. Future research may want to incorporate this perspective into a protocol.5,6
For primary care, this study underlines the need for personalized and adaptive treatment plans for smoking cessation. Providers should be prepared to adjust dosages or switch medications when patients struggle to quit, knowing that higher doses of either varenicline or CNRT or switching from CNRT to varenicline may offer significant benefits for those who did not achieve early abstinence.
Ellen Feldman, MD, works for Altru Health System, Grand Forks, ND.
References
- National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The health consequences of smoking — 50 years of progress: A report of the Surgeon General. Published 2014. https://www.ncbi.nlm.nih.gov/books/NBK294311/table/ch3.t1/
- Levy DT, Huang AT, Havumak JS, Meza R. The role of public policies in reducing smoking prevalence: Results from the Michigan SimSmoke tobacco policy simulation model. Cancer Causes Control 201627:615-625.
- Kwon OB, Jung C, Kim A, et al. Associations between nicotine dependence, smartphone usage patterns, and expected compliance with a smoking cessation application among smokers. Healthc Inform Res 2024;30:224-233.
- United States Public Health Service Office of the Surgeon General; National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. Smoking cessation: A report of the Surgeon General [Internet]. Published 2020. https://www.ncbi.nlm.nih.gov/books/NBK555591/
- Onwuzo CN, Olukorode J, Sange W, et al. A review of smoking cessation interventions: Efficacy, strategies for implementation, and future directions. Cureus 2024;16:e52102.
- Choi HK, Ataucuri-Vargas J, Lin C, Singrey A. The current state of tobacco cessation treatment. Cleve Clin J Med 2021;88:88-393-404.
This randomized trial found that, for patients unable to stop smoking after six weeks of treatment, increasing the dose of either varenicline or combination nicotine replacement therapy (CNRT) or switching from CNRT to varenicline, leads to an increased likelihood of success.
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