Cytisine vs Varenicline for Smoking Cessation: Results From a Noninferiority Trial

quitting smoking
hand throwing unused cigarettes in the bin. The beginning of giving up nicotine and becoming a non smoker on medical advice
The researchers wanted to know if standard cytisine treatment for 25 days was at least as effective for smoking cessation as standard varenicline treatment for 84 days.

Results from a study published in JAMA fail to demonstrate the noninferiority of cytisine compared with varenicline as a smoking cessation agent. Although cytisine was better tolerated by patients, varenicline was associated with greater likelihood of continuous smoking abstinence.

Prior trials have demonstrated that cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, its relative efficacy compared with varenicline, the most effective known smoking cessation agent, is unclear.

To better illustrate the efficacy of cytisine, investigators conducted a noninferiority, open-label randomized clinical trial across care centers in Australia. Adult daily smokers willing to make a quit attempt were enrolled beginning in 2017; follow-up concluded in January 2020.

Patients were randomly assigned 1:1 to receive either cytisine or varenicline according to manufacturers’ recommended dosing schedules. Cytisine was provided in 1.5-mg capsules 6 times every day then gradually reduced over a 25-day course. Varenicline dosing began at 0.5 mg and was titrated to 1 mg twice daily for 84 days. Participants were offered access to telephone behavioral support throughout the trial duration.

The primary outcome was 6-month continuous abstinence from smoking. Abstinence was verified using a carbon monoxide breath test. A noninferiority margin of 5% was used.

The trial enrolled 1452 adults: 725 in the cytisine group and 727 in the varenicline group. Mean age at enrollment was 42.9±12.7 years; 51.1% of participants were women. A total of 1108 (76.3%) patients completed the trial.

Demographic characteristics and attrition rates were comparable between study arms. The 6-month continuous abstinence rates were 11.7% in the cytisine group and 13.3% in the varenicline group. With a calculated risk difference of -1.62% and a lower 97.5% CI bound of -5.023%, cytisine failed to meet the threshold for noninferiority. However, adverse events occurred less frequently in the cytisine group: The incidence rate ratio (IRR) for side effects was 0.88 (95% CI, 0.81-0.95) compared with the varenicline group (P =.002).

Results from this randomized clinical trial suggest that a 25-day treatment course of cytisine may be less effective than an 84-day course of varenicline for smoking cessation. However, the difference in treatment duration is a potential limitation; further investigation of cytisine efficacy over a longer interval is warranted.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Courtney RJ, McRobbie H, Tutka P, et al. Effect of cytisine vs varenicline on smoking cessation: a randomized clinical trial. JAMA. 2021;326(1):56-64. doi:10.1001/jama.2021.7621