Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial

Abstract

Importance: Cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, cytisine has not been tested against the most effective smoking cessation medication, varenicline, which is associated with adverse events known to lead to discontinuation of therapy.

Objective: To examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation.

Design, setting, and participants: This noninferiority, open-label randomized clinical trial with allocation concealment and blinded outcome assessment was undertaken in Australia from November 2017 through May 2019; follow-up was completed in January 2020. A total of 1452 Australian adult daily smokers willing to make a quit attempt were included. Data collection was conducted primarily by computer-assisted telephone interview, but there was an in-person visit to validate the primary outcome.

Interventions: Treatments were provided in accordance with the manufacturers' recommended dosage: cytisine (n = 725), 1.5-mg capsules taken 6 times daily initially then gradually reduced over the 25-day course; varenicline (n = 727), 0.5-mg tablets titrated to 1 mg twice daily for 84 days (12 weeks). All participants were offered referral to standard telephone behavioral support.

Main outcomes and measures: The primary outcome was 6-month continuous abstinence verified using a carbon monoxide breath test at 7-month follow-up. The noninferiority margin was set at 5% and the 1-sided significance threshold was set at .025.

Results: Among 1452 participants who were randomized (mean [SD] age, 42.9 [12.7] years; 742 [51.1%] women), 1108 (76.3%) completed the trial. Verified 6-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group (risk difference, -1.62% [1-sided 97.5% CI, -5.02% to ∞]; P = .03 for noninferiority). Self-reported adverse events occurred less frequently in the cytisine group (997 events among 482 participants) compared with the varenicline group (1206 events among 510 participants) and the incident rate ratio was 0.88 (95% CI, 0.81 to 0.95; P = .002).

Conclusions and relevance: Among daily smokers willing to quit, cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation.

Trial registration: anzctr.org.au Identifier: ACTRN12616001654448.

Figure 1.. Screening, Randomization, and Follow-up of Participants in the Trial

^aLost contact or participant did not respond. ^bThe reasons for withdrawal were not provided (n = 8), not interested in taking medication (n = 1), experienced adverse event (n = 1), and not interested in continuing the study (n = 1). ^cThe reasons for withdrawal were not provided (n = 8), not interested in taking medication (n = 4), experienced adverse event (n = 3), and not interested in continuing the study (n = 2).

Figure 2.. Distributions of Quit Rates for Cytisine and Varenicline

Each curve represents the frequency distribution for the corresponding quit rate proportion and is centered at the expected value of the quit rate. The taller and narrower the distribution, the less uncertainty there is around the quit rate. For cytisine, the posterior distribution is located around halfway between the prior and likelihood distributions because of available data from only 1 previous trial with a similar sample size as the current trial. For varenicline, the posterior distribution is located closer to the prior distribution because of available data from previous trials that generated a larger combined sample size. ^aThe prior distribution incorporates data from the previous trials. ^bThe likelihood distribution is based only on the observed quit rate from the current trial. ^cThe posterior distribution is the combination of the prior and likelihood distributions under a bayesian framework (see Methods for details).