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Original Investigation
July 6, 2021

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

Author Affiliations
  • 1National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia
  • 2Department of Experimental and Clinical Pharmacology, University of Rzeszow, Rzeszow, Poland
  • 3School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
  • 4Centre for Health Economics, Monash Business School, Monash University, Clayton, Australia
  • 5No affiliation
  • 6Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia
  • 7St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia
  • 8National Institute for Health Innovation, School of Population Health, University of Auckland, Auckland, New Zealand
  • 9School of Public Health, University of Queensland, Herston, Australia
  • 10Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Australia
  • 11Faculty of Health Sciences and Medicine, Bond University, Robina, Australia
  • 12School of Population Health, University of New South Wales, Sydney, Australia
  • 13Cluster for Resilience and Wellbeing, Appleton Institute, Central Queensland University, Brisbane, Australia
  • 14National Centre for Youth Substance Use Research, University of Queensland, Herston, Australia
  • 15Department of Behavioural Science and Health, University College London, London, England
JAMA. 2021;326(1):56-64. doi:10.1001/jama.2021.7621
Key Points

Question  Is cytisine noninferior to varenicline regarding smoking cessation?

Findings  In this noninferiority randomized clinical trial that included 1452 participants, verified 6-month continuous abstinence rates were 11.7% for the cytisine group vs 13.3% for the varenicline group, a difference that did not meet the noninferiority margin of 5%.

Meaning  The study findings failed to demonstrate noninferiority of cytisine compared with varenicline regarding smoking cessation.


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