BACKGROUND: Tobacco smoking is one of the leading causes of deaths worldwide. 
Nearly one-fifth of adults in the UK regularly smoke cigarettes. The ill-health 
associated with smoking costs the NHS over £3B every year. A number of 
pharmacological interventions are available that can help people to quit 
smoking. These include nicotinic receptor partial agonists such as varenicline 
or cytisine. Varenicline is a synthetic product licensed for use in the UK, 
while cytisine is derived naturally from the seeds of the plant Cytisus 
laborinum L. (golden rain acacia).
OBJECTIVES: To review the evidence on the clinical effectiveness and safety of 
cytisine from smoking cessation compared with varenicline; to develop an 
economic model to estimate the cost-effectiveness of cytisine and varenicline; 
and to provide recommendations based on value of information analyses as to 
whether or not a head-to-head trial of cytisine and varenicline would represent 
effective use of resources.
DATA SOURCES: Efficacy and adverse events data were sourced from a recent 
Cochrane review. These data were supplemented with an updated search of twelve 
electronic databases, including MEDLINE, EMBASE, Cumulative Index to Nursing and 
Allied Health Literature and The Cochrane Library, for the period from December 
2011 to January 2013. The review included randomised controlled trials (RCTs) of 
adult smokers attempting to quit using varenicline or cytisine. Further 
interventions were considered (placebo, nicotine replacement therapy, bupropion) 
to allow an indirect comparison between varenicline and cytisine. The primary 
outcome was abstinence at a minimum of 6 months' follow-up. Secondary outcomes 
were common adverse events such as abnormal dreams, headache, nausea, insomnia 
and serious adverse events.
REVIEW METHODS: A systematic review and network meta-analysis of the clinical 
evidence was undertaken. A random-effects model was used to allow for 
heterogeneity between studies. The economic model structure was based on a 
published model. Probabilistic sensitivity analyses were undertaken to estimate 
the treatment expected to be most cost-effective given current information. 
Formal expected value of perfect information, perfect partial information and of 
sample information were performed.
RESULTS: Twenty-three (RCTs) were included in the systematic review, comprising 
a total of 10,610 participants. Twenty-one trials of varenicline of differing 
dosing schedules and two trials of cytisine at standard dose met the inclusion 
criteria. No head-to-head trials comparing varenicline with cytisine were 
identified. The methodological quality of the studies was judged to be moderate 
to good. Cytisine was more efficacious than placebo [hazard ratio (HR) 4.27, 95% 
credible interval (CrI) 2.05 to 10.05], as was standard-dose varenicline (HR 
2.58, 95% Crl 2.16 to 3.15). Standard-dose varenicline treatment was associated 
with significantly higher rates of headache, insomnia and nausea than placebo; 
there was no significant difference in the rates of abnormal dreams. There were 
no significant differences in the rates of headache or nausea between cytisine 
and placebo; data were identified for neither abnormal dreams nor insomnia. 
Using expected values, cytisine is anticipated to dominate varenicline, in that 
it produces more quality-adjusted life-years at a lower associated cost. This 
occurred in approximately 90% of the scenarios performed. However, owing to the 
large number of people who wish to quit smoking (estimated to be 3 million over 
a 10-year period), the implications of making an incorrect decision is large. 
The expected value of sample information indicated that conducting a 
head-to-head trial of cytisine and varenicline was worthwhile, and that 1000 
smokers per arm was an appropriate number to recruit.
CONCLUSIONS: On the basis of the evidence included in this review, varenicline 
and cytisine are both effective interventions to aid smoking cessation when 
compared with placebo. Cytisine is estimated to be both more clinically 
effective and cost-effective than varenicline. However, there is uncertainty in 
the decision, and a head-to-head trial of cytisine and varenicline would appear 
to be an effective use of resources.
STUDY REGISTRATION: The study was registered as PROSPERO CRD42012003455.
FUNDING DETAILS: The National Institute for Health Research Health Technology 
Assessment programme.