NETSCC, HTA 20 December 2012 The Health Technology Assessment programme is managed by NETSCC, HTA as part of the NIHR Evaluation, Trials and Studies Coordinating Centre at the University of Southampton. Alpha House, University of Southampton Science Park tel: +44(0)23 8059 5586 Southampton SO16 7NS fax: +44(0)23 8059 5639 Suggest a topic for research via our online form at www.hta.ac.uk/suggest email: [email protected] www.hta.ac.uk The NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC), based at the University of Southampton, manages evaluation research programmes and activities for the NIHR Health Technology Assessment Programme tel: +44(0)23 8059 5586 email: [email protected] National Institute for Health Research Evaluation, Trials and Studies Coordinating Centre University of Southampton, Alpha House fax: +44(0)23 8059 5639 web: www.hta.ac.uk Enterprise Road, Southampton, SO16 7NS Cytisine for smoking cessation HTA 12/46 Protocol 29 October 2012 1. Title of the project: What is the clinical and cost effectiveness of cytisine compared with varenicline for smoking cessation? 2. Project lead The University of Sheffield, School of Health and Related Research (ScHARR) Dr Joanna Leaviss Research Associate ScHARR University of Sheffield Regent Court 30 Regent Street Sheffield, S1 4DA Tel: 0114 22 20895 Email: [email protected] 1 3. Background Tobacco smoking is a major cause of a number of chronic diseases, including heart disease and cancers, and is attributed as the leading cause of preventable deaths worldwide (Peto et al. 1996, Mokdad 2004). Despite these statistics, one fifth of adults in the UK are regular cigarette smokers (Allender et al 2008). In 2006-07, smoking-related ill-health cost the NHS £3.3 billion (Scarborough et al 2011). Stopping smoking is known to reduce the risk of smoking-related disease, but it is challenging. Without smoking cessation aids, only between 2% and 5% of quit attempts are successful (Hughes et al 2004, West et al 2000). Smoking cessation strategies have varied success rates. Behavioural interventions designed to encourage people to stop smoking, for example individual, group or telephone counselling, have shown modest efficacy (Motillo et al 2009). A number of pharmacological interventions exist that aid smoking cessation. These include Nicotine Replacement Therapy (NRT), typical antidepressant medications such as buproprion, and nicotine receptor partial agonists e.g. varenicline, cytisine, dianicline. Nicotine receptor partial agonists offer a pharmacological method to aid smoking cessation. varenicline (Champix or Chantix), and cytisine (Tabex), are included in this class of drug. These drugs may aid smoking cessation by the relief of the symptoms of nicotine withdrawal and cigarette craving through agonist actions, whilst blocking the reinforcing effects of nicotine through an antagonist action (Jorenby et al 20061). Cytisine is a naturally occurring product, extracted from the seeds of the plant Cytisus Laborium. It has been used as an aid to smoking cessation for over 40 years, and is manufactured by the Bulgarian pharmaceutical company Sopharma. Varenicline is a synthentic product developed by Pfizer, with a similar structure to cytisine. Varenicline is licensed for use as an aid to smoking cessation in the US and Canada and across Europe including the UK. Cytisine is considerably less expensive than varenicline, and whilst costs vary between countries, the cost of a course of cytisine is generally about 10 – 20% that of varenicline (West et al 20112). A recent Cochrane review of nicotine receptor partial agonists as aids to smoking cessation (Cahill et al 20123) showed a modest efficacy for cytisine over placebo in helping people to stop smoking, and a two-fold increase in quit rates for varenicline over placebo. No head to head trials between varenicline and cytisine were identified in the review, and no indirect comparisons of the two drugs have been conducted to date in the absence of such trials. Concerns have been raised regarding the safety profile of varenicline. The US Food and Drug Administration (FDA) has issued a series of warnings, resulting from post-marketing reports of increased risk of suicidal behaviour or depression, serious adverse cardiac events and 2 gastrointestinal complaints. A meta-analysis of adverse gastrointestinal events by Leung et al (2011) showed an increased risk after treatment with varenicline. In a review of ten trials, Tonstad (2010) found no evidence of a link between varenicline and serious neuropsychiatric events. Reviews by Singh et al (20114) and Prochaska et al (20125) report conflicting findings, with Singh et al showing an increased risk of serious cardiovascular events after treatment with varenicline, and Prochaska finding no evidence of a link. Cahill et al (20123) found a lack of trial evidence indicating serious adverse events for varenicline. However they do not rule out the possibility of a link. It is beyond the scope of this short report to conduct a systematic review of adverse events for varenicline and cytisine, taking into account long- term observational studies. Therefore this assessment will adopt the same approach to adverse events as the Cahill review, extracting this information from RCTs retrieved through an update of their efficacy search. This assessment aims to review the efficacy of varenicline and cytisine as an aid to smoking cessation by updating the Cahill et al (2012)3 review, and conducting indirect comparisons where appropriate. A mathematical model to compare the cost-effectiveness of cytisine with varenicline in the context of NHS stopping smoking services will also be developed. 3 4. Decision problem 4.1 Purpose of the decision to be made The assessment will address the questions: What is the clinical and cost effectiveness of cytisine compared with varenicline for smoking cessation? Specifically, the assessment will: i) Review evidence on the effectiveness and safety of Cytisine in smoking cessation compared with Varenicline; ii) Develop an economic model to estimate the cost effectiveness of Cytisine in the context of NHS smoking cessation services; and iii) provide recommendations based on value of information analyses as to whether a head to head trial of cytisine and varenicline would represent effective use of resources. 4.2 Clear definition of the intervention Cytisine, a nicotine receptor partial agonist, used as an aid to smoking cessation. 4.3 Place of the intervention in the treatment pathway(s) This review will focus on the use of interventions in the treatment of smoking cessation. 4.4 Relevant comparators Varenicline, in any formulation. Varenicline is a nicotine receptor partial agonist used as an aid to smoking cessation. In the absence of data from head to head studies of Cytisine with Varenicline, any comparators (e.g. placebo, Nicotine Replacement Therapy, Buproprion, Dianicline) will be considered that would allow an indirect comparison or network meta- analysis. 4.5 Population and relevant sub-groups Adult smokers. 4.6 Key factors to be addressed 1. Update the Cochrane review of clinical effectiveness and safety for Cytisine compared with Varenicline in helping people to stop smoking. Updated searches from December 2011 to 2012 will be undertaken. 2. Model the cost-effectiveness of Cytisine in the context of NHS smoking cessation services. 3. Make recommendations for commissioning a full trial. 4 5. Report methods for synthesis of evidence of clinical effectiveness and safety An updated review of the evidence for clinical effectiveness and safety will be undertaken systematically following the general principles recommended in the PRISMA statement. English and non-English language studies will be included. The updated review will include papers from December 2011-2012. 5.1 Population Adult smokers. 5.2 Intervention Cytisine at any dose. 5.3 Comparator Varenicline at any dose. 5.4 Settings Smoking cessation programmes/trials. 5.5 Outcomes 5.5.1 Clinical outcomes. Outcomes relating to clinical effectiveness will follow the same criteria as the existing Cochrane review: 1. The primary outcome is abstinence from smoking: minimum 6 months abstinence. Sustained cessation rates will be used in preference to point prevalence. Biochemically verified cessation rates will be used in preference to self-reported cessation. 2. Adverse events: Any reported adverse events from retrieved RCTs will be recorded. It is beyond the scope of this short report to perform specific searches for adverse events. Therefore this data will be based on adverse events reported in RCTs retrieved for the efficacy search, as in the Cahill 2012 review. Studies of long-term observational data will not be included. 5. 6 Study design Randomised Controlled Trials (RCTs) only. 5 5.7 Search strategy The search strategy will update the existing Cochrane review and comprise the following main elements: . Searching of electronic databases . Contact with experts in the field . Scrutiny of bibliographies of retrieved papers The search will update the recent Cochrane Review and rerun their search strategy for trials in the period December 2011-2012, excluding ‘dianicline’ from the interventions. Although dianicline was included in the Cahill searches, development of the drug has been discontinued and will therefore not be included in the comparisons for this report. Additionally, the search will be rerun with a cost effectiveness filter with no date restriction for cost effectiveness literature. All searches