© 2011 NHS Centre for Smoking Cessation and Training (NCSCT)
Author:Paul Aveyard
Editor: Andy McEwen
Reviewers: Melanie Chambers, Jennie Kenyon, Andrea Dickens, Hayden McRobbie, John Stapleton and Robert West
The need for this briefing was established when the NHS Centre for Smoking Cessation and Training (NCSCT) accompanied the Department of Health (DH) Tobacco Control Delivery Team on a number of regional seminars. Commissioners and managers of NHS local stop smoking services stated that, despite the evidence on safety and efficacy, getting primary care trusts to accept varenicline as an equal ‘first line’ treatment option was in some cases difficult.
This briefing is intended as a resource for commissioners, managers and staff of stop smoking services and is set out as answers to a series of questions.
For more information on the NCSCT and on the NCSCT ethical policy please visit our website: www.ncsct.co.uk
1. Is varenicline more effective than NRT?
Answer: It is almost certainly more effective than NRT used in single forms (e.g. patch or gum).
The evidence: In its technical appraisal of varenicline for smoking cessation the National Institute of Health and Clinical Excellence (NICE) conducted a meta-analysis and indirect comparison to examine the efficacy of varenicline compared with NRT. These analyses showed that varenicline was superior to NRT in achieving long-term quit rates (odds ratio = 1.54; 95% CI: 1.10–2.16). 1
Data from the NHS stop smoking services also support this conclusion. In a sample of clients attending the Maudsley Hospital Smokers’ Clinic four-week CO-verified abstinence rates were significantly greater among those who used varenicline (72%) compared to NRT users (61%) with an odds ratio of 1.70 (95%CI: 1.09–2.67). 2 In addition, smokers given varenicline in the NHS stop smoking services are 40% more likely to be CO-verified four-week successes than those given NRT. 3
2. Does varenicline increase risk of suicide?
Answer: While it is never possible to rule out a very small increased risk the evidence to date shows no evidence of this.
The evidence: There have been media reports of cases of suicide and suicidal thoughts in people taking varenicline. However in epidemiology, case reports are seen as very weak evidence of an association and can be misleading. A famous example is the Andrew Wakefield MMR-autism-bowel disorder case series, which alleged that MMR caused autism. This has now been investigated with better designed studies and no link has been shown, but it took many years to do so.
The crucial questi1on that needs to be answered is whether the risk is greater than it would have been in the same individuals had they not taken this medication.
One study looked at whether the reported number of suicides on varenicline was more than would be expected given the number of smokers using varenicline for a number of weeks. 4 The modelling showed that varenicline use was not associated with an increased risk of suicide. In addition to this, two published studies have examined the association between varenicline use and psychiatric events and neither found an increased risk. 5,6 One of these studies examined the occurrence of psychiatric adverse events in the randomised placebo controlled trials of varenicline versus placebo. Combined, these studies randomly allocated 3,901 smokers to varenicline and 2,005 to placebo. The number of adverse mood-related or agitation-related events was similar on varenicline to on placebo and the confidence intervals excluded any substantial risk (RR = 1.02; 95% CI: 0.86–1.22). 5 Another study examined GP prescription data and examined whether the incidence of suicide related events was similar in varenicline users to NRT users. 6 It reported no increase in such events.
Whilst it is impossible to rule out any effect at all, these studies indicate that if there is an increased risk it must be very small.
Notwithstanding this, it is important to remain vigilant to this and other possible rare neuropsychiatric side effects while not losing sight of the fact that because of its high level of effectiveness varenicline is an important life-saving medication.
The Medicines and Healthcare products Regulatory Authority (MHRA) issues the following advice 7
3. Does varenicline increase risk of cardiovascular events?
Answer: There may be a very small increased risk but any such risk is far outweighed by the benefit of the increased chance of quitting that varenicline offers.
The evidence: A recently published meta-analysis looked at the number of cardiovascular events seen in 8,216 clients taking either varenicline or placebo. 8 It found that events were rare in both groups but that there was a slightly increased number in the people taking varenicline: 1.06% (52 out of 4,908) compared with 0.82% taking placebo (27 out of 3,308). However, a number of limitations of this meta-analysis have been identified, including the low number of events seen, the types of events counted, the higher drop-out rates in people receiving placebo, the lack of information on the timing of events, and the exclusion of studies in which nobody had an event.
The findings of the review therefore indicate that it may be worth investigating the link between cardiovascular events and varenicline further, but currently there is little reason to avoid this medication on these grounds. This view is in line with European Medicines Agency that confirmed a positive benefit-risk balance for varenicline and concluded that its benefits as a smoking cessation medicine outweigh any slight increase in cardiovascular events. 9
4. Is varenicline safe to be used by people with mental health problems?
Answer: There are no good grounds for excluding patients with mental health problems from taking varenicline and because of its high level of effectiveness it may be their best chance of stopping smoking, especially given their generally high level of nicotine dependence.
The evidence: There has been no suggestion in the published studies or case reports that smokers with pre-existing mental health problems are more vulnerable to neuropsychiatric side effects than other patients.
A recent review 10 of the use of varenicline in patients with mental health problems states:
‘Although the risk of potential neuropsychiatric events is evident through voluntary reporting systems and reported cases in the literature, multiple studies and case reports support the use of varenicline in the mental health population’
The authors recommend that when using varenicline in smokers with mental health illness that there should be:
5. Varenicline is a ‘black triangle’ drug. Are not such drugs considered potentially unsafe?
Answer: New medications are often tested in clinical trials that have a relative small number of users. This means that clinical trials may not show all possible side effects of the new medication. This does not mean that these medicines are unsafe, but only when large numbers of people have taken the medication do rare or long-term adverse effects become known. Therefore when these new medications are introduced to the market the Commission on Human Medicines (CHM) and the MHRA encourages the reporting of all suspected reactions to new medicines which are denoted by an inverted Black Triangle symbol (▼).
Varenicline has been examined by NICE and advised for use in the NHS 1 and no further consideration of this is planned.
6. Varenicline is more expensive than other medications, is it cost-effective?
Answer: Varenicline typically costs more than other smoking cessation medications. However, it is also more effective, so when examined as cost per quitter, the figures are very similar.
All smoking cessation pharmacotherapies are amongst the best buys in modern medicine, being hugely more cost-effective per quality adjusted life year gained (QALY) than other commonly used NHS treatments. 11
7. What is varenicline’s role in treatment?
Answer: NICE has indicated that it should be a first line treatment and smokers should be routinely offered it as one of the options available to them. 12 It should not be necessary for people to have failed to stop smoking with other medication before using varenicline. Given that it is almost certainly more effective than single forms of NRT, to deny smokers access to this treatment will lead to avoidable loss of life. After the age of 35 years every year that cessation is delayed results in a loss of three months’ life expectancy 13 so every quit attempt must be given the best possible chance of success and it is not appropriate to wait for quit attempts to fail before offering effective help.
1. National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 123: Varenicline for smoking cessation. London: National Institute for Health and Clinical Excellence, 2007.
2. Stapleton JA, Watson L, Spirling LI, Smith R, Milbrandt A, Ratcliffe M, et al. Varenicline in the routine treatment of tobacco dependence: a pre-post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction 2008; 103(1): 146–54.
3. The Health and Social Care Information Centre. Statistics on NHS Stop Smoking Services: England, April 2009 – March 2010: NHS, 2010.
4. Stapleton J. Do the 10 UK suicides among those taking the smoking cessation drug varenicline suggest a causal link? Addiction 2009; 104(5): 864–5.
5. Tonstad S, Davies S, Flammer M, Russ C, Hughes J. Psychiatric adverse events in randomized, double-blind, placebo-controlled clinical trials of varenicline: a pooled analysis. Drug Saf 2010; 33(4): 289–301.
6. Gunnell D, Irvine D, Wise L, Davies C, Martin RM. Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database. BMJ 2009; 339: b3805.
7. Medicines and Healthcare products Regulatory Agency. Varenicline: adverse psychiatric reactions, including depression. Drug Safety Update 2008; 2(4): 2–3.
8. Singh S, Loke YK, Spangler JG, Furberg CD. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ 2011, online 4 Jul. doi: 10.1503/cmaj.110218.
9. European Medicines Agency. (21.07.2011). Press release: European Medicines Agency confirms positive benefit-risk balance for Champix. www.ema.europa.eu/
10. Purvis TL, Nelson LA, Mambourg SE. Varenicline use in patients with mental illness: an update of the evidence. Expert Opin Drug Saf 2010; 9(3): 471– 82.
11. Parrott S, Godfrey C, Raw M, West R & McNeill A (1998) Guidance for Commissioners of the Cost Effectiveness of Smoking Cessation Interventions. Thorax, 53 (Suppl): S2–S37.
12. National Institute for Health and Clinical Excellence. NICE public health guidance 10: Smoking cessation services in primary care, pharmacies, local authorities and workplaces, particularly for manual working groups, pregnant women and hard to reach communities. London: National Institute for Health and Clinical Excellence, 2008.
13. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004; 328(7455): 1519.