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18 July 2011
A meta-analysis of 14 randomised controlled trials found that varenicline▼ was associated with a small, significantly increased risk of serious adverse cardiovascular (CV) events, compared with placebo (Peto odds ratio [OR] 1.72, confidence interval [CI] 1.09 to 2.71). However, due to some important limitations of the analysis there is considerable uncertainty around this result.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
We have been advised by the MHRA that the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) and its Pharmacovigilance Working Party will look at the new data from this meta-analysis and determine the need for any further changes to the product information. In the meantime, health professionals should continue to follow NICE guidance on varenicline and consider it as an option within its licensed indications for smokers who have expressed a desire to stop smoking.
Health professionals should also consider MHRA advice on the risk of psychiatric reactions with varenicline. People taking varenicline who develop suicidal thoughts, agitation, depressed mood, or display any changes in behaviour or thinking that are of concern for the doctor, patient, family, or caregiver should be advised to stop varenicline and contact their doctor immediately.
Varenicline is one of several options for patients who wish to stop smoking. In discussions with individual patients clinicians need to balance the benefits of varenicline in helping people to stop smoking (and the associated health benefits) with the possible risks, including this possible safety signal of an increased risk of CV events. Any adverse effects thought to be associated with varenicline use should be reported via the Yellow Card scheme.
What is the background to this?
NICE guidance (technology appraisal 123) and Department of Health guidance on stop smoking services recommend the use of varenicline as an option (preferably in combination with a behavioural support programme), where clinically appropriate and within licensed indications for smoking cessation. A Cochrane review found that varenicline increased four-week quit rates by between two- and three-fold, compared with pharmacologically unassisted quit attempts. As with other drug treatments (e.g. bupropion, nicotine replacement therapy [NRT]), varenicline is more effective when used in combination with behavioural support.
The MHRA has advised that changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, depression, suicidal thoughts, suicide attempts and completed suicides have been reported in patients attempting to quit smoking with varenicline. Some of the patients had no known pre-existing psychiatric condition and some continued to smoke. Other common side effects of varenicline include nausea, headache, abnormal dreams and insomnia.
CV disease is an important cause of mortality and morbidity among smokers and the CV benefits of smoking cessation are well established. However, concerns have been raised that varenicline may be associated with a small, increased risk of certain CV adverse events in patients with stable CV disease. This systematic review and meta-analysis of randomised controlled trials (RCTs) analysed the CV effects of varenicline, compared with placebo.
What does this study claim?
The authors of this meta-analysis claim that the use of varenicline among tobacco users was associated with an increased risk of serious adverse CV events (e.g. myocardial infarction [MI], stroke, congestive heart failure), compared with placebo — 1.06% vs. 0.82%, Peto OR 1.72, 95%CI 1.09 to 2.71. The majority of patients (7,502/8,216) had no previous history of CV disease, although most CV events occurred in the one study (Rigotti, et al) were participants had stable CV disease — 45 events vs. 34 events (see below). There were inadequate data on all-cause mortality.
How does this relate to other studies?
The authors state that no other systematic review and meta-analysis has evaluated the CV effects of varenicline. In the Rigotti, et al study (n=714) in patients with stable CV disease (other than, or in addition to, hypertension), certain CV adverse events were reported more frequently with varenicline, compared with placebo. These events included non-fatal MI, angina, and the need for coronary revascularisation. However, the study was not powered to detect differences between study arms on the safety endpoints.
In June 2011, following a review of this RCT, the FDA announced that varenicline may be associated with a small, increased risk of certain cardiovascular adverse events in patients who have CV disease. This safety information is being added to product labelling and patient information leaflets in the US. The FDA has requested the manufacturer to conduct a large, meta-analysis of RCTs to evaluate the CV safety of varenicline.
So what?
This meta-analysis raises concerns about a possible small absolute increase in CV events with varenicline, compared with placebo. However, this meta-analysis has a number of important limitations as the authors recognise. The trials enrolled different populations with different baseline CV risk. Although 13 of the 14 included studies were conducted in people who did not have CV disease, the majority of CV events occurred in the one trial were participants had stable CV disease, and therefore a higher baseline CV risk. Furthermore, the meta-analysis evaluated different doses of varenicline and had different lengths of follow-up and proportions of participants who were lost to follow-up. There is considerable uncertainty around the results as CV event rates were low overall and were not pre-specified outcomes, and none of the trials was powered to detect true differences in CV events between groups. Most trials were designed to measure efficacy outcomes e.g. continuous abstinence rate. In addition, none of the studies included people with unstable CV disease and so the applicability of the findings in these patients is uncertain.
This possible increased risk of CV events with varenicline, in addition to the known increased risk of psychiatric disorders and other side-effects, needs to be balanced against the benefits of varenicline for smoking cessation and the considerable risks of continuing to smoke. The authors estimated the number needed to treat (NNT) with varenicline for one additional person to quit smoking was 10 (95%CI 8 to 13), compared with placebo, and most studies included behavioural support. Four-week quit rates in people using varenicline alone are 37%, compared with 16% with no intervention. If varenicline is used in combination with group behavioural support, four-week quit rates reach 74%, compared with 32% with group behavioural support alone. This compares favourably with other drug interventions e.g. NRT monotherapy, combination NRT and bupropion.
Study details
Singh S, et al. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ First published July 4, 2011, doi:10.1503/cmaj.110218
Design
Systematic review and meta-analysis of 14 double-blind RCTs reporting data on CV events, with at least one week of follow-up. RCTs involving non-tobacco users and observational studies were excluded. Open-label trials and trials of varenicline versus active comparators were evaluated in sensitivity analyses.
Patients
8,216 smokers or people who used smokeless tobacco (4,908 in the varenicline arms, 3,308 in the placebo arms). Mean age ranged from 39 to 57 years. All but one trial excluded patients with a history of CV disease, and the remaining trial excluded patients with unstable CV disease.
Intervention and comparison
Varenicline versus placebo. In most trials the dose of varenicline was 1mg twice daily. Three trials reported on lower doses. Duration of treatment ranged from 7 to 52 weeks, with the total duration of the studies, including follow-up, ranging from 24 to 52 weeks.
Outcomes and results
Primary outcome was any ischaemic or arrhythmic adverse CV event – defined as MI, unstable angina, coronary revascularisation, coronary artery disease, arrhythmias, transient ischaemic attacks, stroke, sudden death or CV-related death, or congestive heart failure. Secondary outcome was all-cause mortality.
See ‘What does this study claim?’ for results. Sensitivity analyses produced similar results.
Sponsorship Not stated.
Further information can be found on NHS Evidence and in the NPC e-learning materials on smoking cessation.
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