Recent analysis of clinical trial data suggests a greater rate of serious cardiovascular events with varenicline compared with placebo1,2; however, the size of any increased risk is uncertain.3

Meta-analysis in people with and without cardiovascular disease

A recent meta-analysis of 14 placebo-controlled trials in a total of 8216 people reported an association between use of varenicline and an increased risk of serious cardiovascular events (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.09 to 2.71).1

The meta-analysis included randomised double-blind placebo-controlled trials of varenicline in smokers that reported on cardiovascular events and had a follow-up period of at least 1 week. Thirteen of the trials excluded people with a history of cardiovascular disease, while one included people with stable cardiovascular disease. The duration of treatment was between 7 and 52 weeks. The outcome of interest was any ischaemic or arrhythmic adverse cardiovascular event.1

From the 14 eligible trials, few serious cardiovascular events were reported overall — 79 in total, but there were more in people treated with varenicline (1.06% [52/4908]) than in people treated with placebo (0.82% [27/3308]).

Most of the cardiovascular events came from the trial in smokers with cardiovascular disease (45 of 79 events identified in the meta-analysis); however, in a sensitivity analysis that excluded this trial, the difference in event rates between varenicline and placebo was similar to that of the main analysis (OR 2.54, 95% CI 1.26 to 5.12).

Methodological limitations of the meta-analysis mean that questions remain about the causal link to varenicline and the size of any increased cardiovascular risk. These limitations include: lack of independent adjudication of cardiovascular events for most trials, use of summary data rather than patient-level data, lack of data on time to onset of events, low event rates (and therefore a wide confidence interval for the increased risk), and differences in populations, doses, durations of therapy, and losses to follow-up.1,3

Study in people with stable cardiovascular disease

On 16 June 2011, the US Food and Drugs Administration (FDA) issued a safety announcement stating that varenicline may be associated with a 'small increased risk of certain cardiovascular adverse events in patients who have cardiovascular disease.'2 The announcement was based on cardiovascular event data from a randomised placebo-controlled study with varenicline involving about 700 people with stable cardiovascular disease.4

Cardiovascular events were uncommon overall and the study was not powered to detect small differences in cardiovascular event rates. Nonetheless, more people treated with varenicline experienced certain cardiovascular events than people treated with placebo: non-fatal MI (2% vs 0.9%), need for coronary revascularisation (2.3% vs 0.9%), and new diagnosis of peripheral vascular disease (PVD) or admission for a procedure to treat PVD (1.4% vs 0.9%).4

The US product information for varenicline was updated to include this information. The FDA stated that they were continuing to evaluate the safety of varenicline, and that they had asked the manufacturer to conduct a meta-analysis of trials (note that this is not the meta-analysis described above).2

What is the advice of the TGA?

The Therapeutic Goods Administration (TGA) is currently reviewing cardiovascular event data with varenicline. In December 2010, the TGA updated the product information for Champix (varenicline) to include post-marketing reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischaemic and haemorrhagic events. While in most cases, people had pre-existing cardiovascular disease and/or other risk factors, the product information states that 'a contributory role of varenicline cannot be ruled out.'5

What does this mean for managing smoking cessation?

Consider other smoking cessations options (e.g. counselling support alone, nicotine replacement therapy) for people with cardiovascular disease who wish to quit smoking. There are limited safety data for varenicline in people with stable cardiovascular disease and no safety data for people with unstable cardiovascular disease.

For people with no history of cardiovascular disease who are starting varenicline for smoking cessation, advise that there is information to suggest the medicine may cause a small increase in their absolute risk of a cardiovascular event.1 However, this small risk needs to be weighed up against the cardiovascular benefits varenicline may provide in assisting them to quit.

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Information for people taking varenicline

For anyone taking varenicline who is concerned about cardiovascular side effects, encourage their efforts to quit, remind them of the cardiovascular benefits of quitting, and suggest an alternative treatment based on clinical suitability if they prefer.

Advise everyone taking varenicline that the risk of cardiovascular side effects appears to be small, but to see a doctor immediately if they experience new or worsening symptoms of cardiovascular disease, such as2:

  • chest pain
  • shortness of breath or trouble breathing
  • pain in the legs when walking.

The NPS RADAR review Varenicline (Champix) for smoking cessation has been updated in light of this new evidence and is available on the NPS website.