Varenicline (Champix) — clearing the air on cardiovascular safety
Published in Health News and Evidence
Date published: About this date
Key points | Varenicline and cardiovascular safety concerns | Safety concerns confirmed | Apparent discrepancy in FDA advice | The new meta-analysis data | Does the risk of smoking outweigh the risk of treatment? | What does this mean for managing smoking cessation?
Varenicline is a neuronal nicotinic acetylcholine-receptor partial agonist used for smoking cessation. Concerns about the possible increase in risk of serious cardiovascular events in people using varenicline have been addressed in a recent meta-analysis reported by the US Food and Drug Administration (FDA). Results showed a small, statistically non-significant increase in cardiovascular events in people taking varenicline. Nevertheless the FDA conclude that because this increase was consistent throughout different analyses it is likely to be drug-related and not purely a chance finding. The health benefits of quitting smoking are immediate and substantial and the incidence of cardiovascular adverse events was low. Health professionals are advised to weigh up the small risk of cardiovascular adverse events against the cardiovascular benefits of quitting smoking when considering varenicline.
- Following an FDA warning in 2011 of a possible increase in risk of serious cardiovascular events in people using varenicline, the sponsor was required to conduct a meta-analysis of randomised placebo-controlled trials.
- The completed meta-analysis reported on the FDA website indicates a small, statistically non-significant increase in cardiovascular events in people taking varenicline.
- The FDA Drug Safety Communication concludes that, although these findings were not statistically significant, they were consistent and more likely to be drug related than purely a chance finding.
- The incidence of cardiovascular adverse events was very low in both the varenicline and placebo groups.
- The health benefits of quitting smoking are immediate and substantial.
- Health professionals are advised to weigh up the small risk of cardiovascular adverse events against the cardiovascular benefits of quitting smoking when considering varenicline.
In June 2011 the FDA published a Drug Safety Communication announcement warning of a possible increase in risk of serious cardiovascular events in people using varenicline.3 In August 2012, NPS MedicineWise published an updated version of its NPS RADAR review on varenicline4 and an In Brief article5 to reflect this concern.
In the 2011 Drug Safety Communication announcement the FDA indicated that the sponsor had been requested ‘to conduct a large, combined analysis (meta-analysis) of randomized, placebo-controlled trials’ and that the FDA ‘will update the public when additional information is available’.3
The meta-analysis is now complete and has been referenced in a new Drug Safety Communication announcement6 as well as published on the FDA MedWatch site.7 However, there is an apparent discrepancy in interpretation of the results of this analysis between the FDA MedWatch site and the FDA Drug Safety Communication site, which has the potential to confuse the issues for health professionals.
The FDA MedWatch site states:7
A higher occurrence of major adverse cardiovascular events (a combined outcome of cardiovascular-related death, nonfatal heart attack, and nonfatal stroke) was observed in patients using Chantix compared to placebo. These events were uncommon in both the Chantix and placebo groups, and the increased risk was not statistically significant, which means it is uncertain whether the excess risk for the Chantix group was due to the drug or due to chance.
The FDA Drug Safety Communication site repeats the previous statement but adds the following:6
However, the data were analysed many different ways and consistently showed a higher occurrence of events in patients using Chantix, which makes it seem more likely that it is related to the drug and not purely a chance finding.
Since the MedWatch safety alerts are available via email by subscribing at the MedWatch site, it is likely that some health professionals may only have seen the MedWatch version of the text.
The most recent meta-analysis incorporated data from 7002 patients (4190 using varenicline and 2812 placebo) enrolled in 15 randomised, double-blind, placebo-controlled clinical trials of ≥ 12 weeks’ treatment duration.6 The primary cardiovascular safety assessment included an analysis of the occurrence and timing of major adverse cardiovascular events (MACE), including cardiovascular-related death, non-fatal myocardial infarction, and non-fatal stroke.
There was a low overall incidence of MACE (varenicline 0.31% [13/4190] vs placebo 0.21% [6/2812]) with an adjusted hazard ratio of MACE of 1.95 (95% confidence interval 0.79 to 4.82). This equates to an estimated increase of 6.3 MACE per 1000 patient-years of exposure (95% confidence interval –2.40 to 15.10), which was not statistically significant.6
Of note, because the number of adverse cardiovascular events was small overall, the power for finding a statistically significant difference in a signal of this magnitude is low.
Due to the very low overall incidence of these events, FDA advice to health professionals emphasises that ‘smoking is an independent and major risk factor for cardiovascular disease, and Chantix (vareniciline) is effective in helping patients quit smoking. The health benefits of quitting smoking are immediate and substantial’.6,7
- for people with no history of cardiovascular disease who are starting varenicline for smoking cessation, advise that there is information to suggest that the medicine may cause a small increase in their absolute risk of a cardiovascular event.
- this small risk needs to be weighed up against the cardiovascular benefits varenicline may provide in assisting them to quit.
- consider other smoking-cessation options (e.g. counselling support alone, nicotine replacement therapy) for people with cardiovascular disease who wish to quit smoking.
- advise patients to seek medical attention if they experience new or worsening symptoms of cardiovascular disease while taking varenicline.
Report suspected adverse events to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. Serious psychiatric adverse events have been reported in people taking varenicline, with and without a history of psychiatric illness. Advise all patients to stop varenicline and to see a doctor as soon as possible if they experience any unusual or serious change in mood, thinking or behaviour.
- Pfizer Australia Pty Ltd. Varenicline (Champix) product information. 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06102-3 (accessed 18 December 2012).
- Pfizer Inc. Chantix Prescribing Information. 2012. http://labeling.pfizer.com/showlabeling.aspx?id=557 (accessed 19 December 2012).
- US Food and Drug Administration. FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease. 2011. http://www.fda.gov/Drugs/DrugSafety/ucm259161.htm (accessed 18 December 2012).
- National Prescribing Service. Varenicline (Champix) for smoking cessation. 2011. http://www.nps.org.au/publications/health-professional/nps-radar/2011/april-2011/varenicline (accessed 18 December 2012).
- National Prescribing Service. Varenicline (Champix) safety update: possible increase in serious cardiovascular events. 2011. http://www.nps.org.au/publications/health-professional/nps-radar/2011/august-2011/brief-item-varenicline (accessed 18 December 2012).
- US Food and Drug Administration. FDA Drug Safety Communication: Safety review update of Chantix (varenicline) and risk of cardiovascular adverse events. 2012. http://www.fda.gov/Drugs/DrugSafety/ucm330367.htm (accessed 18 December 2012).
- US Food and Drug Administration. Chantix (Varenicline): Safety Communication – Updated Safety Review On The Risk of Cardiovascular Adverse Events. 2012. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm331626.htm?source=govdelivery (accessed 18 December 2012).