Smoking cessation pharmacotherapy does not increase CV risk
Cardiovascular Safety of Varenicline, Bupropion, and Nicotine Patch in Smokers A Randomized Clinical Trial
Introduction and methods
For all smokers who try to quit smoking guidelines recommend cessation pharmacotherapy, which has documented efficacy, although there have been concerns regarding adverse events (AEs), including cardiovascular (CV) safety [1-4].
The Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) randomized clinical trial was conducted to evaluate the safety of varenicline and bupropion, due to concerns raised by the US Food and Drug Administration and the European Medicines Agency . The present analysis reports the CV safety findings from the EAGLES trial and an extension trial, which consisted of an additional 28 weeks of follow-up to allow for CV event monitoring after treatment. .
EAGLES was a 24-week randomized, double-blind, triple-dummy, placebo- and active-controlled trial in cohorts of smokers with and without psychiatric disease, assessing the safety and efficacy of varenicline, 1 mg twice daily, and bupropion, 150 mg twice daily, for smoking cessation. The active control was nicotine replacement therapy (NRT) with a 21 mg/day patch.
The primary end point was time to a major adverse CV event (MACE), defined as CV death, non-fatal MI, or non-fatal stroke, during treatment (starting with the first dose and up to the date of the last dose of study drug). Time to MACE was also evaluated up to the date of the last dose of study drug plus 30 days, and until the end of the study (up to 52 weeks for those who enrolled in the extension trial and up to 24 weeks for those who did not).
Secondary end points included the occurrence of MACE and evaluation of MACE+, defined as any MACE, new onset of peripheral vascular disease (PVD), or worsening of PVD requiring intervention, need for coronary revascularization, or hospitalization for unstable angina.
- Out of 8058 participants in the EAGLES study, 4595 participants were enrolled in the extension trial.
- The observed incidence of MACE, MACE+, and all component CV safety end points was low across all treatment groups and observation periods (<0.5% for MACE; <0.8% for MACE+).
- Compared with the placebo group, individuals on active study treatments had no significant differences (P>0.05) in time to MACE or MACE+, neither in the overall population, nor in patients with or without PC.
- At week 12, there was no significant difference in the primary safety endpoint for either varenicline (HR: 0.29; 95%CI: 0.05-1.68) or bupropion treatment vs placebo (HR: 0.50; 95%CI: 0.10-2.50).
- The results were similar for other observation periods (end of treatment plus 30 days and end of study), as well as for the secondary endpoint time to MACE+ and comparisons between each active treatment group and NRT with placebo.
- There were no significant differences in the incidence of CV events by treatment group when evaluated according to low, medium, or high Framingham CV risk scores.
- The risk differences for MACE and MACE+ were not significantly different for varenicline, bupropion, or NRT vs. placebo and when comparing varenicline, bupropion and NRT.
- A total of 13 participants died during the 52-week study period, and 5 of these deaths were judged to be CV-associated: 1 in the varenicline group, 2 in the bupropion group, and 2 in the placebo group.
Smoking cessation pharmacotherapy did not increase the risk of serious CVD or CV AEs in a general population of smokers without a history of CVD. The authors conclude that the benefit of improved CV health from pharmacotherapy assisted smoking cessation exceeds any risk of medication induced CV harm.