Smoking-cessation interventions safe for heart, study shows

Pharmacotherapies for smoking cessation—including varenicline, bupropion, and nicotine patches—don’t increase the risk of severe cardiovascular (CV) adverse events in smokers, according to the results of the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) trial and its extension, recently published in JAMA Internal Medicine.

Moreover, the benefits of improved health from quitting smoking outweigh any risk of medication-induced heart disease, the researchers found.

“Despite the proven efficacy of smoking cessation medications, many clinicians have been hesitant to prescribe them because of concerns regarding adverse events (AEs), including CV safety,” wrote corresponding author Neal L. Benowitz, MD, professor, Departments of Medicine, Biopharmaceutical Sciences, Psychiatry, and Clinical Pharmacy, University of California, San Francisco, CA.

Researchers have previously shown that use of nicotine patches (nicotine replacement therapy, or NRT) is safe in smokers with heart disease. Although bupropion can raise blood pressure, bupropion clinical trials did not heighten the risk of cardiovascular AEs in smokers with cardiovascular disease. Additionally, results from early clinical trials indicated that the prevalence of CV events in smokers with cardiovascular disease taking varenicline is low and comparable with that of those taking placebo. Subsequent studies of varenicline, however, have yielded mixed findings.

“The FDA and the European Medicines Agency requested the manufacturers of varenicline [Pfizer] and bupropion [GlaxoSmithKline] to conduct a randomized clinical trial to assess neuropsychiatric AEs to these medications vs an active control (NRT)—the results of which have been published—and that the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) randomized clinical trial be extended to allow for CV event monitoring during and after treatment,” the researchers wrote.

The investigators examined the three major classes of smoking-cessation therapies in this multicenter, multinational, placebo-controlled clinical trial and its extension. After 12 weeks of administering treatment, the team followed a large cohort of smokers with and without psychiatric disorders for up to 52 weeks. Interventions included varenicline (1 mg BID), bupropion (150 mg BID), tapering regimen of 21-mg/day nicotine patch, and placebo.

During the screening visit for the EAGLES trial, the researchers gathered information about pre-existing CV risk factors and they calculated Framingham CV risk scores. Subsequently, they clinically evaluated subjects every 4 weeks for up to 52 weeks. At week 24, participants could elect to continue follow-up in an extension trial. During clinical visits, the researchers reviewed AEs and performed physical examinations, conducted laboratory tests, and administered electrocardiograms.

In total, 8,058 patients took part in the initial EAGLES trial (mean age 46.5 years, 44.1% men). Of these, 4,595 patients took part in the extension trial. The researchers’ primary objective was to assess the CV safety profiles of varenicline and bupropion vs placebo. Their secondary objectives were to compare the CV safety profiles of varenicline vs bupropion, varenicline vs NRT, bupropion vs NRT, and NRT vs placebo.

Dr. Benowitz and colleagues observed that the number of CV events during treatment and follow-up was low for all groups and did not significantly differ among groups. Specifically, the incidence of major adverse CV events (cardiovascular death, nonfatal heart attack, or nonfatal stroke) was <0.5%. Additionally, the incidence of major adverse CV events plus other pertinent CV events (new-onset or worsening peripheral vascular disease requiring intervention, coronary revascularization, or hospitalization for unstable angina) was <0.8%.

The team acknowledged that one major limitation of this study was that none of the participants had acute or unstable CV disease, with most being in good health. Nonetheless, they did include patients with CV risk factors. Specifically, 8% of subjects were high risk and 22% were medium risk according to Framingham scores.

“No evidence that the use of smoking cessation pharmacotherapies increased the risk of serious cardiovascular adverse events during or after treatment was observed,” the authors concluded. “The findings of EAGLES and its extension trial provide further evidence that smoking cessation medications do not increase the risk of serious cardiovascular events in the general population of smokers.”

This study was funded by Pfizer and GlaxoSmithKline.