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Original Investigation
April 9, 2018

Cardiovascular Safety of Varenicline, Bupropion, and Nicotine Patch in SmokersA Randomized Clinical Trial

Author Affiliations
  • 1Department of Medicine, University of California, San Francisco
  • 2Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco
  • 3Division of Prevention and Rehabilitation, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
  • 4Health Behaviour Research Centre, Department of Epidemiology and Public Health, University College, London, United Kingdom
  • 5Nicotine Dependence Center and General Internal Medicine, Mayo Clinic, Rochester, Minnesota
  • 6Department of Preventive Cardiology, Oslo University Hospital, Oslo, Norway
  • 7Global Product Development, Pfizer, New York, New York
  • 8Department of Psychiatry, University of California, San Diego
JAMA Intern Med. Published online April 9, 2018. doi:10.1001/jamainternmed.2018.0397
Key Points

Question  What is the relative cardiovascular safety of smoking cessation medications comparing varenicline, bupropion, nicotine replacement therapy, and placebo?

Findings  In this randomized clinical trial including 8058 individuals who smoked, the incidence of major cardiovascular events during treatment and follow-up was low and did not differ significantly by treatment.

Meaning  These findings provide evidence that, in a general population of smokers, smoking cessation medications do not increase the risk of serious cardiovascular events.


Importance  Quitting smoking is enhanced by the use of pharmacotherapies, but concerns have been raised regarding the cardiovascular safety of such medications.

Objective  To compare the relative cardiovascular safety risk of smoking cessation treatments.

Design, Setting, and Participants  A double-blind, randomized, triple-dummy, placebo- and active-controlled trial (Evaluating Adverse Events in a Global Smoking Cessation Study [EAGLES]) and its nontreatment extension trial was conducted at 140 multinational centers. Smokers, with or without established psychiatric diagnoses, who received at least 1 dose of study medication (n = 8058), as well as a subset of those who completed 12 weeks of treatment plus 12 weeks of follow up and agreed to be followed up for an additional 28 weeks (n = 4595), were included.

Interventions  Varenicline, 1 mg twice daily; bupropion hydrochloride, 150 mg twice daily; and nicotine replacement therapy, 21-mg/d patch with tapering.

Main Outcomes and Measures  The primary end point was the time to development of a major adverse cardiovascular event (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) during treatment; secondary end points were the occurrence of MACE and other pertinent cardiovascular events (MACE+: MACE or new-onset or worsening peripheral vascular disease requiring intervention, coronary revascularization, or hospitalization for unstable angina).

Results  Of the 8058 participants, 3553 (44.1%) were male (mean [SD] age, 46.5 [12.3] years). The incidence of cardiovascular events during treatment and follow-up was low (<0.5% for MACE; <0.8% for MACE+) and did not differ significantly by treatment. No significant treatment differences were observed in time to cardiovascular events, blood pressure, or heart rate. There was no significant difference in time to onset of MACE for either varenicline or bupropion treatment vs placebo (varenicline: hazard ratio, 0.29; 95% CI, 0.05-1.68 and bupropion: hazard ratio, 0.50; 95% CI, 0.10-2.50).

Conclusions and Relevance  No evidence that the use of smoking cessation pharmacotherapies increased the risk of serious cardiovascular adverse events during or after treatment was observed. 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.

Trial Registration  clinicaltrials.gov Identifier: NCT01574703

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