1. JAMA Intern Med. 2018 May 1;178(5):622-631. doi: 10.1001/jamainternmed.2018.0397.

Cardiovascular Safety of Varenicline, Bupropion, and Nicotine Patch in Smokers: A
Randomized Clinical Trial.

Benowitz NL(1)(2), Pipe A(3), West R(4), Hays JT(5), Tonstad S(6), McRae T(7),
Lawrence D(7), St Aubin L(7), Anthenelli RM(8).

Author information: 
(1)Department of Medicine, University of California, San Francisco.
(2)Department of Bioengineering & Therapeutic Sciences, University of California,
San Francisco.
(3)Division of Prevention and Rehabilitation, University of Ottawa Heart
Institute, Ottawa, Ontario, Canada.
(4)Health Behaviour Research Centre, Department of Epidemiology and Public
Health, University College, London, United Kingdom.
(5)Nicotine Dependence Center and General Internal Medicine, Mayo Clinic,
Rochester, Minnesota.
(6)Department of Preventive Cardiology, Oslo University Hospital, Oslo, Norway.
(7)Global Product Development, Pfizer, New York, New York.
(8)Department of Psychiatry, University of California, San Diego.

Importance: Quitting smoking is enhanced by the use of pharmacotherapies, but
concerns have been raised regarding the cardiovascular safety of such
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
(nā€‰=ā€‰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
(nā€‰=ā€‰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
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.

DOI: 10.1001/jamainternmed.2018.0397 
PMCID: PMC6145797 [Available on 2019-04-09]
PMID: 29630702