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

Abstract

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.

Figure 1.. CONSORT Diagram of Nonpsychiatric Disease Cohort

Figure 2.. CONSORT Diagram of Psychiatric Disease Cohort

Figure 3.. Estimated Risk Difference for the Overall Incidence of a Major Adverse Cardiovascular Event (MACE) and Any MACE or a New-Onset or Worsening Peripheral Vascular Disease Requiring Intervention, a Need for Coronary Revascularization, or Hospitalization for Unstable Angina (MACE+)

Risk differences in MACE (A) and MACE+ (B) treatment groups. NRT indicates nicotine replacement therapy (transdermal nicotine patch).