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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Benowitz has served as a consultant to pharmaceutical companies, including Pfizer, which markets smoking cessation medications, and has been a paid expert witness in litigation against tobacco companies. Dr Pipe has served as a consultant to pharmaceutical companies that market smoking cessation medications, including Pfizer, and has received research funding from Pfizer for conduct of this study and from Johnson & Johnson. Dr West is a consultant to Pfizer, Johnson & Johnson, and GlaxoSmithKline and has received research funding from Pfizer and Johnson & Johnson; Dr West’s salary is funded by Cancer Research UK. Dr Hays has received research support from Pfizer for the conduct of this study. Dr Tonstad has received honoraria for lectures and consulting for Pfizer. Drs McRae, Lawrence, and St Aubin are employees and stockholders of Pfizer. Dr Anthenelli reports his university receiving grants from Pfizer and Alkermes, and providing consulting and/or advisory board services to Pfizer, Arena Pharmaceuticals, and Cerecor; Dr Anthenelli’s contributions to this article were supported, in part, by National Institute on Alcohol Abuse and Alcoholism grants U01 AA013641 and R01 AA019720, and National Institute on Drug Abuse/Veterans Affairs Cooperative Studies 1031 and 1032.

Figures

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).