The Lancet APRIL 22, 2016

Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial

Robert M. Anthenelli, Neal L. Benowitz, Robert West, et al.

Bottom Line

The EAGLES trial demonstrated that neither varenicline nor bupropion significantly increased the risk of serious neuropsychiatric adverse events compared to nicotine patch or placebo in smokers with or without psychiatric disorders, while varenicline proved to be the most efficacious pharmacological intervention for smoking cessation.

Key Findings

1. The incidence of the composite primary safety endpoint (moderate to severe neuropsychiatric adverse events) did not differ significantly across treatment arms; specifically, in the psychiatric cohort, event rates were 6.5% for varenicline, 6.7% for bupropion, 5.2% for nicotine patch, and 4.9% for placebo.

2. Varenicline demonstrated superior efficacy for biochemically confirmed continuous abstinence at weeks 9-12 compared to placebo (OR 3.61; 95% CI 3.07-4.24), nicotine patch (OR 1.68; 95% CI 1.46-1.93), and bupropion (OR 1.75; 95% CI 1.52-2.01).

3. Both bupropion and nicotine patch were significantly more effective than placebo for smoking abstinence, with odds ratios of 2.07 (95% CI 1.75-2.45) and 2.15 (95% CI 1.82-2.54), respectively.

4. The efficacy advantage of varenicline over other active treatments and placebo was consistent across both participants with and without psychiatric disorders.

Study Design

Design

RCT

Double-Blind

Sample

8,144

Patients

Duration

24 wk

Median

Setting

Multicenter, 16 countries

Population Adult motivated-to-quit smokers with and without clinically stable psychiatric disorders.

Intervention Varenicline (1 mg twice daily) or bupropion (150 mg twice daily) for 12 weeks.

Comparator Nicotine patch (21 mg per day with taper) or placebo for 12 weeks.

Outcome Incidence of a composite measure of moderate and severe neuropsychiatric adverse events.

Study Limitations

• The study specifically enrolled psychiatrically stable individuals; therefore, results may not generalize to those with acute, unstable psychiatric conditions.

• Participants were limited to those motivated to quit, which may influence the success rates compared to real-world populations with lower baseline motivation.

• The definition of the composite neuropsychiatric endpoint, while rigorous, necessarily relies on subjective reporting and specific, predefined adverse event categories.

Clinical Significance

This landmark study provided the robust evidence required for the FDA and other global regulatory bodies to remove the 'black box' warning regarding neuropsychiatric risks from the labeling of varenicline and bupropion, facilitating their use as first-line, safe options for smoking cessation in patients with psychiatric comorbidities.

Historical Context

Prior to this trial, concerns about potential neuropsychiatric side effects—such as suicidality and mood disturbances—had led to restrictive labeling and clinician reluctance to prescribe varenicline and bupropion, particularly in vulnerable populations with existing mental health diagnoses.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Varenicline and bupropion utilize different neurochemical pathways to aid in smoking cessation; how do their specific mechanisms of action contribute to reducing both the 'reward' of smoking and the 'distress' of nicotine withdrawal?

Key Response

Varenicline is a partial agonist at the alpha-4-beta-2 nicotinic acetylcholine receptor, providing a low-level dopamine release to mitigate withdrawal while simultaneously blocking nicotine from binding, which reduces the reward from a lapse. Bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) and a non-competitive nicotinic antagonist, which primarily helps by mimicking some of nicotine's dopaminergic effects and reducing the irritability and concentration deficits associated with withdrawal.

Resident

Based on the safety results of the EAGLES trial, how should you counsel a patient with a history of stable bipolar disorder who is hesitant to start varenicline due to concerns about potential neuropsychiatric side effects?

Key Response

The EAGLES trial is the landmark study that led to the removal of the FDA 'black box' warning for varenicline and bupropion. You should counsel the patient that in a cohort of over 4,000 patients with psychiatric disorders, there was no significant increase in serious neuropsychiatric adverse events (NPSAEs) compared to nicotine patches or placebo. The risk of NPSAEs is higher in psychiatric patients generally, but it is not specifically increased by these medications, making the most effective therapy (varenicline) a safe option.

Fellow

The EAGLES trial demonstrated a hierarchy of efficacy (Varenicline > Bupropion ≈ Nicotine Patch > Placebo). In the context of the psychiatric cohort, which had lower overall quit rates than the non-psychiatric cohort, how should this influence your long-term management strategy for smoking cessation in patients with severe mental illness?

Key Response

The lower quit rates in the psychiatric cohort (despite identical relative efficacy of the drugs) suggest that biological dependence or environmental factors may be more intensive in this group. For a fellow, this implies that pharmacotherapy is necessary but may require longer durations of treatment, combination therapies (e.g., varenicline plus NRT), and more robust behavioral support integration than in the general population.

Attending

EAGLES effectively neutralized the 'neuropsychiatric safety' deterrent for varenicline. Given that varenicline outperformed NRT and bupropion, why might 'efficacy-first' prescribing be considered the most ethical approach to smoking cessation in contemporary practice?

Key Response

Tobacco use is the leading cause of preventable death, especially among psychiatric patients who lose an average of 25 years of life. Since EAGLES proved that varenicline does not increase NPSAEs relative to placebo, and it is significantly more effective than other options, delaying its use in favor of less effective methods (like NRT) unnecessarily prolongs the patient's exposure to the high mortality risks of combustible tobacco.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of a composite endpoint for 'serious neuropsychiatric adverse events' in the EAGLES trial. What are the statistical and interpretative trade-offs of combining diverse events like 'agitation' and 'suicidal ideation' into a single primary safety outcome?

Key Response

Using a composite endpoint increases statistical power to detect a signal for rare events in a non-inferiority design. However, it assumes that the mechanism and clinical significance of all components are similar. In EAGLES, this could potentially mask a significant increase in a specific, rare event (like suicide) if it were diluted by more common, less severe events (like moderate anxiety), although the study's large N and secondary analyses largely mitigated this risk.

Journal Editor

The EAGLES trial excluded patients with 'unstable' psychiatric disease or active suicidal ideation within the last six months. As a reviewer, how would you address the potential for 'healthy trial participant' bias when interpreting the safety data for the broader, real-world psychiatric population?

Key Response

Editors would flag that the 'stable' nature of the psychiatric cohort limits the external validity to patients in acute crisis or with treatment-resistant conditions. While the study is robust for the majority of outpatients, the findings cannot be reflexively generalized to the most vulnerable psychiatric populations, requiring a cautionary note in the discussion regarding clinical monitoring for unstable patients.

Guideline Committee

How did the EAGLES trial findings directly impact the 2020 American Thoracic Society (ATS) clinical practice guidelines regarding the first-line choice of pharmacotherapy for smoking cessation?

Key Response

Prior to EAGLES, guidelines were often cautious, suggesting clinicians choose between NRT, bupropion, or varenicline based on patient preference and side effect profiles. Following EAGLES, the 2020 ATS guidelines issued a 'strong recommendation' with 'high certainty of evidence' for varenicline as the first-line treatment over NRT or bupropion, specifically citing the trial's evidence for both superior efficacy and the lack of neuropsychiatric harm.

Clinical Landscape

Noteworthy Related Trials

2006

BATS Trial

n = 651 · Arch Intern Med

Tested

Bupropion sustained-release

Population

Smokers with a history of major depression

Comparator

Placebo

Endpoint

Smoking abstinence at 7 weeks

Key result: Bupropion improved smoking cessation rates in depressed smokers without worsening depressive symptoms.

2006

COAST Trial

n = 1,027 · JAMA

Tested

Varenicline vs. Bupropion

Population

Healthy adult smokers

Comparator

Placebo

Endpoint

Continuous abstinence at 9-52 weeks

Key result: Varenicline showed superior long-term abstinence rates compared to both bupropion and placebo.

2008

TONES Trial

n = 746 · JAMA

Tested

Varenicline 1mg twice daily

Population

Healthy adult smokers

Comparator

Placebo

Endpoint

Continuous abstinence rate at weeks 9-12

Key result: Varenicline was significantly more effective than placebo for smoking cessation over 12 weeks of treatment.

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