New England Journal of Medicine FEBRUARY 12, 2009

A Placebo-Controlled Trial of Dronedarone for the Management of Atrial Fibrillation or Flutter (ATHENA)

Stefan H. Hohnloser, John J.V. McMurray, et al.

Bottom Line

In patients with paroxysmal or persistent atrial fibrillation or flutter and additional cardiovascular risk factors, the addition of dronedarone to standard background therapy significantly reduced the risk of first cardiovascular hospitalization or death.

Key Findings

1. The primary composite endpoint of first cardiovascular hospitalization or death occurred in 31.9% of patients in the dronedarone group compared with 39.4% in the placebo group (Hazard Ratio 0.76; 95% CI, 0.69 to 0.84; P<0.001), representing a 24% relative risk reduction.

2. Dronedarone treatment was associated with a 30% reduction in the risk of cardiovascular death (HR 0.70; 95% CI, 0.51 to 0.96; P=0.03).

3. The rate of death from any cause was similar between the two groups (11.6% in the dronedarone group vs. 13.9% in the placebo group; HR 0.84; 95% CI, 0.69 to 1.02; P=0.08).

4. Arrhythmic death was significantly reduced by 45% in the dronedarone group compared to placebo (HR 0.55; 95% CI, 0.34 to 0.88; P=0.01).

Study Design

Design

RCT

Double-Blind

Sample

4,628

Patients

Duration

21 mo

Median

Setting

Multicenter, international

Population Patients aged 75 or older, or younger than 75 with at least one cardiovascular risk factor (hypertension, diabetes, stroke/TIA, left atrial diameter >=50mm, or LVEF <40%), who had paroxysmal or persistent atrial fibrillation or flutter.

Intervention Dronedarone (400 mg twice daily)

Comparator Placebo

Outcome Time to first cardiovascular hospitalization or death from any cause

Study Limitations

• The study excluded patients with NYHA class IV heart failure or recent (within 4 weeks) decompensated heart failure, limiting generalizability to patients with severe or acute heart failure.

• A significant proportion of patients (approximately 30%) discontinued the study drug, although rates were balanced between groups.

• While the primary composite endpoint was met, the study did not demonstrate a statistically significant reduction in all-cause mortality.

• The study primarily evaluated cardiovascular hospitalization as a surrogate for total burden of illness.

Clinical Significance

The ATHENA trial established dronedarone as an effective pharmacological option for rhythm control in non-severe heart failure patients with atrial fibrillation, specifically highlighting its ability to reduce cardiovascular morbidity without the high proarrhythmic risk typically associated with other antiarrhythmic agents like amiodarone.

Historical Context

Prior to ATHENA, management of atrial fibrillation was largely limited to symptom relief or rate control, as previous antiarrhythmic trials (such as those involving amiodarone) often failed to demonstrate clear morbidity-mortality benefits and were frequently associated with significant toxicity. ATHENA served as a landmark trial in the development of dronedarone as a potentially safer alternative.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Dronedarone is often described as a non-iodinated derivative of amiodarone. How do its pharmacokinetic properties and side-effect profile differ from amiodarone, and what is the mechanistic basis for these differences?

Key Response

Dronedarone was designed to lack the iodine moieties found in amiodarone, significantly reducing the risk of thyroid dysfunction and pulmonary fibrosis. Additionally, it has a much shorter half-life (13-19 hours vs. several weeks for amiodarone) due to less lipophilicity, leading to less tissue accumulation but requiring twice-daily dosing.

Resident

The ATHENA trial enrolled patients with paroxysmal or persistent AF and at least one additional cardiovascular risk factor. How should the results of ATHENA be reconciled with the findings of the ANDROMEDA trial when selecting a patient for dronedarone therapy?

Key Response

While ATHENA showed a reduction in CV hospitalizations and death in stable AF patients with risk factors, the ANDROMEDA trial was stopped early because dronedarone increased mortality in patients with recently decompensated heart failure or severe LV dysfunction. Therefore, dronedarone is indicated for stable AF but strictly contraindicated in patients with NYHA Class III-IV heart failure or a recent HF hospitalization.

Fellow

In the ATHENA trial, a post-hoc analysis suggested a significant reduction in the risk of stroke. Given that rhythm control historically failed to show superiority over rate control in trials like AFFIRM, what unique properties of dronedarone or the ATHENA study design might account for this finding?

Key Response

Unlike AFFIRM, which used various AADs and focused on mortality, ATHENA focused on a composite of hospitalization and death. The stroke reduction may be attributed to a higher success rate in maintaining sinus rhythm, the drug's inherent rate-controlling (Vaughan-Williams Class II) properties during AF paroxysms, or potentially its effect on reducing the total 'AF burden' which is increasingly recognized as a stroke risk modifier.

Attending

The ATHENA trial was landmark for using a composite primary endpoint of CV hospitalization and all-cause mortality. How has the 'ATHENA model' shifted the clinical paradigm of rhythm control from 'maintaining sinus rhythm' to 'improving clinical outcomes'?

Key Response

Before ATHENA, rhythm control was primarily judged by the ability to maintain sinus rhythm (an electrophysiological surrogate). ATHENA shifted the goalpost to 'hard' clinical outcomes, demonstrating that even if AF recurs, the drug's collateral effects (rate control, blood pressure reduction) can reduce the morbidity and healthcare resource utilization associated with the arrhythmia.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The primary outcome in ATHENA was 'time to first event.' Critically analyze the limitations of using a composite endpoint that includes both a 'soft' outcome like hospitalization and a 'hard' outcome like death, especially regarding the potential for hospitalization to mask mortality data in a competing-risk framework.

Key Response

In a 'time-to-first-event' analysis, once a patient is hospitalized, they are no longer at risk for 'first' event death in the primary analysis. If a drug reduces hospitalizations but increases mortality (or vice versa), the composite can be misleading. Researchers must use secondary analyses (like all-cause mortality or CV death alone) and competing risk models to ensure the treatment effect on the softer endpoint isn't obscuring a signal in the harder endpoint.

Journal Editor

A known pharmacodynamic effect of dronedarone is a modest, non-pathological increase in serum creatinine due to inhibition of tubular secretion. As an editor, how would you evaluate the risk that this effect unblinded investigators and potentially biased the adjudication of 'cardiovascular hospitalization'?

Key Response

Because clinicians might recognize the creatinine rise as a signature of dronedarone, the blinding could be compromised. This is a threat to internal validity, especially for the subjective decision to hospitalize. A rigorous trial would require a blinded, independent adjudication committee that does not have access to laboratory data that could unblind them to ensure the hospitalization endpoint is robust.

Guideline Committee

Based on the ATHENA trial evidence, current AHA/ACC/HRS and ESC guidelines provide specific recommendations for dronedarone. How do these guidelines balance the Class I recommendation for rhythm control in stable patients against the Class III (Harm) recommendation in specific subpopulations?

Key Response

The 2023 ACC/AHA/ACCP/HRS guidelines give Dronedarone a Class 1 recommendation for rhythm control in AF patients without HFrEF (Stage C/D HF). However, due to ANDROMEDA and PALLAS (which showed harm in permanent AF), it carries a Class 3: Harm recommendation for those with HFrEF or permanent AF where rhythm control is abandoned. The guidelines must emphasize rigorous patient selection to avoid using the drug in the 'wrong' AF phenotype.

Clinical Landscape

Noteworthy Related Trials

1997

DIAMOND-CHF Trial

n = 3,111 · NEJM

Tested

Dofetilide

Population

Patients with symptomatic heart failure

Comparator

Placebo

Endpoint

All-cause mortality

Key result: Dofetilide had no effect on survival in patients with heart failure but was effective in restoring and maintaining sinus rhythm.

2002

AFFIRM Trial

n = 4,060 · NEJM

Tested

Rate-control strategy

Population

Patients with atrial fibrillation at risk for stroke

Comparator

Rhythm-control strategy

Endpoint

All-cause mortality

Key result: The study found no significant difference in survival between rhythm-control and rate-control strategies in patients with atrial fibrillation.

2020

EAST-AFNET 4 Trial

n = 2,789 · NEJM

Tested

Early rhythm-control therapy

Population

Patients with early-stage atrial fibrillation

Comparator

Usual care

Endpoint

Composite of cardiovascular death, stroke, or hospitalization

Key result: Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes compared to usual care.

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