Impact of dronedarone in atrial fibrillation and flutter on stroke reduction

Q: What is the clinical evidence from this study?

Study design: Review. Population: Atrial fibrillation or atrial flutter (n=6487). Intervention: Dronedarone vs. Placebo or amiodarone (in DIONYSOS). Primary outcome: Stroke (predominantly from a post hoc analysis of the ATHENA trial) (HR 0.66, 95% CI 0.46 to 0.96, p=0.027).

Q: What does this research mean for the field?

Dronedarone maintains sinus rhythm and significantly reduces the incidence of stroke in patients with atrial fibrillation or flutter receiving usual care. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Christine Benn Christiansen

doi:10.2147/cia.s8883

March 1, 2010Clinical Interventions in AgingOpen Access

Impact of dronedarone in atrial fibrillation and flutter on stroke reduction

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Key result

Dronedarone reduces annual stroke rates ~34% vs placebo in AF/AFL.

HR 0.66
95% CI 0.46 to 0.96
P=0.027
n=6,487

Why the study?

Does dronedarone maintain sinus rhythm, control ventricular rate, and reduce cardiovascular morbidity, mortality, and stroke in patients with atrial fibrillation or atrial flutter?

Key Points

To review clinical evidence from seven trials evaluating the efficacy, safety, rhythm control, and stroke reduction of dronedarone in patients with atrial fibrillation or atrial flutter.
Reviewed seven clinical trials of dronedarone: DAFNE (dose-finding), ADONIS, EURIDIS, and DIONYSOS (sinus rhythm maintenance), ERATO (ventricular rate control), and ANDROMEDA and ATHENA (morbidity and mortality).
Assessed outcomes including maintenance of sinus rhythm, ventricular rate reduction, cardiovascular hospitalizations, overall mortality, and stroke incidence.
EURIDIS and ADONIS demonstrated dronedarone (target dose 400 mg twice daily established in DAFNE) was superior to placebo for maintaining sinus rhythm, whereas DIONYSOS found it less effective than amiodarone, and ANDROMEDA was halted early due to increased mortality in severe heart failure.
In the ATHENA trial, post hoc analysis showed a significant stroke reduction with dronedarone versus placebo (annual rate 1.2% vs 1.8%; hazard ratio 0.66, 95% confidence interval 0.46 to 0.96, P = 0.027).
Across studies, 54 stroke cases occurred in 3439 patients (crude rate 1.6%) receiving dronedarone compared with 76 strokes in 3048 patients on placebo (crude rate 2.5%).

Structured PICO

Does dronedarone maintain sinus rhythm, control ventricular rate, and reduce cardiovascular morbidity, mortality, and stroke in patients with atrial fibrillation or atrial flutter?

P

Population

6,487 patients with atrial fibrillation, atrial flutter, or heart failure pooled for stroke outcomes across reviewed clinical trials of dronedarone.

I

Intervention

Dronedarone oral, target dose 400 mg twice daily (also tested at 600 mg and 800 mg twice daily in DAFNE) added to usual care (including antithrombotic therapy and heart rate control)

C

Comparator

Placebo added to usual care (in DAFNE, EURIDIS, ADONIS, ERATO, ANDROMEDA, and ATHENA) or active comparator amiodarone (in DIONYSOS)

O

Outcome

Efficacy, safety, and prevention of stroke (specifically post hoc stroke incidence in ATHENA and pooled crude stroke rates across trials, alongside trial-specific primary endpoints including AF recurrence, ventricular rate, and composite death or cardiovascular hospitalization)hard clinical

Main Result

Hazard Ratio: 0.66 (95% CI 0.46–0.96)

Absolute Event Rate: 1.2% vs 1.8%

p-value: p=0.027

This review highlights that dronedarone 400 mg twice daily safely reduces cardiovascular hospitalizations and post hoc stroke incidence in stable elderly patients with non-permanent AF and cardiovascular risk factors, while being contraindicated in severe or recently hospitalized heart failure due to excess mortality.

Limitations

The reduction in stroke in ATHENA was not anticipated or prespecified, and was found retrospectively in a post hoc analysis.
The results of the post hoc analysis do not provide clear mechanistic information on why dronedarone reduces the risk of stroke.
Direct comparison of sinus rhythm maintenance across different antiarrhythmic drug trials is not possible because study populations vary considerably.
Whether the beneficial effects found in ATHENA can be extrapolated to patients with permanent AF is unknown.
DIONYSOS trial data were not formally published at the time of review, relying on a press release.
The reduction in stroke in the ATHENA trial was a retrospective post hoc analysis and was not prespecified.
The post hoc analysis does not establish the mechanism by which dronedarone reduces stroke.
Populations across different antiarrhythmic studies vary considerably, making direct comparisons of efficacy impossible.
DIONYSOS trial results were only available via an unpublished press release.
Extrapolation of ATHENA benefits to patients with permanent AF is unknown.

Implication

Post hoc stroke reduction with dronedarone in AF warrants prospective validation; leaves open its role in stroke prevention.

Abstract

BACKGROUND: Dronedarone has been developed for treatment of atrial fibrillation (AF) or atrial flutter (AFL). It is an amiodarone analogue but noniodinized and without the same adverse effects as amiodarone. OBJECTIVE AND METHODS: This is a review of 7 studies (DAFNE, ADONIS, EURIDIS, ATHENA, ANDROMEDA, ERATO and DIONYSOS) on dronedarone focusing on efficacy, safety and prevention of stroke. There was a dose-finding study (DAFNE), 3 studies focusing on maintenance of sinus rhythm (ADONIS, EURIDIS and DIONYSOS), 1 study focusing on rate control (ERATO) and 2 studies investigating mortality and morbidity (ANDROMEDA and ATHENA). RESULTS: The target dose for dronedarone was established in the DAFNE study to be 400 mg twice daily. Both EURIDIS and ADONIS studies demonstrated that dronedarone was superior to placebo for maintaining sinus rhythm. However, DIONYSOS found that dronedarone is less efficient at maintaining sinus rhythm than amiodarone. ERATO concluded that dronedarone reduces ventricular rate in patients with chronic AF. The ANDROMEDA study in patients with severe heart failure was discontinued because of increased mortality in dronedarone group. Dronedarone reduced cardiovascular hospitalizations and mortality in patients with AF or AFL in the ATHENA trial. Secondly, according to a post hoc analysis a significant reduction in stroke was observed (annual rate 1.2% on dronedarone vs 1.8% on placebo, respectively [hazard ratio 0.66, confidence interval 0.46 to 0.96, P = 0.027]). In total, 54 cases of stroke occurred in 3439 patients (crude rate 1.6%) receiving dronedarone compared to 76 strokes in 3048 patients on placebo (crude rate 2.5%), respectively. CONCLUSION: Dronedarone can be used for maintenance of sinus rhythm and can reduce stroke in patients with AF who receive usual care, which includes antithrombotic therapy and heart rate control.

Discussion

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Cite This Study

Christine Benn Christiansen (2010) conducted a review in Atrial fibrillation or atrial flutter (n=6,487). Dronedarone vs. Placebo or amiodarone (in DIONYSOS) was evaluated on Stroke (predominantly from a post hoc analysis of the ATHENA trial) (HR 0.66, 95% CI 0.46 to 0.96, p=0.027). Dronedarone reduced annual stroke rates compared to placebo (1.2% vs 1.8%, HR 0.66, 95% CI 0.46-0.96, P=0.027) in a post hoc analysis of patients with AF/AFL.

synapsesocial.com/papers/6a77913b137c7dcc81bde8e3 https://doi.org/10.2147/cia.s8883

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Impact of dronedarone in atrial fibrillation and flutter on stroke reduction

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Impact of dronedarone in atrial fibrillation and flutter on stroke reduction

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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