Dronedarone: A New Treatment for Atrial Fibrillation

Authors, Journal, Affiliations, Type, DOI

• Authors: James C. Laughlin, Peter R. Kowey
• Journal: Journal of Cardiovascular Electrophysiology 2008;19(11):1220–1226
• Affiliations: Thomas Jefferson University College of Medicine; Main Line Health Heart Center, Lankenau Hospital, Wynnewood, Pennsylvania
• Type: Narrative review ("Review – Therapy"), written before regulatory approval
• DOI: 10.1111/j.1540-8167.2008.01251.x

Overview

This 2008 review summarises the rationale, preclinical data and early clinical trials for dronedarone, a non-iodinated benzofuran analogue of amiodarone developed to retain amiodarone's multichannel efficacy while avoiding iodine-related thyroid, pulmonary, ocular, hepatic and neurological toxicity. It reviews DAFNE, EURIDIS/ADONIS, ERATO and ATHENA, and discusses the ANDROMEDA mortality signal in advanced heart failure. The authors position dronedarone as a promising agent for paroxysmal and persistent AF — especially in younger patients and those with compensated NYHA I–II heart failure — while explicitly withholding endorsement in NYHA III/IV or decompensated heart failure. The review predates DIONYSOS, PALLAS and the current label restrictions.

Keywords

Amiodarone; Atrial fibrillation; Dronedarone; Rate control; Rhythm control

Key Takeaways

Rationale and pharmacology

• Amiodarone is the most effective agent for maintaining sinus rhythm and has low proarrhythmic potential because of its multireceptor affinity: it blocks IKs (with less reverse use-dependence than IKr-selective agents), shows class I use-dependence with chronic dosing, blocks L-type calcium channels, and has alpha- and beta-adrenergic antagonism — activity spanning all four Vaughan Williams classes.
• Dronedarone is a non-iodinated benzofuran derivative with a similar multichannel profile. Amiodarone is 37.5% organic iodine by weight, which produces thyroid dysfunction and increases lipophilicity and tissue distribution.
• Amiodarone's principal metabolite N-desethylamiodarone (DEA) accumulates in tissue and strongly inhibits the T3 receptor; dronedarone's principal metabolite N-debutyldronedarone (DBD) does not accumulate significantly and has weak receptor effects.
• Elimination half-life: 30–55 days for amiodarone vs 1–2 days for dronedarone.
• Unlike pure class III agents, dronedarone decreases transmural dispersion of repolarization, reducing the substrate for reentrant proarrhythmia. Chronic dronedarone does not prolong QTc significantly in these data.

Preclinical findings

• In rat ischaemia–reperfusion models, dronedarone was more potent than amiodarone: 1 mg/kg reduced mortality from 90% to 20%, and 3–10 mg/kg suppressed VF, whereas amiodarone below 10 mg/kg had no effect on reperfusion VF or mortality.
• In anaesthetized pigs and in conscious dogs with healed myocardial infarction, dronedarone reduced resting and exercise-induced heart rate comparably to amiodarone without reducing LVEF, fractional shortening or dP/dt.
• In dogs with complete AV block, intravenous dronedarone shortened the QT interval and did not prolong repolarization; no proarrhythmia was seen in holter-monitored post-infarction rats.

DAFNE — dose ranging

• Prospective phase II, placebo-controlled, dose-ranging study in 270 patients with persistent AF; 199 entered the maintenance phase after cardioversion.
• Dronedarone 800 mg/day reduced AF recurrence versus placebo (relative risk reduction 55%; 95% CI 0.28–0.72; P=0.001); median time to recurrence 60 vs 5.3 days over 6 months.
• 1,200 and 1,600 mg/day were not significantly better than placebo, and 1,600 mg caused significant QTc prolongation and a 22.6% discontinuation rate (mostly gastrointestinal).
• No thyroid, ocular or pulmonary toxicity was observed.

EURIDIS and ADONIS — phase III rhythm control

• Double-blind, placebo-controlled trials of dronedarone 400 mg twice daily for 12 months in 1,237 patients (409 placebo, 828 dronedarone) with paroxysmal or persistent AF/flutter; permanent AF, NYHA III–IV heart failure and severe renal impairment were excluded.
• Median time to first AF/AFL recurrence: EURIDIS 96 vs 41 days; ADONIS 158 vs 59 days; pooled 116 vs 53 days.
• 12-month recurrence 64.1% vs 75.2% (HR 0.75; 95% CI 0.65–0.87; P<0.001); 62.3% vs 54.0% remained free of symptomatic recurrence.
• Benefit was consistent in subgroups with recent cardioversion, prior amiodarone and structural heart disease.
• No proarrhythmia, torsades, pulmonary or thyroid toxicity among 828 treated patients over 12 months; serious adverse events 16.5% vs 13.5%; discontinuation for adverse events 15.3% vs 9%.
• Serum creatinine rise 2.4% vs 0.2% (P=0.004) — a recognised tubular-secretion effect.

ERATO — rate control in permanent AF

• 174 elderly patients with permanent AF and resting heart rate ≥80 bpm despite standard rate-control therapy; dronedarone 400 mg twice daily or placebo for 6 months.
• Dronedarone reduced mean ventricular rate at rest by −11.0 bpm and at maximal exercise by −27.4 bpm versus baseline; treatment effect versus placebo −11.7 bpm at rest and −24.5 bpm during exercise (both P<0.001), with unchanged exercise duration.

ATHENA — morbidity/mortality trial

• 4,628 patients with AF/flutter and ≥1 cardiovascular risk factor (age >70, hypertension, diabetes, prior stroke/TIA, LA enlargement or LVEF <40%) randomized to dronedarone 400 mg twice daily or placebo for 12 months.
• Primary endpoint (CV hospitalization or all-cause death): 24.2% relative reduction (P=0.001); CV death −30% (P=0.03); CV hospitalization −25.5%; all-cause death −16% (P=0.18, not significant); arrhythmic death −45% (non-prespecified).
• Patients with acute pulmonary oedema, cardiogenic shock, NYHA IV or recent revascularization were excluded; most heart-failure patients were NYHA II.
• Adverse events: gastrointestinal 26% vs 22%, skin disorders 10% vs 8%, creatinine rise 4.7% vs 1%; no excess heart-failure hospitalization and no proarrhythmia signal.

ANDROMEDA — the safety signal

• Trial in patients with moderate-to-severe heart failure and LV dysfunction, terminated prematurely after 627 of a planned 1,000 patients at a median follow-up of ~2 months.
• Mortality 8% with dronedarone vs 3.8% with placebo (P=0.027).
• No torsades was recorded, so proarrhythmia is an unlikely explanation. A retrospective analysis identified withdrawal of ACE inhibitors/ARBs after transient creatinine rises as a possible contributor — whether de-optimisation of heart-failure therapy caused pump-failure death is unknown.
• The authors conclude dronedarone is not recommended in cardiogenic shock, acute pulmonary oedema or NYHA IV.

Future/positioning at the time

• DIONYSOS (dronedarone vs amiodarone) was ongoing; the authors anticipated a role in younger patients needing therapy but in whom amiodarone's cumulative organ toxicity is undesirable, and in compensated NYHA I–II heart failure — with further data needed in NYHA III.

Limitations of the document

• Narrative review, not systematic. No search strategy, no formal risk-of-bias assessment and no meta-analysis.
• Written before regulatory approval and before the definitive safety trials. DIONYSOS (amiodarone comparison) was still recruiting; PALLAS (2011, permanent AF → excess cardiovascular events) and the current label restrictions are entirely absent. The favourable safety framing is therefore superseded.
• Some cited data are conference abstracts (the ICD study, and ERATO is referenced partly through an AHA poster), not peer-reviewed full papers.
• ANDROMEDA is described from an interim perspective ("trend toward increased mortality") although the mortality difference was statistically significant and led to termination; the review understates the strength of that signal.
• ATHENA's all-cause mortality result was not significant, yet the review emphasises the composite and arrhythmic-death findings; the absolute event rates and follow-up duration are not given in enough detail to judge clinical importance.
• No discussion of drug interactions, hepatic monitoring or QT surveillance in the depth found in later reviews; the statement that dronedarone "does not significantly prolong QTc" conflicts with the DAFNE 1,600 mg finding and later label warnings.
• The population is selected — permanent AF, severe renal impairment and NYHA III–IV were excluded from EURIDIS/ADONIS, so the safety database does not represent the patients in whom the drug later proved harmful.

Key Concepts Mentioned

• entities/Dronedarone — the drug under review
• concepts/Antiarrhythmic-Drugs — Vaughan Williams classification and rhythm- versus rate-control strategy
• entities/Atrial-Fibrillation — the indication
• entities/Heart-Failure — ANDROMEDA contraindication and ATHENA's compensated-HF subgroup
• entities/Amiodarone — parent compound and comparator
• concepts/Drug-Induced-Arrhythmia — torsades and proarrhythmia risk

Key Entities Mentioned

• Sanofi-aventis — manufacturer of dronedarone (Multaq) and review author disclosure
• EURIDIS, ADONIS, ERATO, ATHENA, ANDROMEDA, DAFNE, DIONYSOS — clinical trial programmes
• European Society of Cardiology / ACC / AHA — guideline context

Wiki Pages Updated

• Created: wiki/sources/dronedarone-jce-2008.md
• Updated: wiki/entities/Dronedarone.md
• Updated: wiki/concepts/Antiarrhythmic-Drugs.md
• Updated: wiki/entities/Atrial-Fibrillation.md
• Updated: wiki/sourceindex.md
• Updated: log.md