Dronedarone

Authors, Journal, Affiliations, Type, DOI

• Chinmay Patel MD; Gan-Xin Yan PhD; Peter R. Kowey MD
• Circulation. 2009;120:636-644
• Main Line Health Heart Center and Lankenau Hospital, Wynnewood PA; Jefferson Medical College, Thomas Jefferson University, Philadelphia PA; Lankenau Institute for Medical Research, Wynnewood PA
• Review article
• DOI: https://doi.org/10.1161/CIRCULATIONAHA.109.858027
• COI: Kowey was ad hoc consultant to Wyeth and Sanofi-Aventis during preclinical and clinical development of amiodarone and dronedarone; no trial enrollment or equity interest declared.

Overview

Dronedarone is a non-iodinated benzofuran derivative of amiodarone developed for the treatment of atrial fibrillation and atrial flutter. This 2009 review summarises its multichannel electrophysiology, pharmacokinetics, drug interactions, and clinical trial programme up to the ATHENA publication. The drug showed a favourable safety profile compared to amiodarone (no thyroid, pulmonary, or neurological toxicity) but a significant mortality hazard in patients with severe systolic heart failure (ANDROMEDA). ATHENA demonstrated a 24.2% relative risk reduction in the composite primary endpoint of cardiovascular hospitalisation or death, making dronedarone the first antiarrhythmic drug to demonstrate mortality–morbidity benefit in a high-risk AF population at that time.

Keywords

Amiodarone; arrhythmia; atrial fibrillation; dronedarone

Key Takeaways

Structure and Mechanism vs Amiodarone

• Dronedarone differs structurally from amiodarone by: (1) removal of the iodine moiety, eliminating thyroid/pulmonary toxicity; (2) replacement of ethyl groups on the terminal nitrogen with butyl groups; (3) addition of a methanesulfonyl group to the benzofuran ring to reduce lipophilicity, shortening the half-life from amiodarone's ~40–55 days to approximately 24 hours.
• Like amiodarone, dronedarone blocks multiple ion currents: IKr, IKs, IK1, IK-Ach, peak INa, and ICa-L, and exerts non-competitive beta-adrenergic antagonism via inhibition of adenylate cyclase activity.

In Vitro Electrophysiology

• INa: At 3 µmol/L, dronedarone blocked 97% of peak sodium current in human atrial myocytes vs only 41% for amiodarone — 10-fold more potent INa blockade. This greater sodium channel blockade is proposed to explain the contractility impairment seen in ANDROMEDA.
• IK-Ach: Dronedarone blocked acetylcholine-activated potassium current with IC50 ~10 nmol/L in guinea pig atrial myocytes — 100-fold more potent than amiodarone (amiodarone IC50 ~1 µmol/L). IK-Ach blockade is therapeutically relevant because IK-Ach is constitutively active in chronic AF and drives vagally mediated AF.
• IKr: IC50 ~3 µmol/L in guinea pig ventricular myocytes (amiodarone IC50 ~10 µmol/L); IC50 ~59 nmol/L in mammalian cell system.
• IKs, IK1, ICa-L: Comparable blockade to amiodarone across models.
• EAD suppression: In canine Purkinje fibres, dronedarone reduced dofetilide-induced EADs; in canine LV tissue slices, it reduced transmural dispersion of repolarisation and abolished d-sotalol-induced EADs.

In Vivo Electrophysiology

• Acute vs chronic administration yield opposite APD effects: acute dronedarone abbreviates repolarisation (animal models); sustained administration prolongs QTc.
• Sustained 20 mg/kg BID for 4 weeks increased QTc by 31% in complete AV block dogs. Similar QT/RR prolongation seen in rabbit models with chronic dosing.
• In rat and pig ischaemia-reperfusion models, intravenous dronedarone (but not amiodarone) prevented ventricular fibrillation — possibly attributable to its superior INa and IK-Ach blockade.
• In conscious dogs with healed MI, dronedarone reduced resting heart rate without compromising LV function and matched amiodarone in reducing exercise- and isoprenaline-induced tachycardia.

Pharmacokinetics and Drug Interactions

• Oral absorption: 70–94%; significant first-pass metabolism reduces net bioavailability to 15%. Absorption increases 2–3-fold with food. Steady-state at 400 mg BID reached within 7 days (84–167 ng/mL). Terminal half-life ~24 hours. Clearance primarily non-renal.
• CYP3A4 substrate and moderate inhibitor: Potent CYP3A4 inhibitors (ketoconazole, antifungals, macrolide antibiotics, protease inhibitors) may increase dronedarone exposure by up to 25-fold — co-administration is contraindicated. Moderate inhibitors (verapamil, diltiazem) require dose reduction of the concomitant drug to avoid bradycardia and conduction block.
• Digoxin: 1.7–2.5-fold increase in serum digoxin concentration via P-glycoprotein-mediated renal interaction. Requires frequent monitoring and dose reduction of digoxin.
• Simvastatin: 2–4-fold increase in simvastatin levels via CYP3A4 inhibition; risk of statin-induced myopathy.
• CYP2D6 inhibitor: Modestly increases bioavailability of metoprolol in extensive metabolisers. All beta-blockers co-administered with dronedarone may have enhanced effect.
• Serum creatinine: Dronedarone inhibits tubular secretion of creatinine (as does amiodarone), causing apparent creatinine elevation that does not reflect reduced GFR. Effect is reversible.
• Fixed dose only: 400 mg BID. No dose adjustments for age, sex, race, or renal function have been studied.

Clinical Trials — Rhythm Control

DAFNE (Dose-Finding)

• Double-blind RCT; n=270 patients with persistent AF; randomised to dronedarone 800/1200/1600 mg daily vs placebo for 6 months.
• Reverse dose-effect on rhythm control: The 800 mg dose achieved the best SR maintenance at 6 months (35% vs 10% placebo; time to AF recurrence 60 vs 5.3 days). Higher doses were superior for rate control during AF recurrence.
• Dose-dependent QTc prolongation but no cases of torsades de pointes. No thyroid, pulmonary, neurological, or ocular toxicity.
• Higher doses caused more gastrointestinal adverse events leading to drug discontinuation.

EURIDIS and ADONIS (Rhythm Control Phase 3)

• Two parallel phase 3 RCTs; pooled n=1237 patients in sinus rhythm; 2:1 dronedarone 400 mg BID vs placebo; 12-month follow-up. Mean age 63 years; mean LVEF 58%.
• Primary endpoint (pooled): Median time to first AF recurrence 116 days (dronedarone) vs 53 days (placebo).
• AF recurrence rate at 12 months: 64.1% vs 75.2%.
• Post hoc: 27% relative risk reduction in hospitalisaton and death.
• Adverse events comparable to placebo; serum creatinine elevation in 2.4% dronedarone patients.

Clinical Trials — Rate Control

ERATO

• Randomised study; n=174 elderly patients with permanent AF on background rate-control therapy; dronedarone 400 mg BID vs placebo for 6 months.
• Primary endpoint: Mean ventricular rate reduction of 11.7 bpm at rest on day 14; sustained over 6-month follow-up.
• Exercise heart rate: Additional reduction of 24.5 bpm during exercise (day 14). Improvement did not translate into improved exercise duration.
• 41% increase in serum digoxin concentration noted.

Clinical Trials — Mortality/Morbidity

ANDROMEDA (TERMINATED — Safety)

• Randomised mortality trial; planned n=1000 NYHA class III/IV CHF + LVEF ≤35%; dronedarone 800 mg vs placebo.
• Terminated early after 627 patients due to excess mortality: dronedarone 8.1% vs placebo 3.8%; HR 2.13 (statistically significant). Primary driver was worsening congestive heart failure.
• Risk highest in patients with most severe LV systolic dysfunction.
• Proposed mechanism: potent INa blockade → impaired ventricular contractility in a failing, sodium-current-dependent myocardium.
• Establishes absolute contraindication: dronedarone should not be used in NYHA III/IV + LVEF ≤35%.

ATHENA (Morbidity/Mortality Pivotal Trial)

• Randomised, double-blind; n=4628 patients with paroxysmal or persistent AF/flutter + ≥1 CV risk factor (age ≥75 or age ≥70 + HTN/DM/stroke/TIA/LA >50 mm/LVEF <40%); dronedarone 400 mg BID vs placebo; 12-month follow-up.
• Primary composite endpoint (CV hospitalisation or all-cause death): 24.2% RRR (HR 0.76; p<0.001).
• Secondary endpoints: CV death 29% RRR (HR 0.71); CV hospitalisation 26% RRR (HR 0.74); stroke 34% RRR (independent of antithrombotic co-therapy); arrhythmic death HR 0.55 (p<0.01).
• All-cause mortality: HR 0.84, not statistically significant — a critical limitation.
• Principal adverse effects: diarrhea 9.7%, nausea 5.3%, bradycardia 3.5%, rash 3.4%, serum creatinine increase 4.7%, QT prolongation 1.7%. No thyroid (hypothyroidism 0.5%, hyperthyroidism 0.3%), no interstitial lung disease signal.
• Only 4.4% of patients had NYHA class III and 3.9% had LVEF <35% — ATHENA cannot be used to rebut ANDROMEDA's safety concern in severe HF.

Clinical Trials — Comparative Efficacy

DIONYSOS

• Dronedarone 400 mg BID vs amiodarone (600 mg/day × 28 days then 200 mg/day) in 504 patients with persistent AF; minimum 6-month follow-up. Results were preliminary at time of publication.
• Primary composite endpoint (ECG-documented AF recurrence or premature drug discontinuation for intolerance/lack of efficacy): dronedarone 73.9% vs amiodarone 55.3% — amiodarone significantly superior in sustained efficacy.
• Dronedarone arm had more gastrointestinal adverse events (diarrhea, vomiting, nausea); amiodarone arm had more cardiac adverse events (bradycardia, QT prolongation).

Limitations of the Document

• 2009 publication: PALLAS trial (2011) — which demonstrated doubled cardiovascular events with dronedarone in permanent AF — is entirely absent. This is the most significant post-market safety gap.
• DIONYSOS data were preliminary and not fully peer-reviewed at time of writing; final results subsequently confirmed amiodarone's greater sustained efficacy.
• Review article by a consultant to the drug's developer (Kowey/Sanofi-Aventis); narrative framing may underemphasise ANDROMEDA findings.
• No long-term (>12 months) safety or efficacy data available from any included trial.
• Fixed-dose population (400 mg BID only); no data on dose individualisation.
• Rate and rhythm control trials (EURIDIS/ADONIS, ERATO) excluded NYHA III/IV patients — the safety boundary was not defined until ANDROMEDA.

Key Concepts Mentioned

• concepts/Antiarrhythmic-Drugs — dronedarone pharmacology and clinical role
• concepts/Cardiac-Action-Potential — multichannel blockade effects on APD

Key Entities Mentioned

• entities/Dronedarone — primary subject of review
• entities/Amiodarone — structural and pharmacological comparator throughout
• entities/Atrial-Fibrillation — primary indication; all trials enrolled AF patients
• entities/Heart-Failure — ANDROMEDA safety signal; ATHENA population overlap

Wiki Pages Updated

• Created: wiki/sources/dronedarone-circ-2009
• Created: wiki/entities/Dronedarone
• Updated: wiki/entities/Amiodarone
• Updated: wiki/entities/Atrial-Fibrillation