Dronedarone: An overview

Figures & data

Table I. Physiological effects, ionic and molecular mechanisms of action of dronedarone.

Ref.	Model	Ionic currents affected	Physiological effects
(38)	Guinea-pig papillary muscle	I(Kr), I(Ks), I(K1), and I(Ca(L)) inhibited	- decrease of dV/dt max of the action potential in a concentration- and frequency-dependent manner- no change of resting potential- action potential amplitude decreased only at highest concentration of the drug- reduction of papillary muscle contraction- reduced shortening of ventricular myocytes
(17)	Anaesthetized and conscious dogs	I(Na), I(Kr), I(Ks), I(K1), and I(Ca(L)) inhibited	- decrease of dV/dt max of the action potential- no change of action potential duration
(39)	Guinea-pig atrial cells	I(K(ACh)) inhibited	- dronedarone inhibited the I(K(ACh)) current by inhibition of the channel itself and its GTP-binding proteins- effect of dronedarone more potent than of amiodarone
(20)	Rat heart	Cardiac beta-adrenoceptor inhibited	- in vitro, SR 33589, like amiodarone, was characterized as non-competitive beta-adrenoceptor antagonist- chronic treatment led to a down-regulation of the beta-adrenoceptor
(17,20,39,40)	Anaesthetized and conscious dogs		- in anesthetized dogs:º both dronedarone and amiodarone inhibited alpha-adrenoceptor stimulationº dronedarone inhibited beta1 receptors significantly, but less than amiodaroneº dronedarone inhibited beta2 receptors more than amiodarone did- in conscious dogs:º both dronedarone and amiodarone inhibited an isoprenaline-induced rise of heart rate; the extent of that action was similar for both drugs
(41)	Normal and infarcted rat hearts	I(K) or Isus inhibited, small increase in I(to)	- dronedarone increased action potential duration in normal hearts, but it did not further increase APD that was already prolonged by myocardial infarction- no proarrhythmic effect of the drug- reduction of ventricular premature beats in infarcted hearts
(42)	Rat hearts—ischaemia and reperfusion		- dronedarone reduced the incidence of ventricular fibrillation induced by ischaemia- it reduced mortality during reperfusion and reduced the incidence of ventricular fibrillation- 20% of animals exhibited atrioventricular block at the highest tested dose of dronedarone (10 mg/kg), which was not observed at lower doses
(21)	Acute coronary occlusion in anaesthetized pigs		- dronedarone reduced the occurrence of ventricular arrhythmias (ventricular premature beats, ventricular tachycardia, and fibrillation) during ischaemia
(43)	Rabbit hearts		- dronedarone increased RR, QT, and QTc intervals- it prolonged ventricular action potential duration at 50% and 90% repolarization in a dose-dependent and cycle length-dependent manner- effects of dronedarone were more significant than those of amiodarone- V(max) was decreased by both drugs, and both drugs slowed the sino-atrial node automaticity
(31)	Canine hearts, dronedarone versus amiodarone	I(Ca(L))	- 4-week oral administration of the drug:º small V(max) block, less significant than that caused by amiodarone- acute intravenous infusion:º moderate prolongation of action potential duration in papillary muscle and its shortening in Purkinje fibres- both drugs reduced early and late after-depolarizations
(40)	Isolated canine atria		- dronedarone caused a less marked increase of action potential duration, effective refractory period, diastolic threshold of excitation, and V(max) than amiodarone- dronedarone was also less efficient in termination of AF and prevention of AF recurrence

ACh = acetylcholine; AF = atrial fibrillation; APD = action potential duration; Ca = calcium; GTP = guanosine triphosphate; K = potassium; QT = QT interval as measured in ECG; QTc = value of QT corrected with respect to heart rate; RR = RR interval as measured in ECG.

Table II. Summary of clinical trials of dronedarone.

Trial	Inclusion criteria	Patients included	Intervention	Primary end-point	Results	Secondary end-points	Results
DAFNE (15)	Persistent AF (72 h– 12 months), rhythm converted to sinus with ECV if no SR after 5–7 days of therapy	270 pts, in 199 SR was restored, 21–85 years of age	Dronedarone (800 mg, 1200 mg, 1600 mg daily) or placebo for 6 months	Time to first documented recurrence of AF	Dronedarone (800 mg daily) increased time to first recurrence compared to placebo (60 versus 5.3 days; P = 0.001)	1. Spontaneous conversion of AF following randomization2. VR in case of recurrence3. Incidence of side-effects4. Pharmacokinetics	1. 5.8%–14.8% of patients experienced (dose-dependent) effect, compared to 3.1% in the placebo group2. Reduced in a dose-dependent manner3. GI side-effects were dominant, discontinuation rate 3.9%–22.6% in the dronedarone group4. Steady state reached on day 14 after randomization
ADONIS/EURIDIS (14)	At least 1 episode of AF during 3 months before enrolment, at least 1 h in SR before randomization	828 pts dronedarone, 409 pts placebo	Dronedarone 800 mg daily or placebo	Time to first recurrence of AF or flutter	Time to first recurrence prolonged in the drug group (116 days, 53 days in placebo group)	1. Symptoms related to AF2. Mean VR at first recurrence	1. Rate of symptomatic recurrences was reduced2. Reduced in the drug group compared with placebo (P < 0.001)
ANDROMEDA (23)	Severe symptomatic heart failure (NYHA III or IV, or paroxysmal nocturnal dyspnoea), LWMI no more than 1.2	627 pts	800 mg of dronedarone daily or placebo, median F-U time 2 months	Death from any cause or hospitalization for worsening heart failure	Prematurely terminated for safety reasons (excess mortality in dronedarone group): HR = 2.13; 95% CI = 1.07–4.25; P = 0.03. No difference in primary end-point	1. Death from all causes2. Hospitalization for CV causes3. Hospitalization for worsening CHF4. Occurrence of AF/AFl5. Arrhythmic death6. SCD	1. Increased2. Increased3. N/a4. N/a5. N/a6. N/a
ATHENA (25)	Paroxysmal or persistent AF (at least 1 record within 6 months) and at least one additional risk factor for death:• age > 70 years• AH treated with at least 2 drugs• DM• Previous stroke, TIA, or peripheral embolism• LA diameter ≥50 mm• LVEF no more than 40% SR was restored according to guidelines	4628 pts	Dronedarone 800 mg daily or placebo, at least 12 months of follow-up (F-U); mean time of F-U 21 months.	First hospitalization due to CV events or death	Reduced in the drug group (31.9% versus 39.4% in the placebo group)	1. Death from any cause2. Death form CV causes3. Hospitalization due to CV events	1. No difference2. Reduced (2.7% versus 3.9% in the placebo group; P = 0.03)3. Reduced (29.3% versus 36.9% in the placebo group; P < 0.001)
ERATO (28)	Permanent AF (>6 months), average VR ≥80 bpm	174 pts, 85 received dronedarone, 89 - placebo	Dronedarone 800 mg daily or placebo for 6 months	Change in mean VR on the 14th day of therapy in comparison to the base-line value	Reduction of mean VR by 11.7 bpm (P < 0.0001) compared to placebo	1. Mean VR after 4 months of therapy2. VR at submaximal exercise on the 14th day3. VR at maximal exercise on the 14th day4. Safety and tolerability	1. Reduced (8.8 bpm compared to placebo; P < 0.001)2. VR reduced in the drug group by 25.6 bpm with respect to base-line (P < 0.0001)3. VR reduced in the drug group by 27.4 (P < 0.0001) bpm with respect to base-line4. GI disturbances, increase in digoxin levels
DIONYSOS (29)	Persistent AF with indications for cardioversion and antiarrhythmic treatment	504 pts: 249 received dronedarone, 255 amiodarone	Head-to-head study, dronedarone or amiodarone for 6 months	Time to first AF recurrence or premature drug discontinuation due to intolerance or lack of efficacy	End-point was reached by 75.1% patients receiving dronedarone and 58.8% on amiodarone (P < 0.0001)	Safety end-point: side-effect rate	Dronedarone did not reduce the main safety end-point, but after exclusion of GI side-effects there was a significant difference in the remaining side-effects in favour of dronedarone

AF = atrial fibrillation; AH = arterial hypertension; CHF = congestive heart failure; CV = cardiovascular; DM = diabetes mellitus; ECV = electrical cardioversion; GI = gastrointestinal; LWMI = left ventricular motion index; pts = patients; SCD = sudden cardiac death; SR = sinus rhythm; VR = ventricular rate.

Table III. Clinical efficacy of dronedarone.

	Clinical effect	Source of data
1.	Prolongation of the median time to AF recurrence after sinus rhythm restoration with cardioversion.	DAFNE, ADONIS/EURIDIS (14,15,22,23)
2.	Dose-dependent spontaneous conversion into sinus rhythm.	DAFNE (15,22)
3.	No influence on the success rate of cardioversion.	DAFNE (15,22)
4.	Dose-dependent reduction of ventricular rate in the case of recurrence of AF.	DAFNE (15,22)
5.	Reduction of the percentage of patients in whom AF recurred after 12 months of treatment.	ADONIS/EURIDIS (14,15,23)
6.	Reduction of the percentage of patients with symptomatic arrhythmia recurrence.	ADONIS/EURIDIS (14,15,23)
7.	Reduction of hospitalization rate due to cardiovascular events or mortality in patients with paroxysmal and persistent AF/AFl.	ATHENA (25–27,35)
8.	Reduction of hospitalization rate due to cardiovascular causes.	ATHENA (25–27,35)
9.	Reduction of the percentage of patients with first hospitalization due to cardiovascular causes.	ATHENA (25–27,35)
10.	Reduction of cardiovascular mortality.	ATHENA (25–27,35)
11.	Reduction of mean ventricular rate in the course of permanent AF, both the mean daily rate (after 14 days and 4 months of treatment) and exercise rate (after 14 days of treatment).	ERATO (28)
12.	Recurrence of AF or premature drug discontinuation is more frequent with dronedarone than amiodarone.	DIONYSOS (29)
13.	More AF recurrence but a trend towards less drug discontinuation with dronedarone than amiodarone.	DIONYSOS (29)

AF = atrial fibrillation; AFl = atrial flutter.

Table IV. Electrophysiological effects of dronedarone observed in preclinical and clinical trials.

	Rabbit hearts (Sun et al.) (43)	Dog hearts (Varro et al.) (31)	Dog hearts (Manning et al.) (32)	DAFNE (15,22)	ADONIS/EURIDIS (14,15,23)	ERATO (28)	ATHENA (25–27,35)
HR	reduction		reduction	reduction by 7.2–11.1 bpm, dose-dependent	reduction by 6.8%		bradycardia
WCL			prolongation
AH			prolongation
HV			no change
AERP/AVNERP/VERP			prolongation
PR			prolongation	prolongation by 13.4–28.4 ms, dose-dependent
QRS				no change	no change
QT	prolongation			variable (prolongation, subsequent shortening)	prolongation by 23.4 ms		prolongation
QTc	prolongation	no change			prolongation by 9.0 ms
VR at arrhythmia recurrence				reduction by 17.8 bpm (average), dose-dependent	reduction by 12/15.2 bpmreduction by 10%/13% compared to placebo
VR in the course of FAC, 24 h average						reduction
VR in the course of FAC at submaximal exercise						reduction
VR in the course of FAC at maximal exercise						reduction

AERP = effective refractory period of the atria; AVNERP = effective refractory period of the atrioventricular node; FAC = chronic atrial fibrillation; HR = heart rate; PR = PR interval as measured in ECG; QT = QT interval as measured in ECG; QTc = value of QT corrected with respect to heart rate; VERP = effective refractory period of the ventricles; VR = ventricular rate; WCL = cycle length corresponding to the point of Wenckebach.

Table V. Side-effects observed during therapy with dronedarone.

	Side-effect	Source of data
1.	Transient increase of plasma creatinine concentration, associated directly with drug administration, resulting from impairment of tubular transporter, with no features of toxic renal damage and no reduction of glomerular filtration rate	DAFNE, ADONIS/EURIDIS, ANDROMEDA, ATHENA, ERATO, DIONYSOS (14,15,22–29,35)
2.	Gastrointestinal side-effects	DAFNE, ATHENA, ERATO, DIONYSOS (14,22,25–29,35)
3.	No proarrhythmia, almost no incidents of TdP (only 1 case of TdP in the ATHENA study)	DAFNE, ADONIS/EURIDIS, ERATO, DIONYSOS (14,15,22,28–29)
4.	Increased mortality in patients with severe heart failure—NYHA III or IV, LWMI below 1.2 (which is consistent with LVEF below 35%)	ANDROMEDA (23)
5.	Increase of digoxin concentration if administered concurrently with dronedarone	ERATO (28)

LVEF = left ventricular ejection fraction; LWMI = left ventricular motion index; NYHA = New York Heart Association; TdP = torsade de pointes.

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