Dronedarone for Dronedarone for Maintenance of Sinus Maintenance of Sinus

Rhythm in Atrial Rhythm in Atrial Fibrillation or FlutterFibrillation or Flutter

Singh, B, MD; Connolly, S, MD; Crijns, H, Singh, B, MD; Connolly, S, MD; Crijns, H, MD; Roy, D, MD; Kowey, P, MD; Capucci, MD; Roy, D, MD; Kowey, P, MD; Capucci, A., MD; Radzig, D., MD; Aliot, E, MD for A., MD; Radzig, D., MD; Aliot, E, MD for

the Euridis and Adonis Investigators.the Euridis and Adonis Investigators.

NEJM,NEJM, September 6, 2007 September 6, 2007

Linda Nabha, MDLinda Nabha, MDOctober 23, 2007October 23, 2007

Atrial FibrillationAtrial Fibrillation

Most common arrythmiaMost common arrythmia ~2.2million Americans~2.2million Americans

Characterized by the absence Characterized by the absence

of coordinated atrial systole of coordinated atrial systole Symptoms include palpitations,Symptoms include palpitations,

dyspnea, fatigue, dizzinessdyspnea, fatigue, dizziness associated with a 2-fold higher associated with a 2-fold higher

risk of death, which may be risk of death, which may be

due to thromboembolic strokedue to thromboembolic stroke

Treatment Strategies for Treatment Strategies for AF AF

Rhythm control Rhythm control reversion to NSR reversion to NSR maintenance of NSRmaintenance of NSR

Rate Control – administration of Rate Control – administration of meds to control ventricular rate meds to control ventricular rate

Choosing Rhythm vs. Rate ControlChoosing Rhythm vs. Rate Control Prevention of EmbolizationPrevention of Embolization

AmiodaroneAmiodarone

Most effective drug for maintenance Most effective drug for maintenance of sinus rhythm of sinus rhythm

Side effects:Side effects: Pulmonary toxicityPulmonary toxicity Thyroid DysfunctionThyroid Dysfunction HepatotoxicityHepatotoxicity Ocular ChangesOcular Changes BradycardiaBradycardia

DronedaroneDronedarone

Noniodinated Noniodinated benzofuran derivative benzofuran derivative Electrophysiologic Electrophysiologic effects similar to effects similar to amiodaroneamiodarone and also and also

has antiadrenergic propertieshas antiadrenergic properties Half life 1-2 daysHalf life 1-2 days ANDROMEDA trial was discontinued ANDROMEDA trial was discontinued

early due to an increased incidence of early due to an increased incidence of death in the patients assigned to death in the patients assigned to dronedarone dronedarone

Study HypothesisStudy Hypothesis

Is Dronedarone effective in Is Dronedarone effective in maintaining sinus rhythm in atrial maintaining sinus rhythm in atrial fibrillation?fibrillation?

Does Dronedarone decrease the risk Does Dronedarone decrease the risk of side effects associated with of side effects associated with Amiodarone?Amiodarone?

Selection of SubjectsSelection of Subjects >21 yo age>21 yo age Males and FemalesMales and Females >>1 episode of AF in 1 episode of AF in

preceding 3 monthspreceding 3 months Sinus rhythm at least 1 hour before Sinus rhythm at least 1 hour before

randomizationrandomization Pt previously on amiodarone permittedPt previously on amiodarone permitted

Exclusion CriteriaExclusion Criteria permanent AF permanent AF

((>>12 months)12 months) Torsades de Torsades de

PointesPointes Bradycardia <50 Bradycardia <50

bpmbpm PR interval PR interval

>>0.28ms on EKG0.28ms on EKG 22ndnd degree AV degree AV

blockblock

Taking class I or III Taking class I or III antiarrhythmic antiarrhythmic agentsagents

NYHA class III or IV NYHA class III or IV CHFCHF

Serum CrSerum Cr>> 1.7mg/dL1.7mg/dL

Severe electrolyte Severe electrolyte abnormalityabnormality

Clinically significant Clinically significant hepatic pulmonary hepatic pulmonary endocrine diseaseendocrine disease

Study DesignStudy Design

2 identical multicenter, double-blind, 2 identical multicenter, double-blind, parallel group trialsparallel group trials European, non-EuropeanEuropean, non-European

Randomly assigned to Dronedarone Randomly assigned to Dronedarone or placebo in 2:1 ratioor placebo in 2:1 ratio

Sponsored bySponsored by

Baseline Evaluation, Baseline Evaluation, Randomization, TherapyRandomization, Therapy

Pt evaluation: History, ROS, CV Pt evaluation: History, ROS, CV exam, 12 lead EKG, CXR, lab tests, exam, 12 lead EKG, CXR, lab tests, 2D Echo2D Echo

Eligible pt assigned in 2:1 ratio to Eligible pt assigned in 2:1 ratio to receive 400mg of oral dronedarone receive 400mg of oral dronedarone BID or placebo for one yearBID or placebo for one year

In combined trialsIn combined trials n= 348 received placebon= 348 received placebo n= 828 received dronedaronen= 828 received dronedarone

Follow upFollow up ROS, VS, EKG performedROS, VS, EKG performed

Days 7, 14, 21Days 7, 14, 21 Months 2, 4, 6, 9,12Months 2, 4, 6, 9,12

Blood tests: BMP, LFTs, ThyroidBlood tests: BMP, LFTs, Thyroid Day 21 Day 21 Months 4, 9, 12Months 4, 9, 12

Transtelephonic EKG monitoringTranstelephonic EKG monitoring days 2,3, 5 days 2,3, 5 Months 3,5,7,10 Months 3,5,7,10 Symptomatic Symptomatic

CXR performed in case of pulmonary CXR performed in case of pulmonary symptoms onlysymptoms only

Study End PointsStudy End Points

Primary End Primary End PointPoint Time from Time from

randomization randomization to the first to the first documented documented recurrence of AFrecurrence of AF

Secondary End Secondary End PointsPoints SymtomsSymtoms** related related

to AF during EKG to AF during EKG recording or TTP recording or TTP monitoringmonitoring

Mean Ventricular Mean Ventricular rate during first rate during first occurrence of AFoccurrence of AF

Statistical AnalysisStatistical Analysis

Sample size based upon efficacy Sample size based upon efficacy trials of antiarrhythmic drugs for tx trials of antiarrhythmic drugs for tx of AFof AF

Primary analysis performed Primary analysis performed according to a modified intention-to-according to a modified intention-to-treat principletreat principle

Two-sided Fisher’s exact test used Two-sided Fisher’s exact test used for qualitative measures.for qualitative measures.

Enrollment and OutcomesEnrollment and Outcomes

Enrollment and OutcomesEnrollment and Outcomes

Baseline CharacteristicsBaseline CharacteristicsEuropean

Placebo Dronedarone

Non-European

Placebo Dronedarone

Age (yr)Age (yr) 61.361.3 62.362.3 6363 64.664.6 62.262.2 63.563.5Sex (%F)Sex (%F) 30.330.3 30.730.7 32.732.7 29.729.7 31.531.5 30.230.2StructurStructural HDal HD

33.333.3 36.336.3 45.645.6 48.548.5 39.739.7 42.442.4

LVEF %LVEF % 59.859.833++9.9.3737

59.659.6++1010

57.157.1++12.12.22

57.957.9++11.11.22

58.558.5++1111

58.658.6++1.81.8

Recent Recent cardio-cardio-version* version* %%

37.337.3 37.237.2 22.122.1 21.621.6 29.629.6 29.329.3

Combined

Placebo Dronedarone

ResultsResults Median times from randomization to Median times from randomization to

documented recurrence of AF in documented recurrence of AF in combined trials:combined trials: 53 days with placebo 53 days with placebo 116 days with Dronedarone 116 days with Dronedarone

At 12 mo. AF recurred in At 12 mo. AF recurred in 75% pt in placebo grp 75% pt in placebo grp 64% pt in Dronedarone grp64% pt in Dronedarone grp

(p<0.001, HR=0.75)(p<0.001, HR=0.75)

ResultsResults

ResultsResults In combined trials:In combined trials:

1st symptomatic AF occurred in1st symptomatic AF occurred in 46% for placebo grp46% for placebo grp 38% for dronedarone grp38% for dronedarone grp

VR at first recurrence of AF occurred in VR at first recurrence of AF occurred in

placebo at 117.1placebo at 117.1++30.4 bpm 30.4 bpm dronedarone 103.4dronedarone 103.4++26 bpm26 bpm

30.9% of placebo and 22.8% of 30.9% of placebo and 22.8% of dronedarone resulted in hospitalization dronedarone resulted in hospitalization or death or death

ResultsResults

Adverse EventsAdverse Events

StrokeStroke 4 (0.5)4 (0.5) 3 (0.7)3 (0.7) 0.690.69

CoughCough

DyspneaDyspnea19 (2.3)19 (2.3) 7(1.7)7(1.7) 0.670.67

HyperthyroiHyperthyroidismdism

HypothyroidiHypothyroidismsm

67/801 (8.4)67/801 (8.4)

44/801 (5.544/801 (5.556/396 56/396 (14.1)(14.1)

14/396 14/396 (3.5)(3.5)

0.0020.002

0.150.15

Abnormal Abnormal LFTsLFTs

100/822 100/822 (12.2)(12.2)

55/404(1355/404(13.6).6)

0.520.52

Elev of Elev of Serum Serum CreatinineCreatinine

20 (2.4)20 (2.4) 1 (0.2)1 (0.2) 0.0040.004

BradycardiaBradycardia

Heart Heart FailureFailure

22 (2.7)22 (2.7)

20 (2.4)20 (2.4)8 (2.2)8 (2.2)

4 (1.0)4 (1.0)0.560.56

0.120.12

VARIABLE

DRONEDARONEN=828

PLACEBON=409 P

value

LimitationsLimitations

No direct comparison of Amiodarone No direct comparison of Amiodarone to Dronedaroneto Dronedarone

Follow up EKGs were infrequent Follow up EKGs were infrequent Short duration of trial may not have Short duration of trial may not have

exposed possible adverse events.exposed possible adverse events. Pulmonary toxicity Pulmonary toxicity

DiscussionDiscussion DronedaroneDronedarone

reduced the incidence of reduced the incidence of

first occurrence of AF first occurrence of AF decreased the VR during 1st decreased the VR during 1st

occurrence of arrhythmiaoccurrence of arrhythmia reduced rate of hosp. or death reduced rate of hosp. or death

compared to placebo compared to placebo may increase the risk of mortality in patients may increase the risk of mortality in patients

with CHFwith CHF significantly worsened kidney functionsignificantly worsened kidney function

Low rate of adverse events Low rate of adverse events Comparative trials with amiodarone would be Comparative trials with amiodarone would be

needed to show dronedarone had a better needed to show dronedarone had a better adverse effect profile adverse effect profile

Applications to Clinical Applications to Clinical PracticePractice

The application of Dronedarone may The application of Dronedarone may be useful in low risk patientsbe useful in low risk patients NYHA Class I and IINYHA Class I and II

Amiodarone remains the drug of Amiodarone remains the drug of choice for maintenance of NSR choice for maintenance of NSR despite its multiple, toxic adverse despite its multiple, toxic adverse effects.effects.